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Combination Chemotherapy With Carboplatin and Docetaxel in the Treatment of Cancers of the Ovary and Fallopian Tube and Primary Carcinoma of the Peritoneum

From the Gynecologic Cancer Program, The Cleveland Clinic Taussig Cancer Center, and the Departments of Gynecology/Obstetrics and Hematology/Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH.

Address reprint requests to Maurie Markman, MD, Department of Hematology/Medical Oncology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email: markmam{at}ccf.org

	ABSTRACT

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PURPOSE: Standard chemotherapy for advanced ovarian cancer currently includes a platinum agent (usually carboplatin) and paclitaxel. Because docetaxel is an active agent in platinum-resistant ovarian cancer, it is relevant to evaluate both the toxicity and efficacy of the combination of carboplatin and docetaxel in this clinical setting.

PATIENTS AND METHODS: The Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center conducted a phase II trial of carboplatin (area under the concentration-versus-time curve of 6) and docetaxel (60 mg/m²), delivered every 3 weeks for six courses, in patients with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum who had either received no prior chemotherapy or had experienced a treatment-free interval of greater than 2 years before developing disease recurrence.

RESULTS: Fifty patients (median age, 57 years; range, 44 to 81 years) entered the trial (47 had had no prior chemotherapy). Our toxicity findings included the following: grade 4 neutropenia (64% of patients); hypersensitivity reactions (34%, none requiring discontinuation of therapy); peripheral neuropathy (6%). We had objective responses for 32 of 42 (81%) assessable patients.

CONCLUSION: The combination of carboplatin and docetaxel is highly active in ovarian cancer, with the major toxicity being bone marrow suppression. Hypersensitivity reactions are frequent but do not prevent continuation of treatment. With the dose and schedule employed in this trial, neurotoxicity is uncommon. Defining a role for this regimen in routine clinical practice will require the conduct of randomized controlled clinical trials.

	INTRODUCTION

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ON THE BASIS OF the results of randomized controlled clinical trials, the standard initial chemotherapy for advanced ovarian cancer includes a platinum agent (cisplatin or carboplatin) and paclitaxel.^1-4 Although this two-drug program results in a high objective response rate and prolonged survival for individuals with this malignancy, investigators continue to examine new agents and combination regimens in ovarian cancer to improve overall survival and reduce the toxicity associated with therapy.⁵

Docetaxel has been demonstrated in several phase II trials to be an active drug in platinum-resistant ovarian cancer.^6-9 In addition, the agent has been successfully combined with cisplatin, and the combination has produced a high objective response rate in advanced ovarian cancer.^10,11 As anticipated, this regimen was shown to be associated with considerable bone marrow toxicity (from docetaxel) and nonhematologic side effects (from cisplatin).

One might speculate that a combination of docetaxel and carboplatin (rather than cisplatin) also would produce a high response rate in this malignancy and be associated with a more favorable toxicity profile.¹² In addition, there is interest in defining the incidence and severity of peripheral neuropathy associated with a carboplatin/docetaxel program because this toxicity is one of the more serious concerns associated with the combination of either cisplatin or carboplatin plus paclitaxel.^2-4,13,14

To directly examine these clinically relevant questions, we initiated a phase II trial of this two-drug program in individuals with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. We report here the results of this trial.

	PATIENTS AND METHODS

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Eligibility
To be eligible for entry into this phase II study, patients had to meet the following requirements: (a) histologically confirmed diagnosis of ovarian cancer, fallopian tube cancer, or primary adenocarcinoma of the peritoneum; (b) no prior therapy for their malignancy, or if previously treated, a treatment-free interval of more than 2 years; (c) age of at least 18 years old; (d) Gynecologic Oncology Group (GOG) performance status of 0 to 2; (d) any prior radiotherapy administered more than 1 year before protocol entry; (e) conformity with the following laboratory parameters: serum creatinine no more than 1.6 mg/100 mL; WBC of at least 3,000/mm³, absolute neutrophil count of at least 1,500/mm³, platelets of at least 100,000/mm³, and serum bilirubin no more than 1.5 times upper limit of normal; (f) no investigational drug therapy received within 30 days before study entry; (h) signing of an informed consent document stating that the patient was aware of the investigational nature of the protocol.

Treatment Plan
The initial chemotherapy doses were carboplatin, area under the concentration-versus-time curve (AUC) of 6, and docetaxel, 60 mg/m². The carboplatin was infused over 30 minutes and the docetaxel, over 1 hour. Treatment was repeated every 21 days, assuming recovery from toxicity of the previous cycle. A maximum of six cycles of therapy were planned in patients responding to treatment or with no measurable or nonmeasurable but assessable disease at the initiation of the treatment program.

Standard antiemetics and hydration for carboplatin were employed. Dexamethasone, 8 mg orally, was delivered twice a day, beginning 24 hours before chemotherapy and continuing for a total of five doses.¹⁵

Bone marrow colony–stimulating agents were not routinely employed in this trial but were permitted as clinically indicated in the presence of neutropenic fever or sepsis. Patients were administered prophylactic oral ciprofloxacin in the presence of grade 4 neutropenia (without fever) if it was anticipated that the duration of neutropenia would exceed 3 to 5 days.¹⁶ With subsequent courses, dose reductions (see below), rather than prophylactic bone marrow colony–stimulating factors, were employed as a strategy to prevent the recurrence of grade 4 neutropenia.

Treatment Modifications
Treatment was to be delayed 1 week if the baseline laboratory parameters had not been achieved at the time of scheduled retreatment. If delay was required, subsequent therapy was to be delivered at a reduced dose level (level -1; see below).

For patients experiencing any of the following toxicities, the dose of therapy was also reduced one dose level (level -1). If a similar degree of toxicity was experienced with any subsequent courses, the dose was to be reduced by a second dose level (level -2).

Toxicity Requiring Dose Modifications
The following indications of toxicity led to dose modification: (a) nadir platelet count less than 60,000/mm³, (b) nadir neutrophil count less than 500/mm³, (c) nadir neutrophil count less than 1,000/mm³ and with fever, or (d) any nonhematologic toxicity more than grade 2 (excluding emesis, anemia, and alopecia). Toxicity was graded on a scale of 1 to 4 according to the National Cancer Institute Common Toxicity Criteria.

Treatment Dose Levels
Dose levels were as follows for carboplatin and docetaxel, respectively. Initial dose level, AUC 6 and 60 mg/m²; level -1, AUC 5 and 50 mg/m²; level -2, AUC 4 and 40 mg/m².

Statistical Considerations
This study was designed as a phase II trial. We planned to enter 50 patients to obtain a preliminary estimate of the overall clinical activity of the regimen, as well as toxicity of the two-drug combination in this specific patient population.

Criteria for Response
Standard Gynecologic Oncology Group response criteria for measurable disease were employed in this trial. A complete response was defined as disappearance of all gross evidence of disease for at least 4 weeks. Partial response was defined as a 50% or greater reduction in the product obtained from measurement of each measured lesion lasting 4 weeks or more. Progressive disease was defined as a 50% or greater increase in the product from any lesion documented within 2 months of study entry or the appearance of any new lesion within 8 weeks of entry into study. Any other condition was considered to be stable disease. In this study, stable disease or progressive disease was considered to be no response to the treatment program.

In addition, decreases in the level of CA-125 antigen were considered evidence of response in the absence of other measurable or nonmeasurable but assessable disease. To be considered a responding patient by CA-125 criteria, the patient had to meet all of the following criteria: (a) a minimum baseline CA-125 at the initiation of chemotherapy (not before surgery) of 60 U/mL; (b) a decline in the antigen level of at least 50% compared with baseline; and (c) persistence of the decline for at least 2 months.¹⁷

	RESULTS

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Patient Characteristics
A total of 50 women (median age, 57 years; range, 44 to 81 years) with cancers of the ovary, fallopian tube, and primary carcinoma of the peritoneum were entered onto this phase II trial. Additional characteristics of the patient population are outlined in Table 1.

Two patients had therapy on this protocol initiated at level -1, rather than the planned initial dose level. This was done to ensure safety if performance status immediately after surgery was compromised or if the extent of disease before chemotherapy (rather than the presence of comorbid medical conditions) was felt to significantly interfere with the patient’s ability to tolerate the full dose level. Patients entered at a lower dose level were informed of this fact and of the justifications for initially employing this modified regimen.

Thirty-nine (78%) patients received all six planned treatment courses, whereas only six (12%) received no more than two cycles.

Toxicity
Toxicity results are summarized in Table 2. As anticipated, the major toxicity observed during this phase II trial was grade 4 neutropenia, which occurred in 32 (64%) of treated patients. Eight individuals (16%) developed neutropenic fever requiring antibiotics. Seven additional patients received prophylactic ciprofloxacin in the presence of grade 4 neutropenia without fever.

Somewhat surprising was the high incidence of hypersensitivity reactions (34% of patients) observed in this trial. In all cases, patients were able to continue with treatment without further incident, using the following standard protocol:

Upon the initial manifestations of a reaction (eg, erythema, tachycardia, dyspnea, wheezing, anxiety, feeling of warmth), the infusion was immediately discontinued. The patient was then administered diphenhydramine (50 mg IV) and hydrocortisone (50 mg IV). Approximately 30 minutes after the discontinuation of the infusion (and with disappearance of any signs/symptoms of the reaction), the infusion was reinitiated at a standard rate.

One patient treated on this study did elect to discontinue treatment with docetaxel because of hypersensitivity reactions during each of her first three treatment cycles, even though each cycle was delivered successfully after the procedure noted above.

Three (6%) patients developed peripheral neuropathy either during this treatment or in the several months after the completion of this treatment. Two of these individuals were considered to have symptoms of grade 2 in severity. No grade 3 neuropathy was observed. Arthralgias, a relatively common side effect of 3-hour infusional paclitaxel, were also infrequently observed in this protocol.

Antineoplastic Activity
A total of 42 patients were assessable for response. Six individuals initiated therapy without measurable or nonmeasurable but assessable disease. In addition, there was one early death (as previously described), and one patient elected to withdraw from the treatment program and was lost to follow-up.

Thirty-four of 42 (81%) assessable patients demonstrated objective evidence of a response to the treatment program. Although the number of women in specific histologic subgroups was limited, we observed no major difference in the response rate for individuals with ovarian cancer versus those with primary peritoneal carcinoma.

To date, 19 (38%) patients have experienced a relapse of their disease, and 13 (26%) have died. The median progression-free survival has not been reached but will exceed 16 months (range, 1 to 41+ months). The median follow-up of the surviving patient population is 21+ months (range, 12+ to 41+ months).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this trial, we have again demonstrated the ability of a combination chemotherapy regimen containing a platinum agent and a taxane to produce a high objective response rate in epithelial ovarian cancer and primary carcinoma of the peritoneum. Although the number of patients with fallopian tube cancer treated on this trial does not permit any specific statement regarding therapeutic efficacy, there is no reason to suspect that this regimen will be less active in this condition than that observed with the other two closely related and more common malignancies.

In view of the noncomparative nature of this phase II trial and the relatively small and heterogeneous population treated (eg, stage, grade), it would be inappropriate to specifically comment on the progression-free or overall survival of our patients or to contrast this experience with other published data employing alternative treatment strategies (ie, carboplatin/paclitaxel) in this clinical setting.

As anticipated, the major toxicity of this regimen, containing carboplatin and docetaxel, was severe bone marrow suppression (grade 4 in 64% of patients). It might be argued that the use of bone marrow colony–stimulating agents, rather than mandated dose reductions in the presence of grade 4 neutropenia, would have permitted a more dose-intensive management strategy. Unfortunately, although this is probably correct, there is currently no evidence, based on the results of randomized controlled phase III trials, that such a strategy would have resulted in a superior clinical outcome in this disease setting.^17-23

The low incidence of peripheral neuropathy, particularly severe neuropathy, observed in this trial is noteworthy. Whether this represents an important clinical difference between docetaxel and paclitaxel or simply reflects the relatively low dose of docetaxel employed in this trial is unknown. Assessment of this point will require the conduct of a randomized trial, comparing a standard carboplatin/paclitaxel regimen to a carboplatin/docetaxel program. We were somewhat surprised at the high incidence of hypersensitivity reactions observed in this trial (34% of patients experiencing at least one episode). However, this experience is not inconsistent with previous reports of docetaxel-associated allergic events.¹⁵ Of importance is that these reactions did not interfere with our ability to administer docetaxel to individuals participating in the trial. However, patients initiating treatment with docetaxel must be advised appropriately regarding the potential for such a reaction, the possible signs and symptoms, and how they will be managed.

Finally, the question of the overall clinical relevance of our results should be addressed. Because a carboplatin/paclitaxel regimen is generally well tolerated and highly active in ovarian cancer,^3,4,14 is there any role for a carboplatin/docetaxel regimen outside a clinical study? In the absence of data from randomized trials, a definitive answer to this important clinical question cannot be provided.

Our data do suggest that a patient at a particularly high risk for the development of a treatment-related peripheral neuropathy (eg, preexisting mild diabetic neuropathy) might experience a reduced risk for serious toxicity by receiving a docetaxel-containing combination chemotherapy regimen. Similarly, alternating carboplatin/docetaxel with carboplatin/paclitaxel (eg, three cycles of each combination) might result in a lower incidence of neuropathy while maintaining therapeutic efficacy. Unfortunately, as previously discussed, in the absence of data from a controlled phase 3 trial, this hypothesis remains unproven. Of note is that a large randomized trial comparing a carboplatin/paclitaxel program with a carboplatin/docetaxel regimen has recently been completed. The results of that study will, one hopes, provide important data regarding the issue of the relative incidence of various side effects, including neurotoxicity, of the two programs. Of perhaps greater interest are data suggesting the lack of complete cross-resistance between paclitaxel and docetaxel in ovarian cancer.⁹ If it can be convincingly demonstrated that docetaxel produces objective responses in individuals with both platinum- and paclitaxel-resistant ovarian cancer, then the addition (not substitution) of docetaxel to a carboplatin- (or cisplatin-) plus-paclitaxel regimen (eg, three to four cycles of each two-drug combination) has the realistic potential to improve the overall effectiveness of therapy for this malignancy.

On the basis of these considerations, further exploration of a possible role for docetaxel in the management of advanced ovarian cancer appears indicated.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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7. Kaye SB, Piccart M, Aapro M, et al: Docetaxel in advanced ovarian cancer: Preliminary results from three phase II trials. Eur J Cancer 31A: S14-S17, 1995 (suppl 4)

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12. Meyer A, Huober JB, Goerner R, et al: Chemotherapy with carboplatin/docetaxel for primary and recurrent epithelial ovarian cancer. Proc Am Soc Clin Oncol 18: 379a, 1999 (abstr 1465)

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14. Markman M, Kennedy A, Webster K, et al: Neurotoxicity associated with a regimen of carboplatin (AUC 5-6) and paclitaxel (175 mg/m² over 3 hours) employed in the treatment of gynecologic malignancies. J Cancer Res Clin Oncol 127: 55-58, 2001[Medline]

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Submitted September 6, 2000; accepted December 12, 2000.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Articles by Belinson, J. Search for Related Content PubMed PubMed Citation Articles by Markman, M. Articles by Belinson, J.