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Phase II Trial of Irinotecan in Patients With Metastatic Epithelial Ovarian Cancer or Peritoneal Cancer

Diane C. Bodurka, Charles Levenback, Judith K. Wolf, Jacalyn Gano, J. Taylor Wharton, John J. Kavanagh, David M. Gershenson

From the Departments of Gynecologic Oncology and Gynecologic and Medical Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Diane C. Bodurka, MD, Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 440, Houston, TX 77030; email: dcbodurka{at}mdanderson.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer.

Patients and Methods: Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m² intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m² because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response.

Results: The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred.

Conclusion: Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer.

	INTRODUCTION

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OVARIAN CANCER is the most lethal gynecologic malignancy, accounting for almost 14,000 deaths annually in the United States.¹ Although the majority of women have disease that initially responds to treatment consisting of cytoreductive surgery followed by platinum and paclitaxel chemotherapy, more than 60% will die of recurrent disease. Because these recurrent tumors are often refractory to chemotherapy, the discovery and development of new agents is of utmost importance, as this may ultimately improve the survival of women with recurrent disease.

Camptothecin is an alkaloid obtained from plants such as the Chinese tree Camptotheca acuminata. The original clinical preparation, camptothecin sodium, was evaluated in clinical trials in the late 1960s and early 1970s.^2,3 Use of this drug was abandoned because it caused severe and unpredictable cystitis and enteritis.⁴ Irinotecan (CPT-11; Camptosar, Pharmacia, Peapack, NJ) is a semisynthetic derivative of camptothecin that possesses greater aqueous solubility and greater in vitro and in vivo activity; it is associated with less-severe and more-predictable toxicity than camptothecin.^5–7 Although irinotecan is a prodrug with little inherent topoisomerase I inhibitory activity, it is converted by carboxylesterases to its more active metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin). In vitro, SN-38 is 250 to 1,000 times more potent than irinotecan as an inhibitor of topoisomerase I activity.⁸

Preclinical studies have evaluated the activity of irinotecan in several cell lines and in human tumors xenografted to nude mice.^9–13 O’Meara and Sevin¹⁴ examined fresh tumor samples from 20 patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC). The tumors were plated in an in vitro system and treated with varying doses of CPT-11 and SN-38, the active metabolite of irinotecan. Of the 12 tumors evaluable for response, seven had median effect doses significantly less than the clinically achievable peak plasma concentration. Eleven of the 12 tumors displayed sensitivity to SN-38.

A phase I study conducted in France by Abigerges et al¹⁵ identified the maximum-tolerated dose of irinotecan when given as a 30-minute, 600 mg/m² intravenous infusion, with the dose-limiting side effect being granulocytopenia. Although diarrhea was dose-limiting at 350 mg/m², use of high-dose loperamide reduced this toxicity and permitted dose escalation. Ultimately, the authors recommended 350 mg/m² every 3 weeks as the appropriate dose.

Several Japanese phase II trials of irinotecan in patients with EOC showed that the drug had efficacy in both chemotherapy-naïve patients and in those who had been previously treated with standard therapies, including platinum-based compounds, radiation, or both.^16,17 The purpose of our study was to evaluate the efficacy and toxicity of irinotecan in the treatment of women with metastatic platinum-resistant or platinum-refractory EOC or primary peritoneal cancer (PPC). To date, this is the first reported trial in the United States that studies irinotecan in this clinical setting. On the basis of the previously cited data, this trial was developed with a starting dose of 300 mg/m² of irinotecan administered intravenously every 3 weeks.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
After obtaining both approval from The University of Texas M.D. Anderson Cancer Center institutional review board and patient consent, 31 patients were entered into this trial from May 1998 through April 2001. All slides were reviewed by an expert gynecologic pathologist who confirmed the diagnosis of EOC or PPC. Platinum resistance was defined as tumor progression within 6 months of completion of platinum-based therapy.¹⁸ Platinum-refractory disease was defined as patients who had stable disease or disease progression during primary therapy.¹⁹ Patients may have failed only one platinum-based regimen. Any regimen that contained a platinum drug was counted as one regimen for the purpose of this study.

All patients were required to have measurable disease. This was defined as lesions that could be measured by physical examination or imaging techniques. Ascites and pleural effusions were not considered to be measurable disease. An elevated serum CA 125 level without an associated measurable tumor was not considered measurable disease.

Patients were required to be at least 18 years of age; have a Zubrod performance status of 0, 1, or 2; and have an estimated life expectancy of 12 weeks or greater. Patients were required to have adequate bone marrow, renal, and hepatic function as demonstrated by a pretreatment granulocyte count (ie, segmented neutrophils and bands) greater than 1,500/µL; hemoglobin level greater than or equal to 9.0 gm/dL and platelet count greater than 100,000 µL; serum creatinine level less than or equal to 2.0 mg/dL; and a serum bilirubin level less than or equal to 1.5 mg/dL, regardless of whether the patient had liver involvement secondary to tumor. The serum level of aspartame transaminase was required to be less than or equal to three times the institutional upper limit of normal. If the liver was involved by tumor, then the serum level of aspartame transaminase was required to be less than or equal to five times the institutional upper limit of normal.

Patients who had previously been treated with irinotecan, topotecan, or other aminocamptothecins were ineligible to participate. Patients with any active or uncontrolled infection, patients with any psychiatric disorders that might interfere with consent or follow-up, and patients who were pregnant or lactating were ineligible. Patients who had been treated for other malignancies, except for adequately treated basal cell or squamous cell skin cancer, cervical carcinoma-in-situ, or other cancer from which the patient had been disease-free for at least 5 years, were excluded. Patients with significant comorbid conditions (eg, a history of previous myocardial infarction within the past 6 months, congestive heart failure requiring therapy, a history of seizure or uncontrolled diabetes) as well as clinically apparent central nervous system metastases or carcinomatous meningitis were ineligible. Patients receiving phenytoin, phenobarbital, or other antiepileptic prophylaxis were excluded. In addition, patients with known Gilbert’s disease were ineligible, as these patients might develop excessive irinotecan-induced neutropenia.

Treatment Plan, Dose Modifications, and Response Evaluation
Irinotecan was administered intravenously over 90 minutes once every 3 weeks. The starting dose was 300 mg/m². For patients over 65 years of age, the starting dose was 250 mg/m². The drug was administered at 250 mg/m² for dose level-1, at 200 mg/m² for dose level-2, and at 150 mg/m² for dose level-3. Patients could receive a dose escalation to 350 mg/m² if they did not experience any toxicities during cycle 1. Doses were reduced one level for grade 3 thrombocytopenia (25,000 to 49,900/µL), grade 3 diarrhea (seven to nine stools per day more than pretreatment), and other grade 3 nonhematologic toxicities. Doses were reduced two levels for neutropenic fever (grade 4 neutropenia and grade 2 fever), grade 4 thrombocytopenia (< 25,000/µL), grade 4 diarrhea (10 stools per day more than pretreatment), and other grade 4 nonhematologic toxicities. All dose modifications were based on the worst preceding toxicity in the course. If multiple toxicities were seen, the dose administered was based on the most severe toxicity experienced. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0.²⁰

Patients received atropine 0.5 mg subcutaneously, dexamethasone 10 mg intravenously, and ondansetron 8 mg intravenously 30 minutes before the administration of irinotecan. Patients who experienced early cholinergic syndrome symptoms (lacrimation, diaphoresis, abdominal cramping, or diarrhea) during or shortly after irinotecan administration despite pretreatment atropine were given an additional dose of atropine 0.5 mg intravenously. All patients were instructed to begin taking loperamide (4 mg at the first onset of diarrhea, and then 2 mg every 2 hours around the clock until the diarrhea had ceased for at least 12 hours) if diarrhea and abdominal cramping occurred after being discharged from the chemotherapy unit. Patients were instructed to take 8 mg of ondansetron orally every 12 hours as needed for nausea and vomiting experienced during the first 24 hours after irinotecan administration. Use of prochlorperazine was not advised until the day after irinotecan administration because of an association with akathisia. The use of drugs with laxative properties was discouraged because of the potential exacerbation of diarrhea. Routine use of prophylactic growth factors was not recommended.

Patients continued with treatment until they experienced documented progression of disease, symptomatic tumor progression after one or more cycles, or unacceptable toxicity that did not respond to dose modifications. All patients who received chemotherapy were considered evaluable for toxicity. Patients who were removed from the study before the first tumor re-evaluation because of disease progression were also considered evaluable for efficacy. Patients removed from the study before the first tumor re-evaluation for other reasons (eg, patient request or drug-related toxicity) were considered unevaluable for efficacy. For the purpose of analysis, but not patient treatment, neutropenic fever was defined as fever greater than 38.1°C (> grade 2) in conjunction with a granulocyte count less than 500 cells/µL (grade 4). One criterion of grade 3 diarrhea is a need for parenteral support. This was interpreted as clinically required intravenous hydration and did not include elective fluid supplementation.

A pretreatment evaluation was performed within 4 weeks of study entry and included obtaining informed consent, contraceptive counseling, a review of the patient’s medical history, and tumor evaluation by chest radiograph and computed tomography scan. A physical examination, including vaginal and rectal examinations, and a laboratory panel were performed within 7 days of protocol entry and before each subsequent course. Patients were seen by a physician at the start of each treatment course. Tumor reassessment was performed after cycles 2 and 4 (at 6 and 12 weeks) and then every third course by the same imaging method used to establish baseline tumor measurements. Patients with either complete or partial response were required to have their response confirmed 4 to 6 weeks after the first documentation of response.

Complete response was defined as complete disappearance of all clinically evident malignant disease for at least 4 weeks. In addition, all measurable and evaluable lesions and sites were assessed. No new lesions could appear during that time, and there could be no evidence of nonevaluable disease. Partial response was defined as greater than or equal to a 50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions lasting at least 4 weeks. All measurable and evaluable lesions and sites were assessed. No new lesions could appear, and no progression of evaluable disease was permitted.

Progressive disease was defined as a 25% or greater increase in the sum of the products of measurable lesions over the smallest sum observed or over baseline if no decrease, reappearance of any lesion that had disappeared, or appearance of any new lesion or site. Stable disease was defined as any disease that did not meet the above criteria for complete responses, partial responses, or progressive disease.

Statistical Considerations
To evaluate the toxicity of irinotecan, time-to-event data were analyzed using the Kaplan-Meier Survival Curve Method. Time to response was defined as the time from the date of initial treatment with irinotecan until the first documentation of response. Duration of response was defined as the time from the first documentation of response to the documentation of disease progression or relapse. Time to tumor progression was defined as the time from the date of initial treatment with irinotecan to the first documentation of tumor progression. Survival time was defined as the time from the date of diagnosis to the date of death or the date of last known contact.

	RESULTS

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Patient Characteristics
Thirty-one patients with EOC were entered into this trial. The median patient age was 57 years, with a range of 38 to 74 years. All patients had a good performance status, with the majority (84%) having a Zubrod performance status of zero. Twenty-three patients (74%) were categorized as having platinum-resistant disease, and eight patients (26%) were platinum-refractory. All patients had previously received paclitaxel. Twenty-five patients (81%) were treated with irinotecan at a starting dose of 300 mg/m²; six patients (19%) were treated at a starting dose of 250 mg/m² because of an age greater than 65 years. All patients were evaluated for toxicity, and 29 patients (94%) were assessable for response. Both of the patients not evaluable for response refused additional treatment after the first cycle. Patient characteristics are presented in Table 1.

Responses
Twenty-nine patients received two or more cycles of irinotecan and were evaluable for response. Five patients demonstrated objective responses to irinotecan. One patient (3%) achieved a complete response lasting 7.5 months, and four patients (14%) demonstrated partial responses lasting from 3.4 to 10.1 months (median response duration, 5.9 months). This represents a 17% response rate (95% confidence interval, 5.8% to 35.8%) for the 29 patients assessable for response. One of the patients who demonstrated a partial response had platinum-refractory disease. All other responses were seen in patients with platinum-resistant disease.

Although not a prospectively identified end point for this trial, an additional 14 patients (48%) had stable disease (median duration, 3 months; range, 0.7 to 8.0 months). Ten patients (35%) had disease progression on this regimen. The median progression-free survival for evaluable patients was 2.8 months, with a range of 1.1 to 16 months, and median duration of response was 1.4 months, with a range of 0.7 to 10.1 months. Median survival from primary diagnosis was 24.3 months, with a range of 6.5 to 85.7 months. Median survival from initiation of irinotecan was 10.1 months, with a range of 2.3 to 34 months.

CA 125 Levels
Twenty-three patients (74%) had an elevated CA 125 level (> 35 U/mL) before the first cycle of irinotecan. Of these, seven patients (30%) experienced a reduction of their CA 125 level by more than half. Six (86%) of these seven patients had a more than 50% decrease in their CA 125 after only one cycle of chemotherapy, and the seventh patient received three cycles before a similar decrease. The median pretreatment CA 125 level of the seven patients who experienced a reduction in CA 125 by more than half with administration of irinotecan was 402 U/mL, with a range of 74.8 to 1126.4 U/mL. Of these seven patients, one had a complete response, three had partial responses, and three patients had stable disease.

Toxicity
The adverse effects reported by the 31 patients treated with irinotecan are presented in Tables 2 and 3. Twenty-two of the 31 patients (71%) experienced grade 3 or 4 toxicities. Sixteen patients (52%) required dose reductions. Eleven patients (35%) received dose reductions for toxicity. The starting dose was prescribed at -1 dose level (250 mg/m²) for six patients (19%) because of an age greater than 65 years. One of these six patients also required a second dose reduction to the -2 dose level (200 mg/m²) due to grade 4 neutropenia after cycle 1. Of 149 cycles administered, 66 (44%) were at a reduced dose.

Although none of these patients had prior bowel surgery, two patients developed bowel obstructions during their participation on the study. One patient underwent exploratory laparotomy and loop ileostomy early in her treatment course. The other patient had a percutaneous gastrostomy tube placed and requested hospice placement. Both patients developed bowel obstructions resulting from progressive disease.

	DISCUSSION

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In this trial, we observed a 17% response rate to irinotecan in patients with platinum-refractory or platinum-resistant EOC or PPC. Our findings are consistent with Japanese investigators who evaluated patients on a variety of dosing schedules. In an early phase II study, Takeuchi et al¹⁶ treated 14 EOC patients with irinotecan on schedules of 100 mg/m² weekly, 150 mg/m² every 2 weeks, or 200 mg/m² every 3 to 4 weeks. The response rate was 21.4%. Three of the six patients with an objective response had received previous chemotherapies that included cisplatin, indicating that irinotecan was effective for patients who had not responded to or were refractory to these therapies. The subsequent late phase II study by Takeuchi et al¹⁷ evaluated two schedules of irinotecan in 55 patients with EOC. Patients on regimen I were prescribed 100 mg/m² of irinotecan intravenously weekly, and those on regimen II were prescribed 150 mg/m² every 2 weeks, also intravenously. The response rate by regimen was 24% and 14%, respectively. Sugiyama et al²¹ evaluated 52 patients with recurrent EOC. Response rates were 30% in patients treated on a weekly regimen and 16% in patients treated biweekly, again consistent with our results. In our study, rapid reduction in CA 125 level seemed to correlate with response to irinotecan. Of the seven patients who experienced a reduction in CA 125 by more than half, one patient had a complete response, three had partial responses, and three had stable disease.

Neutropenia, nausea and vomiting, anorexia, diarrhea, and fatigue were identified as the dose-limiting toxicities in our study. Fifty-eight percent of the patients experienced greater than or equal to grade 2 granulocytopenia, a rate virtually identical to the 60% rate reported by Takeuchi et al¹⁶ in the early phase II study. Their late phase II study reported an 87% incidence of greater than or equal to grade 2 granulocytopenia, and the authors commented that the dosing schedule did not affect the toxicity rate.¹⁷ Despite the incidence of granulocytopenia, only two of our patients (6%) developed neutropenic fever. The median absolute neutrophil count was 1.50 in our study, with a range of 0.070 to 3.85. No growth factors were administered. There were no cases of sepsis in our study group.

The majority of patients in our study experienced nausea and vomiting. Twenty patients (65%) reported greater than or equal to grade 2 nausea, and 16 patients (52%) noted greater than or equal to grade 2 vomiting. As with neutropenia, these rates are similar to those reported by Takeuchi et al,¹⁶ with 60% of their patients having greater than or equal to grade 2 nausea or vomiting.

One study participant required a dose reduction because of nausea, vomiting, and anorexia after cycle 1. Two of the patients who experienced grade 3 vomiting developed small bowel obstructions during the second and fourth cycles of irinotecan, respectively. The bowel obstructions were associated with progressive disease rather than with the chemotherapy.

Seventeen of the patients (55%) also reported greater than or equal to grade 2 anorexia. All seven of the patients who reported grade 3 anorexia also reported grade 3 nausea and/or grade 3 vomiting. This is not surprising, as anorexia can often be associated with nausea and vomiting.

Diarrhea was also a dose-limiting toxicity in this study. Twenty-seven (87%) of the 31 patients experienced diarrhea. Seventeen patients (55%) had grade 1 or 2 diarrhea, and 10 patients (32%) had grade 3 or 4 diarrhea. Although these numbers are somewhat higher than those reported by Takeuchi et al,¹⁶ who identified 44% of their patients as having grade 2 or greater diarrhea, the studies are difficult to compare because the Japanese group did not specifically report toxicities as grade 3 or 4. Rather, they grouped the toxicities as grade 2 or greater. Further evaluation of our 10 patients with grade 3 or 4 diarrhea failed to reveal similarities to women in the study by Takeuchi et al¹⁶ other than the fact that three of the 10 were older than 65 years of age. Their treatment courses were begun at one dose at level -1 because of age.

Two types of diarrhea are caused by irinotecan. The first is early in onset and is thought to be caused by a cholinergic reaction.²² It may begin during drug administration or may occur up to 24 hours after drug administration. Early-onset diarrhea may be associated with additional symptoms such as flushing, abdominal cramping, diaphoresis, nasal stuffiness, or a runny nose. Intravenous atropine is the recommended treatment. Late-onset diarrhea is a cytotoxic reaction that occurs 2 to 14 days after administration of irinotecan. The median time to onset is 11 days.²³ Aggressive treatment with loperamide is recommended.¹⁵ Anecdotal reports indicate that older age, poor performance status, and greater number of prior chemotherapy regimens may be possible risk factors predictive for late-onset diarrhea.^24,25 It is interesting to note that these potential risk factors were not predictive of late-onset diarrhea in our study. Patients were mostly young, had a good performance status, and had previously received only paclitaxel and carboplatin.

Fatigue was a significant toxicity experienced by patients in this study, as 23 of the patients (74%) reported grade 2 or greater fatigue. Because anemia was not a prominent adverse event, one must consider the possibility that fatigue is a direct drug-related adverse event. Several other factors may have contributed additionally to this toxicity. As noted above, patients treated with irinotecan experienced significant nonhematologic toxicities, including nausea, vomiting, anorexia, and diarrhea. Although the medications prescribed to manage these symptoms (ondansetron, atropine, loperamide, etc.) did not likely cause fatigue, patients may have been taking other medications such as antianxiety or pain medications, which can cause fatigue. In addition, poor nutritional status and dehydration may have contributed to their fatigue. A substantial proportion of the patients experienced significant gastrointestinal toxicities. These toxicities may have also affected the intensity of the fatigue reported by our patients.

Fatigue has been characterized as both a subjective and multidimensional concept that may be expressed physically (eg, increased need to rest), cognitively (eg, decreased attention), or via an affective mode (eg, decreased motivation).²⁶ Guidelines for the evaluation and management of fatigue recommend careful assessment and identification of potential causes including but not limited to the underlying disease, disease treatments, comorbid conditions, and psychological disorders.²⁷ Possible interventions include treatment of anemia, depression, insomnia, and other potentially contributing symptoms, as well as exercise, nutritional support, and cognitive therapies.²⁷

Importantly, many cancer patients state that fatigue affects their daily lives more than pain.^28–30 We offer the following suggestions to help combat this adverse event, especially in patients treated with irinotecan. In addition to assessing the patient’s baseline level of fatigue, further identification of possible etiologies of fatigue in each patient should be performed. Each patient’s medication record should be reviewed and evaluated in terms of contribution to the patient’s fatigue. Assessment of possible depression and insomnia should be performed. Treatment should be provided as indicated. Finally, patients’ nutritional status should be optimized. Improved control of nausea, vomiting, and diarrhea by optimization of antiemetics for both acute and delayed nausea and vomiting as well as dose reduction of irinotecan may help reduce the fatigue experienced by patients receiving this drug.

Patients treated with irinotecan in this study experienced both hematologic and nonhematologic toxicities. Although our data indicate that irinotecan has moderate activity in patients with platinum-resistant platinum-refractory EOC and PPC, there are several issues that should be addressed when considering further study of this drug.

First, it is important to consider the patient population at hand. The primary goal of treatment for patients with platinum-resistant or platinum-refractory EOC or PPC is palliation. Although we recognize that virtually all antineoplastic agents have some degree of toxicity, it is important to balance the probability of response versus the toxicity profile of the drug in question. Because many of these patients may be relatively asymptomatic, one should evaluate this drug in the context of palliative chemotherapy regimens.

Close examination of our data does not enable us to predict who will experience the most severe toxicities associated with this drug. Toxicities were not age dependent, as 71% of patients less than 65 years of age reported grade 3 or grade 4 toxicities, as did 70% of patients greater than or equal to 65 years of age. Also, the one patient who experienced the most severe toxicities was only 38 years of age and had no pre-existing comorbid conditions.

Further examination of the data reveals that patients seemed to tolerate the drug better and to experience less toxicity once the dose was reduced. It is interesting to note that, in the five patients who responded, two had no reduction in dose, two patients received treatment at the -1 dose level, and the last patient received treatment at dose level -2.

Quality-of-life issues are clearly important, especially in the setting of palliative chemotherapy for EOC and PPC. Although our study population had an excellent performance status overall, these patients experienced significant chemotherapy-associated toxicities. Strategies for reducing these toxicities include prescribing a lower dose level of irinotecan and optimizing supportive care strategies. Although a combination of several antiemetics was administered, improved control of nausea and vomiting in both the acute and delayed phases might help reduce a substantial amount of the gastrointestinal toxicities experienced by these patients.

We recognize that there are many alternative options in this clinical setting, including tamoxifen, liposomal doxorubicin, topotecan, gemcitabine, and myriad other second-line agents. We recommend that patients facing this situation be counseled about the response rates and toxicity profiles of the various treatment options. We also recommend that quality-of-life issues be studied in conjunction with symptom assessment in an effort to more fully understand the effect of the treatment the patient is receiving.

To date, the optimal dosing schedule for irinotecan has yet to be established. No regimen shows clear clinical superiority in nonrandomized clinical trials. Preclinical data are inconsistent, with some studies indicating that a low-dose protracted schedule is superior and others concluding that this agent is not schedule dependent.^31–33 Clinical data are also inconclusive. In addition to the studies by Takeuchi et al,^16,17 Gerrits et al³⁴ were unable to demonstrate a difference in efficacy according to dosing schedule. Recent studies now question the use of body-size measures to determine dosage of this drug.³⁵ Some authors argue that less-frequent, higher-dose schedules should be used (eg, every 3 weeks) because of saturation of plasma SN-38 formation at higher doses.³⁶

Several investigators have administered irinotecan together with other drugs, including cisplatin and mitomycin C, to patients with recurrent EOC. Response rates have ranged from 20% to 60% using different combinations of drugs and different dosing schedules.^37,38 Further research is warranted, especially of combinations demonstrating a high rate of response, although one must again be cognizant of treatment-related toxicities.

Until more phase II clinical experience is gained with this agent, we recommend that irinotecan be used within the context of a clinical trial. Confirmatory evidence from other groups is required regarding different doses and dosing schedules to more thoroughly evaluate this drug. Given the therapeutic index of irinotecan reported to date, we do not recommend that irinotecan be considered for inclusion in a phase III clinical trial as either triplet or sequential doublet therapy for patients with newly diagnosed EOC or PPC. Careful thought should be given to prescribing irinotecan at a starting dose of 250 mg/m² for patients younger than 65 years of age and at 200 mg/m² for patients aged 65 or more years. Pharmacogenetics may ultimately be used to prospectively identify patients who may have the greatest risk of toxicity and help determine this drug’s therapeutic index.³⁹ Improved antiemetic regimens, especially for delayed nausea and vomiting, and heightened recognition of the causes and treatment of fatigue may help the severity of irinotecan-associated toxicity. However, until the optimal treatment dose has been established, it is prudent to consider a dose that may be better tolerated and cause fewer side effects.

In summary, our data reveal that irinotecan demonstrated moderate activity and substantial toxicity in patients with metastatic platinum-resistant and platinum-refractory EOC and PPC. Additional studies are warranted to further evaluate this drug. Attention should be given to determining the optimal dosing schedule and minimizing treatment-related toxicities.

	NOTES

 
Supported by Pharmacia & Upjohn, Inc., Peapack, NJ.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted February 25, 2002; accepted September 30, 2002.

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