Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.

OBJECTIVE: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. METHODS: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, ß = 80%, one sided. RESULTS: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. CONCLUSION: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Homologous recombination repair deficiency (HRD) testing in newly diagnosed advanced-stage epithelial ovarian cancer: A Belgian expert opinion.

Ovarian cancer (OC) has a poor prognosis as most patients present with non-specific symptoms and the disease is mostly diagnosed at advanced stages. Approximately 90% of cases are classified as epithelial OC (EOC), a category comprising histologically and molecularly distinct tumours. Identifying reliable biomarkers and employing personalised therapies in OC subgroups is crucial for battling the disease. EOCs are often characterised by homologous recombination repair deficiency (HRD), frequently caused by inactivation of the breast cancer susceptibility (BRCA) genes. These findings have led to the development of poly- (adenosine diphosphate [ADP])- ribose polymerase inhibitors (PARPi), which are synthetically lethal to HRD tumour cells. Both patients with HRD and non-HRD tumours can benefit from PARPi therapy in the recurrent setting. Moreover, recent phase III trials in patients with newly diagnosed advanced-stage OC have demonstrated greater clinical benefit from PARPi in treating HRD than non-HRD tumours. These findings offer new opportunities for the use of PARPi as maintenance therapy after first-line chemotherapy based on the presence of HRD. In the current article, we provide recommendations for HRD testing and treatment of patients with newly diagnosed advanced-stage EOC.

Treatment algorithm in patients with ovarian cancer.

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, andwhen therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancerincludes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted andantiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovariancancer subtypes and stages has increased considerably. This has enabled the development and improvement ofseveral options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly,therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecularfeatures of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing ofgermline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In orderto implement the best individual medical strategies, in this article, we present an algorithm of treatment options,including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium.

A radical approach to achieve complete cytoreductive surgery improve survival of patients with advanced ovarian cancer.

INTRODUCTION: Cytoreductive surgery of locally advanced ovarian cancer has evolved in the last few years from surgery to remove macroscopic residual disease (<1cm; R2b) to macroscopic complete cytoreductive surgery with no gross residual disease (R1). The aim of this study was to evaluate the impact of the adoption of a maximalist surgical approach on postoperative complications, disease recurrence and survival. MATERIALS AND METHODS: This was a retrospective study using prospectively collected data on patients who received either conservative approach (CA) or radical approach (RA) surgical treatment for primary ovarian cancer stage IIIc/IVa/IVb between June 2006 and June 2013. RESULTS: Data for 114 patients were included, 33 patients in the CA group and 68 patients in the RA group were consequently analysed. In the RA group, operative time was longer, in relation to more complex surgical procedures; with more blood losses and a higher rate of compete macroscopic resection. Totally, 77% of the patients had postoperative complications, with more grade I/II complications in the RA group but the same rates of grade III/IV complications in the both groups (P=0.14). For all patient study population, the overall and disease-free survivals were improved in case of no macroscopic residual disease. Overall survival was improved in the RA group (P=0.05), with no difference in terms of disease-free survival (P=0.29) CONCLUSION: A radical approach in advanced ovarian cancer allows a higher rate of complete cytoreductive surgery impacting overall survival. However, a non-significant trend for increased mild complications (grade I/II) rate is observed in this group.

Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study.

BACKGROUND: Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks. PATIENTS AND METHODS: Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m(2) both) at day 1 and weekly cetuximab 250 mg/m(2) (loading dose of 400 mg/m(2)), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m(2) every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m(2) were not allowed. The primary end point was objective response rate (ORR) after four cycles. RESULTS: Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9-58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3-17.3) and 6.2 months (95% CI 5.4-7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death. CONCLUSIONS: The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population. CLINICALTRIALGOV: NCT01289522.

Potential interactions with anticancer agents: a cross-sectional study.

BACKGROUND: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. METHODS: The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. RESULTS: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. CONCLUSIONS: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.

BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Cancer and renal insufficiency results of the BIRMA study.

BACKGROUND: half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. METHODS: primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. RESULTS: a total of 1218 patients were included. The prevalence of elevated SCR (> or =1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min(-1) per 1.73 m(2). In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. CONCLUSIONS: the RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.

Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer.

BACKGROUND: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab [initial dose 400 mg/m(2) intravenous given 1 week before the beginning of radiation followed by 250 mg/m(2)/week for 5 weeks] and capecitabine for the duration of radiotherapy (650 mg/m(2) orally twice daily, first dose level; 825 mg/m(2) twice daily, second dose level). RESULTS: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m(2) twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response. CONCLUSIONS: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.

Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.

BACKGROUND: Preoperative radiotherapy has been shown to decrease the local recurrence rate of patients with locally advanced rectal cancer. Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer and have radiosensitizing properties. Therefore, these drugs would be expected to improve effectiveness of preoperative radiotherapy in terms of local control and prevention of distant metastases. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4 and/or N+) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformational technique) in combination with intravenous oxaliplatin 50 mg/m2 once weekly for 5 weeks and oral capecitabine 825 mg/m2 twice daily on each day of radiation. Surgery was performed 6-8 weeks after completion of radiotherapy. The main end points were safety and efficacy as assessed by the pathological complete response (pCR). RESULTS: The most frequent grade 3/4 adverse event was diarrhea, occurring in 30% of patients. pCR was found in five (14%) patients. According to Dworak's classification, good regression was found in six (18%) additional patients. CONCLUSIONS: Combination of preoperative radiotherapy with capecitabine and oxaliplatin is feasible for downstaging rectal cancer.

Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I-II feasibility study.

PURPOSE: To determine the safety profile and activity of the combination of docetaxel, cisplatin and 5-fluorouracil (5-FU) in chemotherapy-naive patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with locally advanced unresectable SCCHN were treated with docetaxel and cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5-FU for 5 days. Cycles were planned every 3 weeks up to four cycles, whereafter the patients were treated with locoregional radiotherapy. Two dose levels were studied. Doses in level I were 75 mg/m(2) of docetaxel, 75 mg/m(2) of cisplatin and 750 mg/m(2)/day of 5-FU; in level II the cisplatin dose was escalated to 100 mg/m(2). Following chemotherapy, all patients were to receive curative radiotherapy according to the standards in the different institutions. RESULTS: Twenty-five patients were treated at dose level I with 86 cycles (median four; range one to four), and 23 at dose level II with 84 cycles (median four; range two to four). The median relative dose intensity was 0.99 (range 0.86-1.04) at level I and 0.94 (range 0.79-1.02) at level II. The response rate in the intention-to-treat population was 64% [95% confidence interval (CI) 42.5% to 82%] in level I and 78.3% (95% CI 56.3% to 92.5%) in level II; all were partial responses. The maximum tolerated dose was reached at level II with renal toxicity, nausea, stomatitis and thrombocytopenia as principal dose-limiting toxicities. The median survival of the 48 patients was 18.5 months. The survival at 12, 18, 24 and 30 months was 69, 54, 41 and 31%, respectively. CONCLUSIONS: The combination of docetaxel, cisplatin and 5-FU associated with prophylactic ciprofloxacin is feasible and active in patients with SCCHN. Dose level I is recommended for phase III testing.

Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer.

BACKGROUND: The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. PATIENTS AND METHODS: S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate. RESULTS: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped. CONCLUSIONS: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.

PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.

A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors.

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule.

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 microg m(-2). According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 microg m(-2), the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 microg m(-2). From the dose level 170 microg m(-2), the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 microg m(-2). The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml(-1)) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values.

Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.

Thirty-nine tumor-bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE-3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease-free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE-3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced.

Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients.

The semisynthetic taxoid docetaxel was investigated in a phase II study in non-chemotherapy pretreated patients with metastatic urothelial cell cancer. Thirty patients (median age 61, range 45-72) were treated with docetaxel 100 mg m(-2) administered as a 1-h infusion every 3 weeks. Of 29 evaluable patients, four achieved a complete response and five a partial response, for an overall response rate of 31%. The median duration of response was 6 months (range 4-51+). A total of 104 cycles were administered. The median number of cycles given was three (range 1-9). Toxic effects of docetaxel mainly consisted of neutropenia, which, however, rarely caused infectious complications (5%). Fluid retention or neuropathy necessitated treatment cessation in two patients. We conclude that docetaxel is an effective agent in urothelial cell cancer, and should be further tested in combination chemotherapy.

Mitomycin C and vinblastine in combination with amifostine in metastatic breast cancer. A feasibility study of the EORTC--Investigational Drug Branch for Breast Cancer (IDBBC).

Mitomycin C (MMC)-vinblastine (VBL) is a regimen that has commonly been used as salvage therapy for advanced breast cancer for many years. The hematologic toxicity of this combination is one aspect that limits its usefulness. Amifostine, an organic thiophosphate, has been developed as a selective chemoprotective agent. In this pilot study, we tested the feasibility of MMC/VBL administration in combination with amifostine and we monitored the hematologic toxicity closely. Patients having failed one or two chemotherapy regimens for advanced breast cancer, with a good performance status scored at 2 or better and measurable or evaluable lesion(s), were eligible. They were treated according to the following schedule: mitomycin C 10 mg/m2 i.v. day 1, vinblastine 5 mg/m2 i.v. day 1 and 15, amifostine 910 mg/m2 in short i.v. infusion prior to MMC. Premedication consisted of dexamethasone 3 x 20 mg, haloperidol 2 x 0.5 mg p.o., hydration with 11 of normal saline, metoclopramide 1.5 mg/kg in short infusion and procyclide HCl 10 mg i.v. Cycles were repeated every 4 weeks. In all, 14 cycles were administrated to six heavily pretreated patients. Following the first cycle, five of the six patients experienced grade 3 or 4 neutropenia on day 15, and consequently did not receive the second vinblastine administration as planned. Three out of four patients receiving two or more cycles had moderate thrombocytopenia. There were no patients with neutropenic fever or major bleeding problems. The MMC/VBL+amifostine regimen was well tolerated regarding other toxicities. Neither amifostine-related acute vomiting nor any significant decrease in blood pressure was observed. Administration of amifostine in combination with MMC/VBL was feasible but in this group of heavily pretreated patients there were no hints of a protective effect of amifostine on the hematologic toxicity profile of this chemotherapy regimen.

Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity.

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade > or = 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade > or = 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn.