Metastatic melanoma
Authors: Ragini R. Kudchadkar, Michael C. Lowe, Mohammad K. Khan, Stephanie M. McBrien
Journal: CA A Cancer Journal for Clinicians (2020)

W.V. is a 39-year-old Caucasian male who, on July 4, 2017, presented with right arm numbness while running a 10-K race. Magnetic resonance imaging (MRI) of the brain revealed a 3-cm, peripherally enhanced mass (Fig. 1), and computed tomography (CT) with contrast of the chest, abdomen, and pelvis revealed subcentimeter (2-4 mm) pulmonary nodules with no other sites of disease. On July 7, 2017, he underwent craniotomy with resection of a parietal tumor. Frozen section was initially suspicious for primary glioma; however, final pathology showed metastatic melanoma that was positive for S100, MITF, and SOX10 by immunohistochemistry. There was no history of prior melanoma or nonmelanoma skin cancers, and no primary tumor was identified on a total body skin examination. In addition, a standard comprehensive examination for mucosal, ocular, and other occult sources was performed, and no definitive primary was identified. The tumor was positive for the BRAF V600E mutation by next-generation sequencing. The patient subsequently underwent radiation to the postoperative bed, receiving 30 grays (Gy) in 5 fractions. In August 2017, the patient began systemic therapy with ipilimumab 3 mg and nivolumab 1 mg/kg. He received 2 doses of therapy, which was then discontinued because of the development of colitis. After a 6-week course of steroids, he was initiated on maintenance nivolumab at 480 mg intravenously every 4 weeks. He received 1 year of nivolumab without complication. CT scans of the body and MRI scans of the brain remained stable during this time. For surveillance and to monitor tumor response to treatment, CT scans were used rather than positron emission tomography (PET)/CT scans because the small pulmonary nodules were below the limits of PET detection and were better imaged by dedicated CT scans. One month after the completion of nivolumab, CT scans showed enlargement of a left upper lobe pulmonary nodule, and the patient subsequently underwent video-assisted thoracoscopic surgery wedge resection. Pathology showed metastatic melanoma 1 cm in size. It was noted on pathology that 15% of nucleated cells in the periphery and 5% of cells in the center were CD8-positive lymphocytes. Although the significance of this observation is unclear, preliminary data demonstrate better outcomes for patients who have increased CD8 infiltration of their melanoma.1 After he underwent video-assisted thoracoscopic surgery resection, the patient was followed with active surveillance. In August 2019, slow but steady growth was noted in the subcentimeter pulmonary nodules over an approximately 18-month period. All nodules had grown by approximately 2 to 3 mm, with the largest measuring 1 cm. After discussion with the patient, he was started on encorafenib and binimetinib on October 1, 2019. At the time of publication, the patient was tolerating treatment without complications and has had a near complete response to treatment. At presentation, this is a young male with stage IV, BRAF-mutated melanoma to the brain from an unknown primary. The first branching point of discussion is whether this is an adjuvant, resected, stage IV melanoma versus an active melanoma with lung metastases. Approved therapies for adjuvant, fully resected melanoma include single-agent, anti–PD-1 agents (nivolumab; pembrolizumab) or BRAF and MEK inhibitors (dabrafenib and trametinib). It should be noted that the numbers of patients with resected brain metastases in adjuvant trials are limited, although some trials have included patients with resected stage IV disease. For active stage IV disease, approved therapies include nivolumab or pembrolizumab as a single agent, anti–PD-1 therapies, combination CTLA-4 and PD-1 antibodies (ipilimumab and nivolumab), as well as BRAF and MEK inhibitors (dabrafenib and trametinib, or encorafenib and binimetinib, or vemurafenib and cobimetinib). Subcentimeter lung nodules are difficult to interpret—they are too small to biopsy or to be detected by PET/CT. The patient did not have prior imaging studies to compare, nor did he have any obvious reasons for having multiple lung nodules (ie, prior infections, smoking, active asthma). Given the brain lesion and the number of nodules, we were highly suspicious that the patient had active, stage IV disease; therefore, we elected to proceed with therapeutic options for active disease. The second point of decision making is whether to pursue immunotherapy or targeted therapy with BRAF/MEK inhibitors. Key clinical factors for decision making include age and performance status, the presence or absence of brain metastases, and medical comorbidities (history of transplantation or autoimmune disease). Patient input into this decision making is critical because the side-effect profiles of both options are quite different. In addition, one should consider the patient's symptomatology from cancer and overall disease burden. The rapid responses and high response rate of targeted therapy often lead clinicians to choose BRAF and MEK inhibitor therapy in patients with symptomatic disease. At the time of diagnosis, this patient had an excellent performance status of 0. He had no known medical problems before the diagnosis but, upon imaging to evaluate for other sites of disease, it was noted that he had radiologic features of ankylosing spondylosis, although he was largely asymptomatic. Given imaging findings that were suspicious for ankylosing spondylosis, the patient was evaluated by a rheumatologist, who confirmed the diagnosis. However, because of this diagnosis and because the patient did not have technically measurable disease according to Response Evaluation Criteria in Solid Tumors, he did not qualify for the treatment-naive trials available at that time. From our standpoint, this fact and the presence of brain metastases were key in choosing a systemic treatment. Single-agent anti–PD-1 drugs, combination immunotherapy, as well as dabrafenib and trametinib have data showing activity in central nervous system (CNS) disease. Ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg have shown equivalent intracranial and extracranial responses in patients with asymptomatic brain metastases who were not receiving systemic steroids.2 Long and colleagues also demonstrated a high response rate for this combination, with a 46% intracranial response rate.3 Updated data from the 204 study4 also demonstrated durable responses intracranially from combination immunotherapy. Single-agent pembrolizumab showed an objective response rate of 25% in melanoma brain metastases.5, 6 Single-agent nivolumab showed an intracranial response rate of 20%.3 From these early and small studies, one can conclude that immunotherapy has activity in controlling CNS metastases of melanoma and that combination therapy has a higher activity rate in the CNS than single-agent therapy. Dabrafenib and trametinib also demonstrated activity in the CNS in the Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation (COMBI-MD) study.7 Although that study demonstrated a high intracranial response rate for dabrafenib and trametinib of 58%, the duration of response was quite limited, with a median progression-free survival of 6.5 months in patients with previously untreated, asymptomatic brain disease. As a result, in patients with a good performance status, with no urgent symptomatology, without contraindications, and without trial options, immunotherapy is our preferred initial approach. Although all CNS data are from studies with relatively small numbers of patients, there is still strong evidence that both immunotherapy therapy and targeted therapy can control CNS disease. On the basis of the data we have to date, the highest response rate is with either ipilimumab and nivolumab or dabrafenib and trametinib. Given the durability seen in updates from the CheckMate 204 study (An Investigational Immunotherapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself), it appears that combined ipilimumab and nivolumab may also have the best durability of response in this population. This was the primary reason to choose this therapy for our young, healthy, asymptomatic patient. This choice also comes with great toxicity risk, which was discussed in detail with the patient to ensure that the decision for a treatment with high toxicities was congruent with the patient's goals of treatment. Key factors to discuss with patients are the permanence of some of the immunotherapy toxicities, the risk of hospitalization, as well as the risk of rare but very serious complications. For younger patients, fertility should also be discussed, although there are few data on how long-term fertility is affected by immunotherapy. For combined ipilimumab and nivolumab, the risk of grade 3 and 4 toxicities is approximately 50%, with 20% of patients requiring hospitalization. The endocrinopathies will likely be permanent, lifelong conditions of which all patients should be aware and include thyroid dysfunction, hypophysitis, adrenal insufficiency, and (rarely) type 1 diabetes. More common toxicities that may require a 4-week to 8-week course of high-dose steroids are pneumonitis, colitis, and hepatitis. Rash and pruritus are common, although severe cases are rare. Cardiac complications such as myocarditis are rare but can be fatal. In addition, neurologic complications must be taken seriously, as myasthenia gravis, peripheral neuropathy, and Guillain-Barre have been reported.8, 9 It is essential to educate patients and caregivers about how to recognize symptoms and the need to contact their health care provider early in course of symptoms. Teaching by a team is most effective (using nursing staff and pharmacists, if possible) to provide a broad, patient-focused education about immune-related adverse events (Table 1). After progression on immunotherapy with an increase in the number of lung nodules, the patient was initiated on encorafenib and binimentinib. There are 3 combination BRAF/MEK inhibitors on the market currently (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimentinib). There is no known, definitive efficacy advantage to using one combination over another, although no trials have compared these drugs head-to-head. Side-effect profiles do vary, with a higher incidence of fevers using combined dabrafenib and trametinib and a higher incidence of rashes using combined vemurafenib and cobimetinib compared with encorafenib and binimentib. Encorafenib and binimetinib can be taken with food, which may be more convenient for patients and thus was chosen for this patient. The follow-up regarding our patient's tolerance of therapy and response to treatment was not yet available at the time of this publication. In between laboratory work, clinic, and treatment appointments, nurses are frequently on the front lines when it comes to patient communication and initial contact. Telehealth nursing as well as communication through patient portals are increasingly common forms of patient-to-clinician toxicity reporting.10 Patients may also present in person via walk-in nursing appointments. This patient's preferred method of communication has been through portal messages. Education has been provided to the patient regarding contact through the portal occurring during business hours only, and he knows that any urgent concerns after hours or over the weekend should not be sent electronically. The patient initially started treatment with combination ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Before any patient's first dose of immunotherapy, nursing has the opportunity to stress both the side effects most frequently seen as well as those that pose the highest clinical risk to patients, regardless of how commonly they occur. With all immunotherapies, but with this combination in particular, the nursing team should spend a significant part of direct patient education focused on immunotherapy-induced colitis. Not only is this a frequently reported toxicity, but, untreated, this can lead to hospitalization, perforation of the bowel, and sepsis.11 The nurse can present information early on to prevent later complications of colitis and stress the importance of early reporting of diarrhea to the clinical team. This patient was provided this education and reached out through the patient portal when the first episodes of diarrhea occurred. In many oncology patients who are receiving chemotherapy or other forms of treatment, diarrhea protocols may differ. With immunotherapy, our approach to assessing patients with diarrhea leads to early diagnosis of autoimmune colitis. Similar assessment questions should be used, including focus on consistency (diarrhea, by definition, is liquid-like) and frequency. In addition, the nurse should establish the patient's baseline before the change in bowel movements. Like with chemotherapy-induced diarrhea, infectious causes should be ruled out, so the provider may order stool studies while simultaneously addressing the possibility of colitis. Immunotherapy-induced colitis may come on quickly with frequent bowel movements, but it can also start with abdominal cramping or “churning.” These early signs can often predict the start of diarrhea shortly thereafter. To manage this patient's diarrhea, loperamide in combination with budesonide was prescribed initially. However, the diarrhea continued, and, at the beginning of October 2017, the patient was prescribed high-dose steroids at 1 mg/kg. With persistent colitis, the team expects a longer steroid course as well as a slow taper once the colitis is on its way out. Nursing should educate the patient about prophylactic medications that should be taken alongside a longer term steroid course: an antibiotic, antiviral, and antifungal. With this patient, additional written information was sent through the portal, which can help patients recall conversations held in clinic. The portal message reads “…we will call in an antibiotic (Bactrim [sulfamethoxazle and trimethoprim]; Sun Pharmaceutical Industries Ltd), antiviral (acyclovir), and antifungal (fluconazole) to protect you while we suppress your immune system with the steroids. This is a standard practice that we do to prevent any microorganisms that might take advantage while we use the steroid to bring down your heightened immune system. Rather than a treatment, this is a preventative measure.” This explanation can assist in medication compliance, so that the patient understands what each medication is and why it was prescribed. In addition, the provider team will likely prescribe a proton-pump inhibitor in anticipation of acid reflux caused by the high-dose steroids. In this patient's case, the colitis responded to the steroids. However, it is important to educate patients on next steps should the steroids not work. Some patients require infliximab infusions for immunotherapy-induced colitis that is nonresponsive to steroids.11 Another educational point to stress is the importance of reporting any symptoms while a patient tapers off high-dose steroids. This is true for colitis as well as any other autoimmune toxicity requiring a course of high-dose steroids. Symptoms related to adrenal insufficiency (weakness, dizziness upon standing, decreased appetite, just to mention a few) should be addressed. Also, as the patient starts to taper, education should be provided on the possibility of the need for a cortisol-stimulation test. If, upon completing the steroid course, the morning cortisol level is low, the provider will order this test to determine whether the patient has developed adrenal insufficiency. This patient reported fatigue, myalgia, and other nonspecific symptoms in mid-January 2018; a cortisol-stimulation test was performed at that time to rule out adrenal insufficiency and, fortunately, the results were normal. For care teams that do not predominantly work with immunotherapy, one of the most important takeaways is to remember that standard protocols developed for chemotherapy patients often do not apply. Immunotherapy causes different, albeit serious, side effects that should be addressed urgently to prevent greater damage. Nurses on the front lines play a crucial role in the recognition and managements of immunotherapy-induced toxicities. National Comprehensive Cancer Network (NCCN) guidelines for the management of metastatic melanoma are based on the extent of disease. For patients with limited and resectable metastases, upfront surgery should be considered as an option. This is a considerable shift in the treatment paradigm given that, historically, patients with metastatic disease were almost uniformly started on systemic therapy. In general, exceptions included the need to obtain tissue for diagnosis and operations that provided palliative benefits. More and more data are emerging that support the role of upfront surgery for patients with limited and resectable metastatic melanoma, particularly from the adjuvant clinical trials showing significant improvements in recurrence-free and/or overall survival (OS) with systemic therapies after complete surgical resection. There are no randomized clinical trials evaluating the role of upfront surgery compared with conventional treatment using systemic therapies. However, numerous prospective trials and retrospective data sets suggest that upfront surgery may provide a benefit over upfront systemic therapy, or at least compared with systemic therapy alone. In SWOG study 9430, 64 patients with completely resected metastases were followed prospectively; the 3-year and 4-year survival rates were 36 and 31%, respectively, suggesting that patients with stage IV disease who are able to undergo surgery have a survival advantage compared with historic controls.12 Of 291 patients who developed distant metastatic disease during long-term follow-up on Multicenter Selective Lymphadenectomy Trial I (MSLT-I), 161 underwent surgery as part of their treatment. The median survival for patients who underwent surgery for distant metastatic melanoma was 15.8 months compared with 6.9 months for those who did not undergo surgery.13 Although some bias exists toward surgery in more medically fit patients, the consistent survival improvement with surgery in these studies argues for more prospective trials comparing upfront surgery versus systemic therapy. SWOG study 1801 (clinicaltrials.gov identifier NCT03698019) is an actively enrolling, international trial randomizing patients who have resectable stage III and IV melanoma14 (the American Joint Committee on Cancer's AJCC Cancer Staging Manual, eighth edition, M1a, M1b, and M1c) to receive neoadjuvant therapy with pembrolizumab versus upfront surgery. All patients receive adjuvant pembrolizumab; the primary endpoint is event-free survival. This trial not only will evaluate the role of neoadjuvant therapy in the metastatic setting but also likely will provide the most definitive data to date on the role of surgery for patients with metastatic melanoma in the era of effective systemic therapies. Of note, this trial excludes patients with CNS metastases, and very few of the patients in the previously mentioned trials included these patients. Given that CNS metastases portend a worse survival, it is reasonable to offer surgery only for patients with CNS metastases who are in need of diagnosis or palliation. In this patient with multifocal, systemic metastases, including brain and lung, surgery played an integral part in the treatment algorithm. The initial operation established the diagnosis of melanoma, and because there was no evidence of clear-cut, significant disease outside the brain at presentation, the patient appropriately underwent adjuvant radiation and systemic therapy. When there appeared to be progression of disease in the lung, surgery served the dual purpose of diagnosis of recurrence and therapeutic resection. Removal of all clear and clinically significant, known disease allowed the patient to remain off systemic therapy for a considerable period of time. This case highlights the need to involve surgeons in every aspect of the care for patients with stage IV melanoma. NCCN 2019 cutaneous melanoma guidelines state that, for melanoma metastases, stereotactic radiosurgery (SRS) is considered an acceptable standard of care. Because the patient had a 5.51-cm3 parasagittal cavity, the recommendation was for a radiation dose of 30 Gy in 5 fractions (Fig. 2). In this young patient, the altered radiation dose was chosen to limit the risk for late side effects, especially radiation-induced necrosis. Whole-brain radiation (WBRT) was not offered to minimize the risks for neurocognitive impacts because it has not been shown to improve OS for these patients. Because MRI characteristics were not definitive and the patient did not have a previous diagnosis of melanoma, the differential on the presenting brain lesion was broad. As such, surgical excision was needed for diagnostic purposes in our case. An older, prospective, randomized trial compared biopsy followed by WBRT versus surgical excision followed by WBRT (36 Gy in 12 fractions) for a single metastasis to the brain and found that surgical excision improved: 1) median survival from 15 weeks to 40 weeks (P < .01), 2) the local recurrence rate from 52% down to 20% (P < .01), 3) the time to neurologic death from 26 weeks to 62 weeks (P < .01), and 4) functional independence from 8 weeks to 38 weeks (P < .01).15 Safe surgical resection of larger lesions (typically approximately 3.5 cm) and those that are causing neurologic symptoms secondary to mass effect is also recommended. Patchell et al16 demonstrated that the addition of radiation after surgery for a single brain metastasis improved control of the tumor cavity and prevented additional tumors from developing in the brain. The probability of recurrence after surgery was 46%. This was improved to only 10% with the addition of radiation. WBRT also reduced the probability of additional brain metastases developing from 70% down to 18% but, as noted above, is associated with significant sequelae and thus is not a preferred approach. Aoyama et al17 randomized 132 patients to receive SRS plus WBRT versus SRS alone. There was no difference in OS between the 2 arms. Thus, SRS alone without offering WBRT was deemed acceptable, especially considering the associated toxicity of WBRT. This concern was further demonstrated by Chang et al18 in a study that randomized patients who had ≤3 brain metastases to receive SRS alone with or without the addition of WBRT. Their trial demonstrated that the addition of WBRT decreased neurocognitive function without extending OS. Preoperative and postoperative MRIs were used to assess for gross total resection of the brain metastasis and for radiation treatment-planning purposes. The treatment-planning MRI is ordered 2 to 4 weeks after excision. By then, the postoperative cavity would have reduced in size and would be timed close to the actual radiation treatment-planning scans. One important consideration when administering radiotherapy is the timing of radiation with systemic therapy. Radiation may interact with emerging immunotherapy agents as well as BRAF inhibitors; therefore, receipt of radiation at the same time should be coordinated carefully through multidisciplinary input. In our case, we elected to proceed with radiation and dual checkpoint therapy around the same time with the hope that the combination would be synergistic based on preclinical work that included a small number of patients.19 This preclinical work suggested that the combination of radiation, anti–CLTA-4, and anti–PD-L1 therapies would promote response and antimelanoma tumor immunity through distinct mechanisms. Future trials in melanoma should investigate immunotherapy combination approaches that include radiotherapy. For our patients who are receiving anti–PD-1 therapy, we have supported the practice of concurrent radiation. There are some early, retrospective data from our institution suggesting that that the simultaneous delivery of concurrent anti–PD-1 therapy and SRS appears to be safe.20 Our current prospective trial (clinicaltrials.gov identifier NCT02858869) of SRS and pembrolizumab, which is evaluating the safety of this combination, is ongoing. We hope to have some preliminary results from that trial by the end of 2020. Regarding the concurrent use of radiotherapy and dual checkpoint inhibitors, there are limited data, and this should be approached on a case-by-case basis. For BRAF inhibitor (BRAFi) therapy, we have avoided using concurrent radiotherapy and BRAFi therapy because of concerns about increased toxicity. We have typically stopped BRAFi therapy from 1 to 3 days before radiotherapy and then resumed it from 1 to 3 days after the completion of radiotherapy. “When I first met with Dr. Kudchadkar in the fall of 2017, she was forthright and honest about my situation, which I greatly appreciated. She understood the gravity of a melanoma diagnosis to a person with 2 small kids and a life-partner and took all of that into consideration when she explained the proposed treatment path, with all of its potential pitfalls and successes. She also put things into perspective: that, if I had walked into her office a couple years beforehand with the same diagnosis, I would've been sent home and told to get things in order, since I probably had 6 to 9 months to live. Gratefully, we are now over 24 months into this process. A lot of frustration could have been avoided if there was a mutual understanding of how the key components of communication, time, and advocacy play out on both the provider and patient side. The amount of stress this process produces for all of the stakeholders involved has been immense. I did not anticipate how much my network of providers, my team, would grow as complications that needed to be treated arose. A lot of frustration could have been avoided if there was a mutual understanding of how the key components of communication, time, and advocacy play out on both the provider and patient side. Most of these relate to the systemic issues that arise from massive health care networks, profit-based insurance models, and patients not knowing their individual rights (although we are provided with 5-page Health Insurance Portability and Accountability Act briefs), but sometimes it came down to conversations of importance that I didn't know I should have had until later in the process.” Multidisciplinary teams are essential to the care of patients with metastatic melanoma. Before the advent of modern systemic therapies for melanoma, surgery and radiation remained the standard of care. Now, surgery and radiation have taken on different roles, and the timing of systemic therapy with these modalities must be discussed by a multidisciplinary team. The patient's medical history, presentation, and preferences should be considered in making the final treatment decisions. Nursing staff is essential to ensure that the patient understands of the plan of care and to address potential complications in a timely manner. Together with the patient, the entire medical team can ensure that patients with melanoma have the best outcome possible. Considerations in this case that are generalizable to most patients with complicated melanoma include the patient's comorbidities, age, performance status, extent of disease in the brain (and other sites of systemic disease), and BRAF mutational status. Factors that affected the patient's course included the development of toxicity from the initial treatment, which required a course of steroids. Active surveillance of the patient permitted the identification of new disease, while surgical intervention both provided a diagnosis and offered potential therapeutic benefit. NCCN guidelines and trial options are both noted in this segment as is the evidence supporting decision making by the multidisciplinary team. Merck & Company provided funding for clinical trials and basic science related to radiation and immunotherapy combinations. Ragini R. Kudchadkar reports grants from Merck & Company, grants and personal fees from Regeneron, and personal fees from Bristol-Meyers Squibb, Novartis, and Immunocore during the conduct of the study. Michael C. Lowe, Mohammad K. Khan, and Stephanie M. McBrien made no disclosures.