First-Line Chemotherapy with Paclitaxel and Platinum for Advanced and Recurrent Cancer of the Cervix—A Phase II Study

Objective. The aim of this study was to assess the role of first-line chemotherapy with paclitaxel and platinum in the treatment of advanced or recurrent cervix cancer.Methods. Twenty patients with advanced or recurrent cancer of the cervix with no prior chemotherapy and measurable disease were entered in a phase II trial from September 1995 to September 1998. Seventeen patients were treated with paclitaxel at 135 mg/m² over 24 h followed by cisplatin at 75 mg/m² every 4 weeks. Three patients with impaired renal function were treated with paclitaxel at 135 mg/m² over 3 h with carboplatin at 300 mg/m².Results. A clinical response rate of 45% was noted (two complete responses and seven partial responses) with a median duration of 6 months (range: 1.5–9). The median progression-free interval and overall survival in patients with a clinical response was 10.5 and 13 months, respectively, compared to 4 (P = 0.015) and 6 months in the nonresponders (P = 0.14). Seven of nine patients (77.8%) with a clinical response are alive. Patients with recurrences outside the radiation field had twice the response rate (60%) than that of those within the radiated field. The chemotherapy was well tolerated; the most significant toxicity was grade 3/4 neutropenia (55%). No patient had discontinuation of chemotherapy due to toxicity.Conclusions. First-line chemotherapy with paclitaxel and platinum for advanced and recurrent cervix cancer is promising and deserves consideration for large phase III trials.     

Paclitaxel and Cisplatin Combination Chemotherapy in Recurrent Epithelial Ovarian Cancer

The objective of this study was to assess the efficacy of chemotherapy in recurrent epithelial ovarian cancer using the sequential combination of 24-hr paclitaxel followed by cisplatin. All patients presenting to the Department of Gynecologic Oncology at Roswell Park Cancer Institute between April 1993 and May 1995 with recurrent epithelial ovarian cancer were offered enrollment in a prospective trial utilizing paclitaxel 135 mg/m²administered in a continuous 24-hr intravenous infusion, followed by intravenous cisplatin 50 mg/m². Forty-nine patients were entered into the study. Of 38 patients evaluable for response, there were 14 complete responders and 6 partial responders for an overall response rate of 53%. Median survival was >23 months for responders and 12 months for the entire study group. All complete responders were still alive with a median follow-up of 23 months. Of 12 evaluable patients whose tumors had progressed on single-agent paclitaxel, 4 achieved an objective response with the addition of cisplatin. Response rates and survival were similar in patients with platinum-resistant tumors compared to patients with platinum-sensitive tumors, and in patients who had received one, two, or multiple prior chemotherapy regimens. The combination of paclitaxel administered in a 24-hr infusion followed by cisplatin is highly active in recurrent epithelial ovarian cancer, even in patients who have previously failed single-agent paclitaxel or cisplatin-based chemotherapy.     

Paclitaxel, topotecan, and carboplatin in metastatic endometrial cancinoma: a Hellenic Co-operative Oncology Group (HeCOG) study

ObjectiveTaxanes, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, topotecan and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity.MethodsThirty-nine consecutive patients were treated on an outpatient basis with paclitaxel 150 mg/m², administered intravenously over a 3-h period and followed by carboplatin at AUC of 5 on day 3, with both agents proceding topotecan that was given at 0.75 mg/m²/day on days 1 through 3. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses.ResultsTwenty-one (60%) patients achieved objective clinical response (95% CI, 42.2–75.7%) including 4 (11.4%) complete and 17 (48.6%) partial responses. The median times to progression and survival for all patients were 8.9 and 17.7 months, respectively. Grade 3 or 4 thombocytopenia and neutropenia occurred in 5 (13%) and 4 (10%) patients, respectively, but only 2 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 23% of patients.ConclusionsThe combination of paclitaxel, topotecan and carboplatin with G-CSF support appears active with acceptable toxicity in patients with metastatic or recurrent carcinoma of the endometrium.     

Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer

ObjectiveTo analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review.Materials and methodsPatients accepted weekly paclitaxel 80 mg/m² on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan.ResultsSixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3–10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3–40.5). The median time to response (TTR) was 29.0 days (range 19.6–38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2–34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%).Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed.ConclusionThis is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS.     

A Phase I Study of Paclitaxel and Cyclophosphamide in Recurrent Adenocarcinoma of the Ovary

We have conducted a disease specific phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary. This was done to take advantage of the cellular and molecular synergism between paclitaxel and DNA-damaging agents, with the hope of avoiding paclitaxel–cisplatin toxicities. Paclitaxel was given as a 24-hr CIVI, after which cyclophosphamide was given as a 60-min infusion. Cycles of therapy were repeated every 3 weeks; and granulocyte colony-simulating factor (G-CSF) was given in a “flexible” dosing fashion. Starting doses were 170 mg/m²paclitaxel and 750 mg/m²cyclophosphamide. Dose-limiting toxicity (DLT) was seen at the doses of 250 mg/m²paclitaxel and 1250 mg/m²cyclophosphamide. DLT was cumulative thrombocytopenia. There were six nonhematologic grade 3 or 4 toxicities experienced in the study. Eleven of 20 evaluable patients (55%) have achieved an objective response (4 CCR;7 PR). Three of four CCRs were confirmed by negative findings at peritoneoscopy. The median number of prior therapies was 2 (range 1–4) and 17 individuals had platinum-refractory disease. We conclude that paclitaxel followed by cyclophosphamide is an active combination in recurrent ovarian cancer and that further study is needed to determine if this combination is truly better than paclitaxel alone.     

Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: a gynecologic oncology group study

Purpose

Intraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle.

Methods

Patients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135 mg/m² IV over 3 h followed by cisplatin 75 mg/m² IP on day 1 and paclitaxel 60 mg/m² IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3–5 non-hematologic toxicity occurring within the first 4 cycles of treatment.

Results

Twenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain.

Conclusions

This modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172.     

Phase I trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies

Background. Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity.Objectives. Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m²) in a cohort of women with recurrent müllerian malignancies.Methods. Topotecan dose was escalated from 0.5 mg/m²/day for 3 days in 0.2 mg/m²/day increments with treatment repeated every 21 days. Eligibility criteria required ECOG ≤2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity.Results. Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40–71) years. Patients received a median 1 (1–6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses.Conclusions. Doxil 30 mg/m² and topotecan 0.5 mg/m²/day by 72-h infusion (total dose 1.5 mg/m²), although a rational combination of cytotoxic therapies, have limited clinical activity.     

Ifosfamide, paclitaxel, and carboplatin, a novel triplet regimen for advanced, recurrent, or persistent carcinoma of the cervix: a phase II trial

Objectives

(1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment.

Methods

Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600 mg/m²) prior to ifosfamide (2 g/m²), paclitaxel (175 mg/m²), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx.

Results

Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10 months. Median progression free survival for evaluable patients was 5.0 months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments.

Conclusion

Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile.     

Combined Cisplatin and Carboplatin Chemotherapy for Treatment of Advanced Epithelial Ovarian Cancer

Purpose. The primary goal of this trial was to evaluate the clinical activity and the toxicity of a combination of cisplatin and carboplatin for women with advanced-stage epithelial ovarian cancer. Patients and methods. Fifty-one consecutive evaluable patients with untreated stage III and IV epithelial ovarian cancer received 360 mg/m² carboplatin on Day 1 and 50 mg/m² cisplatin on Day 2 administered intravenously every 28 days for six cycles. Drug doses were adjusted for hematologic toxicity based on nadir counts during the prior therapy course. Dose levels included 300-400 mg/m² carboplatin and 50-75 mg/m² cisplatin. Second-look surgery was optional. Endpoints were clinical response, surgical response, progression-free survival, and survival. Results. Of 8 patients with measurable disease, 3 (37.5%) had a clinical compete response, and 3 (37.5%) had a clinical partial response, for an overall clinical response rate of 75%. Of 39 patients who began chemotherapy with abnormal serum levels of CA 125, 31 (79%) achieved normalization of CA 125 at the completion of chemotherapy. Thirteen patients underwent second-look laparotomy. Of these, 7 (54%) had a pathological compete response, and 2 (15%) had a partial response. The median progression-free survival was 14 months, and the overall median survival was 32.5 months. Neutropenia and thrombocytopenia were the main dose-limiting toxicities. In addition, 9 patients developed grade 2 and 3 developed grade 3 ototoxicity. Conclusion. This regimen is very active against advanced-stage epithelial ovarian cancer. The degree of ototoxicity observed is worrisome, but such toxicity may be ameliorated by limiting the dose of cisplatin and increasing the dose of carboplatin.     

Case ReportWeekly carboplatin in a frail elderly woman with advanced peritoneal carcinoma

Introduction Standard chemotherapy for ovarian, peritoneal and fallopian tube carcinoma has been a combination of carboplatin (AUC=6) and paclitaxel 175 mg/m² every 3 weeks. For frail and elderly patients who may not tolerate the toxicity associated with combination chemotherapy there is the option of omitting paclitaxel and giving carboplatin (AUC=6) as a single agent every 3 weeks. The toxicity may be reduced further, without decreasing effectiveness, by giving single-agent carboplatin at a reduced dose (AUC=2) every week. Case report A frail 79-year-old woman with advanced peritoneal carcinoma had first-line and second-line chemotherapy with single-agent carboplatin on day 1 every 7 days. This has resulted in disease stabilization, CA-125 partial response and improved quality of life. Toxicity has been negligible. Conclusion Weekly carboplatin is an attractive option for the treatment of frail and elderly patients with ovarian, peritoneal and fallopian tube carcinoma.     

Cycles of Dose-Intensive Chemotherapy with Peripheral Stem Cell Support in Persistent or Recurrent Platinum-Sensitive Ovarian Cancer

Objective.The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer.Methods.Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m²), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m²) and cyclophosphamide (1.5 g/m²with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m²every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval.Results.Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0–35%).Conclusion.Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.     

Pharma Update Genitalkarzinome

Ovarian cancer

In early stage ovarian cancer chemotherapy containing platinum is recommended. In an advanced or recurrent situation combined chemotherapy with carboplatin/paclitaxel (area under the curve AUC5 175 mg/m²) is indicated. The vascular endothelial growth factor (VEGF) targeting agent bevacizumab can prolong the progress-free interval. For the treatment of platinum-sensitive ovarian cancer the preferred agents are carboplatin/gemcitabine, carboplatin/paclitaxel and carboplatin/caelyx. Platinum-resistant recrudescence primarily indicates a monochemotherapy and the recommended therapeutic options are polyethylene glycol (PEG) liposomal doxorubicin/topotecan/gemcitabine/paclitaxel.

Cervical cancer

A combined radiochemotherapy containing cisplatin is considered to be the standard of care in neoadjuvant and adjuvant treatment as well as in recurrent situations. Neoadjuvant dose-dense chemotherapy improves the 5-year survival rate and reduces overall mortality. Adjuvant chemotherapy only is not indicated. In a recurrent or metastasized situation for radiation-naive patients radiochemotherapy is indicated. The only approved regimen in Germany is a combination of cisplatin and topotecan. Results of the GOG 240 trial confirmed an enhancement of the progress-free survival with addition of the antibody bevacizumab.

Endometrial cancer

Of all endometrial cancer patients 20?% are considered to be high risk patients. The recurrence rate is 50?%. According to the current German S2K guidelines in all patients presenting with a TNM stage Ib G3, II and III as well as all serous or small cell endometrial carcinomas, platinum chemotherapy with carboplatin/paclitaxel (AUC5 175 mg/m²) is indicated sequential to radiation. In the palliative situation local surgical treatment or radiation is the main option. A possible combination with either gestagens or cytostatic therapy depends on the hormone receptor status.

Vulvar cancer

Radiochemotherapy is indicated in inoperable situations, extensive recrudescence or in non-in sano resected patients. In metastasized patients the use of a combined chemotherapy is criticized due to the high toxicity and low response rate.     

The Efficacy and Safety of Neoadjuvant Chemotherapy in Treatment of Locally Advanced Carcinoma Cervix

Objective

A prospective cohort study in a teaching hospital to assess the efficacy and safety of neoadjuvant chemotherapy in the treatment of locally advanced carcinoma cervix.

Method

Neoadjuvant chemotherapy in the form of cisplatin 75 mg/m² and paclitaxel 135 mg/m² on day 1 and repeated at 14 days’ interval for up to a maximum of three courses.

Results

Neoadjuvant chemotherapy in cervical cancer was effective in the downstaging of the disease. Downstaging was observed in 19.23 % of patients after two cycles and in 50 % of patients after three cycle of NACT. Operability increases to 33.3 and 38.4 % after two and three cycles of NACT, respectively. Complete pathological response was observed in 37.5 % of patients after NACT. No significant adverse effect in the feasibility of surgery was observed.

Conclusion

The present study showed that neoadjuvant chemotherapy was an effective and well-tolerated mode of therapy with significantly less morbidity and mortality.     

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: a Kansai Clinical Oncology Group study

Objective

A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer.

Methods

Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m² over 3 hours and nedaplatin 80 mg/m² intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy.

Results

Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n = 16, 32.7%), febrile neutropenia (n = 1, 2.0%), anemia (n = 9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9).

Conclusions

Paclitaxel 175 mg/m² and nedaplatin 80 mg/m² intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.     

Investigating the relative efficacies of combination chemotherapy of paclitaxel/carboplatin, with or without anthracycline, for endometrial carcinoma

Purpose

Recently a combination of paclitaxel and carboplatin (TC) (without an anthracycline) has begun to be used as an adjuvant or remission induction therapy, without any critical supportive evidence of its efficacy relative to a combination chemotherapy of taxane, platinum and anthracycline such as TEC (paclitaxel, epirubicin and carboplatin). The aim of our present study was to conduct the required clinical evaluations of the relative effectiveness of TC compared to TEC.

Methods

A retrospective comparison between the efficacy of TEC and TC regimens used for endometrial carcinoma at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, respectively, from 1999 to 2009 was performed. The clinical characteristics of the patients who received either TEC or TC were not significantly different, and TEC and TC therapies were initiated based on similar indications for chemotherapy. TEC regimen was paclitaxel (150?mg/m²), epirubicin (50?mg/m²) and carboplatin (AUC 4). TC regimen consisted of paclitaxel (175?mg/m²) and carboplatin (AUC 5).

Results

TEC was demonstrated to provide significantly better survival than TC as an adjuvant therapy for resected Stage III/IV diseases (p?=?0.017 for progression-free survival and p?=?0.014 for overall survival, by the log-rank test). However, in recurrent or more advanced cases, TC and TEC demonstrated similar effects on survival (p?=?0.55 for progression-free survival and p?=?0.63 for overall survival).

Conclusions

TEC should be offered as an adjuvant therapy to Stage III/IV patients. TC may be considered for recurrent or unresectable cases as a remission induction therapy.     

A multicenter open-label randomized phase II trial of paclitaxel plus EP-100, a novel LHRH receptor-targeted,membrane-disrupting peptide,versus paclitaxel alone for refractory or recurrent ovarian cancer

ObjectiveThis randomized open-label phase II study evaluated the safety and clinical activity of EP-100 plus weekly paclitaxel in patients with recurrent ovarian cancer expressing positive LHRH receptor.MethodsIn a limited “run-in” dose escalation phase for EP-100, six patients were treated with ascending dose levels (13 mg/m², 20 mg/m², 30 mg/m²). In the randomized phase, patients received weekly paclitaxel (80 mg/m² intravenously) plus twice weekly EP-100 (30 mg/m² intravenously; combination arm) or weekly paclitaxel alone (80 mg/m² intravenously; paclitaxel arm). The primary study endpoint was overall response rate (ORR).ResultsForty-four patients were then randomized to either the experimental combination arm (n = 23) or the standard of care paclitaxel monotherapy arm (n = 21). The ORR was 35% (95%CI 16%–57%) for the combination arm and 33% (95% CI 15%–57%) for the paclitaxel arm. An interesting observation from an unplanned analysis was that a subset of patients with target liver lesions showed a greater overall response rate to the combination (69%) compared to paclitaxel alone (16%). The frequency of treatment-related grade 3–4 adverse events was similar between treatment arms: 48% vs 43% for the combination and paclitaxel arms, respectively.ConclusionsORR in the EP-100 combination arm was similar to that in the group treated with paclitaxel alone; however, a subset of patients with liver metastases appeared to benefit from the combination. The addition of EP-100 did not appear to augment the adverse event profile of paclitaxel and was well tolerated.     

Topotecan in Platinum- and Paclitaxel-Resistant Ovarian Cancer

Objective:The purpose of this study was to define the response rate and toxicity of topotecan in patients with ovarian cancer resistant to first-line therapy.Methods:Twenty patients with advanced or recurrent ovarian cancer were enrolled in a phase I/II protocol, and an additional 16 patients were treated following protocol closure at Washington University Medical Center. The starting dose of topotecan was 1.25 mg/m²/day given intravenously over 30 min for 5 consecutive days. Patients were eligible for response evaluation if they completed more than one cycle of topotecan. All patients were evaluated for toxicity.Results:Of 28 patients eligible for response evaluation, 26 were resistant to both platinum and paclitaxel prior to treatment with topotecan. There were four partial responders and no complete responders for a total response rate of 14% (95% confidence interval: 4 to 33%). All responders had exhibited primary resistance to both platinum and paclitaxel. Myelotoxicity was the major toxicity, with 92% of patients experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 neutropenia and 67% experiencing GOG grade 3 or 4 thrombocytopenia. Other toxicity was minimal and easily managed. Fifty percent of patients receiving more than one cycle of topotecan tolerated a dose equal or greater to the starting dose.Conclusions:Topotecan exhibits activity in patients with ovarian cancer resistant to both platinum and paclitaxel. Further study is warranted in less heavily pretreated patients and in combination with other chemotherapeutic agents.     

A Phase I Study of Paclitaxel, Doxorubicin, and Cisplatin in Patients with Previously Untreated Epithelial Ovarian Cancer

Objective.Although doxorubicin is not currently popular as a primary agent in ovarian cancer, overviews of previous studies suggest that the inclusion of doxorubicin may have improved outcome. The purpose of this phase I study was to determine the maximal dose of doxorubicin that could be added to standard doses of paclitaxel and cisplatin with G-CSF support.Methods.Women with FIGO stage III or IV epithelial ovarian cancer were primarily treated with escalating doses of doxorubicin in combination with paclitaxel (135 mg/m²over 24 h) and cisplatin (75 mg/m²) every 3 weeks. Doxorubicin was started at 30 mg/m²and escalated by 10 mg/m²per treatment level. All patients received G-CSF support.Results.Eleven patients were treated at two dose levels. Dose limiting toxicity (DLT) was reached at the 40 mg/m²dose of doxorubicin. All patients experienced grade 4 neutropenia although none required hospitalization. DLT included renal toxicity and prolonged thrombocytopenia. Despite vigorous antiemetic regimens 60% of patients experienced severe nausea and vomiting. Nine patients were assessable for response. Eight patients have had a complete clinical response (89%). Of the five patients undergoing second-look laparotomy two were negative.Conclusions.The maximum tolerated dose of doxorubicin in this three-drug regimen is 30 mg/m²with standard doses of paclitaxel and cisplatin. Hematologic toxicity is manageable using G-CSF. Doxorubicin appears to increase the renal toxicity of cisplatin which may be exaggerated by marked nausea and vomiting. This is an active but toxic regimen and alternative sequences and strategies should be evaluated.     

The feasibility of carboplatin-based intraperitoneal chemotherapy in ovarian cancer

Objective

To reduce toxicities in cisplatin-based intraperitoneal (IP) chemotherapy, we substituted carboplatin for cisplatin. The purpose of this study was to provide preliminary toxicity data of carboplatin-based IP chemotherapy and to evaluate the feasibility of this chemotherapy regimen in patients with ovarian cancer after primary debulking surgery.

Study design

The toxicity data of 19 primary ovarian cancer patients (IP group) who underwent carboplatin-based IP and intravenous (IV) combination chemotherapy (IP carboplatin AUC 5 on day 1, IV paclitaxel 175 mg/m² on day 2, and IP paclitaxel 60 mg/m² on day 8) after primary debulking surgery were retrospectively analyzed and compared to 34 patients (IV group) who were treated with standard platinum-based IV chemotherapy during the same period.

Results

The toxicity data in a total of 118 cycles were analyzed. Grade 3 or 4 leukopenia, neutropenia, and pain were more common in the IP group than the IV group. There were seven catheter-related complications. Fourteen patients (73.7%) were able to complete six cycles or more of IP chemotherapy. Survival results in the IP group were compared with those from the IV group; a prolonged progression-free survival was observed (26.6 vs. 20.7 months; p = 0.038). Compared to the previous results with cisplatin-based IP chemotherapy, there was no significant difference in hematologic events. However, gastrointestinal, neurologic, and metabolic events in this study were definitely lower compared to those of cisplatin-based IP chemotherapy.

Conclusions

Carboplatin-based IP and IV combination chemotherapy is feasible in patients with ovarian carcinoma after primary debulking surgery.     

Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma

OBJECTIVE: This trial investigated the safety and efficacy of paclitaxel and topotecan combination chemotherapy for patients with advanced cervical cancer (ACC). METHODS: Patients with recurrent, persistent, or metastatic ACC and an ECOG performance status < or =2 were treated with 175 mg/m(2) paclitaxel on Day 1 and 1 mg/m(2) topotecan on Days 1-5 of a 21-day cycle with G-CSF support and the standard pretreatment regimen for paclitaxel. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Fifteen patients were enrolled, and 86 cycles of therapy (median, 5; range, 1-14) were administered. Grade 3/4 toxicities included anemia (47%), leukopenia (27%), neurotoxicity (13%), thrombocytopenia (13%), and diarrhea (13%). Among 13 evaluable patients, 7 (54%) responded (1 complete and 6 partial; 95% confidence interval = 29.2%, 76.8%). Three (23%) patients experienced stable disease. Progression-free and overall survival were 3.77 and 8.62 months, respectively. CONCLUSION: The combination of paclitaxel/topotecan was generally well tolerated and active in the relapsed, recurrent, or metastatic ACC setting, with response rates comparable with those of other current ACC systemic therapies.