In this series, we speak with cancer care practitioners about how pathways are being used in their practices, how they are being applied in a particular disease state, and what challenges remain for treatment decision-making.
For this installment of Pathways in Practice, we spoke with a range of specialists at Moffitt Cancer Center regarding the clinical pathway for cutaneous and unknown primary melanoma.
Moffitt has one of the largest multidisciplinary melanoma clinics in the world, with over 1800 new melanoma cases seen annually. In the past fiscal year, Moffitt’s Cutaneous Oncology program surgeons performed over 1600 operative procedures for melanoma and other cutaneous malignancies.
Vernon Sondak, MD, chair of the Department of Cutaneous Oncology and the Richard M. Schulze Family Foundation Distinguished Endowed Chair in Cutaneous Oncology, and surgical oncologist in the Cutaneous Oncology Program; Nikhil Khushalani, MD, vice-chair of the Department of Cutaneous Oncology and medical oncologist in the Cutaneous Oncology Program; and Evan Wuthrick, MD, radiation oncologist in the Cutaneous Oncology Program, provided a comprehensive look at the varying considerations for the melanoma pathway and the anticipated rollout of the later stages (covering American Joint Committee on Cancer [AJCC] stages III and IV) in Moffitt’s electronic health record (EHR) in the coming weeks.
Please describe Moffitt’s clinical pathway for cutaneous and unknown primary melanoma. How was this pathway developed in the early stages (AJCC stages 0-II) of the disease?
Dr Sondak: We started out by implementing a pathway in an environment of early stage melanoma, but we did not expect our expert clinicians would be reliant on the pathway to tell them how to manage the disease. Rather, we anticipated our clinicians would want to use the pathway because it was user-friendly and added value to them in their daily workflow. The goal was to put everything in the EHR related to management of early-stage melanoma in one place, so that clinicians did not feel like the pathway was adding an extra step to their work. That was a big challenge for us; if we could do it right, we could make it a more streamlined workflow and easier for clinicians to take care of their patients exactly the way they wanted.
Most importantly, the idea was to have all of the relevant order sets immediately available. For example, if the pathway said a patient needs a wide excision and a sentinel lymph node biopsy, then as soon as the clinician put in the basic information in the EHR for a stage IIA melanoma, the appropriate order sets appear on the screen for a wide excision and a sentinel lymph node biopsy.
Underneath the pathway recommendation in the EHR is a button for accessing other treatment options and orders. If the physician sees that the pathway does not call for a positron emission tomography (PET) scan, yet a particular patient has a history of kidney cancer, for example, and a PET scan is needed to ensure that the kidney cancer is not back, the physician can obtain the PET scan through the same window. Furthermore, we now have the ability to capture why the physician is deviating from the pathway; we would recognize in this particular case that the physician properly ordered a PET scan in a scenario where a PET scan is not standard for the routine management of early stage melanoma.
That was our intent in setting up the pathway—if physicians used it properly, everything they needed to take care of the patients who were a perfect fit for the pathway would be there, and most of what they needed for the patients who had special needs outside of the pathway would also be right at their fingertips. At the same time, if a trainee, a new faculty person, or anybody who was not intimately familiar with our clinical systems were to become involved in the management of our melanoma patients, it would be relatively obvious to them what they were supposed to do and how they would do it.
Given the substantive challenges of integrating pathway management into the EHR, we wanted to achieve this first in an environment where the disease management algorithm was not constantly changing. That is why we initially developed and rolled out the early stage melanoma pathway. We made sure it was robust before we expanded it into the advanced stages of melanoma, which is what we’re doing now, and in the future we plan to migrate this to other cutaneous malignancies that are managed similarly but not identically to early stage melanoma.
What are some of the specific pre-surgical considerations that are included in the pathway?
Dr Sondak: The most relevant example is clinically node-negative intermediate thickness melanoma: the standard of care calls for wide excision along with a sentinel lymph node biopsy in an otherwise healthy patient with appropriate life expectancy. So the pathway indicates that the preferred management is “wide excision and sentinel lymph node biopsy,” but also recognizes that wide excision alone is appropriate for patients where there is some contraindication to a sentinel node biopsy or a personal preference to avoid it. For this specific scenario, the pathway has multiple branches. One branch is listed as “preferred” and any other branch is listed as an option. When we designed the pathway, we understood that there was a significant percentage of our population who would either choose not to have a sentinel node biopsy or their physician would recommend against it because of appropriate medical considerations. In this way, the pathway supports the physician doing what is medically appropriate and conforms with the patient’s preferences—it doesn’t force the patient and physician to conform to the pathway.
At the moment, early post-surgical care is not incorporated in the pathway. When we see a patient in the first post-operative visit, the pathway may call for the patient to be followed every 6 months, for example. If they are recovering uneventfully from their surgery, that’s the appropriate next step and the EHR now makes it very easy to order that return visit in 6 months. Obviously, however, we instruct our patients to call or come to clinic before that time if they are experiencing any problems. This is not a scheduled on pathway visit, but the patient still remains on the pathway unless their condition changes in some dramatic fashion—like by the development of recurrent disease.
Is surgery incorporated into the advanced stages (III-iV) of the pathway? If so, how have the surgical procedures been modified or added to?
Dr Sondak: We just completed the build for the stage III or IV melanoma patients in the EHR and have begun to use it.
As for surgical choices in late-stage disease, the management becomes very individualized, and as I alluded to earlier, the algorithm has changed over the past few years. Does the sentinel-node positive patient need a node dissection? We prefer not to do a node dissection. Our new pathway calls for observation of the lymph nodes as the preferred option, but recognizes that some patients will want to have node dissection surgery or some physicians will advise for surgery under some scenarios. Once the surgical choices are made and a surveillance plan settled on, decisions from that point involve adjuvant therapy and the surgeon manages the patient in concert with the radiation and medical oncologists—both of whom will be able to utilize our new advanced stage pathway concurrently with the surgical oncologist.
How have radiation considerations been incorporated into the pathway?
Dr Wuthrick: The way we think about radiation therapy in melanoma at Moffitt is to ask the question, “Can radiation therapy help to reduce a risk of local recurrence?” From there, we ask, “Can radiation therapy in selected patients reduce the risk of regional recurrence in a lymph node basin after surgery?” The pathway that we designed essentially asks the clinician to consider at various points, “Is there an opportunity for radiation to positively impact a patient’s chance of local recurrence? Is there a chance for radiation therapy to reduce the risk of regional recurrence?”
In what specific stages or sections of the pathway are radiation treatments most prevalent?
Dr Wuthrick: One of the major risk factors for local recurrence in melanoma is a diagnosis of the desmoplastic subtype. Desmoplastic melanomas are an interesting entity because they are much more likely to have local recurrence compared to the other subtypes of melanoma. At Moffitt, we conducted a retrospective study that looked at patients over a 15-year period with desmoplastic melanoma (n=277). We found that these patients had much higher rates of local recurrence than other subtypes of melanoma and that in many of these cases, postoperative radiation therapy substantially reduced the risk of recurrence. These findings are now reflected in our pathway; we recommend that patients with desmoplastic melanoma discuss the potential of radiation therapy with a radiation oncologist.
A second situation to highlight that is relevant and somewhat controversial is the use of postoperative radiation therapy in the lymph node basin for certain high-risk patients. This is a consideration for patients with bulky lymph nodes in the axilla, groin, or neck who undergo an operation to remove those lymph nodes. If these patients have certain high-risk criteria (ie, high lymph node count, high total size of involved lymph nodes, or extracapsular extension), we recommend that they have postoperative radiation therapy, especially if adjuvant immunotherapy is not an option for them.
What are the benefits of a few of the current therapy options in the advanced disease setting, and which phase-3 trials were most influential in the ultimate pathway decisions?
Dr Khushalani: The old paradigms included high-dose interferon, pegylated interferon, and then, for a brief period, high-dose ipilimumab. All of those standards of care were replaced fairly quickly with current regimens, which are either single-agent anti-PD1 therapy (ie, pembrolizumab or nivolumab) or combination targeted therapy for patients whose tumors harbor a mutation in BRAF-V600. The approved targeted therapy combination is dabrafenib plus trametinib.
All of these options are for patients with stage III resected melanoma, so any node positive or in transit metastases that have been completely resected with no remaining evidence of disease. The intent with these adjuvant therapy options is risk reduction for recurrence. They are also being utilized for patients with stage IV disease that has been resected without any evidence of disease. We refer to that as oligometastatic disease. For example, for a solitary site in the lung that has been taken out and the patient rendered “no evidence of disease,” he or she would be an appropriate candidate for adjuvant therapy, given their extraordinarily high risk for recurrence.
We have utilized the three phase 3 trials that led to the approval of these individual agents as an evidence base for our pathway. Pembrolizumab was tested in an EORTC study (Keynote 054) of pembrolizumab vs placebo in resected patients with stage IIIA, IIIB, and IIIC melanoma. Nivolumab was evaluated in a trial (CheckMate 238) that compared one year of nivolumab vs high-dose ipilimumab, in patients with stage IIIB, IIIC, and resected stage IV melanoma. Even though stage IIIA was not included in the original design of the clinical trial, when the FDA approved nivolumab it was approved for stage IIIA as well. Then, finally, dabrafenib and trametinib, which was tested in a stage III population but not in resected stage IV in the COMBI-AD trial.
Are there any therapies in the pipeline or studies awaiting long-term results that are likely to have a significant impact on the pathway?
Dr Khushalani: I do not believe that we have a good feel yet as to what the next standard of care is going to be for late stage or advanced melanoma for which surgery or radiation is not the first recommended option. Our pathways would typically include either upfront immunotherapy—either single-agent or combination immunotherapy (ipilimumab plus nivolumab). Alternatively, for patients who are BRAF-V600 mutant, we also include the option to proceed with targeted therapy. In the current late-stage melanoma pathway, we have provided suggestions as to how to proceed when a patient is eligible for both immunotherapy and targeted therapy. Our pathways are also strongly endorsing of ongoing clinical trials housed within Moffitt.
In terms of combination immunotherapy, my personal belief is that we have not yet found the most optimal “dance partner” for either nivolumab or pembrolizumab. Currently, the belief is that ipilimumab is still the best in this scenario. However, there are two areas of great interest. The first is with relatlimab, which is an anti-LAG 3 immune checkpoint inhibitor. There is an ongoing phase 3 trial comparing nivolumab plus relatlimab vs nivolumab alone. The second is nivolumab plus NKTR 214 (also referred to as bempegaldesleukin), which is essentially a pegylated version of IL-2. The trial compares nivolumab plus bempegaldesleukin vs nivolumab alone in patients who are therapy naïve.
Those are the two studies that are certainly very interesting, but still may be years away from providing actionable results. I do not anticipate any significant change in the standard of care any time soon. In the resected, stage III, adjuvant setting, the one standard-of-care shift that may occur is if the results are positive for ipilimumab plus nivolumab in the CheckMate 209-915 trial.
What have been the unique and most complex challenges to updating the pathway and incorporating the late stages into the EHR? Were there different challenges to developing the early- vs late-stage treatment options?
Dr Sondak: As Dr Khushalani indicated, there has been a lot of change in the approach to managing stage III and IV melanoma patients over the past few years, and it is likely things will change again in the future. That has certainly been a challenge. Another challenge is in terms of the optimal surveillance approach to various stages of melanoma. The evidence base is simply insufficient to dictate a dogmatic approach to how often to schedule follow-up visits and which imaging tests to order in patients without evidence of disease after surgery. We tried to achieve consensus where we could, and where we could not we left things open-ended and will monitor the real-world use of imaging tests to see if we can drive the development of a consensus in the future.
As the final pathway is rolled out across the Moffitt network, how well do you anticipate it being received? Are there any expected areas within that pathway that are likely to cause problems or negative feedback among the clinicians?
Dr Sondak: Anything that helps people work more efficiently is likely to be well received. Unfortunately, our current EHR systems do not always improve efficiency—often they have the opposite effect. So far, I personally have found the early-stage melanoma pathway to be a big help in streamlining patient management.
The biggest hurdle we have to overcome is the perception that working with pathways means abandoning our commitment to personalized care. In fact, I believe it is quite the contrary; we use pathways to insure that every patient is treated like an individual, but that every individual in the same situation has access to the same high-quality care. For instance, a patient with stage III melanoma may choose not to have radiation or immunotherapy after surgery, but that should be an informed choice—not a by-product of the surgeon not recognizing the patient was an appropriate candidate for additional therapy. But when the surgeon properly recognizes that an elderly, infirm patient with small-volume disease in a sentinel node would be best served not having any postoperative therapy, the pathway system should help them document that—not force them to refer a patient to a medical and radiation oncologist when that referral is unlikely to result in any added value to the patient.
