Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

Successful treatment of murine melanoma with bryostatin 1.

Bryostatins are a novel class of protein kinase C activators which were isolated from the marine bryozoan Bugula neritina and found to possess both antineoplastic and immunoenhancing properties. In this report, we examined the relationship between the in vivo and in vitro antineoplastic effects of bryostatin 1. The in vivo antitumor activity of bryostatin 1 was demonstrated in a B16 melanoma pulmonary metastases model, in which treatment of tumor-bearing C57BL/6 mice with 5 days of bryostatin 1 resulted in a significant reduction in of the number of lung nodules (control, 87; bryostatin, 7). There was a clear dose-response effect, with the optimal antimelanoma dose being 100 micrograms/kg/day, but even low doses of bryostatin 1 of 1 micrograms/kg/day resulted in a 53% reduction in the number of metastases. Although bryostatin 1 shares many biological properties with the phorbol esters, parallel treatment with 12-O-tetradecanoyl 13-phorbol acetate was ineffective against B16 melanoma in vivo. Using a clonogenic assay, bryostatin 1 was found to have a direct antiproliferative effect against B16 melanoma. This inhibition occurred at relatively high bryostatin 1 concentrations (10(-6) M), in comparison with a sensitive cell line REH (10(-10) M). Treatment of mice with bryostatin 1 or preincubation of normal spleen cells with bryostatin 1 failed to enhance nonspecific cell-mediated cytotoxicity against B16 melanoma in vitro. Moreover, bryostatin 1 was found to inhibit both natural killer cell activity and interleukin 2 generation of lymphokine-activated killer cells. Thus, a role for an in vivo immune enhancement mechanism as the basis for the antimelanoma activity observed with bryostatin 1 cannot be invoked from these experiments. These findings indicate that bryostatin 1 may act directly on the B16 melanoma pulmonary metastases. The precise mechanism whereby bryostatin exerts its antimelanoma effects remains unclear.

Effects of topical tretinoin on dysplastic nevi.

PURPOSE: As potential precursors of melanoma and markers of increased melanoma risk, dysplastic nevi are suitable targets of strategies for melanoma chemoprevention. We report the results of a pilot study of topical retinoic acid in patients with dysplastic nevi. PATIENTS AND METHODS: Five male patients with dysplastic nevi applied tretinoin to half of the back for 6 months. Baseline photographs of dysplastic nevi were compared with posttreatment photographs and assessed for morphologic change. At study completion, each subject had four nevi excised from the treated side and four from the untreated side of the back. Biopsies were histologically evaluated for the presence of dysplasia. RESULTS: All patients developed signs of irritation as a result of treatment. One patient was not compliant with treatment due to skin irritation. The four compliant patients showed significant decreases in the clinical atypia of treated lesions, with concomitant fading and even disappearance of many treated nevi. Histologically, only four of 16 treated nevi met histologic criteria for dysplasia, in comparison to 13 of 16 untreated nevi. CONCLUSION: These results suggest that there is concomitant clinical and histologic improvement in a significant percentage of dysplastic nevi treated with topical tretinoin. However, the utility of topical tretinoin for chemoprevention of melanoma is limited by difficulty of application and associated inflammation. While new strategies in chemoprevention of melanoma are explored, sun protection and assiduous avoidance of sunburn must remain the mainstay of melanoma prevention.

Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases.

PURPOSE: To determine whether treatment with an autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP vaccine) is an effective postsurgical adjuvant treatment for melanoma patients with clinically evident nodal metastases. PATIENTS AND METHODS: Eligible patients had regional nodal metastases that were large enough (> or = 3 cm diameter) to prepare vaccine. Following standard lymphadenectomy, patients were treated with DNP vaccine on a monthly or weekly schedule. RESULTS: Of 62 patients with metastasis in a single lymph node bed (stage III), 36 are alive after a median follow-up time of 55 months (range, 29 to 76); the projected 5-year relapse-free and overall survival rates are 45% and 58%, respectively. Of 15 patients with metastases in two nodal sites, five are alive with a median follow-up time of 73 months. An unexpected finding was the significantly better survival of older patients; the projected 5-year survival of patients greater than 50 versus < or = 50 years was 71% and 47%, respectively (P = .011, log-rank test). The development of a positive delayed-type hypersensitivity (DTH) response to unmodified autologous melanoma cells was associated with significantly longer 5-year survival (71% v 49%; P = .031). Finally, the median survival time from date of first recurrence was significantly longer for patients whose subcutaneous recurrence exhibited an inflammatory response (> 19.4 v 5.9 months; P < .001). CONCLUSION: Postsurgical adjuvant therapy with autologous DNP-modified vaccine appears to produce survival rates that are markedly higher than have been reported with surgery alone. Moreover, this approach has some intriguing immunobiologic features that might provide insights into the human tumor-host relationship.

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.

PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Sequential chemotherapy and immunotherapy for the treatment of metastatic melanoma.

Interferon (IFN) has numerous biological properties, and more recently a new role for interferon has emerged, as a modulator of cytotoxic chemotherapeutic agents. This is based upon preclinical data that demonstrate additive and/or synergistic effects of IFN with a number of anticancer drugs including cisplatin against human cancer cell lines. Therefore, we evaluated the outpatient use of recombinant alpha 2a-interferon, 3-15 MU/m2 given on 3 consecutive days, subcutaneously, followed by intravenously administered cisplatin, 25-60 mg/m2, every 21 days. In this phase I clinical study, 23 patients with advanced malignant melanoma were treated. Dose-limiting toxicities included decline in performance status, fatigue, and anorexia. No synergistic or unpredictable toxicities were seen. Of the 20 patients who completed two cycles of therapy, there were three partial responses, for an overall response rate of 15%. Interestingly, responses occurred at the intermediate dose levels.

Exploration of platinum-based dose-intensive chemotherapy strategies with amifostine (Ethyol).

The preclinical evaluation of amifostine confirms selective protection of normal tissues against toxicity due to cisplatin therapy while maintaining the antitumour effects. The mechanism of protection relates to the selective uptake of the free thiol, amifostine, into normal tissue compared with tumour tissue, intracellular binding and therefore detoxification of anticancer drugs, as well as through the scavenging of oxygen free radicals. Although vigorous hydration schedules have helped to alleviate nephrotoxicity, ototoxicity and cumulative dose-related peripheral neuropathy, these side effects remain important dose-limiting toxicities related to cisplatin therapy. The preclinical and clinical results to date demonstrate that amifostine can protect against cisplatin toxicities, in particular nephrotoxicity. Recent studies have demonstrated that higher single and cumulative cisplatin doses have an important impact on survival outcome; however, the improvement in survival comes at the cost of increased acute and cumulative haematological, renal and neurological toxicities that can result in serious morbidity. The role of amifostine as a unique supportive measure to reduce these toxicities offers the possibility of improving the quality of life of patients receiving chemotherapy.

Guidelines for the administration of amifostine.

The preclinical evaluation of amifostine confirms selective protection of normal tissues against toxicity due to radiation therapy and alkylating agent chemotherapy, while largely maintaining the antitumor effects of these therapies. The mechanism of protection mediated by amifostine at the molecular, cellular, and tissue levels is not completely understood but is, in part, through scavenging oxygen-free radicals. Significant side effects related to amifostine include nausea, vomiting, and hypotension, which can be ameliorated with appropriate premedications. Ongoing studies will continue to explore the optimal use of this cytoprotective agent.

Prognostic models in melanoma.

Predicting which patients with primary melanoma are at risk of developing metastastic disease is important for making rational therapeutic decisions. Tumor thickness alone is the most commonly used predictor of survival, but other clinical and pathologic variables also play an important role. We have developed two multivariate logistic regression models to predict survival in patients who have primary melanoma. The first of these models assigns patients to two groups based on radial or vertical growth phase. The probability of survival for those patients with vertical growth phase tumors was further determined based on a model using six variables (mitotic rate, tumor infiltrating lymphocytes, tumor thickness, anatomic site of the primary tumor, sex, and histologic regression) that have the greatest strength as independent predictors of survival. This model is 89% accurate for predicting survival in patients with vertical growth phase tumors. A second model has been developed that uses readily available clinical parameters to predict survival. Four variables (tumor thickness, anatomic site, age, and sex) entered into the model as powerful independent predictors. Clinical algorithms for assessing patient risk are provided.

The current status of toxicity protectants in cancer therapy.

Current therapies for the treatment of malignancies are associated with significant toxicity, as chemotherapy and radiation therapy do not discriminate between normal and malignant cells. One approach to ameliorating the toxicity associated with therapy is through the use of chemoprotective agents. This article reviews a variety of agents that have been evaluated as possible protectants, including WR-2721 and the colony-stimulating factors. It is hoped that the understanding of how to optimally use chemoprotective agents will lead to more tolerable treatments for patients, and possibly allow for dose-escalation, which may contribute to improvement in patient survival.

Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study.

PURPOSE: A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS: Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS: Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION: Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm.

Systemic treatment of metastatic melanoma with chemotherapy.

This article reviews the use of systemic chemotherapy for the treatment of metastatic melanoma, including single-agent chemotherapy, combination chemotherapy with and without tamoxifen, and biochemotherapy.

Current role of protective agents in cancer treatment.

The administration of intensive chemotherapy according to a rigid schedule improves response rates and duration of response. However, dose-limiting toxicities and resulting delays in therapy often interfere with therapy intensification. In recent years, cytoprotective agents have been developed that can protect normal cells, but not tumor cells, from chemotherapeutic or radiation damage. Amifostine (Ethyol), dexrazoxane (Zinecard), and mesna (Mesnex) are true cytoprotectors administered shortly before chemotherapy. Colony-stimulating factors (CSFs) are administered after chemotherapy to rescue the bone marrow and stimulate hematologic recovery. In the appropriate settings, use of these agents has facilitated the intensification of chemotherapy and has significantly attenuated the impact of chemotherapy on normal cells.

Phase II trial of docetaxel (Taxotere) in patients with metastatic melanoma previously untreated with cytotoxic chemotherapy.

A phase II study was undertaken to evaluate the clinical efficacy and safety of docetaxel in patients with malignant melanoma. Between April 1992 and February 1996, 37 patients with metastatic malignant melanoma and no prior chemotherapy were treated with docetaxel 100 mg m-2 administered intravenously over 1 hour every 21 days. Patients were premedicated prior to each course with dexamethasone and diphenhydramine. Toxicity and follow-up were provided. Objective responses were seen in two out of 35 patients evaluable for response, one complete response and one partial response. These two responses were of a duration of greater than two years. The most common toxicity was grade 4 neutropenia, which occurred in 92% of patients; 49% required hospitalization for an episode of neutropenic fever. Additional patients had reversible grade 3-4 toxicities including nausea, vomiting, diarrhea, stomatitis, arthralgias, myalgias, peripheral neuropathy and fatigue. Eighteen patients had hypersensitivity reactions, two were grade 3-4. Fluid retention, grade 1-3 was observed in seven patients. Alopecia occurred in most patients. Docetaxel has definite but low-level activity against malignant melanoma. Further investigation of this drug should be considered in multidrug combination programs.

Stem cell transplantation for metastatic breast cancer: analysis of tumor contamination.

The purpose of this study was to determine the efficacy, engraftment kinetics, effect of bone marrow tumor contamination, and safety of high-dose therapy and granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) support for patients with responding metastatic breast cancer. Forty two patients underwent G-CSF (10 microg/kg) stimulated PBPC harvest. PBPC and bone marrow aspirates were analyzed by histologic and immunocytochemical methods for tumor contamination. Thirty-seven patients received high-dose therapy consisting of cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) given as an infusion over 4 d followed by PBPC reinfusion and G-CSF (5 microg/kg) support. No transplant related deaths or grade 4 toxicity was recorded. CD34+ cells/kg infused was predictive of neutrophil and platelet recovery. With a median follow-up of 38 months, three year survival was 44% with relapse-free survival of 19%. Histological bone marrow involvement, found in 10 patients, was a negative prognostic factor and was associated with a median relapse-free survival of 3.5 months. Tumor contamination of PBPC by immunohistochemical staining was present in 22.5% of patients and found not to be correlated with decreased survival. G-CSF stimulated PBPC collection followed by a single course of high dose chemotherapy and stem cell infusion with G-CSF stimulated marrow recovery leads to rapid, reliable engraftment with low toxicity and promising outcome in women with responding metastatic breast cancer.