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Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma
Annals of Oncology 9: 37-43,1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma A multicenter GINECO (Groupe d'Investigateurs Nationaux pour VEtude des Cancers Ovariens) phase II study
Departments of Medical Oncology, Centres Anticancereux of Clermont-Ferrand, Lyon, Marseille, Nancy, Paris, and Centres HospitaloUniversitaires et Centres Hospitaliers of Avignon, Brive, Bourgen Bresse, Grenoble, Limoges, Paris, Saint-Etienne and Suresnes, France * Seepage 42 for list of participants
responses gave an overall response rate of 42% (95% CI: 30%-54%). Response rates for platinum-refractory patients Background: Platinum compounds are the most active drugs and those with early (5*3 and <12 months) and late (>12 in ovarian cancer treatment; cisplatin and carboplatin demon- months) relapses were 24%, 33% and 70%, respectively. The strated similar efficacies but different toxicity profiles. Pacli- respective median response duration, the median progressiontaxel combined with cisplatin asfirst-linetreatment improved free survival and median overall survival were 8, 6 and 14 overall survival when compared to a cisplatin-cyclophospha- months. Myelosuppression was the most frequent and severe mide combination, but generated higher rates of neutropenia, toxicity. Grade 3 and 4 neutropenia occurred, respectively in febrile neutropenia and neurotoxicity. The paclitaxel-carbo- 30% and 23% of the cycles; 6% of the cycles benefited from platin combination may be better tolerated than cisplatin- medullary growth factors. Only one episode of febrile neutropaclitaxel. penia was observed. Grade 3 and 4 thrombocytopenia occurred, Design: The objective of the present study was to assess the respectively during 3% and 1% of the cycles. Alopecia was efficacy and safety of the combination of paclitaxel and carbo- frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death platin in previously treated advanced ovarian cancer patients. Patients and methods: During or after platinum-based che- was attributed to progressive disease and possibly to therapy. motherapy, 73 patients with progressive advanced epithelial Conclusion: This combined paclitaxel-carboplatin therapy ovarian carcinoma were enrolled to receive every four weeks is effective and can be safely administered to ovarian cancer a three-hour infusion of paclitaxel 175 mg/m2 followed by a patients who relapse after one or two regimens of platinum30-minute carboplatin infusion. The carboplatin dose was based chemotherapy. calculated to obtain the recommended area concentrationversus-time under the curve of 5 mg-mT'-min. Results: Toxicity and response could be evaluated for 72 Key words: carboplatin, chemotherapy, ovarian carcinoma, and 62 patients, respectively. Eleven complete and 15 partial paclitaxel Summary
Introduction
hours [7]. Carboplatin, a cisplatin analog, has been found to be as effective as cisplatin [1] and generates Platinum compounds are considered to be the most fewer non hematologic side effects, including neuroactive drugs for the treatment of ovarian cancer [1, 2]. toxicity, vomiting and nephrotoxicity; however, it is Paclitaxel has been show be highly active in relapsing responsible for more myelosuppression, mainly thrompatients, with response rates ranging from 14% to 48% bocytopenia. Although much hope is invested in the [3-7]. When combined as first-line treatment, cisplatin combination of paclitaxel and carboplatin, it can only and paclitaxel given as a 24-hour infusion improved the be used in the future to replace the reference therapy response rate and the overall survival of patients with of cisplatin and paclitaxel if it is proven to be better suboptimally debulked stage III ovarian cancer as com- tolerated and to have at least comparable efficacy. pared with the standard combination of cisplatin and These observations prompted us to combine paclitaxel cyclophosphamide. However, higher rates of neutrope- and carboplatin to treat patients who had previously nia, febrile neutropenia and neurotoxicity were observed received platinum derivatives but not taxane. The doses [8]. Paclitaxel-induced neutropenia can be attenuated were determined based on preliminary data collected by infusing the drug over three hours rather than 24 from phase I studies underway at the time and since
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J. P. Guastalla, E. Pujade-Lauraine, B.Weber, H. Cure, H. Orfeuvre, M. Mousseau, P.Vincent, V. Dieras, N. Tubiana-Mathieu, J. P. Jacquin, L. Mignot, B. Leduc, P. Viens & D. Pariso
38 of paclitaxel or carboplatin administered per week as a function of body surface area (mg/m2/week). Adjustments of the paclitaxel and carboplatin doses were required for major reversible organ toxicities. The paclitaxel dose for the next cycle was reduced by 20% without changing the carboplatin dose when the absolute neutrophil count (ANC) was <0.5 x 109/l for seven days or longer, or when febrile neutropenia developed (temperature 38 °C and ANC <0.5 x 109/l, requiring antibiotics and hospitalization). Granulocyte growth factors were administered at the investigator's discretion in the case of severe granulocyte toxicity. The carboplatin dose for the next cycle was reduced by 20% without modifying the paclitaxel dose in the case of grade 4 thrombocytopenia. Drug administration was postponed when the ANC was < 1.5 x 1O9/1 and the platelet count was < 100 x 109/l on day 28. The paclitaxel and/or carboplatin doses were reduced by 20% when neutropenia and/or thrombocytopenia persisted beyond day 28 but recovered between days 35 and 42 (treatment delayed one or two weeks). When hematologic recovery was not achieved by day 42, the patient was withdrawn from the study. The paclitaxel dose was reduced by 20% in the case of WHO grade > 2 mucositis or WHO grade 2 neuropathy. The patient was withdrawn from the study when grade 3 neuropathy occurred, the creatininemia concentration increased >2.5 times above the upper normal limit, or arrhythmia or a second- or third-degree atrioventricular heart block occurred.
Patients and methods Study procedure
The protocol was approved by the Bio-Ethics Committee: 'Comite Consultatif de Protection des Personnes dans la Recherche Biomedicale (CCPPRB)' of Hotel-Dieu Hospital in Pans on September 20, 1993. Eligibility criteria To be eligible for this study, a patient had to have a histologically documented primary ovarian adenocarcinoma previously treated with either one or two platinum-based regimens. Other requirements included: progressive disease, presence of at least one bidimensionally measurable target lesion ^ 2 cm, age 18 to 75 years, World Health Organization (WHO) performance status of 0 or 1, plasma creatinine level ^ 1.25 times the upper normal limit, bilirubin level ^ 1.25 times the upper normal limit, transaminases ^2.5 times the upper normal limit except in the patients with hepatic metastases, white blood cell count 3J3.5 X 109/l, granulocyte count >2.0 x 109/l, platelet count 5= 100 x 1O9/1. Patients were excluded when they had received previous taxane-based chemotherapy, intensive chemotherapy requiring stemcell transplant or bone-marrow irradiation of more than 30% of the total bone-marrow volume. Also excluded were those with a past history of atrial or ventricular arrhythmia even when controlled by drugs, atrioventricular heart block, myocardial infarction within the six months prior to the study, WHO grade 2 neurotoxicity or pre-existing neurologic pathology, active infection or severe disease including intestinal occlusion and those with allergic reactions to drugs containing Cremophor®. All patients gave their written informed consent.
Treatment schedule
Paclitaxel (TaxolE, Bristol-Myers Squibb, Paris, France) diluted in 500 ml of a 5% glucose solution was administered at a dose of 175 mg/m2 as a three-hour intravenous infusion, followed by a 30-minute intravenous infusion of carboplatin (Paraplatin®, Bristol-Myers Squibb). The dose of carboplatin was calculated for each cycle using Calvert's formula1 where the glomerular filtration rate (GFR) was calculated based on the serum creatinine level according to the Cockroft-Gault formula.2 All patients were premedicated with oral prednisolone (130 mg) 12 hours and six hours before paclitaxel, and intravenous dexchlorpheniramine (6 mg) and cimetidine (450 mg) or ranitidine (50 mg), 30 minutes before paclitaxel. The treatment was repeated every four weeks. Dose-intensity was calculated in terms of the dose
Thoracic radiography, computed tomography scan of the abdomen and pelvis were performed within four weeks before entry into the study and medical history, clinical examination, performance status assessment, electrocardiogram and blood analyses (complete blood cell count, serum creatinine, bilirubin, transaminases, alkaline phosphatases and CA 125) were performed within two weeks of this date. All patients were registered at the Data Processing Center. Blood cell and platelet counts were repeated weekly. Physical examination, WHO grade toxicity assessments and blood tests were done on day one of each cycle. Radiologic studies to document the status of all measurable disease noted at baseline were carried out systematically after the second and sixth cycles and whenever deemed necessary. A lesion was considered to be measurable when it could be measured in two dimensions and when one of these measurements was > 2 cm. A lesion could be evaluated when it was measurable in only one dimension. The following lesions could not be measured or evaluated: abdominal mass which could be palpated but not measured, pleural effusion, atelectasis, ascites, bone metastases and previously irradiated lesions (but not new lesions in a previously irradiated area). A complete response was defined as the complete disappearance for at least four weeks of all measurable or assessable lesions. A partial response was defined as a reduction that lasted for at least four weeks of at least 50% of the sum of the products of two perpendicular diameters of all measurable lesions, no increase in lesion size and no new lesions. Patients who showed neither a complete response nor a partial response were considered to be non responders. Progressive disease was defined as the appearance of new lesions or an increase of > 25% in existing lesions. The platinum-free interval was defined as the interval between the last day of the previous platinum-based chemotherapy and thefirstday of the paclitaxel-carboplatin regimen. The time to progression (for eligible patients) and overall survival (for all patients) were measured from the date of inclusion. The duration of response for assessable patients was calculated from the day the maximal response was observed until the date of progression for patients with a complete response and from the date of inclusion until the date of progression for patients with a partial response. Platinum-refractory patients were defined as those who did not achieve a partial or a complete response to their last platinum-based chemotherapy or those who relapsed < 3 months after the end of that treatment. An early relapse was defined by a platinum-free interval of ^ 3 months and < 12 months. A late relapse occurred 12 months or later after the completion of the last platinum regimen.
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published [9, 10], and empirically and arbitrarily by taking into consideration known effective doses of carboplatin and paclitaxel [7, 11, 12]. The dose of carboplatin was adjusted to obtain an area under the curve (AUC) of 5 mg-mf1- min (AUC 5), and paclitaxel was administered as a three-hour infusion at a dose of 175 mg/m2. The treatment was repeated every four weeks, an interval deemed optimal to limit toxicity in previously treated patients. Because clinical synergy of carboplatin and paclitaxel had not been ruled out, we prescribed this regimen to patients refractory and resistant to platinum and its derivatives, a situation in which the probability of a response to chemotherapy is particularly low. The aim of this phase II multicenter trial was to assess the clinical efficacy of and the tolerance to the paclitaxel-carboplatin combination in advanced ovarian cancer patients previously treated with platinum compounds.
39 Quality control
Table 1. Patient characteristics (n = 73).
All responses were reviewed by an external panel of independent expert radiologists from the medical schools of Paris, and Lyon, France. A clinical investigator assured the quality control of treatment administration and data collection in the various participating centers and demonstrated that both procedures were comparable in those centers that enrolled only one or two patients and those that contributed more thanfivepatients.
Parameter
Number of patients
Median age, years Histology Serous Undifferenciated Endometrioid Other Ascites
58
Statistical analysis
52 8 4 9
Yes No
26 47
Metastases Peritoneum alone Visceral Tumor size (mm)
Results
40-100 >100 Number of previous regimens
37 36 32 34 7
<40
Patient characteristics Between March 1994 and March 1995, a total of 73 patients were enrolled; their demographic and clinical characteristics are summarized in Table 1. Response Of the 73 patients included in the study, the responses of 62 could be evaluated. Eleven were unassessable for the following reasons: the external panel of radiologists considered that seven patients had no measurable lesions and were ineligible; one patient refused treatment; after the first cycle of chemotherapy, two patients experienced severe toxicity and a third had both prolonged toxicity and disease progression. Twenty-six of the assessable patients responded to therapy (overall response rate 42% (95% CI: 30%54%)) including 11 complete responses (CR 18% (95% CI: 8%-27%)). The overall response rate for all included patients (« = 73) was 36% (95% CI: 25%-47%)). The median response rate duration was 8.3 months (range 1-22+ months). Information was available on the efficacy of the last platinum-based chemotherapy for 59 patients who were classified as platinum-refractory, early relapse or late relapse (Table 2). Among them five (24%), six (33%) and 14 (70%), respectively, responded to paclitaxelcarboplatin {P < 0.01 for late relapse versus pooled platinum-refractory and early relapse patients). Their performance status (0 vs. 1) and disease characteristics such as the presence of ascites (yes vs. no), site of disease (peritoneal vs. visceral) and tumor size (< 40 mm vs. 40 mm) had no significant predictive value for response to the paclitaxel-carboplatin combination. Toxicity One patient did not receive any treatment; the other 72 patients were evaluated for toxicity. They received a total of 340 courses of paclitaxel-carboplatin, with a median
57 16
1 2
Previous platinum Cisplatin Carboplatin Cisplatin + carboplatin Other platinum Response to platinum Pathologic complete remission Clinical complete remission Partial response Stable Progression Unknown Therapy-free interval < 12 months 5= 12 months
38 16 15 4 12 22 12 9 14 4 43 30
Table 2. Response to paclitaxel-carboplatin and sensitivity to previous platinum therapy. Response to paclitaxelcarboplatin
Sensitivity to previous platinum Refractory
Early relapse (3=3mo< 12 mo)
Late relapse (>12mo)
Number of patients Complete response Partial response Total no. (%)
21 1 4 5(24)
18 1 5 6(33)
20 9 5 14(70)
of 5 courses per patient (range 1-9). The received percentage of the scheduled dose-intensity was 99% for paclitaxel and 95% for carboplatin. Grade 3 and 4 neutropenia was observed during 103 (30%) and 79 cycles (23%), in 21 (29%) and 33 (46%) patients, respectively. Granulocyte colony stimulating factor (G-CSF) was administered during only 20 of the 340 cycles (6%). One episode of febrile neutropenia was observed during the study. Grade 3 and 4 thrombocytopenia occurred in 10 (3%) and four cycles (1%) during the treatment of seven and four patients, respectively. The median leukocyte, neutrophil and platelet counts
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Univariate analysis of predictive factors of response was performed using Mantel-Haenzel y} tests or Wilcoxon rank-sum tests. Overall survival for all included patients and progression-free survival for eligible patients were analyzed using the Kaplan-Meyer method.
40 Table 4 Percentages of non hematologic toxicities observed in patients (n = 72) and reported according to WHO grade. Side effect
Alopecia Nausea/vomiting Neuropathy Myalgia/arthralgias Constipation Diarrhea Infection Febrile neutropenia Mucositis Hypersensitivity Cardiac arrhythmia Alkaline phosphatase Transaminases Creatinine Bilirubin
WHO grade 1
2
3
4
_ 18 32 10 10 4 6 4 4 1 3 1 4 4
3 28 14 11 22 8 5 4 1 1 4 -
76 14 1 1 4 2 1 3 -
1 _ _ _ -
attributed to progressive disease and possibly to chemotherapy toxicity. Survival
The median overall survival time for the whole population was 14 months. The median progression-free survival time for eligible patients was six months. Discussion
In this evaluation of the paclitaxel-carboplatin regimen in patients with previously treated advanced ovarian cancer, carboplatin was given at the target dose that gives an AUC 5 as recommended for this drug when it is given in any combination to these patients [13]. The paclitaxel dose of 175 mg/m2 infused over three hours is the routinely prescribed as a single agent in Europe for this patient population. Table 3. Leukocyte, neutrophil, hemoglobin and platelet nadirs during The overall response rate achieved by the 62 assessthe first six cycles of paclitaxel-carboplatin treatment (241 cycles could able patients out the 73 enrolled was 42% (95% CI: be evaluated). 30%-54%). The response rate observed in this study the paclitaxel-carboplatin combination compares with Parameter Cycle number favorably to those obtained with paclitaxel or carbo1 platin given as single agents. The overall response rates obtained with a single three-hour perfusion of paclitaxel Number of cycles 56 48 42 35 35 25 9 14% and 20% for platinum-resistant ranged between Leukocytes (10 /l) Median nadir 2.40 2.10 2.15 2.0 2.1 2.1 ovarian cancer patients [7, 14-16] and those obtained Range 1.1-8.5 0.9-4.1 1.1—4.3 0.7-5.0 1.3-3.5 1.4-4.5 with carboplatin monotherapy in previously treated paNeutrophils(109/1) tients ranged from 8% to 27% [17, 18]. The response rate Median nadir 0.8 0.7 0.8 0.5 0.7 0.8 Range 0.1-5.8 0.1-2.4 0.2-2.3 0.0-2.6 0.0-1.8 0.0-1.9 to the paclitaxel-carboplatin combination appears to be Hemoglobin (g/1) at the upper limit of the 14%-43% range achieved with Median nadir 103 106 104 103 102 105 various carboplatin combinations in this context [18]. Range 54-128 73-147 67-144 75-136 75-121 70-122 Platelets (lO'/l) The higher overall response rate (70%) noted in patients 168 Median nadir 149 157 133 143 117 with late relapse, 12 months or more after the last Range 66-291 12-257 20-309 30-252 35-238 platinum administration, as compared to that achieved
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and hemoglobin concentrations were not significantly different over the first six courses for those patients not given G-CSF and for whom at least one weekly complete blood cell count was available (Table 3). Early discontinuation of treatment was necessary for three patients who had prolonged grade 3 thrombocytopenia after the first cycle and for one patient who had grade 3 peripheral neuropathy after the second one. Thirty-four cycles (10%) were delayed for 18 patients: 12 because of prolonged thrombocytopenia (five patients),fivebecause of prolonged neutropenia (three patients), five because of prolonged thrombocytopenia and neutropenia (one patient), one because of an intercurrent non neutropenic infection and 11 in eight patients for reasons unrelated to toxicity (patient request or administrative reasons). Non hematologic toxicities were mostly moderate (Table 4), with alopecia, nausea/vomiting and moderate peripheral neuropathy (47%) being the most common. Transient symptoms of peripheral neuropathy were severe in only one patient and was felt to be disabling by six others. There was no difference in the incidence of neuropathy between patients who had previously received cisplatin and those who had not (42% and 50%). Three patients experienced grade 1 hypersensitivity reactions; only one patient had asymptomatic atrial extrasystoles. Biologic abnormalities were insignificant except for acute renal insufficiency in one patient who presented an infection that was unrelated to neutropenia and was treated with aminosides three weeks after the end of chemotherapy. The only patient who died early suffered an intestinal occlusion on day 21 after the first cycle of chemotherapy associated with an eight-fold increase of the basal serum transaminase concentration and, on day 26, grade 4 thrombocytopenia and anemia and grade 3 neutropenia. A computed tomography scan showed a small intestinal occlusion, abnormal iliac and aortic lymph nodes, and a tumor mass at the ileocolic junction with a probable hemorrhage. Her performance status deteriorated rapidly and her death, on day 32, was
41 overall response to the combined regimen enables us to regard it favorably. Thrombocytopenia was rare. Grade 3 and 4 thrombocytopenia occurred in only 4% of the cycles in 11 patients. As early reports of this combination suggested, the degree of thrombocytopenia seen was less than that expected from the use of carboplatin alone [25-27]. Despite its rarity, thrombocytopenia was dose-limiting in the paclitaxel-carboplatin regimen. Prolonged thrombocytopenia was totally or partly responsible for half of the cycle delays (5% of the cycles) and was the cause of early discontinuation of therapy for three of the four patients. Is it possible to lower the incidence of thrombocytopenia in the paclitaxel-carboplatin regimen? Carboplatin toxicity particularly concerning thrombocytopenia, has been attributed to its urinary elimination and correlated to the AUC. Calvert developed a formula to determine the dose of carboplatin as a function of the GFR as measured by 51Cr-EDTA [13]. In our study, we used Calvert's formula with a recommended target AUC of 5 m g m r ' - m i n , but we calculated the GFR using the serum creatinine concentration and the Cockroft-Gault formula [28]. Using this approximation to determine the carboplatin dose, particularly in patients who could have platinum-related subclinical alterations of renal clearance that might not be reflected in serum creatinine, may have led to undue toxicities, including thrombocytopenia. Recently, Chatelut et al. developed another formula3 to calculate the carboplatin dose directly by using the serum creatinine concentration [29]. Chatelut's formula appears to give results similar to those obtained with Calvert's formula [30]. In our opinion, it remains necessary to determine, through a large clinical trial, the optimal method of delivering carboplatin in the paclitaxel-carboplatin combination. In conclusion, the combination of carboplatin (AUC 5) and paclitaxel (175 mg/m2 as a three-hour infusion) can be administered safely to outpatients with advanced ovarian cancer who relapse after having received one or two chemotherapeutic regimens. In the case of early relapse ( ^ 3 and <12 months) or outright resistance to cisplatin, the paclitaxel-carboplatin combination does not appear to be better than paclitaxel alone. For patients who relapse ^ 12 months after the end of prior therapy, this combination is an alternative to others that do not include paclitaxel. However, only a randomized comparative study will be able to specify whether the improved overall survival observed with paclitaxel given asfirst-linetherapy holds true for patients with relapsed, advanced disease. This paclitaxel-carboplatin combination is now being compared to cisplatin-paclitaxel as first line therapy in a randomized trial also testing a cycle interval of 22 days, rather than 28 days as in our study [31].
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in platinum-refractory patients (24%) or those who relapsed early (33%) is consistent with previous reports showing the dependence of salvage treatment activity in ovarian cancer on the length of the platinum-free interval and the response to previous platinum-based therapy [19-22]. The 24% response rate observed in platinumrefractory patients is similar to those observed in phase II studies with 24-hour or three-hour perfusion of paclitaxel as a single agent (range 13%-33%) [3, 5, 7, 16, 23]. These findings do not support clinical synergy between paclitaxel and carboplatin and, for those patients who had not received paclitaxel and resisted cisplatin outright, it is preferable, in our opinion, to prescribe paclitaxel alone. For patients relapsing six months and especially 12 months after the end of prior platinum-based chemotherapy, the paclitaxel-carboplatin yields a relatively high reponse rate, similar to those achieved with the best combinations known. It remains to be determined whether the combination of drugs currently administered in this situation is indeed better than monochemotherapy. In first line treatment, overall survival did not differ, regardless of wether cisplatin was given alone and followed in cross-over fashion by paclitaxel or the combination was administered [24], However, the toxicities of the two regimens were different. A similar cross-over strategy could be applied to relapsing patients and should compare the paclitaxel-carboplatin combination to each drug used separately in a crossover fashion in order to determine the response rate, the toxicity and the quality of life of patients in each treatment group. The paclitaxel-carboplatin regimen can be safely administered to outpatients. Non hematologic side effects were mainly limited to alopecia and moderate nausea or vomiting. Neuropathy of any grade was observed in 47% of our patients but only one stopped treatment after the second cycle because of its severity. The occurrence of neuropathy was found to be independent of previous platinum compound administration. Although, in terms of neuropathy the combined regimen was equivalent to paclitaxel alone and more toxic than carboplatin alone, in light of its better overall response rate, these side effects are acceptable. The main toxicity of the paclitaxel-carboplatin combination was myelosuppression. Grade 3 and 4 neutropenia occurred during 53% of the cycles and in 75% of the patients. The frequency of severe neutropenia with the paclitaxel-carboplatin combination was about twice that observed for the same regimen of paclitaxel alone [7, 14-16] but was similar to that reported for paclitaxel given alone at a dose of 135 mg/m2 in a 24-hour infusion to previously treated patients [23]. Neutropenia subsequent to the combined regimen was of limited clinical incidence, was of short duration and it alone was responsible for the postponement of only five of 340 cycles. In addition, only one episode of febrile neutropenia was observed. Again, despite more neutropenic events being attributed to the paclitaxel-carboplatin combination than to each drug alone, the improved
42 Acknowledgements Supported in part by a grant from Bristol-Myers Squibb (Paris, France). The authors are grateful to Prof. Jean Noel Buy, Dr. Luce Malbec, and Dr. Marine Carteret who reviewed the radiological data; Christiane Dumont-Puleo for data management; and Janet Jacobson and Margaret Haugh for editing the English used in the manuscript.
9. 10. 11. 12.
* Participants 13. 14.
15.
16.
Notes 1. Calvert's formula: dose of carboplatin (mg) = target AUC x (GFR + 25) where GFR = glomerular filtration rate. 2. Cockroft-Gault's formula: GFR = 1.04 x (140 - age (years) x weight (kg))/creatininemia (umol/1). 3. Chatelut's formula: carboplatin clearance (ml/min) = 0.134 x weight + (218 x weight x (1 - 0.00457 x age) x (1 - 0.314 x sex)/ creatininemia (umol/1)). Dose of carboplatin = target AUC x carboplatin clearance. Weight in kg; age in years; male: sex = 0; female: sex = 1.
17. 18. 19.
20.
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A. Bareille, Centre Hospitalo Universitaire, Poitiers; J.L. Benbunan, Centre de Rouger, Sarcelles; B. Brun, Hopital Pitie Salpetriere, Paris; M. Dray, Polyclinique de Courbancy, Reims; J.C. Eymard, Institut Jean Godinot, Reims; M. Flesch, Clinique Fondation Clement Drevon, Dijon; A. Goupil, Centre Rene Huguenin, Paris; D. Lepille, Clinique Pasteur, Evreux, J.F. Llory, Clinique Hartman, Neuilly sur Seine; C. Martin, Centre Hospitalier, Annecy; E. Malaurie, Centre Hospitalier, Creteil; P.Y. Peaud, Centre Hospitalier, Valence; C. Platini, Centre Hospitalier Bel-Air, Metz-Thioville; J.C. Slawinski, Groupe de Radiotherapie et d'Oncologie des Pyrenees, Tarbes; V. Trillet-Lenoir, Centre Hospitalo Universitaire Lyon Sud, Lyon; P. Venmn, Centre Oscar Lambret, Lille.
combination therapy with paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with suboptimal stage III and stage IV ovarian cancer: A Gynecologic Oncology Group study. Semin Oncol 1997; 24 (Suppl 2): 13-6. Ten Bokkel Huinink W, Veenhof C, Huizing M et al. Carboplatin and paclitaxel in patients with advanced ovarian cancer: A dosefinding study. Semin Oncol 1997; 24 (Suppl 2): 31-3. Ozols RF. Carboplatin and paclitaxel in ovarian cancer. Semin Oncol 1995; 2: 278-83. Jodrell DI, Egorin MJ, Canetta RM et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 1992; 10 (4): 520-8. Guastalla JP, Lhomme C, Dauplat J et al. Taxol (paclitaxel) safety in patients with platinum pretreated ovarian carcinoma: An interim analysis of a phase II multicenter study. Ann Oncol 1994; 5 (Suppl 6): 33-8. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7 (11): 1748-56. Lhomme C, Guastalla JP, Dauplat J et al. A phase II study of Taxol® (T) (paclitaxel) over 3 hours (H) in 192 platinum pretreated patients (PTS) for ovarian carcinoma (OC). Eur J Cancer 1995; 31A (Suppl 5): 108. Carmichael J, Gordon A, Malfetano J et al. Topotecan, a new active drug, vs. paclitaxel in advanced epithelial ovarian carcinoma: International Topotecan Study Group trial. ASCO 1996; 15 (765): 283 du Bois A, Luck HJ, Bauknecht Tet al. Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer (in process citation). Ann Oncol 1997; 8: 355-61. Kjorstad K, Harris A, Bertelsen K et al. A multicenter phase II study of carboplatin in advanced ovarian carcinoma: Final report. Ann Oncol 1992; 3 (3): 217-22. Christian MC, Trimble EL. Salvage chemotherapy for epithelial ovarian carcinoma. Gynecol Oncol 1994; 55: S143-50. Seltzer V,Vogl SKaplan B. Recurrent ovarian carcinoma: Retreatment utilizing combination chemotherapy including cis-diamminedichloroplatinum in patients previously responding to this agent. Gynecol Oncol 1985; 21 (2): 167-76. Van der Burg ME, Bon GG, Ooosterom R et al. Evaluation of the tumor serum markers ca 125, ca 15.3 and ca m29 in monitoring ovarian cancer (meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1991; 10: A607. Markman M, Rothman R, Hakes Tet al. Late effects of cisplatinbased chemotherapy on renal function in patients with ovarian carcinoma. Gynecol Oncol 1991; 41 (3): 217-9. Blackledge G, Lawton F, Redman CKelly K. Response of patients in phase II studies of chemotherapy in ovarian cancer: Implications for patient treatment and the design of phase II trials. Br J Cancer 1989; 59 (4): 650-3. Trimble EL, Adams JD, Vena D et al. Paclitaxel for platinumrefractory ovarian cancer: Results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 1993; 11 (12): 2405-10. Muggia FM, Braly PS, Brady MF et al. Phase III of cisplatin or paclitaxel, versus their combination in suboptimal stage III and IV epithelial ovarian cancer: Gynecologic Oncology Group (GOG) study. ASCO Proc 1997; (16): 352A. Calvert AH, Boddy A, Bailey NP et al. Carboplatin in combination with paclitaxel in advanced ovarian cancer: Dose determination and pharmacokinetic and pharmacodynamic interactions. Semin Oncol 1995; 22: 91-8; discussion 99-100. Ozols RF. Combination regimens of paclitaxel and the platinum drugs asfirst-lineregimens for ovarian cancer. Semin Oncol 1995; 221-6. Kearns CM and Egorin MJ. Considerations regarding the lessthan-expected thrombocytopenia encountered with combination paclitaxel/carboplatin chemotherapy. Semin Oncol 1997; 24 (Suppl 2): 91-6.
43 28. Cockcroft DWand Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; (16): 31-41. 29. Chatelut E, Canal P, Brunner V et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 1995; 87 (8): 573-80. 30. Barth A, Kochli OR, Kung F et al. Comparison of bedside estimates of GFR for AUC dosing of carboplatin in patients with ovarian cancer. Proc Am Soc Clin Oncol 1996; (15): 292. 31. Neijt JP, Hansen M, Sorensen PGet al. Randomized phase III study in previously untreated epithelial ovarian cancer FIGO stage IIB, IIC, III, IV, comparing paclitaxel-cisplatin and paclitaxel-carboplatin. ASCO Proc 1997; (16): 352a.
Received 2 July 1997; accepted 2 October 1997. Correspondence to: Jean Paul Guastalla, MD, PhD Centre Leon Berard 28, rue Laennec 69008 Lyon France E-mail: [email protected]
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Original article Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma A multicenter GINECO (Groupe d'Investigateurs Nationaux pour VEtude des Cancers Ovariens) phase II study
Departments of Medical Oncology, Centres Anticancereux of Clermont-Ferrand, Lyon, Marseille, Nancy, Paris, and Centres HospitaloUniversitaires et Centres Hospitaliers of Avignon, Brive, Bourgen Bresse, Grenoble, Limoges, Paris, Saint-Etienne and Suresnes, France * Seepage 42 for list of participants
responses gave an overall response rate of 42% (95% CI: 30%-54%). Response rates for platinum-refractory patients Background: Platinum compounds are the most active drugs and those with early (5*3 and <12 months) and late (>12 in ovarian cancer treatment; cisplatin and carboplatin demon- months) relapses were 24%, 33% and 70%, respectively. The strated similar efficacies but different toxicity profiles. Pacli- respective median response duration, the median progressiontaxel combined with cisplatin asfirst-linetreatment improved free survival and median overall survival were 8, 6 and 14 overall survival when compared to a cisplatin-cyclophospha- months. Myelosuppression was the most frequent and severe mide combination, but generated higher rates of neutropenia, toxicity. Grade 3 and 4 neutropenia occurred, respectively in febrile neutropenia and neurotoxicity. The paclitaxel-carbo- 30% and 23% of the cycles; 6% of the cycles benefited from platin combination may be better tolerated than cisplatin- medullary growth factors. Only one episode of febrile neutropaclitaxel. penia was observed. Grade 3 and 4 thrombocytopenia occurred, Design: The objective of the present study was to assess the respectively during 3% and 1% of the cycles. Alopecia was efficacy and safety of the combination of paclitaxel and carbo- frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death platin in previously treated advanced ovarian cancer patients. Patients and methods: During or after platinum-based che- was attributed to progressive disease and possibly to therapy. motherapy, 73 patients with progressive advanced epithelial Conclusion: This combined paclitaxel-carboplatin therapy ovarian carcinoma were enrolled to receive every four weeks is effective and can be safely administered to ovarian cancer a three-hour infusion of paclitaxel 175 mg/m2 followed by a patients who relapse after one or two regimens of platinum30-minute carboplatin infusion. The carboplatin dose was based chemotherapy. calculated to obtain the recommended area concentrationversus-time under the curve of 5 mg-mT'-min. Results: Toxicity and response could be evaluated for 72 Key words: carboplatin, chemotherapy, ovarian carcinoma, and 62 patients, respectively. Eleven complete and 15 partial paclitaxel Summary
Introduction
hours [7]. Carboplatin, a cisplatin analog, has been found to be as effective as cisplatin [1] and generates Platinum compounds are considered to be the most fewer non hematologic side effects, including neuroactive drugs for the treatment of ovarian cancer [1, 2]. toxicity, vomiting and nephrotoxicity; however, it is Paclitaxel has been show be highly active in relapsing responsible for more myelosuppression, mainly thrompatients, with response rates ranging from 14% to 48% bocytopenia. Although much hope is invested in the [3-7]. When combined as first-line treatment, cisplatin combination of paclitaxel and carboplatin, it can only and paclitaxel given as a 24-hour infusion improved the be used in the future to replace the reference therapy response rate and the overall survival of patients with of cisplatin and paclitaxel if it is proven to be better suboptimally debulked stage III ovarian cancer as com- tolerated and to have at least comparable efficacy. pared with the standard combination of cisplatin and These observations prompted us to combine paclitaxel cyclophosphamide. However, higher rates of neutrope- and carboplatin to treat patients who had previously nia, febrile neutropenia and neurotoxicity were observed received platinum derivatives but not taxane. The doses [8]. Paclitaxel-induced neutropenia can be attenuated were determined based on preliminary data collected by infusing the drug over three hours rather than 24 from phase I studies underway at the time and since
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J. P. Guastalla, E. Pujade-Lauraine, B.Weber, H. Cure, H. Orfeuvre, M. Mousseau, P.Vincent, V. Dieras, N. Tubiana-Mathieu, J. P. Jacquin, L. Mignot, B. Leduc, P. Viens & D. Pariso
38 of paclitaxel or carboplatin administered per week as a function of body surface area (mg/m2/week). Adjustments of the paclitaxel and carboplatin doses were required for major reversible organ toxicities. The paclitaxel dose for the next cycle was reduced by 20% without changing the carboplatin dose when the absolute neutrophil count (ANC) was <0.5 x 109/l for seven days or longer, or when febrile neutropenia developed (temperature 38 °C and ANC <0.5 x 109/l, requiring antibiotics and hospitalization). Granulocyte growth factors were administered at the investigator's discretion in the case of severe granulocyte toxicity. The carboplatin dose for the next cycle was reduced by 20% without modifying the paclitaxel dose in the case of grade 4 thrombocytopenia. Drug administration was postponed when the ANC was < 1.5 x 1O9/1 and the platelet count was < 100 x 109/l on day 28. The paclitaxel and/or carboplatin doses were reduced by 20% when neutropenia and/or thrombocytopenia persisted beyond day 28 but recovered between days 35 and 42 (treatment delayed one or two weeks). When hematologic recovery was not achieved by day 42, the patient was withdrawn from the study. The paclitaxel dose was reduced by 20% in the case of WHO grade > 2 mucositis or WHO grade 2 neuropathy. The patient was withdrawn from the study when grade 3 neuropathy occurred, the creatininemia concentration increased >2.5 times above the upper normal limit, or arrhythmia or a second- or third-degree atrioventricular heart block occurred.
Patients and methods Study procedure
The protocol was approved by the Bio-Ethics Committee: 'Comite Consultatif de Protection des Personnes dans la Recherche Biomedicale (CCPPRB)' of Hotel-Dieu Hospital in Pans on September 20, 1993. Eligibility criteria To be eligible for this study, a patient had to have a histologically documented primary ovarian adenocarcinoma previously treated with either one or two platinum-based regimens. Other requirements included: progressive disease, presence of at least one bidimensionally measurable target lesion ^ 2 cm, age 18 to 75 years, World Health Organization (WHO) performance status of 0 or 1, plasma creatinine level ^ 1.25 times the upper normal limit, bilirubin level ^ 1.25 times the upper normal limit, transaminases ^2.5 times the upper normal limit except in the patients with hepatic metastases, white blood cell count 3J3.5 X 109/l, granulocyte count >2.0 x 109/l, platelet count 5= 100 x 1O9/1. Patients were excluded when they had received previous taxane-based chemotherapy, intensive chemotherapy requiring stemcell transplant or bone-marrow irradiation of more than 30% of the total bone-marrow volume. Also excluded were those with a past history of atrial or ventricular arrhythmia even when controlled by drugs, atrioventricular heart block, myocardial infarction within the six months prior to the study, WHO grade 2 neurotoxicity or pre-existing neurologic pathology, active infection or severe disease including intestinal occlusion and those with allergic reactions to drugs containing Cremophor®. All patients gave their written informed consent.
Treatment schedule
Paclitaxel (TaxolE, Bristol-Myers Squibb, Paris, France) diluted in 500 ml of a 5% glucose solution was administered at a dose of 175 mg/m2 as a three-hour intravenous infusion, followed by a 30-minute intravenous infusion of carboplatin (Paraplatin®, Bristol-Myers Squibb). The dose of carboplatin was calculated for each cycle using Calvert's formula1 where the glomerular filtration rate (GFR) was calculated based on the serum creatinine level according to the Cockroft-Gault formula.2 All patients were premedicated with oral prednisolone (130 mg) 12 hours and six hours before paclitaxel, and intravenous dexchlorpheniramine (6 mg) and cimetidine (450 mg) or ranitidine (50 mg), 30 minutes before paclitaxel. The treatment was repeated every four weeks. Dose-intensity was calculated in terms of the dose
Thoracic radiography, computed tomography scan of the abdomen and pelvis were performed within four weeks before entry into the study and medical history, clinical examination, performance status assessment, electrocardiogram and blood analyses (complete blood cell count, serum creatinine, bilirubin, transaminases, alkaline phosphatases and CA 125) were performed within two weeks of this date. All patients were registered at the Data Processing Center. Blood cell and platelet counts were repeated weekly. Physical examination, WHO grade toxicity assessments and blood tests were done on day one of each cycle. Radiologic studies to document the status of all measurable disease noted at baseline were carried out systematically after the second and sixth cycles and whenever deemed necessary. A lesion was considered to be measurable when it could be measured in two dimensions and when one of these measurements was > 2 cm. A lesion could be evaluated when it was measurable in only one dimension. The following lesions could not be measured or evaluated: abdominal mass which could be palpated but not measured, pleural effusion, atelectasis, ascites, bone metastases and previously irradiated lesions (but not new lesions in a previously irradiated area). A complete response was defined as the complete disappearance for at least four weeks of all measurable or assessable lesions. A partial response was defined as a reduction that lasted for at least four weeks of at least 50% of the sum of the products of two perpendicular diameters of all measurable lesions, no increase in lesion size and no new lesions. Patients who showed neither a complete response nor a partial response were considered to be non responders. Progressive disease was defined as the appearance of new lesions or an increase of > 25% in existing lesions. The platinum-free interval was defined as the interval between the last day of the previous platinum-based chemotherapy and thefirstday of the paclitaxel-carboplatin regimen. The time to progression (for eligible patients) and overall survival (for all patients) were measured from the date of inclusion. The duration of response for assessable patients was calculated from the day the maximal response was observed until the date of progression for patients with a complete response and from the date of inclusion until the date of progression for patients with a partial response. Platinum-refractory patients were defined as those who did not achieve a partial or a complete response to their last platinum-based chemotherapy or those who relapsed < 3 months after the end of that treatment. An early relapse was defined by a platinum-free interval of ^ 3 months and < 12 months. A late relapse occurred 12 months or later after the completion of the last platinum regimen.
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published [9, 10], and empirically and arbitrarily by taking into consideration known effective doses of carboplatin and paclitaxel [7, 11, 12]. The dose of carboplatin was adjusted to obtain an area under the curve (AUC) of 5 mg-mf1- min (AUC 5), and paclitaxel was administered as a three-hour infusion at a dose of 175 mg/m2. The treatment was repeated every four weeks, an interval deemed optimal to limit toxicity in previously treated patients. Because clinical synergy of carboplatin and paclitaxel had not been ruled out, we prescribed this regimen to patients refractory and resistant to platinum and its derivatives, a situation in which the probability of a response to chemotherapy is particularly low. The aim of this phase II multicenter trial was to assess the clinical efficacy of and the tolerance to the paclitaxel-carboplatin combination in advanced ovarian cancer patients previously treated with platinum compounds.
39 Quality control
Table 1. Patient characteristics (n = 73).
All responses were reviewed by an external panel of independent expert radiologists from the medical schools of Paris, and Lyon, France. A clinical investigator assured the quality control of treatment administration and data collection in the various participating centers and demonstrated that both procedures were comparable in those centers that enrolled only one or two patients and those that contributed more thanfivepatients.
Parameter
Number of patients
Median age, years Histology Serous Undifferenciated Endometrioid Other Ascites
58
Statistical analysis
52 8 4 9
Yes No
26 47
Metastases Peritoneum alone Visceral Tumor size (mm)
Results
40-100 >100 Number of previous regimens
37 36 32 34 7
<40
Patient characteristics Between March 1994 and March 1995, a total of 73 patients were enrolled; their demographic and clinical characteristics are summarized in Table 1. Response Of the 73 patients included in the study, the responses of 62 could be evaluated. Eleven were unassessable for the following reasons: the external panel of radiologists considered that seven patients had no measurable lesions and were ineligible; one patient refused treatment; after the first cycle of chemotherapy, two patients experienced severe toxicity and a third had both prolonged toxicity and disease progression. Twenty-six of the assessable patients responded to therapy (overall response rate 42% (95% CI: 30%54%)) including 11 complete responses (CR 18% (95% CI: 8%-27%)). The overall response rate for all included patients (« = 73) was 36% (95% CI: 25%-47%)). The median response rate duration was 8.3 months (range 1-22+ months). Information was available on the efficacy of the last platinum-based chemotherapy for 59 patients who were classified as platinum-refractory, early relapse or late relapse (Table 2). Among them five (24%), six (33%) and 14 (70%), respectively, responded to paclitaxelcarboplatin {P < 0.01 for late relapse versus pooled platinum-refractory and early relapse patients). Their performance status (0 vs. 1) and disease characteristics such as the presence of ascites (yes vs. no), site of disease (peritoneal vs. visceral) and tumor size (< 40 mm vs. 40 mm) had no significant predictive value for response to the paclitaxel-carboplatin combination. Toxicity One patient did not receive any treatment; the other 72 patients were evaluated for toxicity. They received a total of 340 courses of paclitaxel-carboplatin, with a median
57 16
1 2
Previous platinum Cisplatin Carboplatin Cisplatin + carboplatin Other platinum Response to platinum Pathologic complete remission Clinical complete remission Partial response Stable Progression Unknown Therapy-free interval < 12 months 5= 12 months
38 16 15 4 12 22 12 9 14 4 43 30
Table 2. Response to paclitaxel-carboplatin and sensitivity to previous platinum therapy. Response to paclitaxelcarboplatin
Sensitivity to previous platinum Refractory
Early relapse (3=3mo< 12 mo)
Late relapse (>12mo)
Number of patients Complete response Partial response Total no. (%)
21 1 4 5(24)
18 1 5 6(33)
20 9 5 14(70)
of 5 courses per patient (range 1-9). The received percentage of the scheduled dose-intensity was 99% for paclitaxel and 95% for carboplatin. Grade 3 and 4 neutropenia was observed during 103 (30%) and 79 cycles (23%), in 21 (29%) and 33 (46%) patients, respectively. Granulocyte colony stimulating factor (G-CSF) was administered during only 20 of the 340 cycles (6%). One episode of febrile neutropenia was observed during the study. Grade 3 and 4 thrombocytopenia occurred in 10 (3%) and four cycles (1%) during the treatment of seven and four patients, respectively. The median leukocyte, neutrophil and platelet counts
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Univariate analysis of predictive factors of response was performed using Mantel-Haenzel y} tests or Wilcoxon rank-sum tests. Overall survival for all included patients and progression-free survival for eligible patients were analyzed using the Kaplan-Meyer method.
40 Table 4 Percentages of non hematologic toxicities observed in patients (n = 72) and reported according to WHO grade. Side effect
Alopecia Nausea/vomiting Neuropathy Myalgia/arthralgias Constipation Diarrhea Infection Febrile neutropenia Mucositis Hypersensitivity Cardiac arrhythmia Alkaline phosphatase Transaminases Creatinine Bilirubin
WHO grade 1
2
3
4
_ 18 32 10 10 4 6 4 4 1 3 1 4 4
3 28 14 11 22 8 5 4 1 1 4 -
76 14 1 1 4 2 1 3 -
1 _ _ _ -
attributed to progressive disease and possibly to chemotherapy toxicity. Survival
The median overall survival time for the whole population was 14 months. The median progression-free survival time for eligible patients was six months. Discussion
In this evaluation of the paclitaxel-carboplatin regimen in patients with previously treated advanced ovarian cancer, carboplatin was given at the target dose that gives an AUC 5 as recommended for this drug when it is given in any combination to these patients [13]. The paclitaxel dose of 175 mg/m2 infused over three hours is the routinely prescribed as a single agent in Europe for this patient population. Table 3. Leukocyte, neutrophil, hemoglobin and platelet nadirs during The overall response rate achieved by the 62 assessthe first six cycles of paclitaxel-carboplatin treatment (241 cycles could able patients out the 73 enrolled was 42% (95% CI: be evaluated). 30%-54%). The response rate observed in this study the paclitaxel-carboplatin combination compares with Parameter Cycle number favorably to those obtained with paclitaxel or carbo1 platin given as single agents. The overall response rates obtained with a single three-hour perfusion of paclitaxel Number of cycles 56 48 42 35 35 25 9 14% and 20% for platinum-resistant ranged between Leukocytes (10 /l) Median nadir 2.40 2.10 2.15 2.0 2.1 2.1 ovarian cancer patients [7, 14-16] and those obtained Range 1.1-8.5 0.9-4.1 1.1—4.3 0.7-5.0 1.3-3.5 1.4-4.5 with carboplatin monotherapy in previously treated paNeutrophils(109/1) tients ranged from 8% to 27% [17, 18]. The response rate Median nadir 0.8 0.7 0.8 0.5 0.7 0.8 Range 0.1-5.8 0.1-2.4 0.2-2.3 0.0-2.6 0.0-1.8 0.0-1.9 to the paclitaxel-carboplatin combination appears to be Hemoglobin (g/1) at the upper limit of the 14%-43% range achieved with Median nadir 103 106 104 103 102 105 various carboplatin combinations in this context [18]. Range 54-128 73-147 67-144 75-136 75-121 70-122 Platelets (lO'/l) The higher overall response rate (70%) noted in patients 168 Median nadir 149 157 133 143 117 with late relapse, 12 months or more after the last Range 66-291 12-257 20-309 30-252 35-238 platinum administration, as compared to that achieved
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and hemoglobin concentrations were not significantly different over the first six courses for those patients not given G-CSF and for whom at least one weekly complete blood cell count was available (Table 3). Early discontinuation of treatment was necessary for three patients who had prolonged grade 3 thrombocytopenia after the first cycle and for one patient who had grade 3 peripheral neuropathy after the second one. Thirty-four cycles (10%) were delayed for 18 patients: 12 because of prolonged thrombocytopenia (five patients),fivebecause of prolonged neutropenia (three patients), five because of prolonged thrombocytopenia and neutropenia (one patient), one because of an intercurrent non neutropenic infection and 11 in eight patients for reasons unrelated to toxicity (patient request or administrative reasons). Non hematologic toxicities were mostly moderate (Table 4), with alopecia, nausea/vomiting and moderate peripheral neuropathy (47%) being the most common. Transient symptoms of peripheral neuropathy were severe in only one patient and was felt to be disabling by six others. There was no difference in the incidence of neuropathy between patients who had previously received cisplatin and those who had not (42% and 50%). Three patients experienced grade 1 hypersensitivity reactions; only one patient had asymptomatic atrial extrasystoles. Biologic abnormalities were insignificant except for acute renal insufficiency in one patient who presented an infection that was unrelated to neutropenia and was treated with aminosides three weeks after the end of chemotherapy. The only patient who died early suffered an intestinal occlusion on day 21 after the first cycle of chemotherapy associated with an eight-fold increase of the basal serum transaminase concentration and, on day 26, grade 4 thrombocytopenia and anemia and grade 3 neutropenia. A computed tomography scan showed a small intestinal occlusion, abnormal iliac and aortic lymph nodes, and a tumor mass at the ileocolic junction with a probable hemorrhage. Her performance status deteriorated rapidly and her death, on day 32, was
41 overall response to the combined regimen enables us to regard it favorably. Thrombocytopenia was rare. Grade 3 and 4 thrombocytopenia occurred in only 4% of the cycles in 11 patients. As early reports of this combination suggested, the degree of thrombocytopenia seen was less than that expected from the use of carboplatin alone [25-27]. Despite its rarity, thrombocytopenia was dose-limiting in the paclitaxel-carboplatin regimen. Prolonged thrombocytopenia was totally or partly responsible for half of the cycle delays (5% of the cycles) and was the cause of early discontinuation of therapy for three of the four patients. Is it possible to lower the incidence of thrombocytopenia in the paclitaxel-carboplatin regimen? Carboplatin toxicity particularly concerning thrombocytopenia, has been attributed to its urinary elimination and correlated to the AUC. Calvert developed a formula to determine the dose of carboplatin as a function of the GFR as measured by 51Cr-EDTA [13]. In our study, we used Calvert's formula with a recommended target AUC of 5 m g m r ' - m i n , but we calculated the GFR using the serum creatinine concentration and the Cockroft-Gault formula [28]. Using this approximation to determine the carboplatin dose, particularly in patients who could have platinum-related subclinical alterations of renal clearance that might not be reflected in serum creatinine, may have led to undue toxicities, including thrombocytopenia. Recently, Chatelut et al. developed another formula3 to calculate the carboplatin dose directly by using the serum creatinine concentration [29]. Chatelut's formula appears to give results similar to those obtained with Calvert's formula [30]. In our opinion, it remains necessary to determine, through a large clinical trial, the optimal method of delivering carboplatin in the paclitaxel-carboplatin combination. In conclusion, the combination of carboplatin (AUC 5) and paclitaxel (175 mg/m2 as a three-hour infusion) can be administered safely to outpatients with advanced ovarian cancer who relapse after having received one or two chemotherapeutic regimens. In the case of early relapse ( ^ 3 and <12 months) or outright resistance to cisplatin, the paclitaxel-carboplatin combination does not appear to be better than paclitaxel alone. For patients who relapse ^ 12 months after the end of prior therapy, this combination is an alternative to others that do not include paclitaxel. However, only a randomized comparative study will be able to specify whether the improved overall survival observed with paclitaxel given asfirst-linetherapy holds true for patients with relapsed, advanced disease. This paclitaxel-carboplatin combination is now being compared to cisplatin-paclitaxel as first line therapy in a randomized trial also testing a cycle interval of 22 days, rather than 28 days as in our study [31].
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in platinum-refractory patients (24%) or those who relapsed early (33%) is consistent with previous reports showing the dependence of salvage treatment activity in ovarian cancer on the length of the platinum-free interval and the response to previous platinum-based therapy [19-22]. The 24% response rate observed in platinumrefractory patients is similar to those observed in phase II studies with 24-hour or three-hour perfusion of paclitaxel as a single agent (range 13%-33%) [3, 5, 7, 16, 23]. These findings do not support clinical synergy between paclitaxel and carboplatin and, for those patients who had not received paclitaxel and resisted cisplatin outright, it is preferable, in our opinion, to prescribe paclitaxel alone. For patients relapsing six months and especially 12 months after the end of prior platinum-based chemotherapy, the paclitaxel-carboplatin yields a relatively high reponse rate, similar to those achieved with the best combinations known. It remains to be determined whether the combination of drugs currently administered in this situation is indeed better than monochemotherapy. In first line treatment, overall survival did not differ, regardless of wether cisplatin was given alone and followed in cross-over fashion by paclitaxel or the combination was administered [24], However, the toxicities of the two regimens were different. A similar cross-over strategy could be applied to relapsing patients and should compare the paclitaxel-carboplatin combination to each drug used separately in a crossover fashion in order to determine the response rate, the toxicity and the quality of life of patients in each treatment group. The paclitaxel-carboplatin regimen can be safely administered to outpatients. Non hematologic side effects were mainly limited to alopecia and moderate nausea or vomiting. Neuropathy of any grade was observed in 47% of our patients but only one stopped treatment after the second cycle because of its severity. The occurrence of neuropathy was found to be independent of previous platinum compound administration. Although, in terms of neuropathy the combined regimen was equivalent to paclitaxel alone and more toxic than carboplatin alone, in light of its better overall response rate, these side effects are acceptable. The main toxicity of the paclitaxel-carboplatin combination was myelosuppression. Grade 3 and 4 neutropenia occurred during 53% of the cycles and in 75% of the patients. The frequency of severe neutropenia with the paclitaxel-carboplatin combination was about twice that observed for the same regimen of paclitaxel alone [7, 14-16] but was similar to that reported for paclitaxel given alone at a dose of 135 mg/m2 in a 24-hour infusion to previously treated patients [23]. Neutropenia subsequent to the combined regimen was of limited clinical incidence, was of short duration and it alone was responsible for the postponement of only five of 340 cycles. In addition, only one episode of febrile neutropenia was observed. Again, despite more neutropenic events being attributed to the paclitaxel-carboplatin combination than to each drug alone, the improved
42 Acknowledgements Supported in part by a grant from Bristol-Myers Squibb (Paris, France). The authors are grateful to Prof. Jean Noel Buy, Dr. Luce Malbec, and Dr. Marine Carteret who reviewed the radiological data; Christiane Dumont-Puleo for data management; and Janet Jacobson and Margaret Haugh for editing the English used in the manuscript.
9. 10. 11. 12.
* Participants 13. 14.
15.
16.
Notes 1. Calvert's formula: dose of carboplatin (mg) = target AUC x (GFR + 25) where GFR = glomerular filtration rate. 2. Cockroft-Gault's formula: GFR = 1.04 x (140 - age (years) x weight (kg))/creatininemia (umol/1). 3. Chatelut's formula: carboplatin clearance (ml/min) = 0.134 x weight + (218 x weight x (1 - 0.00457 x age) x (1 - 0.314 x sex)/ creatininemia (umol/1)). Dose of carboplatin = target AUC x carboplatin clearance. Weight in kg; age in years; male: sex = 0; female: sex = 1.
17. 18. 19.
20.
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Received 2 July 1997; accepted 2 October 1997. Correspondence to: Jean Paul Guastalla, MD, PhD Centre Leon Berard 28, rue Laennec 69008 Lyon France E-mail: [email protected]
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