Objective
We sought to evaluate the toxicity and tolerability of the intraperitoneal/intravenous regimen by comparing the modified regimen that is used at the Moffitt Cancer Center vs the published findings of the Gynecologic Oncology Group Study 172.
Study Design
Using the Moffitt database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage IIC-IV epithelial ovarian, tubal, and peritoneal carcinoma followed by the intent-to-treat with intraperitoneal/intravenous chemotherapy. National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to grade adverse events.
Results
We analyzed patient data from 2006-2011 and identified 69 patients who met our inclusion criteria. The most frequent grade 3/4 toxicities were neutropenia (48%), gastrointestinal (9%), metabolic (9%), and infection (5%). Remaining toxicities occurred in <5% of patients. Patients received a greater number of cycles compared with the Gynecologic Oncology Group Study 172 (4.28 vs 3.66, respectively; P = .0088).
Conclusion
With the use of supportive care and the preemptive management of established side-effects, the associated toxicities and tolerability of intraperitoneal chemotherapy can be improved.
Ovarian cancer is the leading cause of death among patients with gynecologic malignancies. Epithelial ovarian cancers (EOC) comprise 95% of ovarian malignancies and commonly are grouped together with peritoneal and fallopian tube cancer, which share a similar clinical course and response to treatment. Without a method of screening, most patients unfortunately will have advanced (stage III/IV) disease, which results in a Surveillance, Epidemiology and End Results Program–reported 5-year survival rate of 44%. Although primary cytoreductive surgery followed by 6 cycles of taxane- and platinum-based chemotherapy is a well-established treatment, the optimal route, dose, and schedule are areas of ongoing discussion and investigation.
In 2006, the Gynecologic Oncology Group (GOG) published the results of a phase III randomized control trial (Study 172) that compared combined intraperitoneal/intravenous chemotherapy with standard intravenous chemotherapy. This study demonstrated a 6-month progression-free survival and a 16-month overall-survival benefit in patients who were assigned randomly to intraperitoneal/intravenous therapy compared with intravenous therapy, which makes it a highly significant chemotherapy advance for EOC. An article that was published in 2011 included the GOG 172 and 5 additional “high-quality studies” demonstrated a similar survival benefit, which further supports the use of intraperitoneal/intravenous chemotherapy for the treatment of EOC.
Despite this high level of evidence in regard to survival benefit, the inconvenience, toxicities, tolerability, and port-related complications have been cited as barriers to the standard use of intraperitoneal/intravenous chemotherapy. In an effort to reduce the negative factors that are associated with intraperitoneal/intravenous chemotherapy, several institutions have modified the regimen that originally was described in the GOG 172.
At our institution (H. Lee Moffitt Cancer Center and Research Institute [MCC]), intraperitoneal chemotherapy is administered as published in the GOG 172 but with a reduced intraperitoneal cisplatin dose (75 mg/m 2 vs 100 mg/m 2 ). In addition, our institution incorporates a standardized set of supportive and prophylactic medications that include multidrug anti-emetics, amifostine, anxiolytics, and growth factors. Because a survival benefit of intraperitoneal/intravenous chemotherapy has been demonstrated in randomized controlled trials and supported by retrospective cohort studies, our primary objective was to investigate the tolerability and toxicities of our institution’s approach vs those shown in previously reported data. We hypothesized that the proactive management of documented side-effects and the addition of supportive care to a modified intraperitoneal/intravenous regimen will result in improved tolerability and toxicity.
Materials and Methods
This single-institution, retrospective study received approval from the Institutional Review Board at the University of South Florida. Eligible patients received treatment at the MCC from January 2006 through December 2011. The patients who were included in the study had undergone primary optimal cytoreductive surgery (no residual disease ≥1 cm) with a final pathologic diagnosis of stage IIC-IV EOC. Patients were counseled on the known risks and benefits of intraperitoneal/intravenous vs standard intravenous chemotherapy either before or after surgery and had elected to receive intraperitoneal/intravenous chemotherapy.
Our study group was identified through queries within our internal cancer registry of patients who received care at our institution. The Moffitt Cancer Registry maintains a comprehensive dataset for patients who are diagnosed and/or treated for cancer at MCC. The data are reported to the Florida State Cancer Registry and the National Cancer Database. From our database, we extracted eligible patients by identifying those who had been diagnosed with an ovarian, peritoneal, or fallopian tube malignancy who had received placement of an intraperitoneal port. All operative reports, progress notes, and laboratory data were reviewed from the time of initial evaluation to the completion of primary adjuvant treatment.
Our regimen follows: day 1 is intravenous paclitaxel 135 mg/m 2 over 24 hours; day 2 is intraperitoneal cisplatin 75 mg/m 2 ; and day 8 is intraperitoneal paclitaxel 60 mg/m 2 , repeated every 21 days for a goal of 6 cycles. Additionally, the protocol was standardized to include the supportive agents shown in Table 1 . After treatment initiation, there was not a rigid algorithm for the management of toxicities, which provided the gynecologic oncologist the discretion of when dose-delay, dose-reduction, or discontinuation of therapy was warranted.
| Day | Regimen |
|---|---|
| 1: Before paclitaxel (intravenously) | 1. Dexamethasone 20 mg in 100 mL normal saline solution intravenous piggy-back over 30 minutes |
| 2. Ranitidine 50 mg in 5% dextrose in 1/2 normal saline solution intravenous piggy-back over 15 minutes | |
| 3. Lorazepam 0.5 mg intravenously/orally 30 minutes before chemotherapy | |
| 4. Diphenhydramine 50 mg intravenously over 2-5 minutes OR chlorpheniramine 4 mg orally 30 minutes before chemotherapy | |
| 5. 1000 mL 5% dextrose in 1/2 normal saline solution + 20 mEq potassium chloride + 2 g magnesium + 25 g mannitol @ 500 mL/hour starting 2 hours before completion of paclitaxel infusion (before cisplatin hydration). | |
| 2: Before cisplatin (intraperitoneally) | 1. Aprepitant 125 mg orally 60 minutes before amifostine and 80 mg orally every 24 hours on days 3 and 4 |
| 2. Dexamethasone 12 mg in 100 mL normal saline solution intravenous piggy-back over 30 minutes at 60 minutes before amifostine | |
| 3. Odansetron 16 mg orally 60 minutes before amifostine | |
| 4. Ranitidine 50 mg in 50 mL 1/2 normal saline solution intravenous piggy-back over 15 minutes at 60 minutes before amifostine | |
| 5. Lorazepam 1 mg intravenously × 1 before amifostine | |
| 6. Diphenhydramine or chlorpheniramine (see day 1) | |
| 7. Amifostine (910 mg/m 2 ) in 50 mL normal saline solution intravenous piggy-back over 5 minutes at 30 minutes before cisplatin | |
| 8. Warmed (37°C) normal saline solution 500 mL intraperitoneal rapid infusion (before and after cisplatin) | |
| 8: Before paclitaxel (intraperitoneally) | 1. 1000 mL 5% dextrose in 1/2 normal saline solution + 20 mEq potassium chloride at 500 mL/h |
| 2. Ranitidine 50 mg in 5% dextrose in 1/2 normal saline solution intravenous piggy-back over 15 minutes before chemotherapy | |
| 3. Diphenhydramine or chlorpheniramine (see day 1) | |
| 4. Dexamethasone 20 mg in 100 mL normal saline solution intravenous piggy-back over 30 minutes before chemotherapy | |
| 5. Warmed (37°C) normal saline solution 500 mL intraperitoneal rapid infusion (before and after paclitaxel) | |
| Additional | Pegfilgrastim subcutaneously 24-48 hours after completion of chemotherapy |
| Prochlorperazine 10 mg intravenously/orally every 6 hours as needed for nausea/vomiting |
The National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to identify grade 3 and 4 toxicities (which is consistent with the grading used in the GOG 172). Recorded toxicities included bone marrow, gastrointestinal, renal, metabolic, and infectious. Catheter-related complications were also noted. Subjective toxicities were recorded but not included in our statistical analysis. A survival analysis was not performed. Descriptive statistics were considered with the use of frequency tables. To compare results from the GOG and MCC groups vs other variables, we used the χ 2 test with the exact method with Monte Carlo estimation. All probability values that are listed were 2-sided and considered significant at .05. Statistical analyses were performed with SAS software (version 9.3; SAS Institute Inc, Cary, NC).
Results
We identified 69 patients with stage IIC-IV optimally cytoreduced EOC who underwent placement of an intraperitoneal port from 2006-2011. Patient demographics and tumor characteristics are shown in Table 2 . The median age at the time of diagnosis was 56 years (range, 31−87 years). Most of our population had high-grade stage III serous adenocarcinoma of ovarian primary. Four patients (6%) had stage IIC disease, and 1 patient (1%) had stage IV disease. Surgical cytoreduction was complete (no gross residual) in 42 patients (61%) and optimal (<1 cm residual) in 27 patients (39%).
| Tumor characteristic | Patients, n (%) | P value | |
|---|---|---|---|
| Gynecologic Oncology Group Study 172 | H. Lee Moffitt Cancer Center and Research Institute | ||
| Total patients | 205 | 69 | |
| Tumor stage | |||
| IIC | 4 (6) | ||
| IIIA | All stage III | 6 (9) | |
| IIIB | 8 (12) | ||
| IIIC | 50 (73) | ||
| IV | 1 (1) | ||
| Histologic subtype | .0249 | ||
| Serous adenocarcinoma | 158 (77) | 45 (65) | |
| Endometrioid adenocarcinoma | 17 (8) | 5 (7) | |
| Clear cell carcinoma | 11 (5) | 3 (4) | |
| Mixed epithelial/other | 19 (9) | 16 (23) | |
| Histologic grade | |||
| 1 | 25 (12) | 1 (1) | |
| 2 | 72 (35) | 0 | |
| 3 | 106 (52) | 68 (99) | |
| Gross residual disease | .011 | ||
| No | 78 (38) | 42 (61) | |
| Yes (<1 cm) | 127 (62) | 27 (39) | |
| Disease site | .0165 | ||
| Ovarian | 183 (87) | 60 (87) | |
| Primary peritoneal | 27 (13) | 6 (9) | |
| Fallopian tube | 0 | 3 (4) | |
Treatment toxicities among patients who received at least 1 cycle of intraperitoneal chemotherapy (n = 65) are reported in Figure 1 . In Figure 2 , we compare our toxicity rates with those reported in the GOG 172. Neutropenia (48%), gastrointestinal (9%), metabolic (9%), and infectious (5%) toxicities were the most common grade 3/4 toxicities that occurred with our modified regimen. The differences in neutropenia, gastrointestinal, metabolic and infectious toxicities, as compared with the GOG 172, were statistically significant ( P < .0001-.0202). Thrombocytopenia had borderline significance ( P = .0535). There were no treatment-related deaths.
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