Hanauske AR, Dumez H, Piccart M, Yilmaz E, Graefe T, Gil T, Simms L, Musib L, Awada A.

St. Georg Hospital, Ahrensburger Weg 129b, 22359, Hamburg, Germany, hanauskeax@lilly.com.

Abstract

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed–paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m2 on d1; (S2) 400 mg/m2 d1 and 40 mg/m2 d1 and d8; S3) 400 mg/m2 d8 and 30 mg/m2 d1 and d8. MTD was 500/135 mg/m2 (S1), 400/40 mg/m2 (S2), and 500/120 mg/m2 (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m2 (d8) and paclitaxel 90 mg/m2 (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.

Keywords: Pemetrexed – Paclitaxel – Phase I – Combination chemotherapy – Vitamin supplementation

Felip E, Rosell R.

Vall d’Hebron University Hospital Barcelona, Spain.

Abstract

NSCLC accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced, unresectable disease, which remains incurable. In advanced disease, chemotherapy with platinum (cisplatin or carboplatin) in combination with a third-generation cytotoxic drug (vinorelbine, gemcitabine, paclitaxel, or docetaxel) can provide a modest improvement in survival without impairing quality of life. In chemotherapy-naïve, advanced, non-squamous NSCLC patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. Response rates of 20%-40% can now be expected, with a median survival of 8-11 months and a 1-year survival rate of 30%-40%. In second-line treatment, docetaxel has shown superiority to best supportive care in terms of survival and quality of life. A pooled analysis comparing docetaxel administered weekly versus 3-weekly found similar survival rates between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in several tumors, including mesothelioma and NSCLC. In a phase III trial, second-line treatment with pemetrexed demonstrated overall survival comparable to docetaxel, with a more manageable toxicity profile.

Keywords: pemetrexed, second-line therapy, NSCLC

Barone-Adesi F, Ferrante D, Bertolotti M, Todesco A, Mirabelli D, Terracini B, Magnani C.

Unit of Cancer Epidemiology, CeRMS and Center for Oncologic Prevention Piemonte, University of Turin, Turin, Italy.

Abstract

Models based on the multistage theory of carcinogenesis predict that the rate of mesothelioma increases monotonically as a function of time since first exposure (TSFE) to asbestos. Predictions of long-term mortality (TSFE >/= 40 years) are, however, still untested, because of the limited follow-up of most epidemiological studies. Some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3,443 asbestos-cement workers, followed for more than 50 years. The functional relation between mesothelioma rate and TSFE was evaluated with various regression models. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers’ lungs.

Keywords: asbestos, mesothelioma, multi-stage model, latency, clearance

Somer RA, Sherman E, Langer CJ.

Department of Medical Oncology, Cooper Medical Center, Cherry Hill, NJ, USA.

Abstract

Background: In a previous randomized phase II trial evaluating carboplatin and paclitaxel with or without bevacizumab in patients naive to chemotherapy with advanced non-small-cell lung cancer (NSCLC), median survival ranged from 53 weeks to 76 weeks. Sudden life-threatening hemoptysis occurred in 6 of 66 patients receiving chemotherapy and bevacizumab; 4 episodes were fatal, all in patients with squamous cell histology. Squamous histology and bevacizumab therapy were the only factors associated with life-threatening hemorrhage. ECOG 4599 (Eastern Cooperative Oncology Group 4599), a randomized phase III trial of paclitaxel and carboplatin with or without bevacizumab ultimately excluded patients with squamous histology as well as brain metastases, ongoing therapeutic anticoagulation/nonsteroidal anti-inflammatory drugs, antecedent hemoptysis, and performance status (PS) of 2.

Patients and Methods: We performed a retrospective analysis during a defined period to determine the proportion of patients with newly evaluated advanced NSCLC seen at Fox Chase Cancer Center (FCCC) who would have been eligible for ECOG 4599. We reviewed new thoracic oncology patient visits (n = 260) at FCCC scheduled with 6 medical oncologists from March 1, 2002, through August 8, 2002.

Results: Forty-five patients had histology that made them ineligible (8 mesothelioma, 6 small-cell, 5 mixed histology, and 26 non-lung cancers). Of the remaining 215 patients with NSCLC, 8 had incomplete charts for review and 7 had stage I, 8 stage II, and 43 stage III NSCLC. Of the remaining 149 patients, 33 had received chemotherapy previously. Of the remaining 116, only 34 (29.3%) were eligible. Of 82 ineligible patients, 21 (25.6%) had PS > or = 2, 20 (24.3%) had central nervous system (CNS) metastases, 11 (13.4%) had squamous histology, 9 (10.9%) had therapeutic anticoagulation, and 21 (25.6%) had > or = 2 criteria (11 PS > or = 2/squamous histology; 3 PS > or = 2/CNS involvement; 2 PS > or = 2/anticoagulation, 2 CNS metastasis/anticoagulation, 2 PS > or = 2/squamous histology/anticoagulation, 1 PS > or = 2/squamous histology/CNS metastasis). Of 34 eligible patients, only 6 (17.6%) enrolled in the trial.

Conclusion: Based on the data reviewed, > 70% of patients who might otherwise have been eligible for standard advanced NSCLC trials were not candidates for ECOG 4599. Outcome with respect to this study must be interpreted in the context of eligibility restrictions.

Takeuchi K, Fujimoto M, Tsujino T, Takeda Y, Yoshida S.

Department of Obstetrics and Gynecology, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Japan.

Abstract

Background: The results of treatment of malignant peritoneal mesothelioma are quite unsatisfactory, especially in the later stages of the disease, regardless of the treatment modality employed.

Case: We report a case of locally advanced malignant peritoneal mesothelioma, in which the combination of radiotherapy and intraperitoneal paclitaxel was beneficial for long-term disease stabilization. A 71-year-old woman presented with abdominal pain. Abdominal ultrasound and magnetic resonance imaging confirmed the presence of a mass with both cystic and solid components with moderate ascites. Serum CA-125 concentration was 727 IU/ml. At exploratory laparotomy, a large mass originating from the pouch of Douglas was found. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed with partial excision of the mass and involved the peritoneum of the pouch of Douglas. The histologic study showed malignant peritoneal mesothelioma. One year and five months after surgery, significant progression of the residual tumor with increasing ascites was noted. Radiotherapy to the whole pelvis with 45 Gy in 25 fractions was given over five weeks together with intraperitoneal paclitaxel (60 mg/m2) instillation, which was repeated every three weeks. The patient received eight cycles of paclitaxel instillation over seven months. The compliance of the patient was excellent under therapy and her general condition improved significantly one and half year with a marked regression of the tumor masses after this treatment.

Conclusion: The combination of radiotherapy and intraperitoneal paclitaxel seems suitable in palliative settings primarily aimed at improving the quality of life.