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© 2003 American Society for Clinical Oncology Combined Intraperitoneal and Intravenous Chemotherapy for Women With Optimally Debulked Ovarian Cancer: Results From an Intergroup Phase II Trial
From the Vanderbilt-Ingram Cancer Center, Nashville, TN; Southwest Oncology Group Statistical Center, Seattle, WA; Louisiana State University Medical Center, New Orleans, LA; City of Hope National Medical Center, Duarte, CA; University of Texas Medical Branch, Galveston, TX; Albert Einstein Medical Center, Bronx, NY; National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada; Cleveland Clinic Cancer Center, Cleveland, OH; and University of Arizona Cancer Center, Tucson, AZ. Address reprint requests to Southwest Oncology Group (S9619), Operations Office, 14980 Omicron Dr, San Antonio, Texas 78245-3217; email: mace.rothenberg{at}vanderbilt.edu.
Purpose: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. Patients and Methods: Treatment consisted of paclitaxel 135 mg/m2 IV over 24 hours on days 1 to 2, cisplatin 100 mg/m2 IP on day 2, and paclitaxel 60 mg/m2 IP on day 8 administered every 21 days for six cycles. Results: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. Conclusion: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.
THIS YEAR, ovarian cancer will be diagnosed in 23,300 women and claim 13,900 lives in the United States, making it the fifth leading cause of cancer deaths in women.1 Initial surgical therapy for women with advanced-stage disease consists of laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy, with the goal of debulking the tumor to the greatest extent possible. The amount of disease remaining after surgery, as reflected by the largest diameter of residual disease, is a strong prognostic factor for survival. Combining those women with stage IIIA or IIIB disease (ie, those with peritoneal disease  2 cm in greatest dimension) at the outset with those diagnosed with stage IIIC disease who are surgically debulked to less than 1 to 2 cm of residual disease, fully 75% of women with stage III ovarian cancer fall into this optimal disease category.2 In 1996, intravenous (IV) combination chemotherapy with cisplatin and paclitaxel became the standard postoperative treatment regimen for women with advanced-stage ovarian cancer.3 Although originally evaluated only in women with suboptimally debulked stage III and IV disease, this therapy gained widespread acceptance as the treatment of all patients with stage III disease, regardless of the extent of residual disease. Phase III trials have demonstrated that the median disease-free survival time is approximately 20 to 25 months and the median overall survival time is approximately 50 months in women with optimally debulked stage III ovarian cancer who are treated with IV combination chemotherapy consisting of cisplatin or carboplatin plus paclitaxel.4–7 Another approach to the treatment of women with stage III ovarian cancer is the direct instillation of chemotherapy into the peritoneal cavity. First proposed by Dedrick et al,8,9 intraperitoneal (IP) therapy is designed to maximize drug delivery to the tumor while avoiding many of the systemic toxicities associated with IV administration of the drug. Agents that have a high level of intrinsic activity against epithelial ovarian cancer and large molecular weight, and whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Cisplatin and paclitaxel are two such agents with peritoneal-to-plasma concentration ratios of 20 and 1,000, respectively, after IP administration.10,11 High concentrations of these drugs can be achieved and maintained for prolonged periods of time in the IP cavity. In addition, capillary uptake of the drug from the peritoneal cavity allows therapeutic concentrations to be achieved systemically, resulting in control of extraperitoneal disease.12–14 In the 1980s and early 1990s, the activity of IP chemotherapy was demonstrated in a number of single-agent phase II trials in patients with recurrent ovarian cancer.10,12,15–17 Subsequently, phase III trials comparing IP cisplatin plus IV chemotherapy versus IV chemotherapy alone as first-line chemotherapy were performed and yielded largely positive results.5,18 However, concerns regarding the drugs used in the individual regimens and the toxicities associated with IP therapy remained, and these trials did not lead to the widespread adoption of IP chemotherapy as front-line therapy for women with optimal stage III ovarian cancer. This trial was designed to evaluate the activity of the combination of IP cisplatin, IP paclitaxel, and IV paclitaxel in women with optimally debulked adenocarcinoma of the ovary. This regimen was developed to address the following questions: Can IP paclitaxel be safely integrated into a regimen containing IP cisplatin and IV paclitaxel; and if so, is this regimen sufficiently promising to move to a phase III evaluation? Because women with optimally debulked stage III ovarian cancer have no radiographically measurable disease after surgery, and because disease-free survival is subject to interobserver variability, we elected to use 2-year survival rate as the primary end point for this multicenter phase II trial.
To be eligible for this trial, women had to have histologically confirmed adenocarcinoma of the ovary that was surgically staged as International Federation of Gynecology and Obstetrics stage III (tumor extending outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes).19 The patients must have undergone surgical staging in compliance with Gynecologic Oncology Group (GOG) standards.19 Only those women with residual disease that was no greater than 1 cm in largest diameter were considered to have optimally debulked disease and were eligible for this trial. Other eligibility requirements included a baseline performance status of 0 to 2 by Southwest Oncology Group criteria; registration no more than 42 days after laparotomy; no prior chemotherapy, immunotherapy, or pelvic radiation for ovarian cancer; no clinical evidence of residual disease by physical examination and chest x-ray; no active or uncontrolled infection; recovery from all surgery-related toxicities; and no pre-existing peripheral neuropathy that was grade 2 or worse. Patients were required to have a granulocyte count of  1,500 cells/µL, platelet count 100,000 cells/µL, measured or estimated creatinine clearance of 50 mL/min, and serum bilirubin and AST less than or equal to the institutional upper limit of normal. Central pathology review was performed to confirm the diagnosis of adenocarcinoma of the ovary and its histologic grade. All patients were informed of the investigational nature of this study and signed a consent form in compliance with institutional and federal guidelines. A Tenckhoff catheter or totally implantable catheter and port was placed with its distal end in the peritoneal cavity. Protocol treatment consisted of paclitaxel 135 mg/m2 IV administered over 24 hours on days 1 to 2, cisplatin 100 mg/m2 IP administered in 2 L of normal saline that had been warmed to body temperature on day 2, and paclitaxel 60 mg/m2 IP administered in a similar fashion on day 8. All patients were premedicated with dexamethasone, diphenhydramine, and ranitidine or cimetidine before paclitaxel administration. Patients were placed in right side down, left side down, Trendelenburg, and reverse Trendelenburg positions for 15 minutes each after instillation of IP chemotherapy. There was no attempt made to remove the fluid after instillation. Patients were scheduled to receive six cycles of this therapy in 21-day treatment cycles.
Patients had to have a WBC Patients were monitored with physical examinations, complete blood counts, serum creatinine, serum bilirubin, and CA-125 analyses before the initiation of each cycle of therapy. Toxicity was monitored on a weekly basis. A repeat computed tomography scan was obtained at the conclusion of therapy and was repeated as clinically indicated, at least on a yearly basis.
The primary end point for this trial was the 2-year survival rate measured from the date of registration onto this trial. Prior experience with high-dose IV carboplatin followed by IP cisplatin and IV paclitaxel demonstrated an 80% 2-year survival rate and a median survival of 63 months.5 On the basis of these data, it was assumed that the combination of IP cisplatin and IV plus IP paclitaxel would not be of further interest if the true 2-year survival rate was less than 70%. Conversely, it was assumed that a 2-year survival rate of 85% or higher would be of considerable interest for additional testing. The study targeted 65 assessable patients; survival of 52 (80%) or more patients beyond 2 years would be considered adequate evidence to warrant additional testing of this regimen. This design has a significance level (probability of incorrectly declaring a regimen with a 70% or lower 2-year survival rate as one warranting further study) of 0.05 and a power (probability of correctly declaring a regimen with an 85% or higher true 2-year survival rate as warranting further study) of 0.90. With 65 assessable patients, the incidence of any toxicity could be estimated to ± 12%. Any toxicity occurring with at least a 5% probability has a 96% chance of being observed in this study. A secondary end point of the trial was disease-free survival, which was measured from the date of registration to the date of recurrence. Recurrence was defined as the appearance of a new lesion, malignant effusion, or doubling of the CA-125 value of to at least twice the lowest value achieved since registration and
Between May 1996 and May 1998, 85 patients were registered onto this trial. Fifteen patients were considered ineligible because of insufficient documentation (n = 8; lack of information regarding optimal debulking in seven patients and lack of sufficient pathology submission in one patient), other primary cancers (n = 3), or incorrect surgery or pathology (n = 4). Seventy patients were eligible, but two patients never received study treatment and were, therefore, not analyzed. Sixty-eight patients were assessable for efficacy and toxicity.
Patient Characteristics
Efficacy All patients are no longer receiving treatment, and all have been observed for at least 2 years. Six of the 68 women died within the first 2 years, yielding a 2-year survival rate of 91% (95% confidence interval [CI], 84% to 98%; Fig 1  ). The 2-year disease-free survival rate was 66% (95% CI, 55% to 77%; Fig 2). With a median of 45.8 months of follow-up, a total of 27 women have died and 37 have relapsed. The median survival time on this trial was 51 months (95% CI, 48 to 55 months). The median disease-free survival time was 33 months (95% CI, 26 to 55 months).
Analysis of the impact of baseline performance status or histologic grade of the tumor on outcome could not be performed because of the paucity of patients with a performance status of 2 or grade 1 tumors. However, an exploratory analysis was performed to describe the effect of residual disease on overall survival. The 2-year survival rate was 85% for women with macroscopic residual disease and 100% for women with microscopic residual disease (Fig 3 ). When Cox regression analysis was used, the hazard ratio of overall survival for macroscopic versus microscopic residual disease was 2.1 (95% CI, 0.9 to 4.8; P = .07).
Toxicity and Tolerability Seventy-one percent of patients completed all six cycles of combined IV/IP therapy as planned. The most common reason for discontinuation of IV/IP therapy was toxicity. Six patients who discontinued IV/IP therapy received 26 cycles of IV therapy. Ninety-six percent of patients experienced at least one grade 3 to 4 adverse event during therapy. Toxicities are listed in Table 2 . The most common grade 3 to 4 toxicities were neutropenia (occurring at least once in 79% of patients), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Grade 2 to 4 abdominal pain occurred in 24 patients (35%) and was most often associated with instillation of IP chemotherapy. Eleven patients (16%) experienced a catheter-related infection. This led to the removal of the catheter in four patients, all of whom had grade 3 catheter infections. Only two patients (3%) experienced grade 3 peripheral sensory neuropathy.
During the last 20 years, several strategies have been evaluated in an attempt to improve survival for women diagnosed with advanced-stage ovarian cancer. These include the introduction of new agents into front-line chemotherapy, chemotherapy dose-intensification, interval debulking surgery, and IP chemotherapy. Integration of paclitaxel into front-line chemotherapy has improved median survival for women with advanced-stage ovarian cancer by 38% to 58% over non–paclitaxel-containing regimens.3,7 Other active agents, including topotecan, pegylated liposomal doxorubicin, epirubicin, and gemcitabine, have demonstrated activity in ovarian cancer when used alone or in combination with a platinum but have not yet been demonstrated to improve survival over that achieved with paclitaxel plus cisplatin or carboplatin.20–22 Integration of these new agents into front-line chemotherapy has been difficult because of the overlapping patterns of toxicity of these drugs (especially myelosuppression) resulting in the need to attenuate the dosing of each drug in the regimen. This strategy is being evaluated in several large, randomized studies. Interval debulking surgery uses chemotherapy to chemically debulk the tumor before an attempt at optimal cytoreduction. Although one large European phase III trial demonstrated a survival advantage to this approach, preliminary data from a subsequent phase III trial performed by GOG failed to confirm this advantage.23,24 In the late1980s, a retrospective analysis of clinical data from 39 clinical trials and a small prospective randomized trial indicated that systemic chemotherapy dose-intensification could result in improved survival for women with advanced ovarian cancer.25,26 Unfortunately, these findings were not confirmed.27,28 A recent analysis of 53 phase II and III trials found that survival was significantly associated with optimal cytoreduction but not platinum dose-intensity in women with stage III or IV ovarian cancer.2 Higher-dose chemotherapy requiring subsequent stem-cell rescue has also generated promising results in phase II trials, primarily in the chemotherapy-sensitive relapse setting. Unfortunately, attempts to evaluate this strategy as consolidation of response to front-line chemotherapy were unsuccessful because of poor accrual.
IP chemotherapy is one means by which dose-intensification can be achieved on a regional level. Mature results are available from two large randomized trials that compared IP with IV chemotherapy in women with optimal stage III ovarian cancer (Table 3
This trial was designed to address some of these concerns and to take advantage of the high peritoneal-to-plasma ratio that could be obtained through IP administration of paclitaxel.11 The dose selected was based on a phase I trial by Francis et al,14 which demonstrated the tolerability of and the sustained peritoneal and plasma concentrations achievable with paclitaxel 60 mg/m2 IP administered on a weekly basis. This trial did not use systemic induction chemotherapy in an attempt to remove it both as a confounding factor that might influence the therapeutic outcome of the trial and to reduce the toxicities (primarily thrombocytopenia) that could impair the delivery of the planned six cycles of IV/IP therapy. When this trial was designed, no data were available about potential interactions between cisplatin and paclitaxel if instilled into the peritoneal space simultaneously, so their administration was separated by 1 week. It should be noted that this trial was not a pure test of IP therapy because it included IV paclitaxel as part of the treatment regimen. The decision to include IV paclitaxel in this regimen was a pragmatic one because it was believed that a purely IP chemotherapeutic regimen might be difficult for some patients and physicians to accept.
In this trial, 68 fully assessable women with stage III epithelial ovarian cancer and residual peritoneal disease It is important to recognize that factors other than the IP administration of chemotherapy could have influenced these results. First among these could be patient selection. Ninety-seven percent of women enrolled onto this trial had a performance status of 0 to 1. This figure is a bit higher than was reported in the studies by Alberts et al (85%)5 or Markman et al (90%).5,18 Good performance status is a well-established favorable prognostic factor for survival in this disease and for virtually all malignancies. The median age in our trial was 54.8 years, which is somewhat younger than the average age at diagnosis of ovarian cancer in the United States but similar to the median age reported for women included in previous phase II and III studies.30 Lastly, there may have been patient selection bias by the surgeons who evaluated and operated on these patients and who may have offered this therapy only to a potentially favorable subset of patients. In this phase II setting, it is not possible to quantitate the impact of any of these factors on therapeutic outcome. The toxicity associated with this therapy was not trivial. Ninety-six percent of patients experienced at least one grade 3 to 4 toxicity during treatment, with the most common toxicities being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). It is notable that the most common toxicities are similar to those incurred by IV chemotherapy and, therefore, may not be a result of the IP route of chemotherapy administration. However, we also observed grade 2 to 4 abdominal pain in 35% of patients. It is possible that this toxicity, as well as some of the systemic toxicities, might have been a result of use of a high-dose of IP cisplatin (100 mg/m2). Given the apparent lack of benefit for dose-intensity when cisplatin is administered via IV, it may be worthwhile to evaluate lower doses of IP cisplatin in future trials.27 The incidence of grade 3 sensory neuropathy was only 3% (two of 68 patients) despite the use of two neurotoxic agents. This is likely a reflection of the lower peak plasma concentrations that are achieved with the IP administration of cisplatin and paclitaxel. The requirement of an IP catheter and the instillation of chemotherapy into the peritoneal cavity introduced toxicities, such as abdominal pain, that are not commonly seen with IV-administered chemotherapy. However, these toxicities are predictable and occur with a consistent frequency. The incidence of abdominal pain observed in our trial is similar to that reported by others.6 Eleven patients (16.1%) had catheter-related toxicities, requiring catheter removal in four patients (6%). This rate of catheter-related complications is also consistent with the rates reported by others.31 Seventy-one percent of patients completed all six planned cycles of IP chemotherapy. The most common reasons for discontinuation of treatment were toxicity (mainly abdominal pain) or catheter malfunction (primarily infection requiring removal of the catheter or catheter failure). Those women unable to complete the course of therapy with IP chemotherapy had the remaining courses IV administered. The use of an IV subcutaneous catheter, such as a Port-a-Cath (Deltec Inc., St. Paul, MN), for IP administration of chemotherapy may reduce IP fibrous sheath formation as well as the small bowel complications of IP therapy (D.S. Alberts, personal communication, May 2002). An exploratory analysis of our data identified a 100% 2-year survival rate in the subset of women with microscopic residual disease and an 85% 2-year survival rate in women with macroscopic residual disease. This trend is consistent with observations made in other studies that survival with stage III ovarian cancer is inversely related to the largest diameter of residual disease and may be attributed as much to tumor biology as it is to the effect of IP chemotherapy. However, we believe that these figures are also consistent with the use of two IP agents and preclinical evidence that, because of the 2- to 3-mm direct penetration of IP chemotherapy into the tumor, the major impact of the pharmacologic advantage of drugs such as cisplatin and paclitaxel would be most evident in the setting of smallest (ie, microscopic) residual disease. Such trends have not always been observed in clinical trials and need to be further investigated in larger trials with this regimen.18 In summary, the combination of IP cisplatin plus IV and IP paclitaxel is associated with an excellent 2-year survival rate and acceptable toxicities in women with optimally debulked, stage III ovarian cancer. Phase III evaluation of this regimen has been completed by the GOG, and preliminary data confirm the high degree of activity and associated toxicities of this regimen.32 Further follow-up is needed to determine whether these results translate into an improvement in survival when compared with an entirely IV chemotherapy regimen in women with stage III epithelial ovarian cancer.
Supported in part by the following Public Health Service Cooperative Agreements and grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA14958, CA77202, CA58658, CA46368, CA04919, CA45560, CA45450, CA13612, CA42777, CA12644, CA35281, CA35431, CA52386, CA45461, CA96429, CA20319, CA35261, CA35090, CA16385, CA35178, CA58416, CA12213, CA46113, CA22433, CA52654, CA35262, CA35192, and K24 CA82301 (M.L.R.). Presented, in part, at the Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.
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3. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6, 1996 4. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial (GOG 158). Proc Am Soc Clin Oncol 18:356a, 1999 (abstr 1373)
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31. Barakat RR, Sabbatini P, Bhaskaran D, et al: Intraperitoneal chemotherapy for ovarian carcinoma: Results of long-term follow-up. J Clin Oncol 20:694–698, 2002 32. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecology Oncology Group trial (GOG-172).Proc Am Soc Clin Oncol 21:201a, 2002 (abstr 803) Submitted July 5, 2002; accepted December 27, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
