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© 1999 American Society for Clinical Oncology Docetaxel and Cisplatin in Combination as First-Line Chemotherapy for Advanced Epithelial Ovarian CancerFrom the Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow; Belfast City Hospital, Belfast; Bristol Oncology Centre, Bristol; Airedale General Hospital, Steeton, West Yorkshire; Weston Park Hospital, Sheffield; Hammersmith Hospital, London; Stobhill Hospital, Springburn, Glasgow, United Kingdom; and Rhône-Poulenc Rorer, Antony, France. Address reprint requests to Paul A. Vasey, MD, CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, United Kingdom; email pav1y{at}clinmed.gla.ac.uk
PURPOSE: A prospective, nonrandomized, multicenter, open feasibility study of cisplatin and docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV epithelial ovarian cancer was conducted. The primary end point was the incidence of severe fluid retention that necessitated treatment withdrawal. PATIENTS AND METHODS: Cisplatin and docetaxel were administered every 3 weeks for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg two times per day). One hundred patients (median age, 53 years; range, 24 to 71 years) received a total of 512 cycles of chemotherapy in two cohorts: cohort 1, 49 patients, 258 cycles (cisplatin 75 mg/m2 and docetaxel 75 mg/m2); cohort 2, 51 patients, 254 cycles (cisplatin 75 mg/m2 and docetaxel 85 mg/m2). RESULTS: No patients were taken off study because of fluid retention. Sixty-six patients completed six cycles of protocol therapy; 16 stopped early because of toxicity (neurotoxicity in six patients, nephrotoxicity in three, neutropenia in two, and hypersensitivity, diarrhea and vomiting, skin rash, clinical deterioration, and patient's wishes in one patient each). Grade 3/4 neutropenia was observed in more than 75% of patients and seemed to be cumulative. Patients in cohort 2 had significantly more severe neutropenia and lethargy than those in cohort 1. In addition, there were five treatment-related deaths in cohort 2 (three neutropenia and two upper gastrointestinal hemorrhage). Neurotoxicity (mainly sensory, > grade 1) was observed in 23 patients. The overall clinical response rate was 69% (complete response, 38%; partial response, 31%); CA-125 response rate was 73%. Median progression-free survival for the group was 12 months. CONCLUSION: Cisplatin and docetaxel can be administered at doses of 75 mg/m2 and 75 mg/m2, respectively, every 3 weeks, and the utility of this regimen is not limited by fluid retention. However, 33 of 100 patients were unable to complete the planned six cycles, which may explain, in part, the poor overall progression-free survival. Increasing the docetaxel dose to 85 mg/m2 adds unacceptable hematologic toxicity and potential risks to the patient.
OVARIAN CANCER IS the most lethal malignancy of the female genital tract and is the fourth most frequent cause of cancer death in women.1 Most tumors are chemosensitive, and meta-analyses of randomized controlled trials of chemotherapy have suggested that platinum-based chemotherapy is better than nonplatinum therapy and that platinum combinations may offer improved survival over single-agent platinum.2 However, the majority of women with advanced disease are not cured by platinum-based chemotherapy, with fewer than 30% surviving 5 years.3 Although treatment on recurrence is frequently beneficial, relapses that occur within 1 year of completion of primary chemotherapy are difficult to manage with current treatments, because responses are infrequent and of short duration. There is clearly a need for new agents and therapeutic strategies in the front-line setting. The discovery that paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ)4 had promising activity in phase II studies of pretreated ovarian cancer patients, with response rates of up to 37%,5 gave investigators a new antineoplastic agent with a novel mechanism of action6-8 that could be combined with cisplatin. Subsequently, the Gynecologic Oncology Group (GOG) published the results of study GOG-111,9 which showed that in a randomized, prospective phase III trial of patients with advanced disease, a combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide with respect to overall response rates, progression-free survival (PFS), and overall survival. This led most gynecologic oncologists in the United States to adopt this combination as the new standard for first-line therapy of ovarian cancer. This shift in treatment policy was given added weight with the presentation of the European Organization for the Research and Treatment of Cancer–Gynaecological Cancer Cooperative Group, Scandanavian Gynecological Cancer Study Group, National Cancer Institute of Canada, and Scottish Intergroup trial results,10,11 which confirmed the superiority of a paclitaxel-cisplatin combination over cisplatin-cyclophosphamide in terms of both PFS and overall survival. Although there were differences between the two trials (primarily with respect to paclitaxel dose/schedule and amount of cytoreductive surgery allowed), this study added weight to the view that paclitaxel should be included in the front-line treatment of advanced ovarian cancer. Both cisplatin and paclitaxel produce neurotoxicity that is predominantly sensory, and there is evidence that paclitaxel-induced neurotoxicity is dose-dependent12 and may be increased using shorter infusion times.13 Indeed, significant (grade 3 or 4) neuropathy was observed in 20% of patients who received a 3-hour infusion of paclitaxel-cisplatin in the Intergroup study compared with less than 5% in GOG-111, in which a 24-hour infusion of paclitaxel was administered. However, these longer schedules produce greater neutropenia13 and increase patient inconvenience. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a new member of the taxoid family and is currently licensed in the United Kingdom and United States for the treatment of relapsed breast cancer. There is preclinical evidence to suggest that docetaxel may be superior to paclitaxel. Docetaxel has been shown to be more potent (up to fivefold) in vitro than paclitaxel with regard to the promotion of tubulin polymerization and inhibition of depolymerization.14-16 In a direct comparison with paclitaxel in a large number of freshly explanted tumors (including breast, ovarian, lung, and colorectal tumors), docetaxel was found to have at least equivalent cytotoxicity but with incomplete cross-resistance.17,18 Docetaxel also had a longer residence time, accumulated at higher concentrations within cells, and demonstrated a superior therapeutic index in vivo.17-19 Clinical studies have confirmed the presence of incomplete cross-resistance with paclitaxel, reporting activity for docetaxel in paclitaxel-resistant metastatic breast cancer.20 In addition, docetaxel has proved superior to doxorubicin in a direct comparison in metastatic breast cancer,21 whereas paclitaxel has failed to do so.22 In advanced, platinum-refractory ovarian cancer, docetaxel has demonstrated substantial single-agent efficacy at least equivalent to paclitaxel. In a recent overview of four phase II studies that involved 315 assessable pretreated ovarian cancer patients who received docetaxel 100 mg/m2 as a 1-hour infusion every 3 weeks, the overall response rate was 30%, with a response rate in 155 platinum-refractory patients of 28%.23 Median response duration was 6 months, at least equivalent to paclitaxel in the salvage setting.24 In addition, there is preliminary evidence of activity in patients who previously experienced treatment failure with paclitaxel (J. Kavanagh, personal communication, 1998). As with paclitaxel, many patients treated with docetaxel experience potentially reversible sensory large fiber peripheral neuropathies, which are cumulative but not dose-limiting.25,26 However, most neurotoxicity is mild (grade 1 to 2), with only 3.8% graded as severe (all grade 3; data on file, Rhône-Poulenc Rorer), which may indicate a potential advantage for docetaxel over paclitaxel in the management of patients with ovarian cancer, particularly when platinum combinations are used. Docetaxel can produce a fluid retention syndrome most commonly characterized by peripheral edema and weight gain, although pleural/pericardial effusions and ascites also have been reported.27-29 The development of fluid retention seems to be related to the cumulative dose of docetaxel, and premedication with corticosteroids has recently been shown in a randomized trial to delay the onset of this syndrome.30 Moreover, in a retrospective analysis, a 5-day premedication regimen of oral dexamethasone has been demonstrated to be effective in reducing the incidence and severity of fluid retention while also reducing the subsequent frequency of docetaxel treatment discontinuation (data on file, Rhône-Poulenc Rorer). As platinum-paclitaxel combinations become established as the standard treatment of advanced epithelial ovarian cancer and further toxicity information emerges, it is appropriate to evaluate the alternative combination of docetaxel with cisplatin in this patient population. The Scottish Gynaecological Clinical Trials Group performed a pilot study to examine the feasibility of combining docetaxel and cisplatin in the first-line treatment of ovarian cancer after initial cytoreductive surgery. This study was designed as a prospective, nonrandomized, multicenter, open feasibility study, with the primary end point being toxicity: the proportion of patients who terminated study treatment because of fluid retention. In addition, the trial also attempted to acquire data on the potential efficacy of the combination in terms of objective tumor response, duration of response, PFS, and overall survival.
Patients Eligible women had histologically verified epithelial ovarian cancer, were older than 18 years, and had International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV disease with or without successful cytoreductive surgery at staging laparotomy. Stage IC disease was limited to patients with malignant cells in ascitic fluid or peritoneal washings; ruptured capsule or tumor confined to the surface of the ovary only was considered ineligible. Patients were required to have an Eastern Cooperative Oncology Group performance status of less than 4 and adequate bone marrow and hepatic function (neutrophil count > 1.5 x 109/L, platelet count > 100 x 109/L, bilirubin level < the upper limit of normal, AST/ALT levels < 1.5 times the upper limit of normal, and alkaline phosphatase level < three times the upper limit of normal). Adequate renal function was required and defined by a calculated Cockroft-Gault glomerular filtration rate (GFR) greater than 60 mL/min. GFR was measured by a 24-hour urinary creatinine clearance if the calculated Cockroft-Gault GFR was 55 to 60 mL/min; patients were considered eligible if this subsequent GFR was more than 60 mL/min. Written, informed consent in compliance with the recommendations of the Declaration of Helsinki was obtained in all cases. Patients were ineligible for study entry if they had any prior treatment with chemotherapy or radiotherapy or any prior malignancy (except for curatively treated carcinoma-in-situ of the uterine cervix or basal cell carcinoma of the skin). Borderline ovarian tumors or abdominal adenocarcinoma of unknown origin were excluded, as were patients with clinically significant pleural effusions or ascites, unless they were confirmed cytologically to be a result of ovarian cancer. Patients were also ineligible if there was a history of medically significant atrial or ventricular dysrhythmias, congestive heart failure, or documented myocardial infarction within the 6 months before study entry. Additional contraindications included active infection or serious intercurrent illness that was judged by the investigators likely to impair the patients' ability to receive protocol therapy; a history of prior serious allergic reactions; and symptomatic peripheral neuropathy greater than grade 1. Pregnant or lactating women were ineligible, but potentially fertile women who used adequate contraception were allowed treatment. A diagnosis of insulin-dependent diabetes mellitus or other relative contraindications to corticosteroid administration was discussed with the investigators before enrollment.
Treatment Plan and Administration Premedication consisted of oral dexamethasone 8 mg two times per day for 5 days starting the day before chemotherapy. Docetaxel was reconstituted in 250 mL of 5% glucose and administered before cisplatin by intravenous infusion over 60 minutes. Cisplatin was then administered in 1,000 mL of 0.9% NaCl over 4 hours, with adequate hydration before and after. Prophylactic intravenous antiemetics (dexamethasone 8 mg plus either granisetron 3 mg [Kytril; SmithKline-Beecham Pharmaceuticals, Surrey, United Kingdom] or ondansetron 8 mg [Zofran; GlaxoWellcome Ltd, Middlesex, United Kingdom]) were administered to all patients immediately before the docetaxel infusion. All patients were routinely prescribed oral domperidone (Motilium; Sanofi Winthrop Ltd, Surrey, United Kingdom) 20 mg three or four times per day for 5 to 7 days after chemotherapy.
Dose/Schedule Modifications Abnormalities of hepatic function as evidenced by increased aminotransferase (AST/ALT) and/or alkaline phosphatase levels during treatment, in the absence of progressive disease, resulted in dose reductions of docetaxel on subsequent cycles, providing that enzyme levels had returned to baseline values by day 1 of the next cycle. If not, patients were withdrawn from the study.
Treatment delays were planned for patients who developed severe skin toxicity (
Patients with increased serum creatinine levels on day 1 of a treatment cycle underwent measured 24-hour creatinine clearance. Measured values of less than 45 mL/min resulted in discontinuation of further cisplatin and removal from the study. Values between 45 and 59 mL/min resulted in intensified cisplatin hydration by splitting the total dose over 2 days. The primary end point of the study was to determine whether the frequency of severe fluid retention compromised the ability to deliver multiple courses of docetaxel (in combination with cisplatin) to patients with ovarian cancer. A novel fluid retention toxicity scale was developed to help determine this end point. Patients with no fluid retention were considered grade 0; asymptomatic weight gain, grade 1; mild peripheral edema that did not require diuretics, grade 2; symptomatic, moderate edema that required diuretics, grade 3; edema/fluid retention that necessitated treatment withdrawal, grade 4. No dose reductions were planned on the basis of docetaxel-induced fluid retention. The development of grade 3/4 neurotoxicity—motor, sensory, or otologic—necessitated termination of protocol therapy. Mild hypersensitivity reactions were treated by slowing down the docetaxel infusion. Severe hypersensitivity reactions were terminated with appropriate drug therapy (adrenaline, antihistamines, or corticosteroids, depending on the severity). Rechallenge after recovery from a hypersensitivity reaction was allowed if clinically indicated and was generally performed within 3 hours. Later rechallenges (3 to 24 hours) were required to be further premedicated with high-dose dexamethasone and chlorpheniramine (Piriton; Stafford-Miller Ltd, Herts, United Kingdom). Further hypersensitivity reactions necessitated withdrawal from study. Intrapatient dose escalation to docetaxel 85 mg/m2 for cycle 2 was planned for patients in whom the neutrophil and platelet nadir counts in cycle 1 were greater than 0.5 x 109/L and greater than 100 x 109/L, respectively. Similar levels of hematologic nadirs during cycle 2 allowed a second docetaxel escalation to 100 mg/m2 for cycle 3 and the remaining cycles. If prolonged or complicated neutropenia occurred following dose escalation, doses of docetaxel were reduced to the previous level for all subsequent cycles. As the study progressed, it became evident that myelosuppression on the first cycle of treatment was not severe; therefore, a second dose level was introduced, with all new patients starting chemotherapy with docetaxel 85 mg/m2 in combination with cisplatin 75 mg/m2 (cohort 2). However, this higher dose level was found to be associated with significant toxicity (see Results), and all remaining study patients were subsequently treated at the first dose level (docetaxel 75 mg/m2 and cisplatin 75 mg/m2) but with no planned dose escalations.
Patient Evaluation and Clinical Assessments During chemotherapy, patients were monitored weekly for full blood count, serum chemistry, and documentation of treatment-related toxicity using the National Cancer Institute of Canada Expanded Common Toxicity Criteria. Neurotoxicity score was performed after three and six cycles. Before each treatment cycle, patients were weighed and had a full physical examination plus creatinine clearance and CA-125 estimations. Response to chemotherapy was assessed after three and six (and if appropriate, nine) courses of chemotherapy by the same imaging technique used at baseline. Clinical and radiologic tumor response was graded according to standard criteria32; CA-125 responses were graded according to the schema of Rustin et al.33 After completion of protocol chemotherapy, patients were followed-up every 3 months for the first 2 years, every 6 months from 3 to 5 years, and annually thereafter. Pelvic examination was performed at each follow-up visit, along with CA-125 estimations and the structured neurologic assessment. Ultrasound or computed tomography scans were performed if progressive disease was clinically suspected or if CA-125 levels began to increase.
Statistical Methods
Overall survival, PFS, and time to progression were calculated from the date of study registration. All eligible patients were included and all causes of death were analyzed for survival. For PFS, deaths from all causes were again included. For time to progression, causes of death other than malignant disease were treated as censoring events. Kaplan-Meier estimates37 were used to construct the survival curves.
Patient Characteristics and Treatment Summary Between October 31, 1995, and April 4, 1997, 100 patients were enrolled onto this trial by the 12 institutions comprising the Scottish Gynaecological Cancer Trials Group. All patients met the eligibility criteria, and their characteristics are listed in Table 2. The median age was 53 years (range, 24 to 71 years), 89 patients had FIGO stage III/IV disease at presentation, and 90 patients had a performance status of 0 to 1. There were approximately equal numbers of optimally versus suboptimally debulked patients in the group as a whole. In addition, eight patients had secondary cytoreductive surgery either during chemotherapy (two patients after three cycles) or within 1 month after completion of chemotherapy (six patients).
Treatment details are listed in Table 3. A total of 512 cycles of docetaxel and cisplatin were administered to 100 patients in two treatment groups. There were no significant differences in patient characteristics between the two groups. Twenty-five patients received docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 (cohort 1) from cycle 1 (130 cycles), with the possibility of subsequent intrapatient dose escalation. However, only seven patients were actually escalated to 85 mg/m2 docetaxel (five on cycle 2, one on cycle 3, and one on cycle 4), and only two of these patients were escalated further to 100 mg/m2. After an interim assessment of toxicity, 51 patients (cohort 2) received docetaxel 85 mg/m2 plus cisplatin 75 mg/m2 (248 cycles) from cycle 1. After a second interim toxicity assessment, in which a number of treatment-related deaths in this cohort were identified, the remaining 24 patients (128 treatment cycles) were entered onto cohort 1, with no planned intrapatient dose escalation.
Sixty-six patients received the full six cycles of planned protocol treatment. Nine patients (two in cohort 1 and seven in cohort 2) went on to receive further cycles of chemotherapy without docetaxel (single-agent carboplatin or cisplatin) in addition to the six cycles of protocol treatment, up to a maximum of nine cycles. Treatment-related toxicity resulted in a delay of four chemotherapy cycles (1%), modification of cisplatin administration in 16 patients (30 cycles; 6%), and dose reduction of docetaxel in 12 patients. In addition, 34 cycles (7%) of chemotherapy were delayed because of non–treatment-related reasons, and four cycles (1%) of cisplatin were modified in error. No patients had chemotherapy stopped because of fluid retention. Of the 34 patients who did not complete six cycles, 16 (47%) stopped because of treatment-related toxicities, and seven (21%) died during treatment; six of the deaths were related to protocol therapy (Table 4). Six patients (18%) progressed or responded poorly, two (6%) stopped for surgical reasons, two (6%) withdrew consent, and one developed bilateral lower limb venous thromboses.
Toxicity Summary When analyzing the results of the sequential triangular test for the whole group, it became apparent that the lower boundary was crossed after the first 60 patients, which indicated that the null hypothesis could be accepted. At this point, there were another 40 patients still on study (these patients had been recruited during the 6-month period of the sixtieth patient's treatment). The fluid retention results for all 100 patients are listed in Table 5. Significant fluid retention (grade 3) was observed in 14% of patients, and there was no difference observed between treatment cohorts. One patient developed ascites on treatment that was not cytologically proven to be caused by recurrent ovarian cancer; however, because the clinical impression was of progressive disease, this was not graded as edema caused by docetaxel therapy. Of the 14 patients who developed grade 3 peripheral edema, eight developed it before cycle 3. The estimated (median unbiased estimate) percentage of patients who stopped treatment because of edema is 0.7% (95% confidence interval, 0.0% to 3.0%).
Hematologic toxicity was observed in both treatment cohorts. Table 6 compares the incidence of significant neutropenia, thrombocytopenia, and anemia for these cohorts over all treatment cycles. The median neutrophil counts in the two cohorts during cycle 1 only are identical at 1.22 x 109/L (P = .81). No patient in cohort 1 had grade 4 myelogenous toxicity during cycle 1. However, the median nadir neutrophil counts in the two treatment cohorts over all cycles received were 0.5 x 109/L and 0.32 x 109/L, respectively, which is statistically significant (P = .025). There is also evidence for cumulative neutropenia. In Fig 2, the nadir neutrophil counts by treatment cycle are plotted for each cohort, which demonstrates a marked linear downward trend from cycle 1 to cycle 6. Four patients (one in cohort 1 and three in cohort 2) experienced grade 4 neutropenia with fever. Growth factors (granulocyte colony-stimulating factor) were used therapeutically in three patients for four cycles in cohort 2. Two patients (one in each cohort) had their treatment delayed because of a low platelet count on day 1 of the treatment cycle, and one patient in cohort 2 had protocol therapy stopped because the neutrophil count did not recover to baseline values by day 36 after the previous treatment cycle. No other patients experienced delays because of low neutrophil counts.
There were three deaths from neutropenic complications, all occurring in cohort 2. In addition, there were two other treatment-related deaths in this cohort from upper gastrointestinal hemorrhage, probably related to the corticosteroid comedication. This rate of treatment-related mortality led the investigators to stop recruitment at this higher docetaxel dose level (85 mg/m2) and to treat all remaining patients at the 75-mg/m2 docetaxel dose with no planned intrapatient dose escalation. Patients already on treatment with docetaxel 85 mg/m2 were allowed to continue at this dose but were given prophylactic antibiotic therapy (ciprofloxacin 250 mg two times per day) to cover the duration of the expected neutrophil nadir on subsequent cycles. However, three patients underwent a dose reduction to 75 mg/m2 for subsequent treatment cycles. No other deaths occurred after instigation of antibiotic prophylaxis. In cohort 1, only one death occurred on study that was potentially treatment-related: a patient who died in her home on day 11 of her first treatment cycle. No clinical or pathologic information was available for this individual. There was one other death on study that was secondary to a confirmed pulmonary embolism. The most common significant nonhematologic toxicities for all patients are listed in Table 7. Grade 2/3 fatigue/lethargy occurred in 38 patients overall and was significantly more common in cohort 2 (25% v 45%; P = .0055). There were no significant differences in the incidence of any other nonhematologic toxicity between the treatment cohorts. Alopecia was common, with 71 patients experiencing grade 2 (head) or 3 (body) hair loss. Significant episodes of hypersensitivity to docetaxel were rare, occurring only in two patients, one of whom was taken off study as a result. Gastrointestinal toxicities included nausea and vomiting, diarrhea, and mucositis. Nausea and vomiting were generally controllable with coadministered antiemetics, although two patients experienced grade 4 vomiting. The overall incidence of significant (> grade 2) emesis was 11%. Grade 3 or 4 diarrhea occurred in 17 patients, although only five experienced grade 4 diarrhea. All patients were able to be re-treated on subsequent cycles with prophylactic loperamide (Imodium; Janssen-Cilag, High Wycombe, United Kingdom) or codeine phosphate. Significant mucositis (grade 2 or 3) was observed in 16 patients and was generally managed satisfactorily with appropriate mouth care. No patients experienced grade 4 mucositis.
Significant neurotoxicity (> grade 1) was observed in 23 patients and occurred as either sensory (18 patients), motor (seven patients), or both (two patients). A total of 46 patients reported neuropathic symptoms (
Electrolyte disturbances that mainly involved sodium, potassium, or magnesium were observed; hypomagnesemia (> grade 1) occurred in 29 patients, despite routine administration of intravenous magnesium concurrently with cisplatin hydration. Grade 1 to 2 myalgias/arthralgias secondary to docetaxel were reported by 12 and eight patients, respectively. Skin and nail changes were uncommon. Dyspepsia and/or indigestion occurred in 10 patients and were thought to be caused by the coadministered corticosteroids. Three patients suffered corticosteroid withdrawal symptoms after the 5-day dexamethasone administration and on subsequent cycles had dexamethasone tailed off more gradually over 7 days (total dose remained constant). One patient suffered a cardiac dysrhythmia unrelated to protocol chemotherapy.
Response and Survival
To date, 43 patients have died, and 58 have developed progressive disease. Median follow-up duration for living patients is 23 months. Median PFS for the group as a whole is 12 months (95% confidence interval, 10 to 14) and is presented graphically in Fig 3. Individually, the median PFS for cohort 1 is 13 months (95% confidence interval, 10 to 15 months) and for cohort 2 is 11 months (95% confidence interval, 9 to 13 months). These data are presented graphically in Fig 4.
The current standard first-line therapy for advanced epithelial ovarian cancer is the combination of paclitaxel and cisplatin, as evidenced by mature data from two large randomized trials, GOG-111 and European Intergroup.9-11 Despite design differences, these trials produced remarkably similar results, with median PFS durations of 18 and 16 months and overall survival durations of 38 and 36 months, respectively. The main difference in toxicity between these two important trials was the incidence and severity of the peripheral neuropathy observed. Significant neuropathy occurred in more than 25% of all patients when paclitaxel was given by a 3-hour infusion as in the Intergroup trial, compared with less than 5% when given as a 24-hour infusion in GOG-111. Further supporting the 24-hour infusional schedule is experimental evidence that suggests that the cytotoxicity of paclitaxel is schedule-dependent.38 Clinical data on the importance of infusion time for paclitaxel efficacy are less clear; one randomized trial that compared 3- and 24-hour infusions showed no significant difference in response rate,13 but further clinical trials are required to evaluate the importance of this issue. Longer schedules of administration indicate that in Europe (if not the United States), chemotherapy will generally be administered on an inpatient basis, adding to patient inconvenience and costs. Docetaxel is an alternative taxoid that showed no evidence of schedule dependency in preclinical models; phase I trials that used longer infusions of docetaxel demonstrated increased toxicity (including mucositis) without any obvious benefit. The drug is routinely administered over 1 hour as an intravenous infusion and, therefore, has a potential advantage over paclitaxel in ease of administration. Other preclinical studies have suggested a superior therapeutic index to paclitaxel, and significant clinical activity has been observed in the salvage setting. Moreover, a recent in vitro evaluation of seven ovarian cancer cell lines compared the docetaxel-cisplatin combination with the paclitaxel-cisplatin combination and indicated a more pronounced supra-additive effect for the docetaxel-cisplatin combination.39 Such data argue for the evaluation of docetaxel as first-line chemotherapy in combination with cisplatin in ovarian carcinoma. In the current study, 100 women with FIGO stage IC-IV epithelial ovarian cancer were given docetaxel and cisplatin as their primary chemotherapy after initial surgery. This group was generally younger (median age, 53 years) and more fit (89 patients had a performance status of 0 to 1) than the average patient with this disease, which may indicate a degree of selection bias for a new, potentially toxic treatment combination. Despite the good performance status of this patient group, the planned six cycles of chemotherapy was only able to be delivered to 66 patients. Of the 34 patients who stopped chemotherapy before completion, 16 stopped for toxicity reasons, and there were six additional treatment-related deaths. This study was designed to have a specific feasibility end point: the percentage of patients who stopped treatment for fluid retention/edema. This is the appropriate end point for such a study, because the efficacy of the drugs (as single agents) used is already established, and comparative judgments on treatment outcomes in terms of response and PFS can be made sensibly only within the context of a randomized comparative study. Alternative and more general feasibility end points could be considered for such feasibility studies; for example, the percentage of patients who complete three cycles without treatment-related delay or dose reduction (71% in this study). Such an end point would also have the advantage of being available earlier, thus reducing the problem of overrun. The current study recruited 100 patients before it closed, although in theory it could have closed after the sixtieth patient. The equivalent fixed-sample-size study would have required 116 patients. The benefit of the sequential approach in terms of sample size was diminished by the long wait for the feasibility end point and the resultant overrun. Table 5 demonstrates that no patient was withdrawn from the study because of fluid retention, and only 14 patients actually required diuretic therapy for troublesome peripheral edema. Indeed, 55 patients did not develop clinical evidence of fluid retention at all. This consolidates previously published data that premedication with a 5-day corticosteroid regimen delays the onset and reduces the severity of this unusual side effect. More recently, a retrospective analysis that compared patients given a shorter 3-day premedication regimen with those given the 5-day regimen (as used here) demonstrated no differences in the incidence and severity of fluid retention or in the median cumulative dose of docetaxel to its onset (data on file, Rhône-Poulenc Rorer). Interestingly, this retrospective analysis also documented episodes of gastrointestinal hemorrhage (and colonic perforation) in the patients who were given dexamethasone for 5 days, whereas no problems of this nature were observed in the patients who were given corticosteroids for 3 days only. Because two patients died in the current study secondary to upper gastrointestinal hemorrhage, it seems that the benefit/risk ratio is in favor of the 3-day regimen. All new docetaxel studies since 1996 have adopted this shorter corticosteroid dosing schedule. With regard to peripheral neuropathy, the present trial has demonstrated a low rate of neurotoxicity when compared with that reported for cisplatin-paclitaxel combinations, and it seems to be related to cumulative cycles of treatment. Our neurotoxicity incidence of 17% grade 2, 6% grade 3, and no grade 4 compares favorably with the Intergroup (16% grade 3) and German Arbeitgemeinschaft Gynaekologische Onkologie trial40 (34% grade 2; 8% grade 3), both of which used a 3-hour infusion of paclitaxel. Even using a 24-hour infusion, which previously was shown to decrease peripheral neuropathy while increasing myelosuppression,13 the GOG-111 trial reported a 4% grade 3 to 4 incidence. Many investigators are now studying the substitution of carboplatin for cisplatin in combination with paclitaxel in an attempt to decrease this level of neurotoxicity while hopefully maintaining efficacy. However, evidence thus far from two randomized trials in Germany and Holland comparing carboplatin-paclitaxel with cisplatin-paclitaxel shows that significant neuropathy is still a major problem, occurring in 20%40 and 34%41 of patients who receive the combination with carboplatin. More than 75% of patients in the current study demonstrated grade 3 or 4 neutropenia, a rate similar to that observed for docetaxel 75 mg/m2 as a single agent. However, there was a statistically significant difference in the depth of neutropenia between the two cohorts over all treatment cycles, and more patients in cohort 2 experienced complicated neutropenia, including three deaths from neutropenic sepsis. This is an unacceptable rate of treatment-related mortality for a first-line regimen in epithelial ovarian cancer; therefore, the cohort-2 dose level (cisplatin 75 mg/m2 plus docetaxel 85 mg/m2) cannot be recommended for this patient population. Moreover, the significantly higher incidence of troublesome lethargy experienced by patients in cohort 2 reinforces this conclusion. The other troublesome nonhematologic toxicities (eg, emesis, hypomagnesemia, and neurotoxicity) observed in the present study were likely to be related primarily to cisplatin administration. The overall median PFS for the group as a whole seems disappointingly low at 12 months, bearing in mind previous randomized data for the paclitaxel-cisplatin combination in both the GOG-111 and Intergroup studies. Because of the small patient numbers in this study, the differences between cohorts do not approach statistical significance. Moreover, the small increased dose of docetaxel per cycle in cohort 2 does not seem to have a beneficial effect on PFS; in fact, median PFS is slightly shorter for cohort 2, which perhaps reflects its greater toxicity. Any analysis of pre-existing prognostic features and their effect on median PFS suffers from the same lack of statistical power. It is clear that looking for differences in median PFS according to cohort is spurious, and the survival data should be examined for the group as a whole. However, indirectly comparing the survivorship obtained from feasibility studies with that from large randomized trials, such as the Intergroup and GOG-111 trials, is intrinsically unreliable because like is not necessarily being compared with like, even if the patient groups seem similar superficially. However, there are certain factors that perhaps may account for the comparatively poor survival rate observed here for the group as a whole. The number of treatment cycles administered may be crucial. In the current study, nine patients received more than six cycles of chemotherapy, but with platinum alone (ie, carboplatin), not further docetaxel. In the Intergroup study, 31% of patients received more than six cycles of treatment, which included up to nine cycles of paclitaxel in combination. However, in the current trial, patients who received more than six cycles of chemotherapy did so because of a prognostically unfavorable clinical picture, ie, achieving only a partial response after six cycles but with evidence of decreasing CA-125 levels. This contrasts with the Intergroup study, in which patients were allowed to receive further chemotherapy provided that they had not developed progressive disease or that they were designated a pathologic complete response at second-look surgery. Details of further treatment with paclitaxel beyond six cycles in the GOG-111 trial are not available. The impact of treatment duration for taxoid therapy is unknown and is the subject of separate, further trials. In addition, 34 patients stopped treatment before completing six cycles for toxicity or other reasons, compared with less than 14% in the Intergroup trial. This is demonstrated in Fig 5, in which the low lower quartile and long lower "tail" observed for cohort 2 reflects the fact that a higher proportion of patients received less than six cycles of therapy in this group. Several randomized trials have examined the impact of increased platinum dose-intensity and/or total cumulative dose in ovarian cancer. These trials have demonstrated conflicting results, but, interestingly, the majority of "positive" trials have demonstrated the importance of total dose of platinum rather than increased delivered dose-intensity.42 Moreover, the number of patients who stopped protocol treatment because of progressive disease in the current study was five, which is identical to the 5% rate observed in the Intergroup study. Furthermore, the response rates demonstrated for the docetaxel-cisplatin combination are comparable to that reported for paclitaxel and cisplatin in either the Intergroup or GOG-111 trials, which suggests comparable efficacy for docetaxel in this combination. Therefore, one hypothesis is that the toxicity that prevented completion of chemotherapy indicated that a number of patients received less than a full course of chemotherapy, and this inability to deliver sufficient cycles of chemotherapy may be the most significant factor impacting on the PFS of the group as a whole.
To address these concerns, we recently completed a dose-finding study with carboplatin in combination with docetaxel in patients with untreated ovarian cancer.43 Preliminary data suggest that docetaxel 75 mg/m2 plus carboplatin area under the concentration-time curve 5 (GFR via 51Cr EDTA clearance) given every 3 weeks is generally much better tolerated than docetaxel plus cisplatin, with more than 90% of patients able to receive a planned six cycles of chemotherapy. In addition, less than 5% neuropathy (maximum grade 2) has been observed to date in more than 140 patients treated. Furthermore, an early efficacy analysis shows a response rate of 67% (complete response, 40%), and although it is too early to give a definitive declaration of survivorship, preliminary analysis of median PFS is encouraging. Docetaxel 75 mg/m2 plus carboplatin area under the concentration-time curve 5 is the proposed control arm versus carboplatin plus paclitaxel in patients with untreated FIGO stage IC-IV advanced ovarian cancer for an international, multicenter, randomized trial. In conclusion, the present study suggests that the combination of docetaxel and cisplatin can be administered safely at doses of 75 mg/m2 per drug every 3 weeks, whereas increasing the dose of docetaxel to 85 mg/m2 adds unacceptable hematologic toxicity and potential risks to the patient. In addition, this higher dose is generally more poorly tolerated, with more patients experiencing significant lethargy. Overall, only two thirds of all patients were able to complete the planned six cycles. Given the encouraging preliminary data from our docetaxel-carboplatin dose-finding study, which suggests an attenuation of cisplatin-induced toxicity with much improved patient tolerance, this cisplatin-docetaxel combination is not an ideal first-line therapy in advanced epithelial ovarian carcinoma.
Supported by the Cancer Research Campaign and Rhône-Poulenc Rorer. We thank the following individuals who helped to enter patients onto this study: Drs M. Cruickshank and D.E. Parkin, Aberdeen Royal Infirmary, Aberdeen; Dr H. Yosef, Beatson Oncology Centre, Glasgow; Dr V.L. Barley, Bristol Oncology Centre, Bristol; Drs J. Kennedy and M. Soukop, Glasgow Royal Infirmary, Glasgow; Dr I.A. Duncan, Ninewells Hospital, Dundee; Professor J. Smyth, Western General Hospital, Edinburgh; and Dr M. Deeny, Stobhill Hospital, Glasgow, United Kingdom. We also acknowledge the contribution of the research nurses who helped to administer the chemotherapy and conduct patient follow-up.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 x 109/L and the platelet count was 
grade 1, when they could be re-treated with a 15-mg/m2 reduction of docetaxel. No treatment modifications were planned for mucositis, although 
highlight extreme or unusual values).
