AVAHO

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

Showing cancer patients receiving chemotherapy short videos about their treatments has the potential to improve their understanding about the treatments they are receiving, new research in Cancer has shown.

Researchers showed 50 patients at an underserved hospital six 1-minute videos focused on important terms related to their chemotherapy treatments and found that the videos helped them better understand what those key terms mean. Before viewing the videos, 15 of 20 terms were misunderstood by more than one third of patients, with 98% unable to define “maintenance,” 74% unable to define “cancer,” and 58% unable to define “chemotherapy.” Six pilot educational videos describing a narrowed down list of six terms were created, and patient understanding of all six terms improved by at least 20% after watching the videos. The six terms defined in the videos were “palliative chemotherapy,” “curative,” “cancer,” “blood count,” “risk of infection,” and “chemotherapy.”

“Although a current concern is that precision medicines will not be understood due to genetic illiteracy and misunderstandings about the immune system, it is important to remember that the terminology used to describe chemotherapy, the backbone of many cancer treatments, may also be incomprehensible to some patients,” Rebecca Pentz, PhD, of Emory University, Atlanta, and colleagues wrote.

“Our video pilot suggests that multimedia can help patients understand chemotherapy terminology,” Dr. Pentz and colleagues said. “For each term, there was at least a 20% increase in patient understanding after watching the video. None of the patients could define palliative chemotherapy before watching the video, but 72% were able to provide a definition afterward.”

Researchers noted that the term most understood after the video was curative treatment (patients being able to define the phrase grew from 34% to 88%).

“Our study establishes that basic chemotherapy terminology is widely misunderstood by an underserved population, but that video-based education can significantly increase patient understanding,” the investigators concluded, but noted the research was limited by the small number of videos as well as the single underserved hospital, which may limit the generalizablility of the study.

Dr. Pentz and colleagues added that “education of physicians about the severe patient lack of understanding of basic cancer terminology and methods to improve understanding would be most helpful.”

SOURCE: Pentz R et al. Cancer. 2019 Aug 16. doi: 10.1002/cncr.32421.

Showing cancer patients receiving chemotherapy short videos about their treatments has the potential to improve their understanding about the treatments they are receiving, new research in Cancer has shown.

Researchers showed 50 patients at an underserved hospital six 1-minute videos focused on important terms related to their chemotherapy treatments and found that the videos helped them better understand what those key terms mean. Before viewing the videos, 15 of 20 terms were misunderstood by more than one third of patients, with 98% unable to define “maintenance,” 74% unable to define “cancer,” and 58% unable to define “chemotherapy.” Six pilot educational videos describing a narrowed down list of six terms were created, and patient understanding of all six terms improved by at least 20% after watching the videos. The six terms defined in the videos were “palliative chemotherapy,” “curative,” “cancer,” “blood count,” “risk of infection,” and “chemotherapy.”

“Although a current concern is that precision medicines will not be understood due to genetic illiteracy and misunderstandings about the immune system, it is important to remember that the terminology used to describe chemotherapy, the backbone of many cancer treatments, may also be incomprehensible to some patients,” Rebecca Pentz, PhD, of Emory University, Atlanta, and colleagues wrote.

“Our video pilot suggests that multimedia can help patients understand chemotherapy terminology,” Dr. Pentz and colleagues said. “For each term, there was at least a 20% increase in patient understanding after watching the video. None of the patients could define palliative chemotherapy before watching the video, but 72% were able to provide a definition afterward.”

Researchers noted that the term most understood after the video was curative treatment (patients being able to define the phrase grew from 34% to 88%).

“Our study establishes that basic chemotherapy terminology is widely misunderstood by an underserved population, but that video-based education can significantly increase patient understanding,” the investigators concluded, but noted the research was limited by the small number of videos as well as the single underserved hospital, which may limit the generalizablility of the study.

Dr. Pentz and colleagues added that “education of physicians about the severe patient lack of understanding of basic cancer terminology and methods to improve understanding would be most helpful.”

SOURCE: Pentz R et al. Cancer. 2019 Aug 16. doi: 10.1002/cncr.32421.

Showing cancer patients receiving chemotherapy short videos about their treatments has the potential to improve their understanding about the treatments they are receiving, new research in Cancer has shown.

Researchers showed 50 patients at an underserved hospital six 1-minute videos focused on important terms related to their chemotherapy treatments and found that the videos helped them better understand what those key terms mean. Before viewing the videos, 15 of 20 terms were misunderstood by more than one third of patients, with 98% unable to define “maintenance,” 74% unable to define “cancer,” and 58% unable to define “chemotherapy.” Six pilot educational videos describing a narrowed down list of six terms were created, and patient understanding of all six terms improved by at least 20% after watching the videos. The six terms defined in the videos were “palliative chemotherapy,” “curative,” “cancer,” “blood count,” “risk of infection,” and “chemotherapy.”

“Although a current concern is that precision medicines will not be understood due to genetic illiteracy and misunderstandings about the immune system, it is important to remember that the terminology used to describe chemotherapy, the backbone of many cancer treatments, may also be incomprehensible to some patients,” Rebecca Pentz, PhD, of Emory University, Atlanta, and colleagues wrote.

“Our video pilot suggests that multimedia can help patients understand chemotherapy terminology,” Dr. Pentz and colleagues said. “For each term, there was at least a 20% increase in patient understanding after watching the video. None of the patients could define palliative chemotherapy before watching the video, but 72% were able to provide a definition afterward.”

Researchers noted that the term most understood after the video was curative treatment (patients being able to define the phrase grew from 34% to 88%).

“Our study establishes that basic chemotherapy terminology is widely misunderstood by an underserved population, but that video-based education can significantly increase patient understanding,” the investigators concluded, but noted the research was limited by the small number of videos as well as the single underserved hospital, which may limit the generalizablility of the study.

Dr. Pentz and colleagues added that “education of physicians about the severe patient lack of understanding of basic cancer terminology and methods to improve understanding would be most helpful.”

SOURCE: Pentz R et al. Cancer. 2019 Aug 16. doi: 10.1002/cncr.32421.

When it comes to treatment recommendations for high-risk breast cancer, oncologists agree with a leading artificial intelligence platform about half the time, according to investigators.

In the first study of its kind, involving 10 Chinese oncologists, recommendation concordance with the Watson for Oncology treatment advisory tool (WfO) was generally lower for hormone receptor–positive and metastatic cancers than hormone receptor–negative and nonmetastatic cases, reported Fengrui Xu, MD, of the Academy of Military Medical Sciences in Beijing, and colleagues. Refinement could enable broad use of Watson, not to dictate treatment decisions, but instead to propose alternate treatment approaches and offer point-of-care access to relevant evidence.

“[WfO] is an example of a quantitative oncology clinical decision support that leverages the clinical expertise of oncologists at Memorial Sloan Kettering Cancer Center [MSKCC],” the investigators wrote in JCO Clinical Cancer Informatics. The platform uses machine-learning software to interpret patient scenarios in light from MSKCC training cases, MSKCC treatment guidelines, and more than 300 medical textbooks and journals.

To compare WfO with real-world decision makers, the investigators recruited three chief physicians, four attending physicians, and three fellows to provide treatment recommendations for 1,977 patients with complex breast cancer who were treated at 10 hospitals in China. Participating physicians shared the workload; each evaluated an average of 198 different cases.

On average, oncologists and WfO made the same treatment recommendations 56% of the time. Out of the different types of physicians, fellows were most likely to agree with WfO, based on a 68% concordance rate, compared with 54% for chief physicians and 49% for attending physicians. Including all physicians, concordance was lowest for hormone receptor–positive/HER2-positive disease (48%) and highest for triple-negative cases (71%). Adjuvant and metastatic therapies were also evaluated, with high concordance for adjuvant endocrine (78%) and targeted therapy (100%), compared with moderate concordance for first- (52%) and second-line metastatic therapy (50%). The investigators described concordance results as generally “modest;” however, they noted that such levels are promising.

“This degree of concordance is encouraging because therapeutic decisions in these cases are often difficult as a result of the current limits of medical knowledge for treating complex breast cancers and the presence of local contextual factors that affect physician treatment choices,” the investigators wrote. “It is important to note that nonconcordance does not imply that one treatment is correct for a given patient and another is not, nor does it necessarily diminish the potential value of a decision support system that provides access to supporting evidence and insight into its reasoning process.”

The study was funded by Zefei Jiang. The investigators reported affiliations with IBM Watson Health, Pharmaceutical Manufacturer Institution, Merck, and others.

SOURCE: Xu F et al. JCO Clin Cancer Inform. 2019 Aug 16. doi: 10.1200/CCI.18.00159.

When it comes to treatment recommendations for high-risk breast cancer, oncologists agree with a leading artificial intelligence platform about half the time, according to investigators.

In the first study of its kind, involving 10 Chinese oncologists, recommendation concordance with the Watson for Oncology treatment advisory tool (WfO) was generally lower for hormone receptor–positive and metastatic cancers than hormone receptor–negative and nonmetastatic cases, reported Fengrui Xu, MD, of the Academy of Military Medical Sciences in Beijing, and colleagues. Refinement could enable broad use of Watson, not to dictate treatment decisions, but instead to propose alternate treatment approaches and offer point-of-care access to relevant evidence.

“[WfO] is an example of a quantitative oncology clinical decision support that leverages the clinical expertise of oncologists at Memorial Sloan Kettering Cancer Center [MSKCC],” the investigators wrote in JCO Clinical Cancer Informatics. The platform uses machine-learning software to interpret patient scenarios in light from MSKCC training cases, MSKCC treatment guidelines, and more than 300 medical textbooks and journals.

To compare WfO with real-world decision makers, the investigators recruited three chief physicians, four attending physicians, and three fellows to provide treatment recommendations for 1,977 patients with complex breast cancer who were treated at 10 hospitals in China. Participating physicians shared the workload; each evaluated an average of 198 different cases.

On average, oncologists and WfO made the same treatment recommendations 56% of the time. Out of the different types of physicians, fellows were most likely to agree with WfO, based on a 68% concordance rate, compared with 54% for chief physicians and 49% for attending physicians. Including all physicians, concordance was lowest for hormone receptor–positive/HER2-positive disease (48%) and highest for triple-negative cases (71%). Adjuvant and metastatic therapies were also evaluated, with high concordance for adjuvant endocrine (78%) and targeted therapy (100%), compared with moderate concordance for first- (52%) and second-line metastatic therapy (50%). The investigators described concordance results as generally “modest;” however, they noted that such levels are promising.

“This degree of concordance is encouraging because therapeutic decisions in these cases are often difficult as a result of the current limits of medical knowledge for treating complex breast cancers and the presence of local contextual factors that affect physician treatment choices,” the investigators wrote. “It is important to note that nonconcordance does not imply that one treatment is correct for a given patient and another is not, nor does it necessarily diminish the potential value of a decision support system that provides access to supporting evidence and insight into its reasoning process.”

The study was funded by Zefei Jiang. The investigators reported affiliations with IBM Watson Health, Pharmaceutical Manufacturer Institution, Merck, and others.

SOURCE: Xu F et al. JCO Clin Cancer Inform. 2019 Aug 16. doi: 10.1200/CCI.18.00159.

When it comes to treatment recommendations for high-risk breast cancer, oncologists agree with a leading artificial intelligence platform about half the time, according to investigators.

In the first study of its kind, involving 10 Chinese oncologists, recommendation concordance with the Watson for Oncology treatment advisory tool (WfO) was generally lower for hormone receptor–positive and metastatic cancers than hormone receptor–negative and nonmetastatic cases, reported Fengrui Xu, MD, of the Academy of Military Medical Sciences in Beijing, and colleagues. Refinement could enable broad use of Watson, not to dictate treatment decisions, but instead to propose alternate treatment approaches and offer point-of-care access to relevant evidence.

“[WfO] is an example of a quantitative oncology clinical decision support that leverages the clinical expertise of oncologists at Memorial Sloan Kettering Cancer Center [MSKCC],” the investigators wrote in JCO Clinical Cancer Informatics. The platform uses machine-learning software to interpret patient scenarios in light from MSKCC training cases, MSKCC treatment guidelines, and more than 300 medical textbooks and journals.

To compare WfO with real-world decision makers, the investigators recruited three chief physicians, four attending physicians, and three fellows to provide treatment recommendations for 1,977 patients with complex breast cancer who were treated at 10 hospitals in China. Participating physicians shared the workload; each evaluated an average of 198 different cases.

On average, oncologists and WfO made the same treatment recommendations 56% of the time. Out of the different types of physicians, fellows were most likely to agree with WfO, based on a 68% concordance rate, compared with 54% for chief physicians and 49% for attending physicians. Including all physicians, concordance was lowest for hormone receptor–positive/HER2-positive disease (48%) and highest for triple-negative cases (71%). Adjuvant and metastatic therapies were also evaluated, with high concordance for adjuvant endocrine (78%) and targeted therapy (100%), compared with moderate concordance for first- (52%) and second-line metastatic therapy (50%). The investigators described concordance results as generally “modest;” however, they noted that such levels are promising.

“This degree of concordance is encouraging because therapeutic decisions in these cases are often difficult as a result of the current limits of medical knowledge for treating complex breast cancers and the presence of local contextual factors that affect physician treatment choices,” the investigators wrote. “It is important to note that nonconcordance does not imply that one treatment is correct for a given patient and another is not, nor does it necessarily diminish the potential value of a decision support system that provides access to supporting evidence and insight into its reasoning process.”

The study was funded by Zefei Jiang. The investigators reported affiliations with IBM Watson Health, Pharmaceutical Manufacturer Institution, Merck, and others.

SOURCE: Xu F et al. JCO Clin Cancer Inform. 2019 Aug 16. doi: 10.1200/CCI.18.00159.

Long-term survivors of cancer have more age-related functional deficits than do those who have not experienced cancer, and these deficits – as well as their cancer history – are both associated with a higher risk of all-cause mortality, a study has found.

A paper published in Cancer reported the outcomes of a population-based cohort study involving 1,723 female cancer survivors and 11,145 cancer-free women enrolled in the Iowa Women’s Health Study, who were followed for 10 years.

The analysis revealed that women with a history of cancer had significantly more deficits on a geriatric assessment compared with their age-matched controls without a history of cancer. While 66% of women without a cancer history had one or more deficits, 70% of those with a history had at least one age-related deficit, and they were significantly more likely to have two or more deficits.

Cancer survivors were significantly more likely to have two or more physical function limitations than were those without a history of cancer (42.4% vs. 36.9%, P less than .0001), to have two or more comorbidities (41.3% vs. 38.2%, P = .02) and to have poor general health (23.3% vs. 17.4%, P less than .0001). They were also significantly less likely to be underweight.

The study found that both cancer history and age-related functional deficits were predictors of mortality, even after adjustment for confounders such as chronological age, smoking, and physical activity levels. The highest mortality risk was seen in cancer survivors with two or more age-related health deficits, who had a twofold greater mortality risk compared with the noncancer controls with fewer than two health deficits.

Even individuals with a history of cancer but without any health deficits still had a 1.3-1.4-fold increased risk of mortality compared with individuals without a history of cancer and without health deficits.

“These results confirm the increased risk of mortality associated with GA domain deficits and extend the research by demonstrating that a cancer history is associated with an older functional age compared with aged-matched cancer-free individuals,” wrote Cindy K. Blair, PhD, of the department of internal medicine at the University of New Mexico, Albuquerque, and coauthors.

They noted that the study included very long-term cancer survivors who had survived for an average of 11 years before they underwent the geriatric assessment and were then followed for 10 years after that point.

“Further research is needed to identify older cancer survivors who are at risk of accelerated aging,” the authors wrote. “Interventions that target physical function, comorbidity, nutritional status, and general health are greatly needed to improve or maintain the quality of survivorship in older cancer survivors.”

The National Cancer Institute, the University of Minnesota Cancer Center, and the University of New Mexico Comprehensive Cancer Center supported the study. Two authors declared grants from the National Institutes of Health related to the study.

SOURCE: Blair C et al. Cancer 2019, Aug 16. doi: 10.1002/cncr.32449.

Long-term survivors of cancer have more age-related functional deficits than do those who have not experienced cancer, and these deficits – as well as their cancer history – are both associated with a higher risk of all-cause mortality, a study has found.

A paper published in Cancer reported the outcomes of a population-based cohort study involving 1,723 female cancer survivors and 11,145 cancer-free women enrolled in the Iowa Women’s Health Study, who were followed for 10 years.

The analysis revealed that women with a history of cancer had significantly more deficits on a geriatric assessment compared with their age-matched controls without a history of cancer. While 66% of women without a cancer history had one or more deficits, 70% of those with a history had at least one age-related deficit, and they were significantly more likely to have two or more deficits.

Cancer survivors were significantly more likely to have two or more physical function limitations than were those without a history of cancer (42.4% vs. 36.9%, P less than .0001), to have two or more comorbidities (41.3% vs. 38.2%, P = .02) and to have poor general health (23.3% vs. 17.4%, P less than .0001). They were also significantly less likely to be underweight.

The study found that both cancer history and age-related functional deficits were predictors of mortality, even after adjustment for confounders such as chronological age, smoking, and physical activity levels. The highest mortality risk was seen in cancer survivors with two or more age-related health deficits, who had a twofold greater mortality risk compared with the noncancer controls with fewer than two health deficits.

Even individuals with a history of cancer but without any health deficits still had a 1.3-1.4-fold increased risk of mortality compared with individuals without a history of cancer and without health deficits.

“These results confirm the increased risk of mortality associated with GA domain deficits and extend the research by demonstrating that a cancer history is associated with an older functional age compared with aged-matched cancer-free individuals,” wrote Cindy K. Blair, PhD, of the department of internal medicine at the University of New Mexico, Albuquerque, and coauthors.

They noted that the study included very long-term cancer survivors who had survived for an average of 11 years before they underwent the geriatric assessment and were then followed for 10 years after that point.

“Further research is needed to identify older cancer survivors who are at risk of accelerated aging,” the authors wrote. “Interventions that target physical function, comorbidity, nutritional status, and general health are greatly needed to improve or maintain the quality of survivorship in older cancer survivors.”

The National Cancer Institute, the University of Minnesota Cancer Center, and the University of New Mexico Comprehensive Cancer Center supported the study. Two authors declared grants from the National Institutes of Health related to the study.

SOURCE: Blair C et al. Cancer 2019, Aug 16. doi: 10.1002/cncr.32449.

Long-term survivors of cancer have more age-related functional deficits than do those who have not experienced cancer, and these deficits – as well as their cancer history – are both associated with a higher risk of all-cause mortality, a study has found.

A paper published in Cancer reported the outcomes of a population-based cohort study involving 1,723 female cancer survivors and 11,145 cancer-free women enrolled in the Iowa Women’s Health Study, who were followed for 10 years.

The analysis revealed that women with a history of cancer had significantly more deficits on a geriatric assessment compared with their age-matched controls without a history of cancer. While 66% of women without a cancer history had one or more deficits, 70% of those with a history had at least one age-related deficit, and they were significantly more likely to have two or more deficits.

Cancer survivors were significantly more likely to have two or more physical function limitations than were those without a history of cancer (42.4% vs. 36.9%, P less than .0001), to have two or more comorbidities (41.3% vs. 38.2%, P = .02) and to have poor general health (23.3% vs. 17.4%, P less than .0001). They were also significantly less likely to be underweight.

The study found that both cancer history and age-related functional deficits were predictors of mortality, even after adjustment for confounders such as chronological age, smoking, and physical activity levels. The highest mortality risk was seen in cancer survivors with two or more age-related health deficits, who had a twofold greater mortality risk compared with the noncancer controls with fewer than two health deficits.

Even individuals with a history of cancer but without any health deficits still had a 1.3-1.4-fold increased risk of mortality compared with individuals without a history of cancer and without health deficits.

“These results confirm the increased risk of mortality associated with GA domain deficits and extend the research by demonstrating that a cancer history is associated with an older functional age compared with aged-matched cancer-free individuals,” wrote Cindy K. Blair, PhD, of the department of internal medicine at the University of New Mexico, Albuquerque, and coauthors.

They noted that the study included very long-term cancer survivors who had survived for an average of 11 years before they underwent the geriatric assessment and were then followed for 10 years after that point.

“Further research is needed to identify older cancer survivors who are at risk of accelerated aging,” the authors wrote. “Interventions that target physical function, comorbidity, nutritional status, and general health are greatly needed to improve or maintain the quality of survivorship in older cancer survivors.”

The National Cancer Institute, the University of Minnesota Cancer Center, and the University of New Mexico Comprehensive Cancer Center supported the study. Two authors declared grants from the National Institutes of Health related to the study.

SOURCE: Blair C et al. Cancer 2019, Aug 16. doi: 10.1002/cncr.32449.

For patients with grade 3 breast cancer, recurrence score testing may have significant clinical value in determining which patients are likely to benefit from chemotherapy, according to investigators who recently reported results of a large, national cohort study.

Among patients with pN0/1 grade 3 invasive breast cancers, about one-third had a low recurrence score, which was associated with no early benefit from the addition of chemotherapy, wrote senior study author Jane E. Brock, MBBS, PhD, of Harvard Medical School, Boston, and coauthors.

Incorporating recurrence score testing into clinical decision making may help “tailor treatment recommendations” for patients with grade 3 invasive breast cancers, Dr. Brock and coauthors reported in JCO Precision Oncology.

“To our knowledge, these findings represent the largest analysis to date of the potential impact of recurrence score on the outcomes and management of grade 3 tumors, and suggest that the assumption that all pT1c/2 pN0/1, [estrogen receptor–positive] histopathologic grade 3 tumors are high risk and will consequently benefit from adjuvant chemotherapy may be unmerited,” the Dr. Brock and coauthors wrote in the report.

These findings “fill a gap” as the final results of the RxPONDER trial are awaited, according to investigators. Specifically, RxPONDER is designed to evaluate the potential benefit of adjuvant chemotherapy in pN0/1 patients with intermediate range recurrence scores.

Moreover, the findings complement the reported results of the TAILORx trial, which showed that chemotherapy does not provide a benefit in most low and intermediate recurrence score tumors, which suggests some patients may safely omit chemotherapy without affecting outcomes, the investigators added.

The present analysis included a total of 30,864 grade 3 breast cancers from the National Cancer Database, which represents more than 70% of new diagnoses in the United States, according to investigators.

Testing using the 21-gene Oncotype DX Breast Recurrence Score increased over time for pN0 cancers, from 53% in 2010 to 72% in 2015, investigators found; likewise, for pN1 cancers, testing increased from 16% to 36% over that time period. They also found that, overall, 30% of pN0 and 27.1% of pN1 cancers had a low recurrence score.

Adjuvant chemotherapy was not associated with any additional benefit in patients with low recurrence scores, according to the analysis.

For patients with intermediate recurrence scores, chemotherapy was linked to improved survival in univariable analyses, but following adjustment for clinical and pathologic characteristics, intermediate scores were not predictive of a significant overall survival benefit, investigators found.

By contrast, chemotherapy was associated with additional benefit in patients with high recurrence scores in both univariable and multivariable analyses.

For patients with pN0 grade 3 disease and high recurrence score, chemotherapy was linked to significantly improved overall survival, compared with that of patients who received no chemotherapy (hazard ratio, 0.63; 95% confidence interval, 0.43-0.90; P = .01), while a similar survival benefit was reported among patients with pN1 disease and high recurrence scores (HR, 0.24; 95% CI, 0.13-0.47; P less than .001).

These results suggest that recurrence score may aid in determining the anticipated benefit of chemotherapy in this heterogeneous cohort of patients, investigators wrote.

“Furthermore, our findings show significant variability in national patterns of recurrence testing and chemotherapy use for grade 3 disease, which suggests opportunities for more comprehensive national guidelines for recurrence score testing in high-grade tumors,” they concluded.

Dr. Brock reported no potential conflicts of interest. Coauthors provided disclosures related to AstraZeneca, Blade Therapeutics, Eisai, EMD Serono, Galena Biopharma, Genentech, Genomic Health, Novartis, Novartis Institutes for BioMedical Research, Peregrine, Puma Biotechnology, resTORbio, Roche, and others.

SOURCE: Brock JE et al. JCO Precis Oncol. 2019 Aug 14. doi: 10.1200/PO.19.00029.

For patients with grade 3 breast cancer, recurrence score testing may have significant clinical value in determining which patients are likely to benefit from chemotherapy, according to investigators who recently reported results of a large, national cohort study.

Among patients with pN0/1 grade 3 invasive breast cancers, about one-third had a low recurrence score, which was associated with no early benefit from the addition of chemotherapy, wrote senior study author Jane E. Brock, MBBS, PhD, of Harvard Medical School, Boston, and coauthors.

Incorporating recurrence score testing into clinical decision making may help “tailor treatment recommendations” for patients with grade 3 invasive breast cancers, Dr. Brock and coauthors reported in JCO Precision Oncology.

“To our knowledge, these findings represent the largest analysis to date of the potential impact of recurrence score on the outcomes and management of grade 3 tumors, and suggest that the assumption that all pT1c/2 pN0/1, [estrogen receptor–positive] histopathologic grade 3 tumors are high risk and will consequently benefit from adjuvant chemotherapy may be unmerited,” the Dr. Brock and coauthors wrote in the report.

These findings “fill a gap” as the final results of the RxPONDER trial are awaited, according to investigators. Specifically, RxPONDER is designed to evaluate the potential benefit of adjuvant chemotherapy in pN0/1 patients with intermediate range recurrence scores.

Moreover, the findings complement the reported results of the TAILORx trial, which showed that chemotherapy does not provide a benefit in most low and intermediate recurrence score tumors, which suggests some patients may safely omit chemotherapy without affecting outcomes, the investigators added.

The present analysis included a total of 30,864 grade 3 breast cancers from the National Cancer Database, which represents more than 70% of new diagnoses in the United States, according to investigators.

Testing using the 21-gene Oncotype DX Breast Recurrence Score increased over time for pN0 cancers, from 53% in 2010 to 72% in 2015, investigators found; likewise, for pN1 cancers, testing increased from 16% to 36% over that time period. They also found that, overall, 30% of pN0 and 27.1% of pN1 cancers had a low recurrence score.

Adjuvant chemotherapy was not associated with any additional benefit in patients with low recurrence scores, according to the analysis.

For patients with intermediate recurrence scores, chemotherapy was linked to improved survival in univariable analyses, but following adjustment for clinical and pathologic characteristics, intermediate scores were not predictive of a significant overall survival benefit, investigators found.

By contrast, chemotherapy was associated with additional benefit in patients with high recurrence scores in both univariable and multivariable analyses.

For patients with pN0 grade 3 disease and high recurrence score, chemotherapy was linked to significantly improved overall survival, compared with that of patients who received no chemotherapy (hazard ratio, 0.63; 95% confidence interval, 0.43-0.90; P = .01), while a similar survival benefit was reported among patients with pN1 disease and high recurrence scores (HR, 0.24; 95% CI, 0.13-0.47; P less than .001).

These results suggest that recurrence score may aid in determining the anticipated benefit of chemotherapy in this heterogeneous cohort of patients, investigators wrote.

“Furthermore, our findings show significant variability in national patterns of recurrence testing and chemotherapy use for grade 3 disease, which suggests opportunities for more comprehensive national guidelines for recurrence score testing in high-grade tumors,” they concluded.

Dr. Brock reported no potential conflicts of interest. Coauthors provided disclosures related to AstraZeneca, Blade Therapeutics, Eisai, EMD Serono, Galena Biopharma, Genentech, Genomic Health, Novartis, Novartis Institutes for BioMedical Research, Peregrine, Puma Biotechnology, resTORbio, Roche, and others.

SOURCE: Brock JE et al. JCO Precis Oncol. 2019 Aug 14. doi: 10.1200/PO.19.00029.

For patients with grade 3 breast cancer, recurrence score testing may have significant clinical value in determining which patients are likely to benefit from chemotherapy, according to investigators who recently reported results of a large, national cohort study.

Among patients with pN0/1 grade 3 invasive breast cancers, about one-third had a low recurrence score, which was associated with no early benefit from the addition of chemotherapy, wrote senior study author Jane E. Brock, MBBS, PhD, of Harvard Medical School, Boston, and coauthors.

Incorporating recurrence score testing into clinical decision making may help “tailor treatment recommendations” for patients with grade 3 invasive breast cancers, Dr. Brock and coauthors reported in JCO Precision Oncology.

“To our knowledge, these findings represent the largest analysis to date of the potential impact of recurrence score on the outcomes and management of grade 3 tumors, and suggest that the assumption that all pT1c/2 pN0/1, [estrogen receptor–positive] histopathologic grade 3 tumors are high risk and will consequently benefit from adjuvant chemotherapy may be unmerited,” the Dr. Brock and coauthors wrote in the report.

These findings “fill a gap” as the final results of the RxPONDER trial are awaited, according to investigators. Specifically, RxPONDER is designed to evaluate the potential benefit of adjuvant chemotherapy in pN0/1 patients with intermediate range recurrence scores.

Moreover, the findings complement the reported results of the TAILORx trial, which showed that chemotherapy does not provide a benefit in most low and intermediate recurrence score tumors, which suggests some patients may safely omit chemotherapy without affecting outcomes, the investigators added.

The present analysis included a total of 30,864 grade 3 breast cancers from the National Cancer Database, which represents more than 70% of new diagnoses in the United States, according to investigators.

Testing using the 21-gene Oncotype DX Breast Recurrence Score increased over time for pN0 cancers, from 53% in 2010 to 72% in 2015, investigators found; likewise, for pN1 cancers, testing increased from 16% to 36% over that time period. They also found that, overall, 30% of pN0 and 27.1% of pN1 cancers had a low recurrence score.

Adjuvant chemotherapy was not associated with any additional benefit in patients with low recurrence scores, according to the analysis.

For patients with intermediate recurrence scores, chemotherapy was linked to improved survival in univariable analyses, but following adjustment for clinical and pathologic characteristics, intermediate scores were not predictive of a significant overall survival benefit, investigators found.

By contrast, chemotherapy was associated with additional benefit in patients with high recurrence scores in both univariable and multivariable analyses.

For patients with pN0 grade 3 disease and high recurrence score, chemotherapy was linked to significantly improved overall survival, compared with that of patients who received no chemotherapy (hazard ratio, 0.63; 95% confidence interval, 0.43-0.90; P = .01), while a similar survival benefit was reported among patients with pN1 disease and high recurrence scores (HR, 0.24; 95% CI, 0.13-0.47; P less than .001).

These results suggest that recurrence score may aid in determining the anticipated benefit of chemotherapy in this heterogeneous cohort of patients, investigators wrote.

“Furthermore, our findings show significant variability in national patterns of recurrence testing and chemotherapy use for grade 3 disease, which suggests opportunities for more comprehensive national guidelines for recurrence score testing in high-grade tumors,” they concluded.

Dr. Brock reported no potential conflicts of interest. Coauthors provided disclosures related to AstraZeneca, Blade Therapeutics, Eisai, EMD Serono, Galena Biopharma, Genentech, Genomic Health, Novartis, Novartis Institutes for BioMedical Research, Peregrine, Puma Biotechnology, resTORbio, Roche, and others.

SOURCE: Brock JE et al. JCO Precis Oncol. 2019 Aug 14. doi: 10.1200/PO.19.00029.

The U.S. Preventive Services Task Force (USPSTF) has updated its recommendations on assessment of breast cancer susceptibility gene (BRCA)-related cancer, substantially expanding the pool of individuals for whom risk assessment, testing, and counseling would be warranted.

Christian Jasiuk/Thinkstock

In its 2013 recommendation, the USPSTF said referral for genetic counseling and evaluation for BRCA1/2 testing was warranted for women who had a family history linked to increased risk of potentially harmful BRCA1/2 mutations.

The updated recommendations, just published in JAMA, expand the screening-eligible population to include those with personal cancer history, and more specifically call out ancestry linked to BRCA1/2 mutations as a risk factor (JAMA. 2019;322[7]:652-65. doi: 10.1001/jama.2019.10987).

“The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool,” wrote Douglas K. Owens, MD, of Stanford (Calif.) University, and coauthors of the task force report.

Positive results on the risk assessment tool should prompt genetic counseling, and genetic testing if indicated after counseling, the USPSTF added in its statement.

By contrast, the task force recommends against routine assessment, counseling, and testing in women with no family history, personal history, or ancestry linked to possibly harmful BRCA1/2 gene mutations, consistent with their previous recommendation.

Mutations of BRCA1/2 genes occur in an estimated 1 in 300-500 women in the general population, and account for 15% of ovarian cancer and up to 10% of breast cancer cases, according to the USPSTF.

Breast cancer risk is increased up to 65% by 70 years in those women with clinically significant BRCA1/2 mutations, while risk of ovarian, fallopian tube, or peritoneal cancer are increased by up to 39%, according to studies cited by the USPSTF.
 

Important step forward

Including women with prior breast and ovarian cancer in the screening-eligible population is an “important step forward,” Susan Domcheck, MD, and Mark Robson, MD, said in a related editorial.

“While further expansion of the USPSTF recommendation should be considered, the importance is clear: Identification of individuals at risk of carrying a BRCA1/2 mutation can be lifesaving and should be a part of routine medical care,” Dr. Domcheck and Dr. Robson said in their editorial, which appears in JAMA.

While the updated recommendations explicitly call out ancestry as a risk factor, they stop short of endorsing testing for unaffected Ashkenazi Jewish women with no family history, the authors said.

“However, the statement may be interpreted as a step toward supporting unselected testing in this group,” they added.

Among unselected individuals of Ashkenazi Jewish descent, 1 in 40 have 1 of 3 specific BRCA1 or BRCA2 founder mutations, according to one study cited by Dr. Domcheck and Dr. Robson.
 

More research needed

Current research is still “limited or lacking” to address many key questions about the benefits and harms of risk assessment, genetic counseling, and genetic testing in women without BRCA1/2-related cancer, according to authors of a literature review used by the USPSTF.

Notably, the ability of risk assessment, testing, and counseling to reduce cancer incidence and mortality among such women has not been directly evaluated by studies to date, said the review authors, led by Heidi D. Nelson, MD, MPH, of Oregon Health & Science University, Portland.

“Without effectiveness trials of intensive screening, practice standards have preceded supporting evidence,” said Dr. Nelson and coauthors noted in a report on the review findings.

In observational studies, mastectomy and oophorectomy have been associated with substantial reductions in subsequent cancer incidence and mortality; however, they are invasive procedures with potential complications, the authors noted.

“To determine the appropriateness of risk assessment and genetic testing for BRCA1/2 mutations as a preventive service in primary care, more information is needed about mutation prevalence and the effect of testing in the general population,” they added.

Researchers studying BRCA1/2 assessment as preventive service in primary care have generally looked at highly selected patient populations in referral centers, and have reported relatively short-term outcomes, they said.

Research is additionally needed on access to genetic testing and follow-up, effectiveness of risk stratification and multigene panels, and the impact of direct-to-consumer genetic testing, among other key questions, the authors of the review added.
 

Treatment implications

While the USPSTF recommendations do not mention systemic therapy, finding a BRCA mutation in a cancer patient today has important implications for treatment, said Rachel L. Yung, MD, and Larissa A. Korde, MD, MPH

Specifically, poly (ADP-ribose) polymerase (PARP) inhibitors have proved effective in certain BRCA-related cancers, Dr. Yung and Dr. Korde said in an editorial on the updated recommendations appearing in JAMA Oncology.

The Food and Drug Administration has already approved several PARP inhibitors for treatment of BRCA-linked metastatic breast or ovarian cancers, and studies are underway for other tumor types, including prostate and pancreatic cancers that harbor a BRCA mutation.

“Increasing awareness of BRCA mutation as a target for treatment will likely lead to an increase in the identification of patients with cancer harboring germline BRCA mutations, which in turn will increase the need for cascade testing for relatives of affected probands,” wrote Dr. Yung and Dr. Korde.
 

Addressing disparities in care

The USPSTF recommendations for BRCA risk assessment do not address disparities in testing referral and variation in breast cancer phenotypes among women of African ancestry, owing to lack of evidence, according to Lisa Newman, MD, MPH, of the Interdisciplinary Breast Program at New York–Presbyterian/Weill Cornell Medical Center, New York.

“Paradoxically, the data-driven basis for the USPSTF recommendation statement may magnify existing genetic testing disparities,” Dr. Newman wrote in an editorial that appears in JAMA Surgery.

Non-Hispanic black women in the United States have a twofold higher incidence of triple-negative breast cancer, which is a well documented risk factor for BRCA1 mutation carrier status, according to Dr. Newman.

Despite this, she added, genetic counseling and testing referrals remain “disproportionately low” among U.S. patients of African ancestry.

“It remains imperative for clinicians to exercise clinical judgment and to be mindful of patient subsets that do not necessarily fit into recommendations designed for the majority or general populations,” Dr. Newman concluded in her editorial.

The USPSTF is funded by the Agency for Healthcare Research and Quality. Members of the task force receive travel reimbursement and honoraria for participating in USPSTF meetings.
 

The U.S. Preventive Services Task Force (USPSTF) has updated its recommendations on assessment of breast cancer susceptibility gene (BRCA)-related cancer, substantially expanding the pool of individuals for whom risk assessment, testing, and counseling would be warranted.

Christian Jasiuk/Thinkstock

In its 2013 recommendation, the USPSTF said referral for genetic counseling and evaluation for BRCA1/2 testing was warranted for women who had a family history linked to increased risk of potentially harmful BRCA1/2 mutations.

The updated recommendations, just published in JAMA, expand the screening-eligible population to include those with personal cancer history, and more specifically call out ancestry linked to BRCA1/2 mutations as a risk factor (JAMA. 2019;322[7]:652-65. doi: 10.1001/jama.2019.10987).

“The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool,” wrote Douglas K. Owens, MD, of Stanford (Calif.) University, and coauthors of the task force report.

Positive results on the risk assessment tool should prompt genetic counseling, and genetic testing if indicated after counseling, the USPSTF added in its statement.

By contrast, the task force recommends against routine assessment, counseling, and testing in women with no family history, personal history, or ancestry linked to possibly harmful BRCA1/2 gene mutations, consistent with their previous recommendation.

Mutations of BRCA1/2 genes occur in an estimated 1 in 300-500 women in the general population, and account for 15% of ovarian cancer and up to 10% of breast cancer cases, according to the USPSTF.

Breast cancer risk is increased up to 65% by 70 years in those women with clinically significant BRCA1/2 mutations, while risk of ovarian, fallopian tube, or peritoneal cancer are increased by up to 39%, according to studies cited by the USPSTF.
 

Important step forward

Including women with prior breast and ovarian cancer in the screening-eligible population is an “important step forward,” Susan Domcheck, MD, and Mark Robson, MD, said in a related editorial.

“While further expansion of the USPSTF recommendation should be considered, the importance is clear: Identification of individuals at risk of carrying a BRCA1/2 mutation can be lifesaving and should be a part of routine medical care,” Dr. Domcheck and Dr. Robson said in their editorial, which appears in JAMA.

While the updated recommendations explicitly call out ancestry as a risk factor, they stop short of endorsing testing for unaffected Ashkenazi Jewish women with no family history, the authors said.

“However, the statement may be interpreted as a step toward supporting unselected testing in this group,” they added.

Among unselected individuals of Ashkenazi Jewish descent, 1 in 40 have 1 of 3 specific BRCA1 or BRCA2 founder mutations, according to one study cited by Dr. Domcheck and Dr. Robson.
 

More research needed

Current research is still “limited or lacking” to address many key questions about the benefits and harms of risk assessment, genetic counseling, and genetic testing in women without BRCA1/2-related cancer, according to authors of a literature review used by the USPSTF.

Notably, the ability of risk assessment, testing, and counseling to reduce cancer incidence and mortality among such women has not been directly evaluated by studies to date, said the review authors, led by Heidi D. Nelson, MD, MPH, of Oregon Health & Science University, Portland.

“Without effectiveness trials of intensive screening, practice standards have preceded supporting evidence,” said Dr. Nelson and coauthors noted in a report on the review findings.

In observational studies, mastectomy and oophorectomy have been associated with substantial reductions in subsequent cancer incidence and mortality; however, they are invasive procedures with potential complications, the authors noted.

“To determine the appropriateness of risk assessment and genetic testing for BRCA1/2 mutations as a preventive service in primary care, more information is needed about mutation prevalence and the effect of testing in the general population,” they added.

Researchers studying BRCA1/2 assessment as preventive service in primary care have generally looked at highly selected patient populations in referral centers, and have reported relatively short-term outcomes, they said.

Research is additionally needed on access to genetic testing and follow-up, effectiveness of risk stratification and multigene panels, and the impact of direct-to-consumer genetic testing, among other key questions, the authors of the review added.
 

Treatment implications

While the USPSTF recommendations do not mention systemic therapy, finding a BRCA mutation in a cancer patient today has important implications for treatment, said Rachel L. Yung, MD, and Larissa A. Korde, MD, MPH

Specifically, poly (ADP-ribose) polymerase (PARP) inhibitors have proved effective in certain BRCA-related cancers, Dr. Yung and Dr. Korde said in an editorial on the updated recommendations appearing in JAMA Oncology.

The Food and Drug Administration has already approved several PARP inhibitors for treatment of BRCA-linked metastatic breast or ovarian cancers, and studies are underway for other tumor types, including prostate and pancreatic cancers that harbor a BRCA mutation.

“Increasing awareness of BRCA mutation as a target for treatment will likely lead to an increase in the identification of patients with cancer harboring germline BRCA mutations, which in turn will increase the need for cascade testing for relatives of affected probands,” wrote Dr. Yung and Dr. Korde.
 

Addressing disparities in care

The USPSTF recommendations for BRCA risk assessment do not address disparities in testing referral and variation in breast cancer phenotypes among women of African ancestry, owing to lack of evidence, according to Lisa Newman, MD, MPH, of the Interdisciplinary Breast Program at New York–Presbyterian/Weill Cornell Medical Center, New York.

“Paradoxically, the data-driven basis for the USPSTF recommendation statement may magnify existing genetic testing disparities,” Dr. Newman wrote in an editorial that appears in JAMA Surgery.

Non-Hispanic black women in the United States have a twofold higher incidence of triple-negative breast cancer, which is a well documented risk factor for BRCA1 mutation carrier status, according to Dr. Newman.

Despite this, she added, genetic counseling and testing referrals remain “disproportionately low” among U.S. patients of African ancestry.

“It remains imperative for clinicians to exercise clinical judgment and to be mindful of patient subsets that do not necessarily fit into recommendations designed for the majority or general populations,” Dr. Newman concluded in her editorial.

The USPSTF is funded by the Agency for Healthcare Research and Quality. Members of the task force receive travel reimbursement and honoraria for participating in USPSTF meetings.
 

The U.S. Preventive Services Task Force (USPSTF) has updated its recommendations on assessment of breast cancer susceptibility gene (BRCA)-related cancer, substantially expanding the pool of individuals for whom risk assessment, testing, and counseling would be warranted.

Christian Jasiuk/Thinkstock

In its 2013 recommendation, the USPSTF said referral for genetic counseling and evaluation for BRCA1/2 testing was warranted for women who had a family history linked to increased risk of potentially harmful BRCA1/2 mutations.

The updated recommendations, just published in JAMA, expand the screening-eligible population to include those with personal cancer history, and more specifically call out ancestry linked to BRCA1/2 mutations as a risk factor (JAMA. 2019;322[7]:652-65. doi: 10.1001/jama.2019.10987).

“The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool,” wrote Douglas K. Owens, MD, of Stanford (Calif.) University, and coauthors of the task force report.

Positive results on the risk assessment tool should prompt genetic counseling, and genetic testing if indicated after counseling, the USPSTF added in its statement.

By contrast, the task force recommends against routine assessment, counseling, and testing in women with no family history, personal history, or ancestry linked to possibly harmful BRCA1/2 gene mutations, consistent with their previous recommendation.

Mutations of BRCA1/2 genes occur in an estimated 1 in 300-500 women in the general population, and account for 15% of ovarian cancer and up to 10% of breast cancer cases, according to the USPSTF.

Breast cancer risk is increased up to 65% by 70 years in those women with clinically significant BRCA1/2 mutations, while risk of ovarian, fallopian tube, or peritoneal cancer are increased by up to 39%, according to studies cited by the USPSTF.
 

Important step forward

Including women with prior breast and ovarian cancer in the screening-eligible population is an “important step forward,” Susan Domcheck, MD, and Mark Robson, MD, said in a related editorial.

“While further expansion of the USPSTF recommendation should be considered, the importance is clear: Identification of individuals at risk of carrying a BRCA1/2 mutation can be lifesaving and should be a part of routine medical care,” Dr. Domcheck and Dr. Robson said in their editorial, which appears in JAMA.

While the updated recommendations explicitly call out ancestry as a risk factor, they stop short of endorsing testing for unaffected Ashkenazi Jewish women with no family history, the authors said.

“However, the statement may be interpreted as a step toward supporting unselected testing in this group,” they added.

Among unselected individuals of Ashkenazi Jewish descent, 1 in 40 have 1 of 3 specific BRCA1 or BRCA2 founder mutations, according to one study cited by Dr. Domcheck and Dr. Robson.
 

More research needed

Current research is still “limited or lacking” to address many key questions about the benefits and harms of risk assessment, genetic counseling, and genetic testing in women without BRCA1/2-related cancer, according to authors of a literature review used by the USPSTF.

Notably, the ability of risk assessment, testing, and counseling to reduce cancer incidence and mortality among such women has not been directly evaluated by studies to date, said the review authors, led by Heidi D. Nelson, MD, MPH, of Oregon Health & Science University, Portland.

“Without effectiveness trials of intensive screening, practice standards have preceded supporting evidence,” said Dr. Nelson and coauthors noted in a report on the review findings.

In observational studies, mastectomy and oophorectomy have been associated with substantial reductions in subsequent cancer incidence and mortality; however, they are invasive procedures with potential complications, the authors noted.

“To determine the appropriateness of risk assessment and genetic testing for BRCA1/2 mutations as a preventive service in primary care, more information is needed about mutation prevalence and the effect of testing in the general population,” they added.

Researchers studying BRCA1/2 assessment as preventive service in primary care have generally looked at highly selected patient populations in referral centers, and have reported relatively short-term outcomes, they said.

Research is additionally needed on access to genetic testing and follow-up, effectiveness of risk stratification and multigene panels, and the impact of direct-to-consumer genetic testing, among other key questions, the authors of the review added.
 

Treatment implications

While the USPSTF recommendations do not mention systemic therapy, finding a BRCA mutation in a cancer patient today has important implications for treatment, said Rachel L. Yung, MD, and Larissa A. Korde, MD, MPH

Specifically, poly (ADP-ribose) polymerase (PARP) inhibitors have proved effective in certain BRCA-related cancers, Dr. Yung and Dr. Korde said in an editorial on the updated recommendations appearing in JAMA Oncology.

The Food and Drug Administration has already approved several PARP inhibitors for treatment of BRCA-linked metastatic breast or ovarian cancers, and studies are underway for other tumor types, including prostate and pancreatic cancers that harbor a BRCA mutation.

“Increasing awareness of BRCA mutation as a target for treatment will likely lead to an increase in the identification of patients with cancer harboring germline BRCA mutations, which in turn will increase the need for cascade testing for relatives of affected probands,” wrote Dr. Yung and Dr. Korde.
 

Addressing disparities in care

The USPSTF recommendations for BRCA risk assessment do not address disparities in testing referral and variation in breast cancer phenotypes among women of African ancestry, owing to lack of evidence, according to Lisa Newman, MD, MPH, of the Interdisciplinary Breast Program at New York–Presbyterian/Weill Cornell Medical Center, New York.

“Paradoxically, the data-driven basis for the USPSTF recommendation statement may magnify existing genetic testing disparities,” Dr. Newman wrote in an editorial that appears in JAMA Surgery.

Non-Hispanic black women in the United States have a twofold higher incidence of triple-negative breast cancer, which is a well documented risk factor for BRCA1 mutation carrier status, according to Dr. Newman.

Despite this, she added, genetic counseling and testing referrals remain “disproportionately low” among U.S. patients of African ancestry.

“It remains imperative for clinicians to exercise clinical judgment and to be mindful of patient subsets that do not necessarily fit into recommendations designed for the majority or general populations,” Dr. Newman concluded in her editorial.

The USPSTF is funded by the Agency for Healthcare Research and Quality. Members of the task force receive travel reimbursement and honoraria for participating in USPSTF meetings.
 

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

Lipophilic statin therapy significantly reduced the incidence and mortality of hepatocellular carcinoma in adults with viral hepatitis, based on data from 16,668 patients.

The mortality rates for hepatocellular carcinoma in the United States and Europe have been on the rise for decades, and the risk may persist in severe cases despite the use of hepatitis B virus suppression or hepatitis C virus eradication, wrote Tracey G. Simon, MD, of Harvard Medical School, Boston, and colleagues. Previous studies suggest that statins might reduce HCC risk in viral hepatitis patients, but evidence supporting one type of statin over another for HCC prevention is limited, they said.

In a study published in the Annals of Internal Medicine, the researchers reviewed data from a national registry of hepatitis patients in Sweden to assess the effect of lipophilic or hydrophilic statin use on HCC incidence and mortality.

They found a significant reduction in 10-year HCC risk for lipophilic statin users, compared with nonusers (8.1% vs. 3.3%. However, the difference was not significant for hydrophilic statin users vs. nonusers (8.0% vs. 6.8%). The effect of lipophilic statin use was dose dependent; the largest effect on reduction in HCC risk occurred with 600 or more lipophilic statin cumulative daily doses in users, compared with nonusers (8.4% vs. 2.5%).

The study population included 6,554 lipophilic statin users and 1,780 hydrophilic statin users, matched with 8,334 nonusers. Patient demographics were similar between both types of statin user and nonuser groups.

In addition, 10-year mortality was significantly lower for lipophilic statin users compared with nonusers (15.2% vs. 7.3%) and also for hydrophilic statin users, compared with nonusers (16.0% vs. 11.5%).

In a small number of patients with liver disease (462), liver-specific mortality was significantly reduced in lipophilic statin users, compared with nonusers (adjusted hazard ratio, 0.76 vs. 0.98).

“Of note, our findings were robust across several sensitivity analyses and were similar in all predefined subgroups, including among men and women and persons with and without cirrhosis or antiviral therapy use,” the researchers noted.

The study findings were limited by several factors including the potential confounding from variables such as smoking, hepatitis B viral DNA, hepatitis C virus eradication, stage of fibrosis, and HCC screening, as well as a lack of laboratory data to assess cholesterol levels’ impact on statin use, the researchers said. In addition, the study did not compare lipophilic and hydrophilic statins.

However, the results suggest potential distinct benefits of lipophilic statins to reduce HCC risk and support the need for further research, the researchers concluded.

Dr. Simon had no financial conflicts to disclose, but disclosed support from a North American Training Grant from the American College of Gastroenterology. Several coauthors disclosed relationships with multiple companies including AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck Sharp & Dohme. The study was supported in part by the American College of Gastroenterology, the American Association for the Study of Liver Diseases, the Boston Nutrition Obesity Research Center, the National Institutes of Health, Nyckelfonden, Region Orebro (Sweden) County, and the Karolinska Institutet.
 

SOURCE: Simon TG et al. Ann Intern Med. 2019 Aug 19. doi: 10.7326/M18-2753.

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

sworcester@mdedge.com

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

sworcester@mdedge.com

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban are now among the options for thromboprophylaxis in high-risk cancer outpatients with low risk for bleeding and drug interactions, according to a practice guideline update from the American Society of Clinical Oncology.

Sebastian Kaulitzki/Thinkstock

Rivaroxaban also has been added as an option for initial anticoagulation for venous thromboembolism (VTE), and both rivaroxaban and edoxaban are now options for long-term anticoagulation, Nigel S. Key, MB ChB, and colleagues wrote in the updated guideline on the prophylaxis and treatment of VTE – including deep vein thrombosis (DVT) and pulmonary embolism (PE) – in cancer patients (J Clin Oncol. 2019 Aug 5. doi: 10.1200/JCO.19.19.01461).

The addition of DOACs as options for VTE prophylaxis and treatment represents the most notable change to the guideline.

“Oral anticoagulants that target thrombin (direct thrombin inhibitor, dabigatran) or activated factor X (antifactor Xa inhibitors, rivaroxaban, apixaban, and edoxaban) are now approved for treatment of DVT or PE as well as for DVT prophylaxis following orthopedic surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation,” the guideline panel wrote.

A systematic review of PubMed and the Cochrane Library for randomized controlled trials (RCTs) and meta-analyses of RCTs published from Aug. 1, 2014, through Dec. 4, 2018, identified 35 publications on VTE prophylaxis and treatment, including 2 RCTs of DOACs for prophylaxis and 2 others of DOAC treatment, as well as 8 publications on VTE risk assessment. A multidisciplinary expert panel appointed by ASCO and cochaired by Dr. Key of the University of North Carolina, Chapel Hill, used this evidence to develop the updated guideline.

The work was guided by “the ‘signals’ approach that is designed to identify only new, potentially practice-changing data – signals – that might translate into revised practice recommendations,” the authors explained.

DOAC-related updates

VTE prophylaxis. Based in part on findings from the recently published AVERT trial of apixaban in patients initiating a new course of chemotherapy and from the CASSINI trial of rivaroxaban in patients with solid tumors or lymphoma starting systemic antineoplastic therapy, the panel added both agents as thromboprophylactic options that can be offered to high-risk cancer outpatients with no significant risk factors for bleeding or drug interactions (N Engl J Med. 2019;380:711-19; N Engl J Med. 2019;380:720-8).

Low-molecular-weight heparin (LMWH) also remains an option in such patients; consideration of therapy should involve discussion with the patient about relative benefits and harms, drug costs, and “the uncertainty surrounding duration of prophylaxis in this setting,” they wrote.

Anticoagulation for VTE. Options for initial anticoagulation include LMWH, unfractionated heparin (UFH), fondaparinux, and now rivaroxaban, with the latter added based on findings from two RCTs – the SELECT-D trial and the Hokusai VTE-Cancer study – and multiple meta-analyses (J Clin Oncol. 2018;36:2017-23; N Engl J Med. 2018;378:615-24).

Long-term anticoagulation can involve treatment with LMWH, edoxaban, or rivaroxaban for at least 6 months, all of which have improved efficacy versus vitamin K agonists (VKAs), the panel noted. However, VKAs may be used if LMWH and DOACs are not accessible.

Importantly, the literature indicates an increased risk of major bleeding with DOACs, particularly in patients with gastrointestinal malignancies and potentially in those with genitourinary malignancies. “Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding,” the panel wrote.
 

Additional updates

CNS metastases. The anticoagulation recommendations were also updated to include patients with metastatic central nervous system malignancies (those with primary CNS malignancies were included previously). Both those with primary and metastatic CNS malignancy should be offered anticoagulation for established VTE as described for patients with other types of cancer. However, the panel stressed that “uncertainties remain about choice of agents and selection of patients most likely to benefit.”

“Patients with intracranial tumors are at increased risk for thrombotic complications and intracranial hemorrhage (ICH), but the presence of a stable or active primary intracranial malignancy or brain metastases is not an absolute contraindication to anticoagulation,” they wrote.

Limited evidence suggests that therapeutic anticoagulation does not increase ICH risk in patients with brain metastases, but it may increase risk in those with primary brain tumors, the panel added.

Additionally, preliminary data from a retrospective cohort of patients with metastatic brain disease and venous thrombosis suggest that DOACs may be associated with a lower risk of ICH than is LMWH in this population.

Long-term postoperative LMWH. Extended prophylaxis with LMWH for up to 4 weeks is recommended after major open or laparoscopic abdominal or pelvic surgery in cancer patients with high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. Lower-risk surgical settings require case-by-case decision making about appropriate thromboprophylaxis duration, according to the update.

A 2014 RCT looking at thromboprophylaxis duration in 225 patients undergoing laparoscopic surgery for colorectal cancer prompted the addition of laparoscopic surgery to this recommendation. In that study, VTE occurred by 4 weeks in nearly 10% of patients receiving 1 week of prophylaxis and in no patients in the 4-week arm. Major bleeding occurred in one versus zero patients in the thromboprophylaxis arms, respectively (Ann Surg. April 2014;259[4]:665-9).
 

Reaffirmed recommendations

Based on the latest available data, the panel reaffirmed that most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis for the duration of their hospitalization and that thromboprophylaxis should not be routinely recommended for all outpatients with cancer.

The panel also reaffirmed the need for thromboprophylaxis starting preoperatively and continuing for at least 7-10 days in patients undergoing major cancer surgery, the need for periodic assessment of VTE risk in cancer patients, and the importance of patient education about the signs and symptoms of VTE.
 

Perspective and future directions

In an interview, David H. Henry, MD, said he was pleased to see ASCO incorporate the latest DOAC data into the VTE guideline.

The AVERT and CASSINI studies, in particular, highlight the value of using the Khorana Risk Score, which considers cancer type, blood counts, and body mass index to predict the risk of thrombosis in cancer patients and to guide decisions regarding prophylaxis, said Dr. Henry, vice chair of the department of medicine and clinical professor of medicine at Penn Medicine’s Abramson Cancer Center, Philadelphia.

The DOACs also represent “a nice new development in the treatment setting,” he said, adding that it’s been long known – since the 2003 CLOT trial – that cancer patients with VTE had much lower recurrence rates with LMWH versus warfarin (Coumadin).

“Now fast forward to the modern era ... and DOACs now appear to be a good idea,” he said.

Dr. Henry also addressed the recommendation for expanded postoperative LMWH use.

“That I found interesting; I’m not sure what took them so long,” he said, explaining that National Comprehensive Cancer Network and European Society of Medical Oncology recommendations have long stated that, for patients with abdominal cancers who undergo abdominopelvic surgery, DVT prophylaxis should continue for 4 weeks.

Dr. Henry said that a survey at his center showed that those recommendations were “very poorly followed,” with surgeons giving 4 weeks of prophylaxis in just 5% of cases.

“The good news from our survey was that not many people had a VTE, despite not many people following the recommendations, but I must say I think our surgeons are catching on,” he said.

Overall, the updated guideline highlights the importance of considering the “cancer variable” when it comes to VTE prevention and treatment.

“We’ve known forever that when we diagnose a DVT or PE in the outpatient setting – and this is independent of cancer – that you should treat it. Add the cancer variable and we now know that we should worry and try to prevent the VTE in certain high-risk patients, and there are some drugs to do it with,” he said, adding that “you should worry about the person you’ve just provoked [with surgery] as well.”

An important question not addressed in the guideline update is the indefinite use of DOACs in cancer patients with ongoing risk, he said.

“When we see DVT or PE, we usually treat for 3 months – that’s the industry standard – and at the end of 3 months ... you do a time out and you say to yourself, ‘Was this person provoked?’ ” he said.

For example, if they took a long flight or if pregnancy was a factor, treatment can usually be safely stopped. However, in a cancer patient who still has cancer, the provocation continues, and the patient may require indefinite treatment.

Questions that remain involve defining “indefinite” and include whether (and which of) these drugs can be used indefinitely in such patients, Dr. Henry said.

Dr. Key reported receiving honoraria from Novo Nordisk, research funding to his institution from Baxter Biosciences, Grifols, and Pfizer, and serving as a consultant or advisor for Genentech, Roche, Uniqure, Seattle Genetics, and Shire Human Genetic Therapies. Numerous disclosures were also reported by other expert panel members.

sworcester@mdedge.com