Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide, followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification.

PURPOSE OF THE STUDY: Trastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC. METHODS: Preoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET. RESULTS: 43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31-78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes. CONCLUSIONS: This study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.

Cisplatin-gemcitabine as palliative chemotherapy in advanced squamous vulvar carcinoma: report of two cases.

Vulvar cancer (VC) is a rare disease, usually diagnosed in a stage still amenable to potentially curative treatments, including surgery and/or radiation therapy with or without chemotherapy. Several patients however present at diagnosis with metastatic disease and another 30-50% will relapse. Prognosis of metastatic or recurrent disease not amenable to salvage surgery or radiotherapy is very poor. Evidence about the efficacy of chemotherapy in this setting is limited and its role still remains unclear. At present there is no standard treatment for advanced VC and patients are usually treated with schedules adopted for chemoradiation or extrapolated from cervical cancer. We report our experience using a cisplatin-gemcitabine regimen in two cases of metastatic squamous cell VC. No response was obtained with this schedule. No other data are available in the literature about the choice of a cisplatin-gemcitabine regimen in this patient subset. The paucity of evidence about the role of palliative chemotherapy in metastatic VC justifies any effort to implement knowledge. For this reason we think it is notable to also report a negative experience. It is not possible for us to conclude that this chemotherapy would be unable to provide any benefit in a larger sample of patients; nonetheless we think that new agents, rather than combinations of older drugs, could hopefully provide more benefit.

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial.

BACKGROUND: We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases. METHODS: This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2-6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day. RESULTS: Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3-15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21-53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction. CONCLUSION: Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.

Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study.

This trial was conducted to assess the activity and tolerability of the gemcitabine, epirubicin, taxol triplet combination in patients with operable breast cancer. After core biopsy, 43 women with stage II-IIIA breast cancer were treated with gemcitabine 1000 mg m(-2) over 30 min on days 1 and 4, epirubicin 90 mg m(-2) as an intravenous bolus on day 1, and taxol 175 mg m(-2) as a 3-h infusion on day 1, every 21 days for four cycles. The primary end point was the percentage of pathological complete responses (pCR) in the breast; secondary end points were tolerability, clinical response rates, overall and progression-free survival, tumour biomarkers before and after primary chemotherapy (PCT). All patients were included in safety and survival analyses; 41 eligible patients were evaluated for response. The overall clinical response rate was 87.8% (95% CI 77.8-97.8), with 26.8% complete responses (95% CI 13.3-40.3). A pCR in the breast was observed in six patients (14.6%; 95% CI 3.8-25.4); 15 patients (36.6%; 95% CI 21.9-51.3) had negative axillary lymph nodes. Grade 4 neutropenia was observed in 67.4% of the patients; febrile neutropenia occurred in 1.9% of cycles (granulocyte colony-stimulating factor was used in 3.2% of the cycles to shorten the duration of neutropenia). A statistically significant difference between Mib-1 at baseline (> or =20% in 71.4% of the patients) and at definitive surgery (28.6%, P < 0.05) was observed. The gemcitabine, epirubicin, taxol regimen is active and well tolerated as PCT for operable breast cancer. This combination allows the administration of full doses of active agents with a low incidence of febrile neutropenia.

Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer.

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95% CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC.

A Randomized Study of Epithelial Ovarian Cancer: Is Chemotherapy Useful after Complete Remission?

Objective. The aim of this study is to verify whether consolidation chemotherapy with Cisplatin improves disease-free survival and/or overall survival in patients affected by epithelial ovarian cancer.Methods. A multicenter study examined 122 randomized patients in complete remission as judged by laparoscopy or laparotomy following first-line chemotherapy consisting of ACy (Adriamycin + Cyclophosphamide), PCy (Cisplatin + Cyclophosphamide), or Mitoxantrone + Carboplatin. Sixty-one of these patients were treated with 3 cycles of 5-Fluorouracil (FU) 500 mg/m2 for 5 days followed by Cisplatin at 100 mg/m2 on the 6th or 7th day every 28 days; the other 61 received no further treatment (nihil group).Results. Sixty patients in the Cisplatin arm were evaluable. There were 36 relapses in the FU+Cisplatin arm and 30 in the nihil arm. Peritoneal relapses were 25% for Cisplatin treatment vs. 16.4 % for nihil. There were 29 deaths in the Cisplatin arm vs. 27 for nihil. Median overall survival time (95 months with Cisplatin vs. 96 months in the nihil group) and median disease-free survival (66 months with Cisplatin vs. 73 in the nihil group) were similar in both arms (p=0.66 and p=0.41, respectively). There were no significant differences in tumor stage and grade between the two arms. Seven patients presented a second neoplasm during follow-up: six in the nihil arm, but only one patient in the Cisplatin arm. Death in these patients was due to the second neoplasm and not to progression of ovarian cancer.Conclusion. Three courses of additional platinum+FU treatment after five cycles of first-line chemotherapy without FU produced no increase in overall survival or disease-free survival.

Hepatic intra-arterial chemotherapy (HIAC) of high dose mitomycin and epirubicin combined with caval chemofiltration versus prolonged low doses in liver metastases from colorectal cancer: a prospective randomized clinical study.

A multicenter randomized study comparing high dose of mitomycin and epirubicin given as hepatic intra-arterial chemotherapy (HIAC) combined with caval chemofiltration (CF) versus low doses of the same drugs in unresectable liver metastases from colorectal cancer showed a significant improvement in the survival rate of the 20 patients treated with high dose compared to the 22 patients treated with low doses with a 1 year survival of 69% vs 39%. The median survival was 17 vs 11 months and the responses were 65% vs 33%. Toxicity was colangitis in 50% of patients considered. The extrahepatic progression was similar in the two groups (7/20 vs 8/22).

Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer.

Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European-Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin-paclitaxel regimen over cisplatin-cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group.

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.

In the last years, the main topoisomerase I inhibitors (TP1-I) (i.e. topotecan and irinotecan) have been used in combination chemotherapy in non-small cell lung cancer. Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.

Preliminary results of combined therapy with topotecan and carboplatin in advanced non-small-cell lung cancer.

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.

Phase II study of a combination of cyclophosphamide, adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.

D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study.

Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.

Elderly ovarian cancer: treatment with mitoxantrone-carboplatin.

OBJECTIVE: Data concerning optimal treatment of elderly patients with ovarian cancer are scanty. The management of ovarian cancer in the aged patient is many-sided: the diagnosis can be difficult and delayed, and aggressive surgery is often not attempted because of concomitant morbidity. We tested a combination of carboplatin and mitoxantrone potentially associated with low toxicity in elderly patients with ovarian cancer. METHODS: Eighty-two patients older than 70 years (median age, 75; range, 70-88) with epithelial ovarian cancer were referred to our multicenter group and enrolled into this pilot study. Carboplatin (JM8) was given at the dose of 230 mg/m2 and mitoxantrone at the dose of 9 mg/m2 every 28 days. RESULTS: Dose-limiting toxicity was represented by 4 cases of thrombocytopenia and 1 case of gastrointestinal toxicity. These 5 episodes occurred in 328 assessable cycles, representing a low toxicity profile (3%). Of the 68 assessable patients, 36 (53%) did not respond to chemotherapy (no change + progressive disease), complete response was observed in 15 (22%), and partial remission was observed in 16 (23.5%), accounting for an overall response rate of 45%. CONCLUSION: The carboplatin-mitoxantrone combination, at the dosage tested in this study, appears to be well tolerated by elderly patients with advanced ovarian cancer and is associated with an acceptable response rate. Optimally debulked patients also showed improved survival when compared with patients with more extensive tumor.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Efficacy of total androgen blockade in metastatic prostatic carcinoma with transient hypogonadotropic hypogonadism: a case report.

A patient affected by metastatic prostatic carcinoma and hypogonadotropic hypogonadism (HH) was treated with flutamide 750 mg/day plus an LH-RH analog. After confirmation of basal castration during treatment, he continued with antiandrogens alone. Following the normalization of gonadic function and subjective mild bone flare-up, the patient resumed the initial treatment and obtained a partial response. When flutamide was interrupted because of liver toxicity, the patient showed progressive disease in the bone, which was unresponsive to both flutamide resumption and salvage hormone therapy (bicalutamide). The patient is currently receiving chemotherapy with VP16 and estramustine phosphate and is showing both serologic (PSA) and symptomatic response. The interest of this case lies in the incidental detection of HH during therapy and in the responsiveness to treatment.