Published online May 24, 2019. doi: 10.5306/wjco.v10.i5.201
Peer-review started: January 4, 2019
First decision: January 26, 2019
Revised: March 12, 2019
Accepted: March 26, 2019
Article in press: March 27, 2019
Published online: May 24, 2019
Adjuvant chemotherapy using intraperitoneal (IP) treatment has demonstrated survival benefit over intravenous (IV) therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer based on the Gynecologic Oncology Group (GOG) 172 trial. Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy based on the European Organization for Research on Treatment of Cancer study. IP chemotherapy has not been widely adopted in clinical practice for a number of reasons, mainly due to the concern of side effects. With the wide spread use of neoadjuvant chemotherapy, it is unclear whether IP chemotherapy in the adjuvant setting in those patients is safe and beneficial. There is an ongoing phase III study (OV21/PETROC) addressing this questions, and its preliminary result showed increase in progression free survival (PFS) in the IP arm compared to IV arm (42% vs 24.5%) using 9 mo progression rate as the outcome measure.
There are multiple problems to be addressed regarding IP chemotherapy. (1) What are the side effects of IP treatments, especially off clinical trials in a community cancer center? (2) Would patients experience more side effects after they have received neoadjuvant IV chemotherapy and then receive IP chemotherapy in the adjuvant setting? And (3) Is there benefit or improved outcome in those patients who receive IP chemotherapy? As our cancer center recommended IP chemotherapy to all fit patients as a general practice, we decided to analyze our data to answer those questions. We hope to share our community experience and to show the safety and efficacy data, to decrease the concerns regarding the side effects of IP, and to support the use of IP in the right clinical setting.
We wished to evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting, and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who have received neoadjuvant treatment.
We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery (group 1) or after neoadjuvant chemotherapy followed by interim surgery (group 2). We reviewed the electronic records, and documented the regimens used, dose reduction, dose delay, drug variations. We also documented toxicities, patient characteristics.
We performed a sample size calculation to determine the least number of patients to be included in the study to have an 80% power to compare with the historical data (60 mo for the IP group reported in the GOG 172 study), and came up with 31 patients. We actually had 38 patients, which should have the above power to have a comparison.
We specified that PFS will be calculated starting from the date of diagnosis to the date of progression on computed tomography scan or death or last known follow up. Three patients were treated at the first recurrence with IP after surgery, and we defined the diagnosis date to be the date of the second debulking surgery, which was used as the start date for PFS and overall survival (OS) calculations. For some patients who lost for follow up and had Medicare insurance, we checked Medicare data base to extract date of death.
Thirty eight patients were treated with IP chemotherapy, median age was 54 years old (range 38.6 to 71 years). In group 1 (n = 25), 12 (48%) of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery; while in group 2 (n = 13), 8 (61.5%) of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery, and 2 (15.4%) more patients tolerated more than 3 cycles. In those patients who did not get planned IP chemotherapy, most of them were treated with substitutional IV chemotherapy, and the completion rate for 6 cycles of IV + IP was 92%.
Abdominal pain, (64% in group 1 and 38% in group 2), vomiting (36% in group 1 and 30.8% in group 2), dehydration (16% in group 1 and 15.4% in group 2), and hypomagnesemia (12% in group 1 and 15.4% in group 2) were the most common adverse effects in all patients, while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia, fatigue and renal insufficiency.
PFS was 26.5 mo (95% CI 14.9, 38.0) in group 1 and 27.6 mo (95% CI 13.1, 42.1) in group 2. OS was 100.2 mo (95% CI 67.9, 132.5) for group 1 and 68.2 mo (95% CI 32.2, 104.0) for group 2. For the entire cohort, PFS was 26.5 mo (95% CI 15.9, 37.0) and OS was 78.8 mo (95% CI 52.3, 105.4). The 9-mo PFS rate was 88.6% in the entire cohort.
Our result reflected the real world experience of IP administration, in that most of the patients did not get 6 cycles of IP for adjuvant treatment as in GOG 172 study. About half of the patients can get 3 cycles of IP treatment, which was also true in those patients who have received neoadjuvant treatment. There appears to be benefits in PFS and OS even with the above limitations.
The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting. The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable. Despite various modification of the IP regimen, incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved progression free survival and overall survival.
Our data provides community practice experience and supports the data reported in GOG 172 and Cochran review from clinical trials about the benefits and toxicities of IP therapy. The benefit of IP treatment remains sizable even with reduced cycles of IP and dose variations.
Our study provides new information on the benefits and toxicities of administration of adjuvant IP in patients who have received neoadjuvant IV chemotherapy. A phase III OV21/PETROC study has been designed to address this question, and our 9-mo PFS rate was higher than reported in the study.
In our community practices, administration of IP chemotherapy in the adjuvant treatment for ovarian cancer, and in patients who have received IV chemotherapy in the neoadjuvant setting, is feasible, safe and associated with apparent benefit in PFS and OS. This approach should be further studied in randomized phase III clinical trials.