Cisplatin-based Combination Chemotherapy Research Articles

Multicenter phase II study of every-2 week gemcitabine and paclitaxel as first-line chemotherapy in patients with advanced urothelial tract cancer

4583 Background: Patients (pts) with transitional cell carcinoma (TCC) of the urothelium are not always amenable to cisplatin based chemotherapy. We have previously reported a 60% RR in patients who have failed cisplatin based combination chemotherapy (M-VAC) using a convenient every 2-week outpatient regimen of Gemcitabine (G) and Paclitaxel (P) (Cancer 2001 Dec 15;92(12):2993–8). A multicenter trial was initiated in 5 Italian centers to evaluate this regimen as first line chemotherapy. Methods: 48 patients with histologically proven measurable disease (RECIST criteria), WHO PS 0–2, metastatic or inoperable TCC, with no prior systemic cytotoxic or biologic treatment, CrCl ≥ 40 ml/min, bilirubin < 20 μmol/l and signed informed consent were treated with G 2,500 mg/m2 in 30 min and P 150 mg/ m2 in 3 hrs Q 2 weeks. G-CSF was given for 5–7 days for ≥ G3 neutropenia toxicity. 6–12 courses were planned. The median age was 67 (52–77 years), WHO PS 1 (0–2). Metastases occurred in lung in 14 (29%), lymph nodes in 22 (46%), in bladder in 14 (29%), in bone in 8 (17%), and in liver in 6 (13%) of pts. 52% of pts had more than 1 site of disease and 10% had at least 3 sites of disease. Results: 266 cycles were administered. 33/48 pts are currently evaluable, as many pts are still receiving therapy. RR thus far is 42%, with 3 CR (9%) and 11 PR (33%). Hematologic toxicity was predominant but manageable. G-CSF was used in only 6% of cycles. Conclusions: In a multicenter study, G and P was a well-tolerated outpatient regimen. This regimen shows promise and may be considered in pts unable to receive cisplatin. It should be compared to a cisplatin-containing combination regimen in the future. Supported in part by Eli Lilly. No significant financial relationships to disclose.

The impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients (pts) with transitional cell carcinoma (TCC) of the bladder

4586 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in pts with (muscle-invasive) TCC of the bladder. While the data supporting adjuvant chemotherapy are somewhat less compelling, most consider post-operative chemotherapy an acceptable alternative. Many pts who may benefit from such therapy are not candidates for cisplatin due to impaired renal function. We sought to identify the proportion of pts ineligible for adjuvant chemotherapy based on renal impairment alone. Methods: We retrospectively reviewed all pts who underwent radical cystectomy for TCC at our institution between 1990 and 2004. Pts were excluded if they received neoadjuvant chemotherapy. Pts meeting our definition of ‘eligible’ for adjuvant therapy had ≥ pT3 and/or node positive disease. The nadir creatinine value obtained from weeks 6–12 post-cystectomy was used to calculate creatinine clearance (CrCl) using the Jellife formula. A CrCl of < 60 mL/min was considered inadequate for cisplatin-based chemotherapy. Results: 512 pts met the inclusion criteria for our analysis. Baseline characteristics included median age = 69.1 years (31.1–94.6), median serum creatinine = 0.9 mg/dL (0.2–2.8), and median CrCl = 65.8 mL/min (18–280). Sixty-one percent (312/512) had ≥ pT3N0/Nx disease and 39% had pTanyN+ disease. Based on a CrCl of < 60, 39.8% (204/512) of pts would be ineligible for adjuvant chemotherapy. The impact of age on eligibility is presented in the Table. Conclusions: Using calculated CrCl and a commonly used cut-off of 60 mL/min for cisplatin-based chemotherapy, up to 40% of patients with TCC who may benefit from adjuvant chemotherapy may be excluded on the basis of renal function alone. Clinical trials addressing this patient population are needed. No significant financial relationships to disclose.

JGOG2033: Randomized phase III trial of whole pelvic radiotherapy vs cisplatin-based chemotherapy in patients with intermediate risk endometrial carcinoma

5002 Background: Optimal adjuvant therapy for intermediate risk endometrial cancer patients is poorly defined. Methods: A Japan Gynecologic Oncology Group (JGOG) conducted a multi-center randomized Phase III trial of whole pelvic irradiation (WPI) vs. cyclophosphamide-doxorubicin-CDDP (CAP) chemotherapy in women with endometrial carcinoma with deeper than 50% myometrial invasion postoperatively. 425 pts were entered from 1/1994 to 12/2000. Of the 385 evaluable endometrioid adenocarcinoma, 193 were to receive WPI and 192, CAP. WPI arm employed at least 40 Gray (Gy) in 20 fractions. CAP arm consisted of cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) every 4 weeks for 3 or more courses. Results: Pt Characteristics: The treatment arms were well balanced in terms of patient and tumor characteristic, with G1 55%, G2 30%, and G3 15%. Median follow-up was 1825 days (range 65–1825). Response and Survival: There were no statistically significant differences in progression-free survival (PFS) and overall survival (OS) between the 2 regimens for all pts. The PFS of WPI and CAP arms was 84.0% and 82.1%, and the OS of WPI and CAP arms was 85.9% and 87.1%, respectively. Especially, among 229 pts with intermediate risk as stage pTIc, the PFS of WPI and CAP arms was 89.6% and 87.2%, and the OS of WPI and CAP arms was 88.9 and 88.9, respectively. Recurrence in each WPI and CAP arm was 15.1%, 16.5%, respectively, with 30% pelvic and 70% extrapelvic recurrent sites. Toxicity: Adverse effects were not significantly increased in the CAP arm, compared to WPI arm. Conclusions: Adjuvant cisplatin-based combined chemotherapy might have potential as an alternative to radiotherapy for intermediate risk endometrial cancer, such as only deeper than 50% myometrial invasion. No significant financial relationships to disclose.

Antiemetische Prophylaxe bei der Chemotherapie gastrointestinaler Tumoren

Systemic treatment options in gastrointestinal malignancies have increased markedly. At the same time, the need for supportive measures has become more complex. Nausea and vomiting continue to impair the patients' quality of life and to jeopardise the goals of chemotherapy. Antiemetic strategies as proposed by treatment guidelines should be employed consistently in daily clinical practice. Deficits in cancer care exist in this area. In addition, newly available antiemetic drugs should be considered. Aprepitant is the first approved representative of a new drug class. Aprepitant inhibits substance P binding to the neurokinin-1-receptor. Given orally on the first three days of a cisplatin-based chemotherapy in combination with a standard antiemetic regimen, aprepitant proved to be significantly more effective in the prevention of nausea and vomiting compared to the standard regimen without aprepitant. Recently presented results for chemotherapy with moderate emetogenic risks indicate that aprepitant shows superior effectiveness even in this setting. Palonosetron is a new drug in the class of 5-HT (3) (serotonin) receptor antagonists. Compared to older setrones, palonosetron exhibits a higher receptor binding activity, a longer half life, and a slightly improved activity in the prevention of nausea and vomiting after chemotherapy with moderate emetogenic risks. The implementation of standardised treatment guidelines into clinical practice will contribute to a higher patient satisfaction and a more effective utilisation of economic resources.

A Phase II Study of Carboplatin and Paclitaxel in Adenocarcinoma of Unknown Primary

Cisplatin-based combination chemotherapy is commonly used in the treatment of carcinoma of unknown primary site. Paclitaxel has shown promising activity as a single agent in a number of malignancies. This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with adenocarcinoma of unknown primary site (ACUP). Twenty-two patients with ACUP were enrolled in the study. Patients were treated with 200 mg/m2 paclitaxel intravenously (IV) over 3 hours followed by carboplatin IV with a targeted plasma area under the curve (AUC) of 5 mg/h/mL. A total of 73 treatment courses were administered with a median of 5 courses per patient. Five of the 22 registered patients had a major response for an objective response rate of 23% (90% confidence interval [CI], 0.11-0.40) by intention-to-treat analysis. The median response duration was 4.1 months (90% CI, 3.6-7.1). The median survival time was 6.5 months (90% CI, 5.5-10.1) and the 1-year survival rate was 27% (90% CI, 0.11-0.42). The major toxicity observed was neutropenia, with grade 3-4 neutropenia occurring in 3 patients (14%). There were no treatment-related deaths. The combination of carboplatin and paclitaxel is a tolerable and moderately active regimen in ACUP.

Metastatic seminoma treated with either single agent carboplatin or cisplatin-based combination chemotherapy: a pooled analysis of two randomised trials: Bokemeyer C, Kollmannsberger C, Stenning S, Hartmann JT, Horwich A, Clemm C, Gerl A, Meisner C, Rückerl CP, Schmoll HJ, Kanz L, Oliver T, Department of Hematology/Oncology, University of Tuebingen, Tuebingen, Germany.

To study the role of single agent carboplatin chemotherapy in patients with metastatic seminoma based on the data from two randomised trials. In subgroup analyses in patients with different disease characteristics, the outcome treated with either single agent carboplatin or cisplatin-based combination chemotherapy was compared. Individual patient data from two randomised European trials involving patients with metastatic seminoma were gathered. The primary endpoint for all analyses was progression-free survival. The source data of 361 patients, 184 treated with cisplatin-based combinations and 177 treated with carboplatin single agent therapy, were entered into the analysis. Patient characteristics were comparable among the cisplatin-based and the carboplatin single agent treated patient groups with lymph nodes and lungs being the most frequent metastatic sites in 92 and 8% of patients, respectively. Overall, patients treated with single agent carboplatin had an inferior 5-year overall (89 and 94%; P = 0.09) and progression-free survival rate (72 and 92%; P < 0.0001) compared with patients receiving cisplatin-based combinations. For all investigated subgroups (based on age, prior radiation therapy, metastatic sites), carboplatin single agent therapy was found to be inferior to cisplatin-based combination chemotherapy. In conclusion, carboplatin single agent therapy cannot be recommended as standard treatment for any patient subgroup with advanced metastatic seminoma and cisplatin-based combination regimens remain the standard of care.

551Down staging analysis following neoadjuvant cisplatinum based combination chemotherapy for invasive bladder carcinoma. Evaluation of two combined prospective nordic trials

551Down staging analysis following neoadjuvant cisplatinum based combination chemotherapy for invasive bladder carcinoma. Evaluation of two combined prospective nordic trials

A randomized phase II study of vinorelbine plus gemcitabine with/without cisplatin against inoperable non-small-cell lung cancer previously untreated

Phase II studies have suggested that vinorelbine (V) plus gemcitabine (G) treatment has a similar response rate and better toxicity profile than cisplatin-based combination chemotherapy in non-small-cell lung cancer (NSCLC). Our aim was to evaluate whether or not the addition of cisplatin (P) to a VG regimen increases the efficacy or toxicities in chemo-naive inoperable NSCLC patients. From April 2002 to October 2003, 86 patients were enrolled. The treatment dose was V 20 mg/m2 plus G 800 mg/m2 intravenous infusion (i.v.) on days 1, 8 and 15, with/without P 60 mg/m2 i.v. on day 15, every 4 weeks. The efficacy and toxicity of the treatment were recorded. In all, 125 cycles of VG and 178 cycles of VGP were given to the patients in the VG and VGP arms, respectively (P = 0.001). The median cycle of treatment was three in the VG arm and five in the VGP arm. There were 10 partial responses (overall 23.3%) in the VG arm and 1 complete response and 19 partial responses (overall 46.5%) in the VGP arm (P = 0.022). Neutropenia, nausea, vomiting, and peripheral neuropathy were more common in the VGP arm (P = 0.023, 0.002, 0.025, 0.001, respectively). The Lung Cancer Symptom Scale showed no difference between the VG and VGP arms after two cycles of treatment or when the patient went off study. We concluded that the addition of P to VG treatment did increase both the tumor response rate and the toxicities. However, the toxicities were tolerable.

Health-related quality of life in patients with testicular cancer: A comparative analysis according to therapeutic modalities

Investigating health-related quality of life (HRQoL) in testicular cancer patients has become important, because of an increasing number of young survivors with recent advance of multimodal therapy. The objective of this study was to compare the HRQoL in patients with advanced testicular cancer according to the types of treatment they received. Among 130 patients included in this study, 40 underwent surveillance monitoring (group A), 64 received cisplatin-based combination chemotherapy (group B), and 26 underwent infradiaphragmatic radiotherapy (group C). HRQoL in these 3 groups were evaluated using the SF-36 survey containing 36 questions that assess 8 aspects, including physical functioning, role-physical functioning, bodily pain, general health, vitality, social functioning, role-emotional functioning and mental health. Furthermore, HRQoL in group B were analyzed according to the experience with retroperitoneal lymph node dissection (RPLND) or high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT). The follow-up period of the chemotherapy group was significantly shorter than that of the remaining 2 groups; however, scale scores were not affected by the duration of follow-up in these 3 groups. There were no significant differences in any scale scores among the 3 groups. In comparison with the general population in the USA, social functioning in the 3 groups with testicular cancer was significantly lower, whereas vitality in these groups was significantly higher. Furthermore, in group B, there were no significant differences in any scale scores between patients with and without RPLND, while patients undergoing standard-dose chemotherapy alone had a significantly higher score for mental health than those undergoing high-dose chemotherapy following standard-dose chemotherapy despite the absence of a significant difference in the remaining 7 scores irrespective of the experience with high-dose chemotherapy. These findings suggest that 7 of the 8 scale scores of HRQoL examined by the SF-36 survey were satisfactory in patients with testicular cancer regardless of the 3 treatment modalities, and that there were no significant differences in any scale scores among these groups. Moreover, the HRQoL was not affected by experience with RPLND or high-dose chemotherapy except for mental health in patients undergoing high-dose chemotherapy. Therefore, the overall HRQoL in patients with testicular cancer may be generally favorable and not affected by differences in treatment type.

VIP (Etoposide, Ifosfamide, Cisplatin) in Adult Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors

Despite the fact that Ewing sarcoma family of tumors (ET) is chemosensitive, long-term survival is extremely rare for patients with primary refractory or recurrent disease. There is no standard salvage chemotherapy regimen available in this context. In this study the authors reviewed their experience with the combination of etoposide, ifosfamide, and cisplatin in adult patients with recurrent or refractory disease. From February 1997 through December 2001, they evaluated the efficacy of etoposide (75 mg/m2/day for 5 days), ifosfamide (1,200 mg/m2/day for 5 days), and cisplatin (20 mg/m2/day for 5 days) combination chemotherapy (VIP regimen), as second-line salvage therapy in 27 patients with recurrent or refractory ET. All patients were evaluated for response, time to progression, and overall survival. Twenty-one male and 6 female patients with recurrent (n = 14) and refractory (n = 13) disease were treated with the VIP regimen. Median age was 18 years (range, 16-34 years). Twenty-two patients were previously treated with vincristine, Adriamycin, ifosfamide, and actinomycin-D; and 5 patients were treated with cyclophosphamide, Adriamycin, and vincristine. Sites of recurrent or progressive disease included local (n = 3), distant (n = 11), and both local and distant (n = 13). A total of 129 cycles of VIP were given (median, 5 cycles/patient; range, 1-14 cycles/patient). One patient (4%) had a complete response (CR) and 8 patients (30%) had a partial response (PR), for an overall response rate of 34%. The median number of cycles given to patients with CR + PR was 6 (range, 3-14 cycles). Nine patients (33%) had stable disease and 9 (33%) had disease progression. Median time to progression and median overall survival were 6.6 months and 8.1 months respectively for all patients, and 12.8 months and 14.2 months respectively for responders. There were no toxic deaths. Major toxicities included grade IV granulocytopenia in 19 patients and grades III/IV thrombocytopenia in 15 patients. At a median follow-up of 8 months (range, 2-56 months), 24 patients died of disease progression, 2 patients are alive with disease, and 1 patient is alive with no evidence of disease. The authors conclude that the VIP combination is active in patients with recurrent/refractory ET, with acceptable toxicity, and offers good palliation. Cisplatin-based combination chemotherapy merits further investigation, possibly as first-line treatment in this disease.

Prognostic factors and long‐term survivorship in patients with recurrent or metastatic carcinoma of the head and neck

The current study was conducted to identify prognostic factors and report the characteristics of long-term survivors in patients with recurrent or metastatic carcinoma of the head and neck who were treated with cisplatin-based combination chemotherapy in two randomized, Phase III trials conducted by the Eastern Oncology Cooperative Group (ECOG) (E1393 and E1395). The authors analyzed prognostic factors for response and survival by combining data from the E1393 trial, which compared cisplatin plus paclitaxel at two dose levels, with data from the E1395 trial, which compared cisplatin plus paclitaxel with cisplatin plus 5-fluorouracil (5-FU), using logistic regression and Cox regression models. A total of 399 eligible patients were included. The median follow-up was 4.7 years. The 1-year overall survival (OS) rate for all patients was 32%, the median OS was 7.8 months, and the objective response rate was 32%. On multivariate analysis, the following were found to be independent unfavorable predictors of objective response: weight loss of > 5%, an ECOG performance status of 1 (vs. 0), residual disease at the primary tumor site, a primary tumor site other than the oropharynx, prior radiation therapy (RT) (P = 0.056), and well/moderate tumor cell differentiation (P = 0.067). Independent unfavorable prognostic factors for OS were weight loss, an ECOG performance status of 1 (vs. 0), well/moderate tumor cell differentiation, a primary tumor in the oral cavity or hypopharynx, and prior RT. The following were found to be independent unfavorable prognostic factors for time to disease progression: well/moderate tumor cell differentiation, a oral cavity or hypopharyngeal primary tumor, and prior RT. Patients with < or = 2 adverse prognostic factors were reported to have a median OS of 1 year, whereas patients with 3-5 adverse prognostic factors were found to have a median OS of 0.5 years (P < 0.0001). Forty-nine patients (12%) survived for > or = 2 years and 6 patients were alive at 5 years. Two-year survivors were more likely to have achieved an objective response to chemotherapy, have poor tumor cell differentiation, be white, have an ECOG performance status of 0, and have received no prior RT. Clinical parameters and tumor cell differentiation appear to be strong pretreatment predictors of outcome in patients with carcinoma of the head and neck and should be considered in the design of future randomized trials. A small percentage of patients with recurrent head and neck carcinoma can achieve long-term survival.

Advances in the management of non-seminomatous germ cell tumors during the cisplatin era: a single-institution experience.

The objectives of the present study were to review chronological changes in the long-term survival of patients with non-seminomatous germ cell tumor (NSGCT) who were treated at a single institution after the introduction of cisplatin-based combination chemotherapy. One hundred and twenty patients with NSGCT who were treated between January 1978 and October 2001 were enrolled in this study. To evaluate chronological changes in treatment outcome between 1978 and 2001, data were analyzed according to the timing of initial treatment in two consecutive 12-year periods. The numbers of patients who were treated during 1978-1989 and 1990-2001 were 59 and 61, respectively. Patients were classified according to criteria of both the Japanese Urological Association (JUA classification) and the International Germ Cell Cancer Collaborative Group (IGCCCG classification). The mean follow up of surviving patients during the periods 1978-1989 and 1990-2001 was 84 months and 63 months, respectively. The overall 5-year survival rate of patients with NSGCT significantly increased from 72.8% during the period 1978-1989 to 83.6% during the period 1990-2001 (P = 0.02, log-rank test). A significant improvement in survival was found in the patients with stage III disease, according to the JUA classification, and in the patients with poor-risk disease, according to the IGCCCG classification (P = 0.004 and 0.05, respectively). The overall 5-year survival rate of patients with NSGCT increased significantly from 72.8% during 1978-1989 to 83.6% during 1990-2001. This improvement resulted mainly from an increased survival of patients with metastatic poor-risk NSGCT.

Gemcitabine and paclitaxel chemotherapy effective for good risk advanced urothelial malignancies

4675 Background: The prognosis for patients with progressive or recurrent invasive bladder cancer is generally poor. Best responses are seen when patients are treated with a cisplatin based combination chemotherapy. Unfortunately, poor renal function and performance status precludes use of cisplatin in all patients. Identifying those patients who may benefit from a non-platinum combination is important. Poor Performance status and presence of visceral metastases identifies patients who are at a higher risk of relapse and lower survival.Methods: Patients with histological proven metastatic bladder cancer, who have normal organ function and be able to give informed consent, were eligible. Patients received chemotherapy in the outpatient clinic with paclitaxel at110 mg/m2, q weekly day 1 and day 15 and gemcitabine 1000mg/m2 on day 1, and 15 of a 28-day cycle. Patients were evaluated after 2 cycles of therapy with CT scans and bone scans. Response and survival were evaluated in the low risk and intermediate/high risk group.Results: Eleven patients (65%) had an objective response rate. Complete responses were seen in 17% of patients. The median duration of response was 5 months and the toxicity was mild. The median survival was 7.5 months. Grade 3/4 hematological toxicities included fever and neutropenia (9%) and anemia requiring blood transfusions (18%). The most common nonhematologic toxicity was fatigue (36%), anorexia (27%), rash, paraesthesia and myalgias (18%. All patients with low risk disease had a response compared to 27% in intermediate/high risk group (P=0.001) Conclusions:The combination of paclitaxel and gemcitabine given in a q 2 week regimen is very well tolerated and has significant activity in good risk patients with metastatic transitional cell carcinoma of the bladder and disease. Cisplatin based chemotherapy is essential for patients with visceral metastases or impaired performance status. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly

Gemcitabine and ifosfamide (GI) as a second-line systemic chemotherapy for cisplatin-failed advanced urothelial carcinoma (UC)

4739 Background: Cisplatin-based combination chemotherapy is the mainstay treatment for advanced UC. There is no standard salvage regimen for patients who fail cisplatin-based chemotherapy. We evaluated the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced UC. Methods: Between Dec. 1998 and Dec. 2003, 15 patients (M:F = 12:3) with a median age 66 (48 - 76) were enrolled. All did not respond to cisplatin-based chemotherapy or progressed from previously cisplatin-sensitive status in less than 6 months (4 with CMV, 5 with P-HDFL [Proc ASCO 2001 abstr 3128], 6 with TP-HDFL [Proc ASCO 2003 abstr 1637]). GI consisted of gemcitabine 800 mg/m2/d IV 30 min on D 1, 8 & 15; ifosfamide 1500 mg/m2/d IV 24 hr on D 8–10; and mesna 800 mg IV bolus before ifosfamide & 1500 mg/m2/d IV 24 hr on D 8 - 11, repeated every 28 days. Results: A total of 48 courses had been given, with an average of 3.4 courses per patient (range: 1–6). Among 14 patients eligible for response evaluation, there were 1 complete response, 4 partial responses, 4 stable diseases and 2 progressive diseases. One patient is still under the protocol treatment now. The overall response rate was 36% (95% C.I. 10–62%) with 7% complete response. The median survival was 6 months (range: 1 to 26+). Fourteen patients were eligible for analysis of toxicity. Grade III/IV leukopenia, anemia, and thrombocytopenia were noted in 6 (14 cycles), 3 (5 cycles), and 6 (11 cycles) patients, respectively. Grade III/IV nausea, vomiting, mucositis, and diarrhea were noted in 0, 1, 3, and 0 patient, respectively. Conclusions: GI is active against cisplatin-failed advanced UC with an acceptable toxicity profile. No significant financial relationships to disclose.

Gemcitabine and ifosfamide (GI) as a second-line systemic chemotherapy for cisplatin-failed advanced urothelial carcinoma (UC)

4739 Background: Cisplatin-based combination chemotherapy is the mainstay treatment for advanced UC. There is no standard salvage regimen for patients who fail cisplatin-based chemotherapy. We evaluated the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced UC. Methods: Between Dec. 1998 and Dec. 2003, 15 patients (M:F = 12:3) with a median age 66 (48 - 76) were enrolled. All did not respond to cisplatin-based chemotherapy or progressed from previously cisplatin-sensitive status in less than 6 months (4 with CMV, 5 with P-HDFL [Proc ASCO 2001 abstr 3128], 6 with TP-HDFL [Proc ASCO 2003 abstr 1637]). GI consisted of gemcitabine 800 mg/m2/d IV 30 min on D 1, 8 & 15; ifosfamide 1500 mg/m2/d IV 24 hr on D 8–10; and mesna 800 mg IV bolus before ifosfamide & 1500 mg/m2/d IV 24 hr on D 8 - 11, repeated every 28 days. Results: A total of 48 courses had been given, with an average of 3.4 courses per patient (range: 1–6). Among 14 patients eligible for response evaluation, there were 1 complete response, 4 partial responses, 4 stable diseases and 2 progressive diseases. One patient is still under the protocol treatment now. The overall response rate was 36% (95% C.I. 10–62%) with 7% complete response. The median survival was 6 months (range: 1 to 26+). Fourteen patients were eligible for analysis of toxicity. Grade III/IV leukopenia, anemia, and thrombocytopenia were noted in 6 (14 cycles), 3 (5 cycles), and 6 (11 cycles) patients, respectively. Grade III/IV nausea, vomiting, mucositis, and diarrhea were noted in 0, 1, 3, and 0 patient, respectively. Conclusions: GI is active against cisplatin-failed advanced UC with an acceptable toxicity profile. No significant financial relationships to disclose.

Combination chemotherapy with gemcitabine and docetaxel for recurrent germ cell tumors in the central nervous system

1540 Background: Through the use of cisplatin-based combination chemotherapy and radiotherapy, outcomes have improved for patients with intracranial germ cell tumor. An appropriate therapy for recurrent germ cell tumors, however, remains to be established. The present feasibility study investigates the toxicity and activity of a gemcitabine/docetaxel combination in patients with multiply relapsed germ cell tumor. Methods: Gemcitabine was administered at a dose of 1000 mg/m2 over 30 minutes on days 1, 8 followed by docetaxel (1 h-infusion) at a dose of 60 mg/m2 on day 8, with courses repeated every 21 days. Results: From 9/00 to 9/01 5 patients with a median age of 15 [13–32] years were enrolled. Patients had been pretreated with a median of 9 [3–16] platin-containing cycles and 1 patient had previously failed high-dose chemotherapy with PBSCT. All patients were considered cisplatin-refractory. Median number of applied cycles was 2 [2–4]. All patients achieved a radiological partial response with a tumor marker normalization resulting in an objective response rate of 100%. However, the remissions after chemotherapy alone were not durable. Three of the 5 patients received an additional low-dose of irradiation following the chemotherapy. Median progression-free interval was 26 [7–39+] months with 2 patients remaining without disease progression for more than 30 months. Toxicity was generally acceptable: CTC grade III/IV neutropenia of short duration occurred in all patients. No case of grade III/IV non-hematological adverse effect was observed. Conclusions: The combination of gemcitabine/docetaxel is feasible and associated with an acceptable toxicity in patients with multiply relapsed and cisplatin-refractory germ cell tumor. It exhibits a significant activity with responses observed in all patients. No significant financial relationships to disclose.

Combination chemotherapy with gemcitabine and docetaxel for recurrent germ cell tumors in the central nervous system

1540 Background: Through the use of cisplatin-based combination chemotherapy and radiotherapy, outcomes have improved for patients with intracranial germ cell tumor. An appropriate therapy for recurrent germ cell tumors, however, remains to be established. The present feasibility study investigates the toxicity and activity of a gemcitabine/docetaxel combination in patients with multiply relapsed germ cell tumor. Methods: Gemcitabine was administered at a dose of 1000 mg/m2 over 30 minutes on days 1, 8 followed by docetaxel (1 h-infusion) at a dose of 60 mg/m2 on day 8, with courses repeated every 21 days. Results: From 9/00 to 9/01 5 patients with a median age of 15 [13–32] years were enrolled. Patients had been pretreated with a median of 9 [3–16] platin-containing cycles and 1 patient had previously failed high-dose chemotherapy with PBSCT. All patients were considered cisplatin-refractory. Median number of applied cycles was 2 [2–4]. All patients achieved a radiological partial response with a tumor marker normalization resulting in an objective response rate of 100%. However, the remissions after chemotherapy alone were not durable. Three of the 5 patients received an additional low-dose of irradiation following the chemotherapy. Median progression-free interval was 26 [7–39+] months with 2 patients remaining without disease progression for more than 30 months. Toxicity was generally acceptable: CTC grade III/IV neutropenia of short duration occurred in all patients. No case of grade III/IV non-hematological adverse effect was observed. Conclusions: The combination of gemcitabine/docetaxel is feasible and associated with an acceptable toxicity in patients with multiply relapsed and cisplatin-refractory germ cell tumor. It exhibits a significant activity with responses observed in all patients. No significant financial relationships to disclose.

Paclitaxel, cisplatin, and cyclophosphamide (PCC) first-line chemotherapy for advanced ovarian carcinoma: Long-term results of a phase II study

5135 Background: Despite high responses to cisplatin-based combination chemotherapy, the overall survival rate for advanced ovarian cancer remains poor. The combination of PCC as 1st-line treatment for ovarian cancer (OC) has significant activity with high primary response rates. To evaluate long-term results and to assess prognostic factors which have an impact on overall survival we analysed the data from a prospective phase II trial of this treatment combination Methods: 54 patients with OC ( FIGO IIc n=9, IIIc the n=38, IV n=7) were treated between January 1997 and December 2000 with six cycles of P (175mg/m2), C (75mg/m2) and C (600mg/m2) after optimal (n=22) or suboptimal (n=32) debulking surgery. Median age at treatment was 52 years. Tumour histology was adenocarcinoma in all cases (34 of endometrioid subtype, 6 clear cells, and 4 undifferentiated). CA 125 was elevated after surgery in 44 patients and at the end of chemotherapy in 6 patients. A second laparotomy was performed after chemotherapy to 14 patients with macroscopic disease Results: Of 30 evaluable patients for response, 15 achieved a clinical complete response (50%), 12 a partial response (40%), and 3 disease stabilization (10%). With a median follow-up of 56 months (range: 28–153), 26 patients remain alive (49%) and 15 free of recurrence (28%). Median progression-free survival (PFS) was 19 months, and median overall survival (OS) 46 months. 5 years rates of PFS and OS were 26% and 43% respectively. OS rate for FIGO IIIc-IV patients was 35%. In a multivariate analysis, the only negative prognostic factors for survival were: FIGO stage IIIc-IV (p<0.04), suboptimal debulking surgery (p<0.001), and elevated CA 125 at the end of chemotherapy (p<0.05) Conclusions: Our study confirms the effectiveness of PCC regimen in the treatment of epithelial OC in the long term. FIGO stage, extend of debulking surgery, and CA 125 at the end of chemotherapy, are independent prognostic factors for overall survival. These long-term results support the conduct of randomised studies to determine the impact of this triplet in the treatment of advanced ovarian cancer No significant financial relationships to disclose.

Paclitaxel, cisplatin, and cyclophosphamide (PCC) first-line chemotherapy for advanced ovarian carcinoma: Long-term results of a phase II study

5135 Background: Despite high responses to cisplatin-based combination chemotherapy, the overall survival rate for advanced ovarian cancer remains poor. The combination of PCC as 1st-line treatment for ovarian cancer (OC) has significant activity with high primary response rates. To evaluate long-term results and to assess prognostic factors which have an impact on overall survival we analysed the data from a prospective phase II trial of this treatment combination Methods: 54 patients with OC ( FIGO IIc n=9, IIIc the n=38, IV n=7) were treated between January 1997 and December 2000 with six cycles of P (175mg/m2), C (75mg/m2) and C (600mg/m2) after optimal (n=22) or suboptimal (n=32) debulking surgery. Median age at treatment was 52 years. Tumour histology was adenocarcinoma in all cases (34 of endometrioid subtype, 6 clear cells, and 4 undifferentiated). CA 125 was elevated after surgery in 44 patients and at the end of chemotherapy in 6 patients. A second laparotomy was performed after chemotherapy to 14 patients with macroscopic disease Results: Of 30 evaluable patients for response, 15 achieved a clinical complete response (50%), 12 a partial response (40%), and 3 disease stabilization (10%). With a median follow-up of 56 months (range: 28–153), 26 patients remain alive (49%) and 15 free of recurrence (28%). Median progression-free survival (PFS) was 19 months, and median overall survival (OS) 46 months. 5 years rates of PFS and OS were 26% and 43% respectively. OS rate for FIGO IIIc-IV patients was 35%. In a multivariate analysis, the only negative prognostic factors for survival were: FIGO stage IIIc-IV (p<0.04), suboptimal debulking surgery (p<0.001), and elevated CA 125 at the end of chemotherapy (p<0.05) Conclusions: Our study confirms the effectiveness of PCC regimen in the treatment of epithelial OC in the long term. FIGO stage, extend of debulking surgery, and CA 125 at the end of chemotherapy, are independent prognostic factors for overall survival. These long-term results support the conduct of randomised studies to determine the impact of this triplet in the treatment of advanced ovarian cancer No significant financial relationships to disclose.

Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines.

Over 80% of patients with advanced metastatic testis tumors can be cured using cisplatin-based combination chemotherapy. This is unusual as metastatic cancer in adults is usually incurable. Cell lines derived from testis tumors retain sensitivity to cisplatin in vitro. We previously investigated 2 testis tumor cell lines with a low capacity to remove cisplatin-induced DNA damage and found that they had low levels of the DNA nucleotide excision repair proteins XPA, ERCC1 and XPF. To determine whether low levels of XPA, ERCC1 and XPF proteins are characteristic of testis tumor cell lines, we investigated 35 cell lines derived from cancers to determine whether groups of cell lines from diverse tissue origins differ from one another in constitutive levels of these NER proteins. Quantitative immunoblotting was used to compare groups of cell lines representing prostate, bladder, breast, lung, cervical, ovarian and testis cancers. Only the 6 testis tumor cell lines showed significantly lower mean levels of XPA (p = 0.001), XPF (p = 0.001) and ERCC1 (p = 0.004) proteins from the other groups. Our results encourage further investigation of the possibility that low levels of these nucleotide excision repair proteins could be related to the favorable response of testis tumors to cisplatin-based chemotherapy.