Study Finds Adjuvant Immunotherapy of Benefit to Patients With Stage IIB/C Melanoma

Radiation Therapy After Checkpoint Inhibition May Reduce Liver Metastases in Advanced Melanoma, Another Study Reports

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A significant survival advantage accrued to patients with stage IIB and IIC cutaneous melanoma who received adjuvant immunotherapy, a large retrospective cohort study reported at the Society of Surgical Oncology (SSO) 2021 International Conference on Surgical Cancer Care.1 The 3-year overall survival was 82.7% among patients with stage IIB/C disease who received adjuvant immunotherapy vs 71.6% for those who did not (P < 0.001).

“The use of immunotherapy agents is well accepted for stage III and IV disease,” William G. Wong, DO, the study’s lead investigator reported. “This is the first large retrospective study to evaluate the utilization patterns and survival benefits of adjuvant immunotherapy for high-risk stage II melanoma in the United States.” Dr. Wong is a resident physician at Penn State Milton S. Hershey Medical Center, Hershey Pennsylvania.

4% Received Adjuvant Immunotherapy

Using the National Cancer Database, researchers identified 10,592 patients with stage IIB and IIC melanoma who underwent surgical resection between 2013 and 2017. They found that 4% (419 patients) also received adjuvant immunochemotherapy. The majority of patients were male, White non-Hispanic, and had few or no comorbidities.

Patients with stage IIB and IIC melanoma who received adjuvant immunotherapy had a higher rate of 3-year overall survival compared with those who did not.
— William G. Wong, DO

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“Patients with stage IIC melanoma or positive surgical margins were more likely to receive adjuvant chemotherapy than patients with stage IIB or a negative margin status,” Dr. Wong reported. Female patients and those younger than age 65 also seemed to be more likely to have received immunotherapy, as were those traveling up to 50 miles to the hospital for ­treatment.

Higher 3-Year Overall Survival

“With the Kaplan-Meier method, patients with stage IIB and IIC melanoma who received adjuvant immunotherapy had a higher rate of 3-year overall survival compared with those who did not,” Dr. Wong reported. “Significant differences in 3-year overall survival existed even after we subdivided the cohort into stage IIB disease alone and stage IIC disease alone.” The 3-year overall survival rate was 86% for patients with stage IIB melanoma who received adjuvant immunotherapy vs 77% for those who did not (P = .0012) and 79% for patients with stage IIC 3 who received adjuvant immunotherapy vs 61% for those who did not (P < .0001).

“We demonstrated a significant survival advantage with adjuvant immunotherapy and recommend that it should continue to be considered in the postoperative treatment of stage IIB and IIC melanoma,” Dr. Wong remarked.

Other factors associated with poor survival included advanced age, multiple comorbidities, tumors at the head and neck or trunk, higher T stage status, positive surgical margin status, Medicare rather than private insurance, and care in a community cancer hospital rather than in an academic cancer hospital.

One of the limitations of this study is that the National Cancer Database does not provide information on the specific type of immunotherapy received. Therefore, the immunotherapies patients could have received included interferon alpha, CTLA-4 inhibitor, PD-1 inhibitor, or PD-L1 inhibitor,” Dr. Wong said. “Because of its side effects, interferon alpha is the less popular option, especially after immune checkpoint inhibitors became available in 2011. That is why we restricted our study period from 2013 to 2017, making it reasonable to assume that the majority of patients may be receiving immune checkpoint inhibitors.”

“An ongoing randomized clinical trial (KEYNOTE-716; identifier NCT03553836) is “studying the survival benefit of adjuvant PD-L1 inhibitors in patients with surgically resected high-risk melanoma, and its primary completion date is October 2022,” Dr. Wong said. “In the interim, utilization of postoperative immunotherapy for high-risk stage II melanoma will be left to the discretion of patients and their multidisciplinary team.”

Resistance to Checkpoint Inhibitors

“Immunotherapy with checkpoint inhibitors has been revolutionary in the treatment of metastatic melanoma,” Humair S. Quadri, MD, a surgical oncology fellow at Cedars-Sinai Medical Center, Los Angeles, acknowledged in a subsequent presentation.2 However, patients with hepatic metastases may have resistance to immune therapy with checkpoint inhibitors. “The liver has been well known to be an immune-privileged site, and data have shown that hepatic metastases are associated with reduced CD8-positive T-cell infiltration, which suggests resistance to immune therapy with checkpoint inhibitors,” Dr. Quadri explained.

Humair S. Quadri, MD

Humair S. Quadri, MD

Dr. Quadri led an investigation into whether directly treating the liver metastases in patients with metastatic melanoma could potentially release antigens leading to an abscopal effect and improve survival outcomes. As background on the abscopal effect, Dr. Quadri noted: “In 1953, R.H. Mole proposed that localized ionizing radiation to a single lesion could potentially lead to concurrent shrinkage of all other untreated metastatic tumors. The proposed mechanism of this was that antigens were released into the circulation. They were then presented to CD8-positive T cells, and this primed the immune response against other metastatic lesions.”

Largest Liver Metastases Irradiated

An institutional database search identified 25 patients treated at Cedars-Sinai Medical Center and The Angeles Clinic between May 2011 and October 2020. They met three criteria: metastatic melanoma to the liver, treatment with checkpoint inhibitors, and radiation to the largest liver metastases. Chart review determined the size of the largest liver metastases and the largest dimension, response before and after radiation, and the type of checkpoint inhibitor used. A total of 18 patients were alive at chart review.

The primary melanoma site varied, with the head and neck being the most common, followed by the chest, back, and lower extremity. “Sentinel lymph node biopsy was performed on 13 patients, with just 5 having a positive lymph node,” Dr. Quadri reported.

The most common types of immunotherapy used were ipilimumab, pembrolizumab, and nivolumab. “These agents were all well tolerated, with minimal toxicity,” he added.

“The radiation therapy that was given to the largest liver lesion was mostly stereotactic body radiation therapy, with a 30-Gy to 50-Gy dose and a short course between 5 and 10 days; four patients also received yttrium-90,” Dr. Quadri reported. “Two patients underwent liver ablation as well.”

Disease Progression Before Shrinkage

The largest liver metastases on initial diagnosis of metastatic disease averaged 1.3 cm. During treatment with checkpoint inhibitors, the size grew to 3.7 cm, then shrank to 3.3 cm at 6 months after patients received focal radiation, and to 2.8 cm at 12 months. “At the most recent evaluation, they were noted to have a continued reduction in tumor size to 2.6 cm,” Dr. Quadri said.

“Many of these patients actually had multiple liver lesions that also increased with the start of immunotherapy. Once the largest liver lesion was treated with radiation, all of the liver lesions were reduced in size,” Dr. Quadri remarked. “It was a universal response to even the ones that were not treated with radiation.”

Complete Regression

Of the 25 patients, 4 (16%) “were noted to have complete regression of both the irradiated lesion and unirradiated metastatic sites, which rendered them with no evidence of disease,” Dr. Quadri reported. These patients also had progression of disease while on immunotherapy but then significant reduction to complete resolution after receiving liver-directed radiation. “Complete hepatic metastases regression was noted to be complete within 15 months, and systemic regression among all of these four patients was noted within 5 years,” Dr. Quadri reported.

“With all of this information, we concluded that metastasis-directed radiotherapy is feasible and well tolerated in these patients,” Dr. Quadri stated. “In this selected series of patients who had a poor prognosis with liver metastases, this combination rendered 16% of patients with no evidence of disease after liver-­directed therapy, suggesting a potential abscopal effect. This does suggest that combined radiation and systemic approaches may be able to overcome the inherent resistance of hepatic metastases from metastatic melanoma.” 

DISCLOSURE: Dr. Wong and Dr. Quadri reported no conflicts of interest. 


1. Wong WG, Olecki E, Stahl K, et al: Utilization and survival benefit of adjuvant immunotherapy in resected high-risk stage II melanoma: A National Cancer Database Analysis. SSO 2021 International Conference on Surgical Care. Abstract 58. Presented March 19, 2021. 

2. Quadri HS, Crystal JS, Zumsteg SL, et al: Metastatic melanoma patients with progression on checkpoint inhibitors respond to hepatic metastasis directed local therapy. SSO 2021 International Conference on Surgical Care. Abstract 61. Presented March 19, 2021.