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Randomized Phase III Trial of Standard Timed Doxorubicin Plus Cisplatin Versus Circadian Timed Doxorubicin Plus Cisplatin in Stage III and IV or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study

Holly H. Gallion, Virginia L. Brunetto, Michael Cibull, Samuel S. Lentz, Gary Reid, John T. Soper, Robert A. Burger, Willie Andersen

From the Division of Gynecologic Oncology, Magee Women’s Hospital/University of Pittsburgh, Pittsburgh, PA; Roswell Park Cancer Institute, Buffalo, NY; Department of Pathology, University of Kentucky, Lexington, KY; Section on Gynecologic Oncology, Wake Forest University School of Medicine, Winston-Salem; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; Division of Gynecologic Oncology, Riverside Methodist Hospital, Columbus, OH; Department of Obstetrics and Gynecology and Clinical Research Office, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, CA; and Department of Obstetrics and Gynecology, University of Virginia Medical School, Charlottesville, VA.

Address reprint requests to Denise Mackey, GOG Administrative Office, Four Penn Center, 1600 John F. Kennedy Blvd, Suite 1020, Philadelphia, PA 19103; e-mail: hgallion{at}mail.magee.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

 
Purpose: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy.

Materials and Methods: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m² plus cisplatin 60 mg/m², or CT doxorubicin 60 mg/m² at 6:00 AM plus cisplatin 60 mg/m² at 6:00 PM. Cycles were repeated every 3 weeks to a maximum of eight cycles.

Results: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P = .26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P = .31; OS: P = .21, one tail). Median total doses were 209 mg/m² doxorubicin and 349 mg/m² cisplatin in the ST group, versus 246 mg/m² doxorubicin and 354 mg/m² cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths.

Conclusion: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

 
CANCER OF the endometrium is the most common gynecologic malignancy in this country, with 38,300 new cases each year in the United States.¹ Although the majority of women with endometrial cancer have potentially curable stage I disease at diagnosis, a significant number present initially with metastatic disease outside the pelvis or develop metastasis after primary therapy. Although pelvic radiation therapy may be useful for localized disease, hormonal therapy or chemotherapy is generally used when distant metastasis is present.

The most effective hormonal agents are progestins, which result in response rates of 15% to 30% in advanced endometrial cancer.² However, responses are more commonly seen in women with receptor-positive, well-differentiated tumors. Tamoxifen alone or in combination with megestrol acetate has also been shown to have modest activity in endometrial cancer.^3,4 Although there is no standard chemotherapy for endometrial cancer, doxorubicin is one of the most active single agents, with responses observed in up to one third of previously untreated patients. Topotecan has been shown to have minimal activity in recurrent or persistent endometrial cancer.⁵ Other single agents with modest activity include doxorubicin,⁶ cisplatin,^7,8 carboplatin,⁹ ifosfamide,^10,11 and paclitaxel.^12,13 Several clinical trials have revealed that the response rate to doxorubicin can be improved with the addition of other agents, particularly cisplatin.^14,15 In Gynecologic Oncology Group (GOG) protocol 107, the response rate for doxorubicin alone was 27%, compared with 45% with combination doxorubicin plus platinum chemotherapy. Although a modest prolongation in median progression-free survival (PFS) was observed in this trial with combination chemotherapy, no difference in overall survival (OS) was detected.¹⁴ The results of a study by the GOG comparing doxorubicin plus cisplatin versus doxorubicin plus paclitaxel showed similar response rates.¹⁶ Recently, a phase III GOG trial of doxorubicin plus platinum versus doxorubicin plus platinum plus paclitaxel in patients with recurrent or metastatic endometrial cancer showed an improvement PFS and a slight improvement in OS in patients receiving the three-drug combination.¹⁷

Both animal and human studies of doxorubicin and cisplatin support the notion that timing of administration of these drugs may have a significant effect on their toxicity and response rates.^18–20 To take advantage of the potential benefit of circadian administration, the GOG performed a phase II trial of circadian timed (CT) doxorubicin plus cisplatin chemotherapy in advanced or recurrent endometrial cancer.²¹ In this trial, doxorubicin was administered at 6:00 AM and cisplatin at 6:00 PM. This schedule is the optimal circadian schedule for these two drugs on the basis of animal and human trials.²² Although the exact mechanism of potentially reducing toxicity by administering the two drugs at these specific times is unknown, it has been postulated that increased glutathione levels, which occur early in the morning, may result in decreased doxorubicin-associated WBC toxicity. For cisplatin, it is proposed that increased plasma protein binding and decreased urinary concentration of the drug, which occurs in the evening, may diminish nephrotoxicity and neurotoxicity. Because a promising 60% response rate and possibly superior PFS and OS rates were observed in patients receiving CT chemotherapy, this randomized phase III trial comparing standard timed (ST) and CT doxorubicin plus cisplatin in advanced-stage primary or recurrent endometrial cancer was undertaken.

	MATERIALS AND METHODS

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Eligibility
All patients had histologically documented primary stage III, IV, or recurrent endometrial carcinoma; the patients’ potential for cure by radiation therapy or surgery alone or in combination was poor. Tumors were staged according to the International Federation of Gynecology and Obstetrics criteria. All patients had measurable disease. Adequate renal, hepatic, and bone marrow function were required for study entry. This included WBC greater than 3,000/µL, platelets greater than 100,000/µL, creatinine less than 2.0 mg/100 mL, bilirubin no more than 1.5 x normal, and AST no more than 3 x normal, unless abnormal function was secondary to documented hepatic metastases. Patients were required to have a GOG performance status of 0 to 2 and an ejection fraction within institutional normal limits. Patients with active infection, active gastrointestinal bleeding, or a history of congestive heart failure or abnormal cardiac compensation were excluded from the study. Patients who received prior hormonal therapy or biologic response modifiers were eligible, but those who had received prior cytotoxic therapy, more than one prior biologic therapy, or prior radiotherapy within 3 months of study entry to the only area of known disease, were considered ineligible. Patients with a previous or concomitant malignancy, except those with nonmelanoma skin cancer, were not eligible. Patients whose circumstances would not permit study completion or adequate follow-up were also excluded. Informed consent was obtained from each participant before enrollment onto the study.

Study Design
This was a prospective, randomized, phase III multicenter GOG study. Patients were assigned to receive, at any convenient time, doxorubicin 60 mg/m² intravenously (IV) during the course of 30 minutes, followed immediately by cisplatin 60 mg/m² IV during the course of 30 minutes (arm I), or doxorubicin 60 mg/m² IV during the course of 30 minutes scheduled at 6:00 AM plus cisplatin 60 mg/m² IV during the course of 30 minutes given at 6:00 PM (arm II). This schedule usually required hospital admission. Treatment cycles were repeated every 3 weeks for a planned eight cycles. A maximum total doxorubicin dose was set at 420 mg/m². Patients who reached this maximum dose received cisplatin alone on cycle 8. Prehydration, antiemetic, or granulocyte colony-stimulating factor therapy was left to the discretion of the clinical investigator.

No dose modification of cisplatin was permitted. If a patient’s creatinine level increased above 2.0 mg/100 mL, cisplatin was withheld and started only when the creatine level decreased to 2.0 mg/100 mL or less. Cisplatin was withheld if clinically significant hearing loss was observed. For both regimens, treatment modification for doxorubicin was as follows: 60 mg/m² (initial dose), 45 mg/m² (one dose level), 30 mg/m² (two dose levels), and 15 mg/m² (three dose levels). An initial dose reduction of one level was used in patients older than 65 years and those who had completed external pelvic radiation therapy. Patients with hepatic dysfunction and a bilirubin level between 1.1 and 3.0 mg/100 mL had a two-dose-level reduction of initial treatment. Patients who experienced an initial dose reduction were subsequently escalated one level per cycle if no adverse effects greater than grade 1 were observed. Modification of subsequent treatment followed a standard format on the basis of pretreatment WBC and platelet counts, whereby subsequent cycles were not initiated until the absolute granulocyte count (AGC) was greater than 1,500/µL and the platelet count was at least 100,000/µL. If a delay of more than 1 week was necessary, a reduction of one dose level was required. Dose levels were also reduced for severe gastrointestinal toxicity (nausea and vomiting, or stomatitis). Patients with a decrease of 20% or more of baseline value of their cardiac ejection fraction or who developed congestive heart failure or other life-threatening cardiac problems had doxorubicin discontinued and were treated with cisplatin alone.

Adverse effects were recorded and graded according to the standard GOG toxicity criteria. Any grade 4 (life threatening) or unexpected adverse reaction was to be immediately reported to the GOG Administrative Office and the study chair. Patients continued receiving protocol therapy for a maximum of eight cycles unless disease progression or adverse effects necessitated discontinuation of study therapy.

Study Parameters
For each patient, a complete history, physical and pelvic examination, CBC, serum creatinine measurement, and CA-125 level were obtained before study entry and before every cycle. Bilirubin, AST, alkaline phosphatase, chest x-ray, ECG, and urinalysis were obtained before enrollment onto the study. A nuclear ejection fraction was obtained before study enrollment and immediately before cycle 6. If used to determine measurable disease, a computed tomography scan was obtained before enrollment and before every other cycle.

Evaluation Criteria
A complete response (CR) was defined as complete disappearance of all gross evidence of disease for at least 4 weeks. A partial response (PR) was a 50% or greater reduction in the product obtained from measurement of each lesion for at least 4 weeks. Increasing 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 study entry. Stable disease was defined as disease not meeting any of the three previous criteria.

OS was defined as observed length of life from study entry until death, or date of last contact for living patients. PFS was defined as the date from study entry to the date of reappearance or increasing parameters of disease, or death, whichever occurred first, or to date of last contact for patients alive and progression free.

Statistical Considerations
This phase III study was designed to compare the relative therapeutic effect of two timing strategies for delivering standard combination chemotherapy for advanced or recurrent endometrial carcinoma. The GOG Statistical and Data Center (SDC) carried out randomization with equal probabilities, balancing the sequence of assigned regimens within institutions only and using a permuted balanced block design. The sequence was generated by a computerized random number generator and a block length of four treatment assignments. The sequence of treatment assignments was concealed. Individuals from main member institutions called the SDC to verify patient eligibility and obtain a random treatment assignment. Data were collected and reviewed centrally at the SDC. The study chair reviewed patient data to assess protocol compliance, toxicity, and end points. All deaths to which treatment may have contributed were reviewed by the study chair and are summarized in this article. Although treatment assignment and individual patient results were not blinded to SDC staff or the study chair, aggregated results were only available to the study statistician, and these results were kept confidential when reported to the GOG Data Monitoring Committee. Pathology materials, including slides documenting the primary and metastatic disease, were collected at the SDC and reviewed by the GOG Pathology Committee.

The primary end point used to determine the benefit of circadian timing was frequency of objective response (CR + PR). Secondary end points included duration of PFS and OS. This study was designed with a target accrual of 290 patients to detect a common relative odds of response ratio of 1.9, or, equivalently, an average increase in proportion responding from 0.44 to 0.60, with type II error less than 0.20 and a one-tail test of significance at the 0.05 level.²³ This sample size would also allow an 83% chance of detecting a 40% increase in survival duration with 12 months of follow-up and type I error of 0.05.²⁴ In addition, this sample size would provide an 88% chance of detecting a similar increase in duration of PFS.²⁴ Given the actual accrual and follow-up, the power to detect these differences is 85% for response and 91% for PFS and OS. One-tail tests were chosen because of the preference for the ST chemotherapy with regard to ease of administration. In this article, two-sided 95% CIs are reported.

An interim futility analysis of response was planned and carried out after a minimum of 75 patients had been evaluated in each arm.²⁵ Accrual termination was to be considered if the odds of response in the CT arm were less than that in the ST arm. The GOG Data Monitoring Committee opted to continue accrual after reviewing response and toxicity data approximately 33 months after study activation.

A one-tail exact test stratified by performance status was used to test the independence of response and treatment,²⁶ and the conditional maximum likelihood estimate of the common odds ratio is reported with an exact 95% CI.²⁷ A log-rank test stratified by performance status was used to test the independence of treatment with OS and PFS.²⁸ The Kaplan-Meier method was used to obtain estimates of PFS and survival rate.²⁹ A proportional hazards model was used to provide a relative hazard estimate stratified by performance status for both PFS and OS.³⁰ The intention-to-treat principle was applied in all treatment group comparisons after excluding ineligible patients. Tabulation of adverse effects includes only treated patients. The Kruskal-Wallis rank test adjusted for ties was used to test the independence of treatment and the frequency and severity of the reported toxicities.³¹

Box plots were constructed by cycle, treatment arm, and chemotherapy agent to provide visual documentation of compliance to protocol-prescribed timing. The upper and lower edges of the boxes are drawn at the 75th and 25th percentiles, respectively. The median is represented by a line within the box. Lines drawn from the edges of the box represent the inner fence. All values outside the fence are considered outliers and are represented by hollow diamonds or squares. When data are tightly distributed, the boxes and fences can appear as a single straight line.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

 
Patients
Between March 1993 and August 1996, a total of 352 patients were entered onto this study. Of these, 175 were randomly assigned to receive ST cisplatin plus doxorubicin chemotherapy; 177 patients were randomly assigned to receive CT cisplatin plus doxorubicin chemotherapy. Ten of the 352 patients were ineligible: six in the ST regimen (one second primary, two wrong cell type, two wrong primary, and one with inadequate documentation of primary disease) and four in the CT regimen (one wrong cell type, two wrong primary, and one wrong stage).

The clinical and histologic characteristics of the eligible patients according to treatment regimen are listed in Table 1. Forty-nine (29%) patients in the ST arm were stage III or IV disease, and 120 (71%) had recurrent or persistent disease. In the CT arm, 58 (34%) had stage III or IV disease, and 115 (66%) had disease that was recurrent or persistent. The median patient age at entry was 65 years. The two treatment arms were well balanced for pretreatment characteristics, including performance status, cell type, and tumor grade. Slight imbalances were noted for age and race. The majority of patients (79% in the ST arm and 82% in the CT arm) had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy before study entry, and approximately 55% in each group had received prior radiation therapy.

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival by randomized treatment arm. PF, progression free; AP, doxorubicin and platinum.

View larger version (14K): [in this window] [in a new window]   Fig 2. Survival by randomized treatment arm. AP, doxorubicin and platinum.

Compliance
The timing of doxorubicin and cisplatin administration was recorded in each arm to evaluate compliance to protocol (Figs 3 and 4). The median time doxorubicin was administered over all cycles was 2:10 PM in the ST arm and 6:00 AM in the CT arm, as prescribed in the protocol. Similarly, the median time cisplatin was administered over all cycles was 2:40 PM in the ST arm and 6:00 PM in the CT arm.

View larger version (17K): [in this window] [in a new window]   Fig 3. Box plot of hour of doxorubicin infusion by cycle (1 to 8) and randomized treatment arm (I and II).

View larger version (17K): [in this window] [in a new window]   Fig 4. Box plot of hour of cisplatin infusion by cycle (1 to 8) and randomized treatment arm (I and II).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

Of interest are the differences between the two treatment arms with regard to both WBC and AGC toxicity. The proportion of patients experiencing grade 3 or 4 WBC toxicity with ST chemotherapy was 75%, versus 65% of those treated with the CT regimen. Similarly, the percent of patients experiencing grade 3 or 4 AGC toxicity was 82% with ST chemotherapy and 74% with CT chemotherapy.

Forty-three percent of patients completed eight cycles of therapy in the CT arm compared with 40% in the ST arm. Moreover, the cumulative percent of ideal dose of doxorubicin given, on the basis of all eligible patients receiving a total dose of 420 mg/m², was 53% in 8.1 months for the ST arm, compared with 57% in 7.6 months for the CT arm. Similarly, the cumulative percent of ideal dose of cisplatin given, on the basis of all eligible patients receiving 60 mg/m² for eight cycles, was 63% in 8.1 months and 66% in 7.6 months for the CT arm.

In conclusion, no improvements in response rate, PFS, or OS were observed with the CT chemotherapy regimen used in this phase III trial. Although there may be other avenues for study of this concept, the GOG does not plan additional trials of CT chemotherapy in endometrial cancer.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	APPENDIX

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

 
The following Gynecologic Oncology Group institutions participated in this study: University of Alabama at Birmingham, Birmingham, AL; Duke University Medical Center, Durham; University of North Carolina School of Medicine, Chapel Hill; Wake Forest University School of Medicine, Winston-Salem, NC; Abington Memorial Hospital, Abington; Thomas Jefferson University Hospital, Fox Chase Cancer Center, Eastern Pennsylvania Gynecology/Oncology Center, PC, and University of Pennsylvania Cancer Center, Philadelphia; Milton S. Hershey Medical Center, Hershey, PA; University of Rochester Medical Center, Rochester; Albany Medical College, Albany; SUNY at Stony Brook, Stony Brook; SUNY Downstate Medical Center, Brooklyn; Long Island Jewish Medical Center, New Hyde Park, NY; Walter Reed Army Medical Center and Georgetown University Hospital, Washington, DC; Wayne State University, Detroit, MI; University of Minnesota Medical School, Minneapolis; Mayo Clinic, Rochester, MN; Emory University Clinic, Atlanta, GA; University of Mississippi Medical Center, Jackson, MS; Colorado Gynecologic Oncology Group, PC, Denver, CO; University of Miami Medical Center, Miami; Tampa Bay Cancer Consortium, Tampa, FL; University of Cincinnati, Cincinnati; Case Western Reserve University and The Cleveland Clinic Foundation, Cleveland; Columbus Cancer Council, Columbus, OH; University of Iowa Hospitals and Clinics, Iowa City, IA; University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Indiana University Medical Center, Indianapolis, IN; University of California Medical Center at Irvine, Irvine, CA; University of Massachusetts Medical Center, Worcester; Tufts-New England Medical Center, Boston, MA; University of Chicago and Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL; University of Kentucky, Lexington, KY; The University of Virginia, Charlottesville; Eastern Virginia Medical School, Norfolk, VA; Johns Hopkins Oncology Center, Baltimore, MD; Washington University School of Medicine, St Louis, MO; Cooper Hospital/University Medical Center, Camden, NJ; Medical University of South Carolina, Charleston, SC; Women’s Cancer Center, University of Oklahoma, Norman, OK; and Tacoma General Hospital, Tacoma, WA.

	NOTES

 
Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... APPENDIX REFERENCES

 
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Submitted October 16, 2002; accepted July 29, 2003.

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