Andrea Freschi

Cisplatin, Dacarbazine With or Without Subcutaneous Interleukin-2, and Interferon Alfa-2b in Advanced Melanoma Outpatients: Results From an Italian Multicenter Phase III Randomized Clinical Trial

PURPOSE Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.

Pharmacokinetics of vinorelbine in patients with liver metastases

The main elimination pathway of vinorelibine is hepatic metabolism, and the clearance of vinorelbine could be reduced in patients with liver metastases.

Multicentre, open, noncomparative Phase II trial to evaluate the efficacy and tolerability of fotemustine, cisplatin, alpha-interferon and interleukin-2 in advanced melanoma patients.

The efficacy and tolerability of fotemustine, cisplatin, &agr;-interferon and interleukin-2 biochemotherapy were evaluated in advanced melanoma patients. The schedule consisted of fotemustine (100 mg/m2) and cisplatin (75 mg/m2) intravenous on day 1, followed by subcutaneous interleukin-2 at a dose of 4.5 MIU on days 3–5 and 8–12 and &agr;-interferon at a dose of 3 MU three times/week, every 3 weeks for six cycles. Sixty patients were evaluated for tumour response, 12 of whom had brain metastases (BM). One patient (1.7%) with BM achieved a complete response and partial responses were observed in 10 patients (16.7%), including one BM patient. Overall response rate was 18.4 and 16.6% in BM patients (median response duration 8.2 months). Disease control, defined as overall response and stable disease, was 58.4% in all patients and 75% in patients with BM. Median time to progression was 3.2 months (4.2 months in BM patients). Median overall survival was 8.9 months (7.6 months in BM patients). Toxic events were mild to moderate. This combination was well tolerated and showed acceptable clinical activity, especially in BM patients.

Long-term survival in patients with metastatic renal cell carcinoma treated with continuous intravenous infusion of recombinant interleukin-2: the experience of a single institution.

Aim and background Metastatic renal cell carcinoma is one of the few tumors for which a clear benefit of immunotherapy has been demonstrated. The aim of this study was to evaluate the long-term survival of patients with metastatic renal cell carcinoma, along with response rate and other prognostic and predictive factors. Patients and methods Between July 1989 and May 1995, 56 patients with metastatic renal cell carcinoma were treated in a single institution with high-dose recombinant interleukin-2 in continuous infusion. Survival was measured by the Kaplan and Meier method. Prognostic factors were assessed by univariate and multivariate analyses of survival (Cox proportional hazard ratio model). Results Of 56 patients, 15 had objective responses (26.8%), 16 stable disease (28.6%), 18 disease progressions (32.1%), and 7 (12.5%) were not valuable for response. Median overall survival was 20 months, and probability of 2- and 5-year survival was 41% and 21%, respectively. At multivariate analysis, the increased risk of death for: performance status ≥2 vs 0 (HR = 6.20), stable disease (HR = 1.87), disease progression (HR = 10.61) vs partial or complete remission, and for hypotension and oliguria toxicity, G3 + G4 vs G1 + G2 (HR = 2.19). Conclusions Our study confirms the activity of IL-2 based immunotherapy in renal cell carcinoma. Moreover, ECOG performance status, clinical response, hypotension and oliguria toxicity resulted as independent survival prognostic factors.

Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.

The addition of cytokines, such as interferon &agr;-2b and interleukin-2, to chemotherapy in metastatic melanoma has produced conflicting results in phase II and III trials. We report our experience with a chemoimmunotherapeutic regimen using subcutaneous cytokines. Twenty-eight patients with advanced melanoma (median age, 45 years; male to female ratio, 19 : 9) were treated. Doses were as follows: cisplatin, 20 mg/m2 intravenously (iv) days 1–4; vinblastine, 1.6 mg/m2 iv days 1–4; dacarbazine, 800 mg/m2 iv day 1; interferon &agr;-2b, 5 MIU/m2 subcutaneously (sc) days 1–5; interleukin-2, 9 MIU/m2 sc days 1–5 and 8–12. Treatment was repeated every 3 weeks for a maximum of six cycles. The response was assessed after two cycles and toxicity at every cycle, according to World Health Organization (WHO) and National Cancer Institute (NCI) criteria, respectively. At a median follow-up of 8 months, only four patients (14%) were still alive. The overall response rate was 33%, with three (11%) complete responses lasting for 17, 14 and >24 months. There were six (22%) partial responses and three stable disease. Amongst the responders, three patients progressed at the level of the central nervous system. The median time to progression and overall survival were 3.5 and 9 months, respectively. The most common grade 3–4 toxicity was neutropenia, reported in 25 of the 28 patients (92%). Only two patients (7%) experienced neutropenic fever. Thrombocytopenia grade 3–4 occurred in seven of the 28 patients (25%), with only one patient needing transfusional support. One toxic death due to neutropenic fever occurred. It can be concluded that the chemoimmunotherapy schedule evaluated is active and may be considered for patients with metastatic melanoma who have a good performance status and a limited disease burden.

Radiotherapy followed by temozolomide in the treatment of patients with melanoma metastatic to the brain: An Italian multicentre study

7558 Background: Whole Brain Radiotherapy (WBRT) and systemic chemotherapy remain the mainstays of therapy for metastatic brain melanoma not amenable to surgical resection. The proven efficacy of Temozolomide (TMZ) on both primary and metastatic brain tumors prompted us to conduct this phase II study to determine the activity of TMZ treatment following WBRT in patients (pts) with untreated brain metastases from melanoma. METHODS Single CNS metastases eligible to surgery and/or stereotactic radiosurgery, prior treatment for CNS metastases, severe medical conditions interfering with oral intake were the main exclusion criteria. Treatment plan included : WBRT at 6 Gy/day administered over a two-week period (on wks 1-2) for 4 fractions (total dose 24 Gy), followed, on wk 7, by orally TMZ at a dose of 150 mg/m2/day × 5 days every 4 wks, for up to 6 cycles. Pts who received at least one cycle of TMZ were assessable for response. RESULTS Twenty-seven pts (15 M and 12 F, ages 26 to 72) entered the study. Number of CNS metastases was 1 (6 pts), ≥ 2 (21 pts, range 2-6). In most of the pts (85%), extracerebral disease sites were detected (range, 1-5). Ten pts (37%), after received RT as initial management, dropped out due to death or general physical impairment. Among 17 pts who started TMZ chemotherapy, 2 pts lost to follow-up, 6 pts prematurely withdrew from study due to cerebral progression, 9 pts received ≥ 3 cycles, and 5 pts completed treatment plan. The median number of TMZ cycles/pt was 3 (range, 1-6). Among 15 evaluable pts, 5 stabilization of disease and 3 partial responses on cerebral sites were achieved. The median survivals of pts who received RT alone or RT plus TMZ, were 35 days (range, 5-80 days) and 180 days (range, 56-360 days), respectively. Treatment related toxicity was minimal with only two dose-modifications required due to thrombocytopenia and vomiting. CONCLUSIONS Compared with historical data, these preliminary results show that some of the pts who received complete treatment plan could achieve prolonged disease control and survival. Final data analysis will be presented. No significant financial relationships to disclose.

Soluble intercellular adhesion molecule-1 and serum cytokines in melanoma patients treated with liposomes containing muramyl tripeptide

Aims and Background A soluble form of intercellular adhesion molecule-1 (sICAM-1) has been recently identified in patients with malignant melanoma. It has been demonstrated that inflammatory cytokines can modulate the cellular expression of ICAM-1 and the shedding of this molecule by cells. To our knowledge, few data exist on serum sICAM-1 levels in cancer patients treated with immunomodulators. Liposomes containing muramyl tripeptide (MLV MTP-PE) can activate monocytes from cancer patients in vitro and in vivo, making them cytotoxic such as tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6). The purpose of the present study was to evaluate the levels of sICAM-1 and their possible correlation with serum inflammatory cytokine levels in melanoma patients treated with MLV MTP-PE. Methods The sera from 9 patients with metastatic melanoma treated with MLV MTP-PE, 4 mg i.v. twice a week for 12 weeks, were tested in ELISA system to detect sICAM-1, TNF-α, IL-6, Interleukin-1β (IL-β) and Interferon-γ (IFN-γ) before, and 2 and 24 h after the 1st, 12th and 24th infusion of MLV MTP-PE. Results Baseline levels of sICAM-1 were elevated in all patients (median 540 ng/ml: range 400-1030 ng/ml). Twenty-four h after the 1st infusion of MLV MTP-PE, we observed 6 increases in sICAM-1 levels, 1 decrease and 2 stable values (median 720 ng/ml: range 410-1820; P = 0.060). Twenty-four h after the 12th infusion, sICAM-1 increased in 3 patients and did not change in 4 (median 790 ng/ml: range 495-1650 ng/ml; P = 0.069). At the 24th infusion, sICAM-1 increased in 4 of 6 evaluable patients and remained stable in 2 (median 802 ng/ml: range 510-1450 ng/ml; P = 0.045). To better analyze the variations in sICAM-1, the patients were arbitrarily divided into two groups according to their clinical behavior: 4 presented stabilization (all lesions, n = 2; some lesions, n = 2) (Group A); 5 presented progressive disease (Group B). In Group A, sICAM-1 levels remained stable or showed a modest increase during treatment (except in 1 patient, who exhibited a substantial variation after the 12th infusion). In contrast, in Group B very high levels of sICAM-1 were observed at the beginning of the study therapy in 1 patient and after the 1st infusion in 3 patients; these values remained high until the 24th infusion. In most of the patients, TNF-α and IL-6 increased after the 1st infusion, but not thereafter. IFN-γ was never detected; IL-1β was detectable in a few cases, but only before the infusions. Conclusions baseline levels of sICAM-1 were elevated in all patients and further increased during treatment only in patients with more aggressive disease. No correlation was found between sICAM-1 and inflammatory cytokines. It would therefore seem that in patients with advanced disease, higher levels and a progressive increase in sICAM-1 may be unfavorable prognostic factors.

Abstract P3-13-02: Phase II randomised clinical study of first line chemotherapy plus metformin versus first line chemotherapy alone in HER2 negative, non diabetic, metastatic breast cancer patients: Final results of the MYME study

Background: Epidemiological studies indicated that the presence of insulin resistance is an adverse prognostic factor in MBC. Recently increasing interest has focused on metformin, an oral insulin- sensitizing drug widely prescribed for type 2 diabetes; unexpensive and well tolerated, metformin has also been shown to have direct antiproliferative properties in breast cancer. We present here the final analysis of a phase II comparative multicentric study on the addition of metformin to first line chemotherapy in MBC non diabetic patients. Methods: This is a Phase II randomized study of HER-2 negative MBC patients with measurable or non-measurable disease; no prior chemotherapy for MBC was allowed. Patients were allowed to have had prior endocrine therapy for MBC and prior adjuvant chemotherapy if completed at least 1 year prior to study entry. Patients were stratified by HOMA Index (>2,5 vs Results: As of June 8th, 2014, 108 patients had been randomised. Median age was 60 yrs (range 36-77); 87% of patients were ER+, 60% had received prior adjuvant CT, with antracyclines in 51% of patients. Prior endocrine therapy for MBC was used in 39% of the patients. Measurable disease was present in 74% of the patients. 48% of the patients were insulin resistant by HOMA Index >2.5 and 60% were overweight (BMI > 25: 16% were obese, BMI >30). At a median follow up of 16 months (range 1 – 48), median PFS (ITT) was 9 months (95% CI 8-14) with AC + M and 11 months (95% CI 7-16) with AC alone, p=.84. No significant interaction was detected between HOMA Index and treatment arm (p = 0.15). Median OS was 30 months (95% CI 14-NE) in Arm A versus 27 (95% CI 17-33) in Arm B, p = .58. The most common toxicities observed were G3/4 neutropenia in 51.5% of patients in arm A vs 69.6% in arm B, with Febrile Neutropenia observed in 2,2% and 5.4% of patients, respectively. As expected G2 diarrhea was reported by 11.1% of patients in Arm A. Conclusions: The addition of M to AC in MBC patients receiving first line chemotherapy did not improve PFS compared with AC alone. M seems to have a protective effect on hematological toxicity. Final results including translational data will be available at SABCS 2014. Citation Format: Alessandra Gennari, Oriana Nanni, Andrea DeCensi, Samanta Sarti, Andrea Freschi, Alessandra Bologna, Lorenzo Gianni, Laura Amaducci, Francesco Rosetti, Filippo Giovanardi, Anna Fedeli, Massimo Ambroggi, Paolo Bruzzi, Dino Amadori. Phase II randomised clinical study of first line chemotherapy plus metformin versus first line chemotherapy alone in HER2 negative, non diabetic, metastatic breast cancer patients: Final results of the MYME study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-02.

Combined chemo-immunotherapy for metastatic melanoma. A monoinstitutional experience

7569 Background: The combination of Interferon α-2b (INF) and intravenous Interleukin-2 (IL-2) with chemotherapy (CT) has produced encouraging results in metastatic melanoma, as shown in phase II and III trials, but toxicity remains of concern. We report on our experience with a chemo-immunotherapy regimen with subcutaneous administration of IL-2. PATIENTS AND METHODS 28 patients (pts) with advanced melanoma, median age 47.5 years (range 29-70) and male/female ratio 19/9, received CT plus immunotherapy with subcutaneous IL-2 and INF. Doses were as follows: Cisplatinum 20 mg/m2 iv days 1-4, Vinblastine 1.6 mg/m2 iv days 1-4, Dacarbazine 800 mg/m2 iv day 1, Interferon α-2b 5M IU/m2 sc days 1-5, IL-2 9M IU sc days 1-5 and 8-12. Treatment was repeated every three weeks up to a maximum of six cycles. Response was assessed every two cycles and toxicity every cycle, according to WHO and NCI criteria respectively. RESULTS The overall response rate was 33% with 3 (11%) complete responses, lasting for 17, 14 and 24+ months respectively. There were 6 (22%) partial responses and 3 stable disease. 3 responders progressed in the central nervous system (CNS). For the whole population, median time to progression and survival were 3.5 and 9 months respectively. The most common G3-4 toxicity was neutropenia, reported in 25/28 (92%) pts. Only 2 pts (7%) experienced neutropenic fever. Less frequent was G3-4 thrombocytopenia, observed in 6/28 (21%) pts, with only 1 pt needing platelet support. G1-2 nausea and vomiting as well as fever following cytokine injections were reported in all pts. 1 toxic death occurred, due to neutropenic fever. CONCLUSIONS This schedule with sc IL-2 had an acceptable level of toxicity and although the response rate was lower, TTP and OS were comparable to those reported with more intensive regimens. Several pts progressed in the CNS, suggesting that new combinations able to prevent this event are needed. No significant financial relationships to disclose.

Occult small cell lung cancer associated with paraneoplastic neurologic syndrome: Case report

Cancer is often associated with paraneoplastic syndromes, which may be misinterpreted. We report a case of a patient with occult small cell lung cancer that was initially compounded by clinical features of a paraneoplastic neurologic syndrome. The presence of antineuronal antibodies and positron emission tomography scan guided the search for the underlying tumor. Following chemo-radiotherapy the patient showed no evidence of disease for the next 18 months, whereas only a slight improvement in the neurologic disorders was observed. The course of the small cell lung cancer was very indolent and the paraneoplastic neurologic syndrome did not worsen with the use of cisplatin.