ABSTRACT
BACKGROUND: Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety. METHODS: Ovarian and primary peritoneal cancer patients, pretreated with at least one prior platinum-containing regimen, performance status (PS) 0-1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1-15; oxaliplatin was given days 1 and 15; cycles were repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses: (1) 0.2/65; (2) 0.2/75; (3) 0.2/85; (4) 0.3/85; (5) 0.4/85. RESULTS: Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 years (range, 37-77); PS: 0=12 and 1=11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels. CONCLUSION: Topotecan continuous infusion, combined with oxaliplatin, was associated with no grade 4 hematologic toxicity and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1-15 with oxaliplatin 85 mg/m2 on days 1 and 15. A phase II evaluation as second-line treatment for both platinum-sensitive and -resistant ovarian cancer recurrences is ongoing.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma, Papillary/drug therapy , Adenocarcinoma, Papillary/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/pathology , Oxaliplatin , Peritoneal Neoplasms/pathology , Topotecan/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. METHODS: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. RESULTS: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. CONCLUSION: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Immunohistochemistry , Infusions, Intravenous , Liposomes , Male , Middle Aged , Nausea/chemically induced , Neutropenia/chemically induced , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/metabolism , Polyethylene Glycols , Topotecan/administration & dosage , Topotecan/blood , Topotecan/pharmacokinetics , Treatment Outcome , Vomiting/chemically inducedABSTRACT
PURPOSE: To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. PATIENTS AND METHODS: Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 microg/m(2)/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. RESULTS: Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). CONCLUSION: This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/adverse effects , Camptothecin/therapeutic use , Carcinoma/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Antineoplastic Agents/adverse effects , Camptothecin/administration & dosage , Carcinoma/pathology , Disease Progression , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Middle Aged , Neutropenia/chemically induced , Ovarian Neoplasms/pathology , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
Although three large phase III trials have documented the benefit of IP chemotherapy, this therapy as consolidation has been studied in only a few pilot studies. These small studies have included patients with a variety of baseline prognostic characteristics, and only one series had a comparator group of surgically documented pathologic complete response to uniform systemic chemotherapy. No randomized trials have been done to assess the impact of IP consolidation on progression-free survival or survival in either positively or negatively reassessed patients. It is hoped that the current experience will trigger further consideration of future phase III trials to assess the value of IP consolidation after initial induction with chemotherapy (ie, chemical debulking).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Clinical Trials, Phase III as Topic , Disease-Free Survival , Female , Floxuridine/administration & dosage , Humans , Injections, Intraperitoneal , Injections, Intravenous , Ovarian Neoplasms/mortalityABSTRACT
We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Biopsy, Needle , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease-Free Survival , Female , Follow-Up Studies , Gastrectomy , Gastroscopy , Humans , Injections, Intraperitoneal , Irinotecan , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Metastasis , Neoplasm Staging , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate , Treatment OutcomeABSTRACT
Colorectal cancer (CRC) accounts for about 11% of all new cancers in the United States and kills approximately 56,000 people each year. Although the use of antineoplastic agents has demonstrated palliation of symptoms, increased survival, and improved quality of life when compared with best supportive care, improved therapies still are needed. Oxaliplatin, released in August 2002, offers an effective expansion of the CRC treatment armamentarium. Proper dosage and administration of oxaliplatin are vital to maximizing its efficacy and safety. This article reviews administration guidelines, adverse events, side effects, and key areas for patient education.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Guidelines as Topic , Oncology Nursing , Organoplatinum Compounds/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials as Topic , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , Colorectal Neoplasms/nursing , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Organoplatinum Compounds/adverse effects , Oxaliplatin , Prognosis , Risk Assessment , Survival Analysis , Treatment OutcomeABSTRACT
This study's objectives were to determine the maximum tolerated dose (MTD) of 9-aminocamptothecin (9-AC), given as a prolonged continuous infusion (CI) for 7-21 days, when formulated in dimethylacetamide/polyethylene glycol 400 (DMA) and then later as a colloidal dispersion (CD), and to determine the steady-state pharmacokinetics of 9-AC. Patients with solid tumors refractory to standard therapy were enrolled on this study. Total dose/cycle of 9-AC/DMA was initially escalated by duration (7-21 days), while keeping the dose rate constant at 6.2 microg/m/h (1.04-3.12 mg/m/4-week cycle). Then, the dose rate was escalated from 6.2 to 21.1 microg/m/h (3.12-10.6 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days. CD formulation was escalated from 14.1 to 25 microg/m/h (7.11-12.60 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days and then escalated from 28.1 to 37.5 microg/m/h (9.44-12.60 mg/m/3-week cycle) while keeping the infusion duration constant at 14 days. Sixty-two patients were evaluable for toxicity; 61 received prior chemotherapy (median 3 regimens/patient). No consistent dose-limiting toxicity (DLT) was encountered with the DMA formulation until dose level 10.60 mg/m/cycle, when two patients experienced DLTs. With the 21-day CD formulation, the MTD was 12.60 mg/m/cycle with three DLTs out of five patients. When 9-AC was given on the 14-day schedule, DLT was seen at 9.44, 11.20 and 12.60 mg/m/cycle, with consistent DLT at the two highest dose levels. All DLTs for both formulations were grade 4 hematologic toxicities (neutropenia and/or thrombocytopenia), while non-hematologic toxicities were relatively mild (including gastrointestinal toxicities and fatigue). One patient with ovarian cancer had a complete response and three had partial responses (PRs). One patient each with non-Hodgkin's lymphoma and cancer of unknown primary had a PR. Pharmacokinetic studies of both formulations of 9-AC revealed a linear relationship between increasing plasma 9-AC lactone concentration and dose. The median plasma 9-AC lactone concentration for 9-AC/CD was approximately twice that achieved by 9-AC/DMA for the same dose level. Both 9-AC formulations, given as a 21-day CI, were well tolerated with dose-limiting myelosupression at the MTD. This dose intensity exceeds that of other 9-AC phase I/II schedules. The recommended phase II dose (RPTD) is 9.42 mg/m/4-week cycle, given as a 21-day infusion. The 14-day schedule of 9-AC/CD was equally myelosuppressive with the RPTD of 9.44 mg/m/3-week cycle, although two heavily pre-treated patients (one with pelvic radiotherapy) could not tolerate this dose. Objective responses were observed in six out of 57 heavily pre-treated patients, most of which had ovarian cancer.
Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/blood , Neoplasms/pathology , Time FactorsABSTRACT
Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Drug Delivery Systems/methods , Neoplasms/drug therapy , Tubulin , Vinblastine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Estramustine/administration & dosage , Estramustine/adverse effects , Female , Humans , Male , Middle Aged , Neoplasms/physiopathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Vinblastine/administration & dosage , Vinblastine/adverse effects , VinorelbineABSTRACT
The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.
Subject(s)
Clinical Trials, Phase I as Topic , Doxorubicin/pharmacokinetics , Granulocyte Colony-Stimulating Factor/therapeutic use , Taxoids/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols , Area Under Curve , Docetaxel , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Half-Life , Hematologic Diseases/chemically induced , Humans , Infusions, Intravenous , Liposomes , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/pathology , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m(2) in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m(2) was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (+/-SD) was 11.5 (+/-3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.
Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Drug Administration Schedule , Female , Humans , Male , Middle AgedABSTRACT
Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance.