Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer

Authors: Armstrong DK, Bundy B, Wenzel L, et al.
Source: New England Journal of Medicine 2006; 354:34–43.

Background

• Ovarian Cancer (OC) is the leading cause of death among gynecologic cancers in the United States.
• The current standard chemotherapeutic regimen for newly diagnosed OC is a combination of a platinum-based agent with a taxane given intravenously (IV). Treatment is primarily limited by myelotoxicity.
• The rationale for peritoneal administration of chemotherapy is that it directly treats the peritoneum, which is the primary site of tumor spread, and thereby may decrease systemic toxicity.
• Two previous studies have addressed intraperitoneal (IP) versus IV chemotherapy, however they used different regiments and had conflicting results regarding overall survival (OS).
• The Gynecology Oncology Group (GOG) therefore initiated a phase III, randomized clinical trial to study patients with OC treated with either IV paclitaxel followed by IV cisplatin or IV paclitaxel followed by IP cisplatin then IP paclitaxel.

Methods

• Between March 1998 to January 2001, 429 patients were randomized for this study, of which 415 were eligible. Criteria for patient eligibility included:
  • Patients with stage III epithelial ovarian or peritoneal carcinoma with no residual disease greater than 1.0 cm after surgery.
  • Patients with a GOG performance status of 0 to 2.
    • 0=fully active, 4= completely disabled
  • Patients could not have had previous chemotherapy or radiation.
• The primary end points were OS and progression free survival (PFS).
• The study was not strictly blinded but pathological, surgical, and eligibility information was collected prior to registration.
• All surgical and pathologic eligibility information was centrally reviewed.
• At the time of registration patients decided whether to have a second look laparotomy after completion of chemotherapy to check pathological response.
  • Second look laparotomy was performed within 8 weeks of last cycle of chemotherapy and no later than 29 weeks after study entry.
• Quality of life was evaluated using the Functional Assessment of Cancer Therapy (FACT-O) at registration, before cycle four of chemotherapy, 3-6 weeks after cycle six of chemotherapy and 12 months after the completion of chemotherapy.
• 220 patients randomized to IV therapy, five found to be ineligible.
  • Day 1: Patients treated with IV paclitaxel, 135 mg per square meter of body surface area (BSA) over 24 hours.
  • Day 2: Treated with IV cisplatin, 75 mg per square meter of BSA.
• 223 patients randomized to IP therapy, nine were ineligible.
  • Day 1: Patients treated with IV paclitaxel, 135 mg per square meter of BSA over 24 hours.
  • Day 2: Treated with IP cisplatin, 100 mg per square meter of BSA.
  • Day 8: Treated with IP paclitaxel, 60 mg per square meter of BSA.
• Patient had to have absolute neutrophil count ≥1500 per cubic millimeter, platelet ≥100,000 per cubic millimeter, creatinine ≤ 2.0 mg per deciliter, and no grade 3-4 neuropathy to proceed to the next cycle of chemotherapy. In the IP group, dose was reduced for grade 2 abdominal pain. If there was persistent abdominal pain, worsening to grade 3, grade 2 neuropathy, or catheter complications, the patient was switched to IV chemotherapy.
  • In the event that patients did not meet these criteria, treatment was adjusted as follows: cycle delay, dose reduction, treatment with granulocyte colony stimulating factor.
  • If therapy was delayed more than 3 weeks the patient was dropped from the study.
  • In either group, in the event cisplatin had to be discontinued due to toxic effects, the patient was switched to IV carboplatin.

Results

• Median follow-up: 48.2 and 52.6 months for the IV and IP groups, respectively.
• Significant improvement in DFS and OS seen with IP chemotherapy compared with IV chemotherapy.
  • Median PFS: 18.3 and 23.8 months (p=0.05) for the IV and IP groups, respectively.
  • Median OS: 49.7 and 65.6 months (p=0.03) for the IV and IP groups, respectively.
• Relative Risk (RR) in the IP group compared with the IV.
  • RR of recurrence: 0.80 (95% CI 0.64-1.00)
  • RR of death: 0.75 (95% CI 0.58-0.97)
• No statistical difference in risk reduction of OS or PFS between patients with residual gross disease and no residual gross disease.
• Quality of life (QOL) assessment using FACT-O scores.
  • Patients getting IP therapy reported worse QOL compared with IV therapy prior to the fourth cycle of chemotherapy (p<0.001) and at three to six weeks after therapy (p=0.009).
  • No significant difference in QOL between the two groups one year after treatment (p=0.56).
• IV toxicity
  • Of 210 eligible patients 90% (189) completed six cycles of chemotherapy and 83% (174) completed six cycles with cisplatin (15 patients had to have some cycles with IV carboplatin).
  • Four treatment related deaths, all related to infection.
• IP toxicity
  • Of 205 eligible patients 83% (170) completed six cycles of chemotherapy and 42% (86) received all six cycles of IP therapy (84 required IV carboplatin for some cycles).
  • Catheter related complications were the most common reason for switch to IV carboplatin.
  • Five treatment related deaths, all related to infection.
  • Significantly worse grade 3 or 4 fatigue, pain, hematologic, gastrointestinal, metabolic, and neurologic side effects in IP group compared with IV (p≤0.001).
• Second look laparotomy to assess for pathological response (PR).
  • 72 of 102 patients in the IV group who elected to have laparotomy, underwent the procedure. Complete PR seen in 41% of patients.
  • 69 of 100 patients in the IP group who elected to have laparotomy, underwent the procedure. Complete PR seen in 57% of patients.

Discussion

• Contrary to the belief that IP therapy would be less toxic than IV therapy, IP proved to be significantly more toxic.
  • May have been due to the higher cisplatin dose used in the IP group.
  • May be secondary to IP paclitaxel which persists in the peritoneum for one week after administration.
• A significant amount of toxicity in the IP treatment group was associated with the IP catheter.
  • Specifying the type of catheter and the timing of placement, which was not specified in the protocol for this study, may decrease toxicity.
  • Use of single lumen venous catheter with a subcutaneous port for access may be superior to the fenestrated IP catheters.
  • Patients with left colonic/rectosigmoid resections were less likely to receive all doses of IP therapy.
  • It may be possible to reduce toxicity through modification of the dose, administration schedule, and type of chemotherapeutic used, however these could all affect the efficacy of the treatment and would require further clinical trials.

Authors' Conclusions

• Though fewer than 50% of IP patients completed six cycles of treatment, there was a 25% reduction in risk of death with IP chemotherapy, along with the longest median survival seen in any of the phase III GOG trials (65.6 months).
• This study was not designed to study the effects of the duration of IP therapy and retrospective analysis of this may introduce bias. It is therefore not possible to determine if the benefit seen with IP therapy occurs early in treatment, or if completion of the full course of therapy could be of greater benefit.
• This study demonstrated a PFS and OS advantage to IP chemotherapy in Stage III OC that has been optimally resected. Though this advantage comes with increased toxicity and reduced QOL during treatment, it appears that QOL is the same after one year. The results are encouraging for the use of IP therapy in OC.