|Year : 2016 | Volume
| Issue : 4 | Page : 607-611
Study of efficacy and safety of modified adjuvant intraperitoneal chemotherapy regimen in carcinoma ovary
P Dash1, V Goel1, V Talwar1, DC Doval1, S Raina1, P Goyal1, A Upadhyay1, N Patnaik2
1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Pathology, Action Cancer Hospital, New Delhi, India
|Date of Web Publication||21-Apr-2017|
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Source of Support: None, Conflict of Interest: None
OBJECTIVE: It has been demonstrated in few trials that intraperitoneal and intravenous (IP/IV) chemotherapy improves survival in advanced stage ovarian cancer (OC). However, in view of high treatment-related toxicities, various modifications in treatment schedules have been tried. In this study, response and tolerability of IP paclitaxel on day 8 with IV paclitaxel on day 1 and IV cisplatin day 2 in carcinoma ovary were evaluated. PATIENTS AND METHODS: In this prospective observational study, from March 2013 to December 2015, the efficacy and tolerability of adjuvant IP/IV chemotherapy in optimally cytoreduced Stage III epithelial OC (EOC) patients were assessed. RESULTS: Totally, sixty patients were enrolled. The median age of patients was 53 years (32–67 years). Out of a total of 360 IP cycles, 316 cycles (88%) were completed. Forty-five patients (76%) received all the 6 cycles by IP route. Eight out of those 45 patients had one or more adjustment including delay or dose reduction. After median follow-up of 22 months, eight patients (14%) had local or systemic recurrence. Median progression-free survival not reached yet. Catheter block was seen in five cases. Two cases had needle displacement and extravasations of drug around the port chamber. Six patients had Grade 3 abdominal pain and cramp. Grade 3/4 leukopenia was experienced by thirty patients (50%), but febrile neutropenia occurred in only 6 (10%) patients. Renal complication present in 4 (7%) patients. CONCLUSIONS: In Indian patients, adjuvant chemotherapy with day 8 I/P paclitaxel in optimally cytoreduced EOC is associated with comparable survival outcomes, less side effects and high treatment completion rate relative to literature published from Western countries.
Keywords: Adjuvant, carcinoma ovary, intraperitoneal, platinum
|How to cite this article:|
Dash P, Goel V, Talwar V, Doval D, Raina S, Goyal P, Upadhyay A, Patnaik N. Study of efficacy and safety of modified adjuvant intraperitoneal chemotherapy regimen in carcinoma ovary. Indian J Cancer 2016;53:607-11
|How to cite this URL:|
Dash P, Goel V, Talwar V, Doval D, Raina S, Goyal P, Upadhyay A, Patnaik N. Study of efficacy and safety of modified adjuvant intraperitoneal chemotherapy regimen in carcinoma ovary. Indian J Cancer [serial online] 2016 [cited 2019 Aug 22];53:607-11. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/607/204753
| » Introduction|| |
The most common route of ovarian cancer (OC) spread is within the peritoneal cavity. The benefit of administering chemotherapy directly into the peritoneal cavity is supported by preclinical and pharmacokinetic data. Compared with intravenous (IV) treatment, intraperitoneal (IP) administration permits a several fold increase in drug concentration to be achieved within the abdominal cavity. In addition, clinical trials have demonstrated a survival advantage to the incorporation of IP treatment in the upfront management of OC in the vast majority of patients of epithelial OC (EOC, which includes fallopian tube and peritoneal cancers) confined to the peritoneal cavity at initial diagnosis and in recurrence. Because of this natural history, OC is an ideal target for IP therapy. Pharmacokinetic studies demonstrated that IP administration of chemotherapy results in high peritoneal to plasma ratios for peak concentration, including for cisplatin, paclitaxel, carboplatin, and docetaxel.
IP therapy is best suited to patients with no or minimal residual disease (RD) after surgical cytoreduction because penetration of chemotherapy into tumor tissue is limited to a few millimeters of tumor on the peritoneal surface layers. Therefore, IP chemotherapy is indicated for women with optimally debulked (to ≤1.0 cm) Stage III EOC.
The benefits of IP therapy as part of first-line treatment for women with optimally cytoreduced EOC have been consistently demonstrated in clinical trials, with at least two meta-analyses confirming benefits of treatment in terms of both progression-free and overall survival (OS).,
Increased toxicity associated with IP therapy frequently results in discontinuation of planned treatment compared with standard IV administration of chemotherapy. As an example, in Gynecologic Oncology Group (GOG) 172%, 42%, and 83% completed planned IV/IP versus IV therapy, respectively, leading to very less use of IP chemotherapy by medical oncologists. Hence, various modifications in treatment schedules have been tried to reduce toxicities.
Most of these studies are from Western countries, and there is a paucity of data from the Indian subcontinent, so we decided to study the feasibility and tolerability of IP chemotherapy in carcinoma ovary in Indian population.
The primary aim of this study is to evaluate response and tolerability of adjuvant IP chemotherapy in optimally cytoreduced Stage III EOC.
| » Patients and Methods|| |
This is a single-center, a prospective observational study conducted in the Department of Medical Oncology, Rajiv Gandhi Cancer Institute (RGCI) and Research Centre, New Delhi, India.
Patient eligibility criteria
Patients who had confirmed the histological diagnosis of optimally cytoreduced Stage III EOC were enrolled. Other inclusion criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, age >18 years and up to 70 years, adequate bone marrow reserve (white blood cell count: >4000/mm 3, absolute neutrophil count: >1500/mm 3, platelet count >100,000/mm 3; and hemoglobin, >9 g/dl), adequate hepatic and renal function (bilirubin, <1.5 times the upper limit of normal; alkaline phosphatase and transaminase levels, <2.0 times the upper limit of normal or <4 times in case of liver involvement; serum creatinine <1.5 mg/dl, calculated creatinine clearance, >45 ml/min), and adequate birth control measures if in reproductive age group. Other exclusion criteria included active infection, pregnancy and lactation, uncontrollable diabetes or hypertension, other primary malignancy, and ECOG PS 3 or 4.
The study protocol was approved by Institutional Ethic Review Boards, and all patients provided informed written consent before treatment.
At the time of surgery, a small transverse incision slightly larger than the port was made in the midclavicular line, overlying the lower ribs. An S.C. pocket was then developed over the fascia covering the ribs. The catheter was tunneled under the cutaneous tissue, above the fascia, for at least 10 cm, pulled into the peritoneal cavity, and then flushed with heparin. The port was then anchored with three permanent sutures to the fascia, to prevent rotation or migration. Two types of port were used: An IP port with a 14.3-fenestrated catheter and an intravascular port with a single-lumen catheter. During the postoperative stay, planning with the division of medical oncology occurred to finalize treatment plans, and the patients had another opportunity to discuss the pros and cons of IP chemotherapy.
Intraperitoneal chemotherapy regimen
IP treatment consisted of 135 mg/m 2 of IV paclitaxel over a 3-h period on day 1 followed by area under the curve 5 carboplatin IV on day 2 and 60 mg/m 2 of IP paclitaxel on day 8. Standard premedication with dexamethasone, famotidine, and diphenhydramine was given to prevent hypersensitivity reactions to paclitaxel. For IP therapy, paclitaxel was reconstituted in 1000–2000 ml of warmed normal saline (according to patients' tolerance of intraabdominal volume) and infused as rapidly as possible through the peritoneal catheter. After the paclitaxel IP infusion, the patient changed position at 15-min intervals for 2 h to ensure intraabdominal distribution. No attempt was made to retrieve the infusate; however, ascites were drained before instillation of the drug, if a large amount of ascites was present. The standard antinausea regimen consisted of granisetron (p.o.) and dexamethasone (IV) given before initiation of chemotherapy. Frequently, palonosetron and aprepitant were added, and granisetron was eliminated from this regimen. Prochlorperazine, lorazepam, and/or ondansetron or dexamethasone was used as take-home antiemetics on an as-need basis. Treatments were administered every 3 weeks for six cycles in an inpatient setting. This allowed a strict observation, with administration of supportive treatment (hydration and nausea medications) when needed.
Toxicity profiles were evaluated according to the National Cancer Institute—Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
All analyses were performed with the statistical software SPSS version 22 (SPSS, Inc., Chicago, IL, USA). For response and progression data, two-sided 95% confidence intervals were calculated based on an exact binomial probability at an α level of 0.05. The OS and time to tumor progression were estimated using the Kaplan–Meier method. Data were analyzed using Chi-square test and Fisher's exact test, wherever appropriate. Statistical significance was defined as P ≤ 0.05.
| » Results|| |
Patients were enrolled from March 2013 to December 2015 at RGCI, a comprehensive tertiary care cancer institute in India. Seventy-five histological proven chemotherapy-naive patients with optimally cytoreduced Stage III EOC were screened. Of these 75 patients, 8 were not enrolled: 4 patients did not meet inclusion or exclusion criteria, 2 withdrew consent, and 1 was not enrolled due to logistics. A total of sixty patients were then enrolled into the study. Sixty patients were evaluated for feasibility and toxicity of IP chemotherapy. Baseline patient and disease characteristics are listed in [Table 1]. The study included sixty women, with good ECOG PS (56, 53.33% had ECOG PS 0–1). The most frequent histology of tumor was serous (75%). The majority of patients were Stage IIIC. All patients were undergone optimal cytoreduction before chemotherapy. Age of the patient ranged from 39 to 67 years, with a median age of 53 years. Most (33) of the patients were in their fifth decade, followed by fourth decade (27 patients) of life. In the present study, we left no visible RD after cytoreduction. Side of insertion was routinely on the left, and only 10% had it on the right. Patients, who had extensive disease or bowel resection and anastomosis on the left side, were chosen for the right side insertion.
Out of a total of 360 IP cycles, 316 cycles (88%) were completed. Forty-five patients (75%) received all the six cycles by IP route, three patients completed five, one patient completed four cycles, five patients completed three cycles, and six completed two IP cycles. Rest of the cycles were given in IV route. Out of 45 patients who completed all six cycles of IP chemotherapy, a total of 5 patients had one or more adjustment including dose delay and 3 patients dose reduction.
Feasibility and toxicity
Catheter-related complications were seen in the initial period of the study. One patient had vaginal leak. Catheter block was seen in five cases. In four cases, it was salvaged by locking the catheter with heparin injection for 2 h. None of the IV catheters had the block. Two cases had backflow of fluid around the catheter and fluid tracked to collect around the port chamber site. Development of ascites or the presence of large amount of infusate itself may create increased pressure in the intra-abdominal compartment for fluid to track out along the gaps available. Two cases had needle displacement and extravasation of drug around the port chamber. The patient had local pain associated with erythema on the overlying skin. Immediate aspiration of fluid with wide bore needle and anti-inflammatory drugs enabled the patient to recover. Six patients had severe abdominal pain and cramp (Grade 3 of Common Terminology Criteria for Adverse Events version 4.0) after infusion of saline.
Hematologic toxicity was evaluated in all patients and in all cycles. Grade 3 or 4 leukopenia was experienced by thirty patients (50%), but febrile neutropenia occurred in only 6 (10%) patients. Grade 3 or 4 anemia occurred in 18 (30%), and Grade 3 or 4 thrombocytopenia was experienced by nine patients (15%). While 18 patients (30%) required red cell transfusions, only 1 patient required platelet support. No patient experienced significant hemorrhage. Renal complication present in 4 patients (6.66%) and transient transfusion reaction developed in 5 patients (8.33%), mucositis present in 21 patients (35%) [Table 2] and [Figure 1].
Response to treatment
Sixty patients were assessable for feasibility and toxicity. After median follow-up of 22 months, eight patients (14%) had local intraabdominal recurrence, and two patients (3.33%) have systemic recurrence along with local recurrence in the form of pulmonary metastasis in one patient and supraclavicular lymphadenopathy in second patient, two patients (5%) had progression during treatment and died due to disease.
| » Discussion|| |
Spread of epithelial ovarian carcinomas primarily follows three routes: Local extension to the adjacent peritoneum and pelvic structures, exfoliation in the abdominal cavity and implantation in multiple peritoneal sites, and lymphatic dissemination, mainly to the pelvic and paraaortic lymph nodes. Hematogenous dissemination to distant organs (mainly the liver) is much less common. As RD after primary surgery and initial recurrences is usually confined to the peritoneal cavity, IP chemotherapy finds its rationale in trying to better control the disease: Drugs can reach a higher concentration as well as a longer half-life in the peritoneal cavity. After it was first proposed in 1978, several trials have tried to compare the efficacy and the safety of different IP chemotherapy regimens as opposed to IV regimens. Following the publication of the results of GOG 172 on January 4, 2006, National Comprehensive Cancer Network recommended IP chemotherapy as the standard of care for patients with Stage III optimally debulked, OC. In GOG 172 trial after median follow-up of 48.2 months, the median progression-free survival was 18.3 months in the IV-therapy group and 23.8 months in the IP-therapy group. The median OS was 49.7 and 65.6 months, respectively. However, in spite of significant improvement in OS, toxicity profile is great hindrance for regular use of IP chemotherapy.
The successful delivery of six cycles of IP chemotherapy was seen in only 42% of the participants in Armstrong's trial and major reason for discontinuation of IP chemotherapy was due to catheter complications. In our study, 75% of the patients completed six cycles. More patients completed all six chemotherapy by IP route; the reason may be modified regimen use in our study.
Optimal timing of catheter insertion has not been established. In our study, port was placed during cytoreductive surgery. Delayed insertion necessitates a second surgical procedure, and many patients are reluctant to have second operation for port placement. It is easier to remove a device that is not required than it is to place one at a second surgery and chemotherapy can be started in time. Delay of IP therapy allows opportunity for adhesion development and may limit access of IP fluid to important locations of tumor spread. Transverse colon will be adherent to anterior abdominal wall after omentectomy, and delayed insertion is associated with difficulty in identifying free IP space to avoid injury to bowel. It can be done by minilaparotomy or laparoscopic method, but peritoneum should be entered under direct vision. Delayed insertion is done when peritoneal cavity is grossly contaminated. Analysis of data from GOG 172 suggests that delayed placement of an IP port did not decrease the likelihood of complications.
Toxicities and catheter-related complications remain the major obstacle for widespread implementation of IP chemotherapy. GOG 172 trial reported one case of vaginal leak and we too had one case. It never required additional treatment but to give adequate time for the vault to heal. In 34% of patients, catheter-related complications contributed to discontinuation of IP chemotherapy in GOG-172 trial. Although we had five patients (12.5%) with catheter-related problems, only one patient had to permanently discontinue further cycles and rest of the patients received six cycles. Catheter infection rate was very high (17.85%) in that trial, but we never had one. Davidson et al. reported catheter infection in 4.3% of women having small bowel surgery, in 16% of those having large bowel surgery, and 15.4% of the women who underwent appendectomy. Makhija et al. stopped inserting IP catheters when bowel resection was performed to avoid contamination. Six patients (15%) in our series underwent bowel resection and primary anastomosis guiding us to place the port on the opposite side; however, it never made any difference in the final outcome. Preoperative bowel preparation was routine in all the cases. There was no relation between initiation of IP therapy and left colon or rectosigmoid resection as against reported in GOG-172 trial.
Walker et al. also reported catheter block in 8.5%, access problem in 4.2%, and catheter leak in 2.5% of patients. In our study, there were no complications related to bowel, though reported to occur at a rate of 3%–5% and include fistulas, catheter migration into the bowel lumen, bowel obstruction, and perforations.,,,,, In our study, none of the venous catheters had obstruction indicating that venous catheters are less prone for obstruction. Fenestrated catheter causes fibrous sheath formation that can cause adhesions although recent studies have reported low complication rates., Formation of adhesions or obstruction is not related to the experience of the surgeon or technique of insertion as most of initial insertions were done by experienced on cosurgeons and technique is standardized. In four cases, heparin lock for 2 h, helped on unblocking the catheter. The exact cause of obstruction and mechanism of action of heparin is unknown. Resistance was only for the first cycle to begin with, and subsequently, there was easy flow. Probably, heparin had some indirect action on not so dense fibrin or continued contact of fluid dissolved the block or it was an evolving clot. It needs further evaluation. Potential benefits of adhesion barriers have not been validated in a randomized trial. IP catheters should be removed after the completion of current therapy, as complication rates are high, on retaining for longer period. It is removed under local anesthesia on outpatient basis.
In our study, IP chemotherapy was started on an average 3 weeks after the cytoreductive surgery, with median 21 days (range between 19 and 25 days). Delay in IP therapy allows opportunity for adhesion development and may limit access of IP fluid spread. Abdominal pain is thought to be related to stretching and distension of bowel-to-bowel adhesions. The symptom of pain is evidence that the distribution of drug is likely to be less than ideal. Low-grade abdominal pain can usually be treated with opioids. GOG trial 172 mandated dose reduction with Grade 2 abdominal pain and change over to IV chemotherapy for those with Grade 3 abdominal pain.
Grade 3 or 4 leukopenia was experienced by thirty patients (50%), but febrile neutropenia occurred in only 6 (10%) patients. In GOG-172 trial, Grade 3 and 4 leukopenia seen in 76% of patients. Grade 3 or 4 anemia occurred in 12 (30%), and Grade 3 or 4 thrombocytopenia was experienced by 6 patients (15%). While 12 patients (30%) required red cell transfusions, only 1 patient required platelet support. No patient experienced significant hemorrhage. Renal complication present in 4 patients (6.66%) and transient transfusion reaction developed in 5 patients, mucositis present in 21 patients. In GOG 172 trial, 7% patients developed renal complications.
In our study after median follow-up period of 22 months, eight patients (14%) had local intraabdominal recurrence and two patients (3.33%) have systemic recurrence. Median progression-free survival not reached yet.
Precautions observed during infusion of IP chemotherapy were access of port by well-trained staff, use of large plain Tegaderm dressing to hold the needle in place after access, and above all complete aseptic precaution. With the use of modified drug regimen, feasibility, and tolerance of IP chemotherapy was good in our study, with minimal toxicity.
| » Conclusions|| |
On the basis of our experience at our center, it can be concluded that the adjuvant IP chemotherapy in optimally cytoreduced EOC is feasible and well tolerated in Indian patients. It is possible to administer more number of cycles by improving port placement techniques, careful delivery of drugs with trained staff, and selecting modified chemotherapy regimen, which provides superior benefit to the patient than IV chemotherapy. More research is required, especially in the Indian subcontinent, to assess the feasibility and tolerability of this regimen in Indian patients for confirmation and deserves further study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]