Neo-adjuvant chemo/immunotherapy in the treatment of stage III (N2) non-small cell lung cancer: a phase I/II pilot study.

In a previous randomized study, we showed that adjuvant immunotherapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 (rIL-2) significantly improved survival in resected N2-non small cell lung cancer (NSCLC) patients. The present study assesses feasibility, safety and potential efficacy of combined neo-adjuvant chemotherapy and immunotherapy with peripheral blood mononuclear cells (PBMC) and rIL-2 in resectable N2-NSCLC patients. Eighty-two consecutive N2-NSCLC patients underwent neo-adjuvant chemotherapy with cisplatin and gemcitabine. Out of the 82 patients, 23 were also subjected to leukapheresis prior to neo-adjuvant chemotherapy while the remaining 59 did not. Collected PBMC were analyzed for viability and phenotype and then stored frozen in liquid nitrogen. Thawed PBMC were infused intravenously, 5 days before surgery. After the infusion, rIL-2 was administered subcutaneously until surgery. Only patients with a partial or complete response to neoadjuvant chemotherapy underwent surgery: 13 patients in the experimental immunotherapy group (A) and 32 in the reference group (B). The two groups were homogeneous for all major prognostic factors. Median leukapheresis yield was 10 billion PBMC, (range 3-24 billions). Two to six billion PBMC were infused. The phenotypic analysis showed that similar proportions of CD4 and CD8 cells were present in leukapheresis products, and thawed PBMC, as well as in T lymphocytes isolated from the removed tumours. No severe adverse effects were observed following immunotherapy. No significant differences in overall survival (OS) and event-free survival (EFS) were seen between the two groups. However, the 5-year OS in group A was almost twice as much compared to group B (59 percent vs 32 percent). After adjustment for major prognostic factors, a statistically significant 66 percent reduction in the hazard of death was seen in patients receiving immunotherapy. The OS benefit was more evident in patients with adenocarcinoma than in those with squamous cell carcinoma. This study supports the favorable toxicity profile and potential efficacy of combining neo-adjuvant chemotherapy and immunotherapy with PBMC and rIL-2 in the treatment of N2-NSCLC patients.

Primary peripheral adenoid cystic carcinoma of the lung. A case report.

We report a rare case of peripheral adenoid cystic carcinoma of the lung, showing unusual pathological and clinical features, namely rapid growth, local aggressive behaviour, huge tumour size, no endobronchial component or submucosal infiltration, and a rapidly progressive clinical course. Extensive surgery resulted in considerable palliation of symptoms, but not in prolonged survival. The reported case emphasizes the malignant potential of peripheral adenoid cystic carcinoma of the lung.

Phase II study of combined immunotherapy, chemotherapy, and radiotherapy in the postoperative treatment of advanced non-small-cell lung cancer.

The association of adoptive immunotherapy (AI) and radiotherapy has been shown to be effective in the control of residual intrathoracic disease, while having no systemic advantages, in patients operated on for locally advanced non-small-cell lung cancer (NSCLC). The potential synergy of coupling immunotherapy and chemotherapy has been emphasized in several tumors including NSCLC. The aim of this work was to determine the feasibility and activity of a combined therapeutic program, including AI, chemotherapy, and radiotherapy in patients who had undergone incomplete resections for NSCLC. In a phase II trial, 13 patients received the combined treatment. AI was given from week 4 after surgery until week 8. Concurrent chemo-(cisplatin and etoposide)-radiotherapy (60 Gy) was given from week 9 to week 14. Twenty eligible patients received chemoradiotherapy only and were used as a non-randomized concomitant group for merely descriptive purposes. At 9-month follow-up, 10 of the 13 patients had progression of disease and the study was stopped. Progression-free survival and survival were similar to those of the chemoradiotherapy group. The present study showed that the sequence of immunotherapy followed by chemotherapy is not effective as adjuvant treatment in patients operated on for stage III NSCLC, at least when used according to the adopted schedule.

Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study.

INTRODUCTION: Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS: This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS: The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION: This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations.

Adoptive immunotherapy of advanced solid tumors: an eight year clinical experience.

BACKGROUND: Adoptive immunotherapy (AI) of cancer, based upon the injection of in vitro manipulated autologous lymphocytes is still in an experimental phase. Our group started different clinical trials of AI in early 1990, and, at present, some specific targets for this approach seem to have been identified. PATIENTS AND METHODS: 296 patients with solid tumors (melanoma, kidney carcinoma, non-small-cell lung cancer, mesothelioma, neoplastic pleural effusion, and liver cancer) were treated with either locoregional or systemic adoptive immunotherapy (AI) using both LAK and TIL cells in combination with s.c. rIL-2. RESULTS: The surgery/AI combination resulted in good clinical results, characterized by enhanced survival and long lasting disease free periods in a significant number of patients. CONCLUSIONS: AI seems to be efficacious in the treatment of melanoma, lung and hepatic cancers. Further studies will expand the application of the treatment to other malignancies.