Complete and Durable Response After Radiation Therapy to Primary Tumor Site of a Patient With Metastatic Anorectal Mucosal Melanoma With Oligoprogression on Nivolumab

Abstract

Introduction Mucosal melanoma is a rare subtype of melanoma, accounting for 1.4% of melanoma diagnoses in the United States. 1 Median overall survival from time of diagnosis for mucosal melanoma has historically been less than that of cutaneous melanoma in part owing to the frequency of occult presentation and the relative lack of evidence-based guidelines specific to mucosal histology. 2 Radiation therapy (RT) in mucosal melanoma has shown promise in certain settings but indications remain poorly defined. 3 , 4 Immune checkpoint inhibitors have shown excellent response rates in metastatic melanoma and are increasingly used for mucosal melanoma; however, most patients will eventually progress. Response patterns are highly variable among patients who respond to immunotherapy. Although a small group of patients will experience complete response, many patients will have other types of responses such as pseudoprogression (disease enlargement followed by shrinking) or oligoprogression (progression at a limited number of sites).5, 6, 7 Patients with oligoprogression after treatment are of particular interest owing to the possibility of controlling the progressive disease with local therapy and achieving long-term survival. This concept has been demonstrated in retrospective studies of patients with melanoma; however, there have been no studies demonstrating this for patients with mucosal melanoma. 5 , 8 Herein, we report a case of a 67-year-old woman with metastatic anorectal mucosal melanoma with primary site oligoprogression on nivolumab who was treated with RT to the primary site, which induced a complete, durable, and ongoing response of almost 3 years. Case Presentation The patient was a 67-year-old woman who initially presented with complaints of difficulty emptying her bowels. A colonoscopy revealed a tumor in her rectum, located 1.0 cm from the anal verge. A biopsy was consistent with primary melanoma of the anus, BRAF wild-type. Further staging workup included a computed tomography (CT) of the chest, abdomen, and pelvis with intravenous contrast (Fig 1), followed by a positron emission tomography (PET)/CT scan 1 week later (Fig 2). The primary lesion was noted to be 2.3 × 2.3 cm with a standardized uptake value (SUV) of 11.1 and with marked thickening of the wall of the anorectum with extension to the anus. Two perirectal lymph nodes were noted (1.6 and 2.1 cm), in addition to 1 lymph node seen above the rectum just posterior to the sigmoid colon (1.5 × 1.0 cm). CT also revealed multiple low-density lesions in the liver: 1.1 cm and 1.0 cm in the right lobe (SUV 6.4) and 1.2 cm in the left lobe. A “left peri-rectal mass” was noted with an SUV of 12.8. An additional 1.2 cm presacral lymph node was noted with an SUV of 4.3. Hyperavidity was also noted in the right sacrum and right iliac bone (SUV 3.1). Biopsy of a liver lesion was performed and confirmed metastatic melanoma. Magnetic resonance imaging (MRI) of the head with intravenous contrast was negative for intracranial disease. Interval CT 4 weeks after initial imaging revealed an increase in the size of the primary to 2.5 cm, a bilobed perirectal mass 4.7 × 2.6 cm, and a new indeterminate 6-mm nodule in the right middle lobe of the lung. Figure 1 Initial staging computed tomography (CT) with contrast (A = axial, B = coronal, C = sagittal). Figure 2 Initial staging positron emission tomography (PET)/computed tomography (CT). Given her stage IV disease, she was started on combined ipilimumab and nivolumab on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network EA6141 clinical trial; she was randomized to the control arm and did not receive sargramostim. After approximately 6 weeks of treatment, she developed mild hypophysitis and ipilimumab was discontinued and she was maintained on nivolumab alone every 2 weeks. Ten weeks after starting treatment, interval restaging imaging was obtained with a CT of the chest, abdomen, and pelvis with intravenous contrast. The previously noted indeterminate right middle lobe nodule appeared to be nearly completely resolved. The liver metastases appeared significantly smaller. No new liver lesions were noted. The pelvic and presacral lymph nodes appeared much improved without any new adenopathy. The maximum thickness of the anorectal primary had decreased from 2.5 cm to 1.8 cm. Interval imaging 12 weeks later continued to show stable findings of treatment response with a stable hypodensity in the left lobe of the liver, no lesions in the right lobe of the liver, stable pelvic lymph nodes, and the primary appearing similar in size compared with prior. The previously noted left perirectal mass was also smaller (1.1 × 0.9 cm, previously 1.3 × 1.0 cm). Follow-up CT imaging at 8 months after treatment initiation suggested progression of disease at the primary site with distant disease control. The anorectal mass had enlarged from 1.8 × 2.5 cm to 2.2 × 3.3 cm. Multiple pelvic lymph nodes appeared slightly larger. Enlarging left and right inguinal nodes measuring 1.2 cm were noted representing a change compared with prior studies. The right liver mass continued to be nondiscernable and the left liver lesion was stable in size. An MRI of the pelvis with intravenous contrast (Fig 3) was obtained that elaborated an infiltrative tumor. A T2 enhancing mass was seen in the anus and lower rectum with transmural extension, invasion of the levator ani muscle on the right laterally, and extension through the pelvic floor musculature anteriorly. Abnormal tissue tracking cephalad was noted on the left, consistent with the infiltrating tumor. Overall, the findings were interpreted as representing progression of disease at the anorectal primary and adjacent lymph nodes and the patient was taken off trial. She was continued on maintenance nivolumab and referred to radiation oncology for consideration of local therapy, given her worsening symptoms of constipation and occasional bleeding. Clinically, rectovaginal septum induration secondary to malignancy was also appreciated at this time. Figure 3 Preradiation therapy (RT) magnetic resonance imaging (MRI) with contrast (A = axial, B = coronal, C = sagittal). It was decided to deliver consolidative RT without interruption of maintenance nivolumab. Nine months after starting initial immunotherapy, 45 Gy in 3 Gy per fraction was delivered using a 3-field 3D conformal technique to the diagnostic MRI and CT simulation-defined primary site gross tumor volume with a 2.0 cm circumferential margin and a 3.0 cm superior/inferior margin without regional coverage (Fig 4). This was felt to be a regimen that would achieve a near definitive effective dose while being safe for the anal canal, with hypofractionation enabling a shorter treatment time and assisting in overcoming resistant melanoma. Figure 4 Radiation therapy treatment plan dose distributions (isodose curves). RT was tolerated without issue. Interval CT imaging 3 months later demonstrated significantly decreased thickness of the primary anorectal lesion measuring 1.3 cm compared with 2.3 cm previously; perirectal lymph nodes also appeared smaller in size. MRI imaging 5 months after RT demonstrated circumferential submucosal thickening involving the distal rectum and anus without enhancing lesion, thought to be consistent with postradiation change; no lymphadenopathy was seen (Fig 5). A linear enhancing band extending from the anterior aspect of the anus through the external sphincter to the lower vagina/vulvar area was visualized and thought to represent a fistulous tract. Clinically, the patient reported improvement in caliber of stools. Serial CT, MRI, and interval MRI 6, 11, and 19 months after RT, respectively, continued to show stable findings. Figure 5 Five months post-radiation therapy (RT) magnetic resonance imaging (MRI) with contrast (A = axial, B = coronal, C = sagittal). A PET/CT obtained 21 months after RT showed minimal residual uptake in the anal canal with no associated mass. An interval PET/CT 4 months later showed stable (SUV 4.6) uptake in the region of the anal canal with no associated mass. A third interval PET/CT was obtained after a subsequent 8 months (33 months after RT and 42 months after the start of initial treatment), showing no areas of hypermetabolism. The patient’s nivolumab was discontinued. The patient has enjoyed excellent performance status and has been without symptom or complaint. Discussion This case shows complete and durable response of metastatic anorectal mucosal melanoma to RT after primary site progression on nivolumab. Although there was radiographic concern for fistula after radiation, the patient has done well clinically, has not required any intervention for it, and it has improved over time. This is a case of “oligoprogression” and supports the hypothesis that prolonged survival may be possible with treatment of limited progressive sites, similar to the paradigm that has been demonstrated in a prospective study of oliogmetastatic disease.8, 9, 10, 11 The optimal management of oligoprogressive patients on immune checkpoint inhibitors remains poorly defined owing to the lack of prospective data. A PubMed search for the terms “oligoprogression” and “melanoma” yields only 2 results, both of which are retrospective and neither of which are specific to RT. 5 , 8 In the larger of the 2 retrospective studies, 52 patients met inclusion criteria of initial treatment with immune checkpoint inhibitor followed by progression at 1 to 3 sites. These patients were treated with a variety of local therapies. Three-year progression-free survival was 31%. Interestingly, improved progression-free survival was found in those with progression limited to previously established tumors. 8 Extrapolating these results to the presented case is difficult given the various other local therapy options included in their analysis such as ablation, surgery, and stereotactic body radiation therapy. This suggests that an optimal consolidative approach to oligoprogression may yet be elucidated, and our case highlights the potential of radiation immunotherapy combination in this situation. The excellent response of the patient in this case raises the possibility that RT may have advantages over other forms of local therapy when used in oligoprogressive patients receiving immune checkpoint inhibitors. One hypothesis for this synergy is the immunogenic effects of radiation, which include increased neoantigen expression, activation of the “cyclic GMP-AMP synthase/stimulator of interferon genes” pathway, and increased dendritic cell activation. 12 Given the strong biological rationale for the combination of radiation and immunotherapy 13 and the observation of such synergy in preclinical models, 14 treatment with both modalities is being investigated in numerous clinical trials (Table 1). Given that our patient only had 1 oligoprogressive site, a nontarget site was not available at which an abscopal response to RT could be assessed. Observation of such an effect would have strengthened our ability to conclude RT-immunotherapy synergy was involved. 15 Table 1 Summary of relevant ongoing immunotherapy + melanoma clinical trials NCT number Title Immunotherapy Radiation Phase Estimated enrollment Patient characteristics Mucosal histology included Primary outcome Estimated start date Estimated primary completion date Estimated final completion date NCT03758729 Phase II Study of Nivolumab in Combination With Radiation Therapy as Definitive Treatment for Patients With Locally Advanced, Unresectable Head and Neck Mucosal Melanoma Nivolumab 2 Gy × 35 Single arm, phase II 26 Locally advanced, unresectable H&N mucosal melanoma Yes, trial is specific for mucosal melanoma Response rate (CR + PR) September 1, 2019 March 2020 December 2020 NCT03646617 Ipilumumab and Nivolumab With or Without Hypofractionated Radiation Therapy in Patients With Metastatic Melanoma (RadVax) Ipilumumab + nivolumab 8 Gy × 3 versus no radiation Phase II 70 Metastatic melanoma, ECOG 0-1 Not specified Safety August 23, 2018 February 23, 2022 February 23, 2023 NCT04042506 SBRT as a Vaccination for Metastatic Melanoma Nivolumab 8-10 Gy × 3 Single arm, phase II 15 Unresectable melanoma (any histology) Yes Safety August 2019 March 2023 March 2028 NCT03340129 Anti-PD 1 Brain Collaboration + Radiation Therapy Extension (ABC-X Study) Ipilumumab + nivolumab SRS 16-22 Gy up-front versus salvage Phase II 218 Cutaneous, acral, or mucosal melanoma with 1 or more brain metastases Yes Neurologic death August 14, 2019 August 2022 August 2024 NCT04017897 The Combination of Anti-PD-1 With Radiation Therapy in Previously Untreated Metastatic Melanoma Ipilumumab + nivolumab Not specified Phase II 52 Unresectable stage III - IV melanoma, ECOG <1, no prior systemic therapy Yes Overall response rate July 3, 2019 July 2022 July 2022 NCT03850691 Radiation and Combination Immunotherapy for Melanoma Aldesleukin + nivolumab OR Aldesleukin + ipilumumab + nivolumab Not specified Phase II 44 At least 3 radiographically distinct lesions (>1.5 cm) previously refractory to standard immunotherapy No Objective response rate, safety May 28, 2019 December 2025 December 2025 NCT03354962 Induction of Immune-mediated aBscOpal Effect thrOugh STEreotactic Radiation Therapy in Metastatic Melanoma Patients Treated by PD-1 + CTLA-4 Inhibitors (BOOSTER MELANOMA) Ipilumumab + nivolumab SBRT versus no radiation Phase I/II 120 Histologically proven unresectable stage III-IV melanoma. PD-L1 expression <1% Yes Dose limiting toxicities, abscopal effect October 15, 2018 September 2022 March 2024 Abbreviations: CR = complete response; CTLA-4 = cytotoxic T-lymphocyte associated protein-4; ECOG = Eastern Cooperative Oncology Group; H&N = head and neck; OR = overall response; PD-1 = programmed cell death protein 1; PR = partial response; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery. It is notable that we achieved durable control given the mucosal histology in this case. Mucosal melanoma differs from cutaneous melanoma in presentation, diagnosis, and genetic profile. 16 , 17 Surgery with the potential to achieve negative margins is considered standard of care for these patients; however, this is often not feasible owing to anatomic location and the higher frequency of metastatic disease at presentation compared with cutaneous melanoma. 17 , 18 Other treatment options are similar to those available for cutaneous melanoma including radiation, chemotherapy, targeted small molecule inhibitors, and immunotherapy. 19 Notable differences in treatment involve the types of inhibitors available and the response to immunotherapy. Mucosal melanomas more frequently harbor KIT mutations as opposed to the BRAF mutations seen in cutaneous melanoma. 20 , 21 Retrospective studies have shown that the utilization of immunotherapy is increasing and it may provide superior results in mucosal melanoma compared with other treatment modalities, especially when combined with RT. 22 , 23 Response to immunotherapy, however, may also be lower for mucosal melanoma than for cutaneous melanoma, possibly owing to lower levels of tumor neoantigens. 24 A large retrospective study showed objective response rates to nivolumab of 23.3% and 40.9% for mucosal and cutaneous melanoma, respectively. 25 Given the decreased immunogenicity of mucosal melanoma and the ability of radiation to enhance immunogenicity, 12 , 24 melanoma with mucosal histology may derive great benefit from the addition of RT to immunotherapy. A retrospective study of 23 patients with head and neck mucosal melanoma treated with RT and immunotherapy reported target local control was highest with an RT and immunotherapy combination (94% at 1 year). 23 A prospective study of an RT/immunotherapy combination in this histology is ongoing with patients with mucosal melanoma included in many melanoma clinical trials (Table 1). 26 , 27 Conclusions Our illustrative single-case experience suggests the dramatic and durable control that may be achieved with a consolidative radiotherapeutic approach to oligoprogression on immunotherapy in a case of a typically poorer responding mucosal melanoma. The management of such patients remains poorly defined. Randomized trials investigating methods of controlling disease progression in the setting of immunotherapy are necessary.