Albrecht Kretzschmar

Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – A randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

BACKGROUND The value of second-line therapy for metastatic gastric cancer is unclear. So far there are no randomised phase III data comparing second-line chemotherapy to best supportive care (BSC). In this prospective, multicenter, open label, randomised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy. METHODS Eligible patients (pts) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma, objective tumour progression during or within 6months after first-line chemotherapy and ECOG performance status 0-2. Stratification for time of progression after first-line therapy, ECOG PS and pretreatment secured even distribution of important prognostic factors. TREATMENT Arm A: Irinotecan 250mg/m(2)q3w (first cycle) to be increased to 350mg/m(2), depending on toxicity. Arm B: BSC. FINDINGS Between 10/2002 and 12/2006 40 pts were randomised. The study was closed prematurely due to poor accrual. Responsefor arm A (19 pts evaluable): No objective responses, SD 53%, PD 47%. Improvement of tumour related symptoms: Arm A 50% of pts, arm B 7%. Overall Survival: (all events in 40 pts have occurred): The hazard ratio for death was reduced to 0.48 (95%CI 0.25-0.92) in the irinotecan-arm (p=0.012). Median survival arm A: 4.0months (95% CI 3.6-7.5), arm B: 2.4months (95% CI 1.7-4.9). INTERPRETATION Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts. Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer. FUNDING The study was supported by a research grant from Aventis and Pfizer.

Docetaxel and Continuous-Infusion Fluorouracil Versus Epirubicin, Cisplatin, and Fluorouracil for Advanced Gastric Adenocarcinoma: A Randomized Phase II Study

PURPOSE A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias. PATIENTS AND METHODS Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks). RESULTS Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively. CONCLUSION DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.

Chemotherapy in alveolar soft part sarcomas. What do we know

Alveolar soft part sarcoma (ASPS) is a rare tumour. Published series about treatment and outcome are scarce. Conclusive data about the response to chemotherapy are not available. The aim of this study was to analyse the efficacy of palliative chemotherapeutic treatment options and the incidence and mode of presentation of brain metastases. We retrospectively analysed our own sarcoma data-base and reviewed the literature. From our registry containing 757 patients, we identified 8 patients with ASPS. From the literature, 47 cases of adult patients and 13 children with sufficient data about chemotherapy were identified. Response to first-line chemotherapy in 68 patients was: complete remission (CR) 4%, partial remission (PR) 3%, stable disease (SD) 41%, progressive disease (PD) 51%. 285 patients with stage IV disease were evaluable for the analysis of metastatic sites. The incidence of brain metastases was 30.5% (87/285). Brain metastases were detected at a median interval of 48 months (range 0-396 months) after the primary diagnosis. Median survival after the diagnosis of brain metastases was 12 months. The median survival for patients with stage IV disease treated by chemotherapy was 36+ months (range 10-132 months) (31 patients evaluable) with a median follow-up of 46 months (range 10-135 months). ASPS shows a high incidence of brain metastases, at least 3 times higher than that of other soft tissue sarcomas. Chemotherapeutic regimens used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. Staging investigations for ASPS should routinely include imaging of the brain. ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. New targets for specific biologically-directed therapies need to be developed.

Oral trofosfamide: an active and well-tolerated maintenance therapy for adult patients with advanced bone and soft tissue sarcomas. Results of a retrospective analysis.

Objectives: Aim of this study was to evaluate the feasibility and toxicity of oral trofosfamide given as maintenance therapy to adult patients with bone and soft tissue sarcomas following first or later line induction chemotherapy, and to determine the clinical efficacy in terms of impact on progression-free and overall survival. Patients and Methods: 49 patients with locally advanced or metastatic high-grade soft tissue and bone sarcomas were identified retrospectively according to the inclusion criteria of the analysis. They were treated with oral trofosfamide at a dose of 100–150 mg per day continuously. All patients were pretreated with one or more lines of chemotherapy resulting in partial remission or stable disease. Patients were treated until progression of disease or unacceptable toxicity occurred. Progression- free and overall survival were measured from the beginning of maintenance therapy. Results: Median follow-up for all patients was 33 months (range 10–98). Toxicity was mild and predominantly hematologic. Only 1 patient had to stop treatment due to renal toxicity. The median progression-free survival was 7 months with 27% of patients continuing maintenance treatment at 1 year. Median overall survival is 14 months. Patients with metastatic disease showed a median survival of 23 months from diagnosis of metastases. 3 patients with stable disease following induction chemotherapy reached partial remission while under trofosfamide maintenance. Conclusion: Oral maintenance therapy with trofosfamide is well-tolerated and seems to prolong progression-free and overall survival compared to the course of advanced soft tissue and bone sarcomas without maintenance chemotherapy.

Weekly 24-Hour Infusion of High-Dose 5-Fluorouracil plus Folinic Acid in Combination with Mitomycin C for the Treatment of Advanced Gastric Cancer

Purpose: This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer. Patients and Methods: Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m2 i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m2) and a 24-hour infusion of 5-FU (2,600 mg/m2) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment. Results: Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1–4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea ≥grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22–53%). Median time to progression was 5 months and median overall survival time was 7 months. Conclusion: This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.

Docetaxel in the treatment of gastric cancer.

Docetaxel is part of the standard chemotherapy in breast, non-small cell lung cancer and androgen-independent metastatic prostate cancer and has recently been approved for advanced gastric cancer. It demonstrated promising single-agent efficacy in gastric cancer and was therefore investigated in different combination regimens. The combination of docetaxel with 5-fluorouracil (5-FU), capecitabine, irinotecan or cisplatin demonstrated high efficacy. The triple combination of docetaxel/cisplatin and 5-FU (DCF) was investigated in randomized Phase II trials and a randomized Phase III study (TAX325). In TAX325, DCF demonstrated superiority in terms of time to tumor progression, response rate and survival against a cisplatin/5-FU combination. Docetaxel was therefore approved for advanced gastric cancer by the US FDA and the European Agency for the Evaluation of Medicinal Products and will evolve as an integral part of routine combination regimens against gastric cancer. This review will discuss and interpret the different Phase II and III trials of docetaxel in gastric cancer.

Phase II Trial of Capecitabine and Oxaliplatin in Patients with Adeno-and Undifferentiated Carcinoma of Unknown Primary

Background: Carcinomas of unknown primary (CUP) account for approximately 2–5% of all cancer diagnoses. Except for some subsets with favorable prognosis, for most of these patients treatment options are limited, and no standard first-line regimen has been identified. We performed a phase II study with oxaliplatin (OX) and capecitabine (CAP) as first-line treatment for patients with histo-or cytologically proven adeno- or undifferentiated CUP. Patients and Methods: Protocol treatment in this multicenter trial consisted of CAP 1,000 mg/m2 twice daily orally (days 1–14) and OX 130 mg/m2 intravenously (day 1), repeated every 21 days at a maximum of 6 cycles. The primary endpoint was the response rate (RR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: 51 patients with CUP (71% with poorly differentiated adenocarcinoma; 41% ECOG performance status (PS) 0, 39% PS 1, 10% PS 2, 55% with elevated lactate dehydrogenase (LDH), and 39% with liver metastases) were enrolled in this study. We observed an objective RR of 11.7% and a median PFS of 2.5 months as well as an OS of 7.5 months with a good toxicity profile. Conclusion: CAP/OX did not reach higher RR compared to a standard regimen with paclitaxel/carboplatin, which discourages further investigation of this schedule in CUP.

Hepatic artery infusion (HAI) of oxaliplatin (Ox) as third and fourth-line therapy for patients with hepatic metastases (M) from colorectal cancer (CRC) pretreated with systemic Ox

3695 Background: The liver is the predominant site of M from CRC. HAI of cytotoxic agents has a long tradition but due to technical complications and lack of a survival benefit compared to systemic treatment it did not become widely accepted as 1st-line treatment of patients (pts) with M from CRC confined to the liver. HAI might serve as a salvage option for pts in whom all available systemic therapies failed and in whom liver M are still dominant. METHODS We retrospectively analysed the outcome of all pts who were treated with HAI of Ox after systemic pretreatment with Ox in our institution. RESULTS All 10 pts (age 35-68) had received fluoropyrimidines, irinotecan and Ox in two (5 pts) or three previous palliative lines and were pretreated with liver resection (1) and local thermoablation (3). In 8 cases disease progressed while systemic Ox was given. 2 pts had small lung M beside advanced liver M; CEA median 67 (3 - 2511). HAI was introduced in median 14 months (8 - 31) from start of first line palliative therapy. Ox 100 mg/m2 (9 pts) and 130 (1) was infused over 2 h via interventionally placed inguinal port (2) or via repeated single-use catheters (8) (tip in the proper hepatic artery) and accompanied by i.v. 5-FU (FA-modulation/bolus/infusion; mg/m2 :400-400-2400/48 h)in 8 pts or oral capecitabine (2.5 g/m2 d1-14)in 2. In median 6 cycles (2-9), q 2-3 weeks, were applied in an outpatient setting. Toxicity was mild beside one port-infection, one case of prolonged but uncomplicated neutropenia IV° and repeated severe but reversible abdominal pain during HAI in 2 cases. No neurosensory toxicity was seen. Beside 3 PR we observed one MR accompanied by CEA and CA 19-9 drop of 94 % and 98 % resp. 4 pts had SD while in 2 pts disease in the liver progressed. Extrahepatic progression occured in 5 pts while they received HAI. Median TTP, TTP in the liver and survival from start of HAI were 4 (1-8), 6 (1-8) and 13 (2 - 15+) months. CONCLUSIONS HAI of Ox via interventionally placed catheters in combination with systemic fluoropyrimidines is a feasible and effective outpatient option for heavily pretreated pts with hepatic M from CRC. [Table: see text].

Recurrent Gastric Adenocarcinoma with Unusual Metastatic Localization and Excellent Responseto Docetaxel and 5-FU Continuous Infusion

Background: Metastatic gastric cancer is usually treated with cisplatin- and 5-FU-based chemotherapy regimens. There are good data for the combination regimen ECF (epirubicin, cisplatin and 5-FU), which is therefore often regarded as a reference treatment. Docetaxel shows promising activity against gastric cancer as single agent and in combinations. To develop a well-tolerable combination chemotherapy for an ambulant setting we initiated a randomized phase II study, comparing docetaxel and 5-FU continuous infusion (DF) with ECF. Case Report: A 66-year-old patient with the history of a curatively resected gastric cancer 2 years previously presented with abdominal masses and lesions in his spleen. Histology proved metastases of gastric adenocarcinoma. The patient was treated with docetaxel (75 mg/m2, d1) and 5-FU continuous infusion (200 mg/m2/d, d1–21, q3w) within our study. Already after 2 cycles of chemotherapy he showed symptomatic improvement and partial remission of his tumor, which was confirmed after the 3rd cycle. In our ongoing study so far 50 patients are evaluable for response. Objective tumor response (CR + PR) could be documented in 44% of patients in the DF arm as well as in the ECF arm. Conclusion: Docetaxel and 5-FU continuous infusion is an active regimen which could possibly be used as an alternative to established treatment protocols.

Long-Lasting Remission of Pulmonary Metastases of Renal Cell Cancer under IFN-b Therapy in a Patient with Multiple Sclerosis

Background: Immunomodulary therapy based on interferon (IFN)-a has been shown to be effective in a subset of patients with advanced renal cell carcinoma (RCC). IFN-ß has occasionally been reported to induce remissions in RCC, but is well established in the treatment of multiple sclerosis (MS). There is an ongoing debate whether hyperactivation of the immune system may convey protection against the development of cancer in MS patients. Patients and Methods: A 54-year-old female MS patient underwent tumor nephrectomy for RCC in 1994. 1 year later, several bilateral pulmonary metastases were documented by computed tomography and were histologically confirmed thereafter. Therapy with IFN-ß was started. Results: Soon after initiation of IFN-ß treatment, the patient achieved an almost complete remission which is still ongoing after 10 years of IFN-ß therapy. Conclusion: To our knowledge, this is the longest remission under IFN-ß treatment ever reported in an RCC patient. We conclude that IFN-ß should be particularly considered as a therapeutic option in the rare occasion of metastatic RCC in patients with MS.