Comments: Policy Accepted during 2013 Annual Review with no changes.

Transcription

1 Health Plan Coverage Policy ARBenefits Approval: 01/01/2012 Effective Date: 01/01/2012 Revision Date: 09/18/2013 Title: Cytoreduction Surgery with Hyperthermic Intraperitoneal Chemotherapy Comments: Policy Accepted during 2013 Annual Review with no changes. Document: ARB0116 Public Statement: Peritoneal carcinomatosis of gastrointestinal origin, typically colorectal, occurs in 10% to 15% of patients with colorectal cancer. Natural history studies show a median survival of 6 months. Cytoreduction in conjunction with hyperthermic intraperitoneal chemotherapy has been proposed for these patients. The cytoreduction is designed to removal visible tumor deposits, and the intraperitoneal chemotherapy is designed to address remaining microscopic disease. This technique continues to be subject of ongoing trials. It is therefore considered experimental and investigational, and is not covered. Medical Policy Statement: Cytoreduction with intraoperative chemotherapy, with or without hyperthermia, or cytoreduction and early postoperative intraperitoneal chemotherpay, for the treatment of peritoneal carcinomatosis of any origin is considered investigational and experimental, and is not covered. This technique continues to the be subject of ongoing trials to determine optimal patient selection and long-term safety and effectiveness. There is no consensus about drugs, doses, times, or technique. Limits:. Page 1 of 10

2 Background: Cytoreduction initially involves mobilization of the liver, exploration of the diaphragm, mobilization of the stomach and lesser sac, exploration of the bilateral abdominal gutters, pelvic recesses, and mobilization of the large and small bowel with examination for tumor deposits along their entire length. Surgical resection can be extensive, depending on the extent of disease, but may include partial gastrectomy, splenectomy, and resection of the tail of the pancreas, omentectomy, multiple small bowel resections, ileocecal resection, rectosigmoid resection, uterine resection, and multiple peritonectomy procedures. The surgical procedure is followed intraoperatively by the infusion of hyperthermic chemotherapy, most commonly mitomycin C. Inflow and outflow catheters are placed in the abdominal cavity, along with temperature probes to monitor the temperature. The skin is then temporarily closed during the chemotherapy perfusion, which typically runs for 1 to 2 hours. Peritoneal carcinomatosis of gastrointestinal origin, typically colorectal, occurs in 10% to 15% of patients with colorectal cancer. Natural history studies show a median survival of 6 months. In a further subset of these patients, tumor recurrence is confined to the peritoneal surface. Surgical cytoreduction in conjunction with hyperthermic intraperitoneal chemotherapy has been proposed for these patients. The cytoreduction is designed to removal visible tumor deposits, and the intraperitoneal chemotherapy is designed to address remaining microscopic disease. By delivering chemotherapy intraperitoneally, drug exposure to the peritoneal surface is increased some 20-fold compared to systemic exposure. In addition, prior animal and in vitro studies have suggested that the cytotoxicity of mitomycin C is enhanced at temperatures greater than 39 degrees Celsius. The coding for this overall procedure would likely involve codes for the surgery, the intraperitoneal chemotherapy, and the hyperthermia. Cytoreduction and intraperitoneal hyperthermic chemotherapy has been investigated for the past 15 years, with many single institution case series and phase II trials reported. However, the two key pieces of data are a retrospective multi-institutional case series involving 28 institutions and 506 patients (Glehen, 2004) and the results of a randomized study (Verwaal, 2003). These 2 studies are reviewed in depth. Multi-institutional Case Series The study population consisted of patients with peritoneal carcinomatosis related to colorectal cancer who underwent the procedure between 1987 and Patients with extra-abdominal metastases were excluded. A variety of protocols for intraperitoneal operative chemotherapy were used; mitomycin C was the most common. Some patients also received intraperitoneal chemotherapy in the early postoperative procedure, sometimes after a prior operative infusion. In the early postoperative setting, fluorouracil was most common. A total of 20 patients (4%) died postoperatively. Major complications occurred in 116 patients (22.9%); digestive fistula was the most common major complication, occurring in 8.3% of patients, and was the cause of death in the 7 of the 20 patients who died. At a mean follow-up of 53 months, the morbidity and mortality rates were 22.9% and 4%, respectively, with a median survival of 19.2 months. Subgroup analysis of outcomes based on the completeness of resection reported that patients with complete resection of macroscopic disease had a median survival of 32.4 Page 2 of 10

3 months compared to only 8 months in those cases for which complete resection was not possible. The completeness of resection was the most significant prognostic indicator. The overall recurrence rate was 73.3%, with peritoneal recurrences noted in 41.9% of patients. The authors concluded that these results echoed those reported in small case series. Randomized Study While studies were considered promising, patient bias could not be excluded, particularly because patients with better prognoses might be preferentially recruited for an aggressive surgical approach. To address these issues, a single institution study was undertaken that randomized 105 patients with peritoneal carcinomatosis to receive standard treatment with systemic chemotherapy (fluorouracil and leucovorin) and palliative surgery, if necessary (i.e., treatment of bowel obstruction) or to a second arm consisting of aggressive cytoreduction and intraperitoneal chemotherapy followed by standard systemic chemotherapy (Verwaal, 2003). Patients with other sites of metastases, i.e., lung or liver, were excluded. The cytoreductive procedure consisted of stripping the parietal peritoneum and resection of infiltrated viscera, if possible. Most often resection of the gall bladder, parts of the stomach, and spleen were performed. The greater omentum was also routinely removed. At the completion of resection, the presence of residual tumor was assessed. Hyperthermic mitomycin C was then administered intraperitoneally for 90 minutes. The most important complications were small bowel leakage and abdominal sepsis, but a total of 24% of patients suffered from severe or life-threatening complications, such as heart failure, arrhythmias, or renal failure. A total of 8 patients (16%) died as the result of treatment at 30 days. The main endpoint was survival, measured from the time of randomization to death from any cause. After a median follow-up of 21.6 months, 20 of 51 patients in the standard therapy group were still alive compared to 30 of 54 patients in the cytoreduction group. Median survival in the control and cytoreduction group was 12.6 months compared to 22.4 months, respectively. Subgroup analysis revealed that survival was particularly poor among patients with either residual tumor measuring greater than 2.5 mm or in patients with tumor involvement in 6 or more regions in the abdomen. In these groups, median survival was only around 5 months, compared to 29 months in patients with no residual tumor. While these results were statistically significant, several issues still remain. In a letter to the editor, Markman )2004) points out that the reported survival benefit may be related primarily to the cytoreduction, with added chemotherapy only contributing to increased morbidity. In another letter, Hildebrandt (2004) raises the same issue, focusing on whether the hyperthermia adds any benefit to the intraperitoneal chemotherapy. Finally, new targeted systemic treatment options have emerged for colon cancer, specifically cetuximab and bevacizumab, which offer additional palliative options for colon cancer. Aside from the issues of the trial methodology, the results of the trial present complicated risk benefit questions that are not adequately addressed. If the main rationale for cytoreductive surgery is to provide a curative option, data regarding disease recurrence would be important. It is not known whether the survivors in either group are alive with or without disease. If the main rationale for the therapy is palliation in terms of prolonging life or relieving specific symptoms (e.g., related to ascites or bowel obstruction), it is important to determine the quality of life associated with the 10- Page 3 of 10

4 month improvement in median survival. Quality of life data were not reported in this randomized trial; however, the high incidence of major complications, and the reported mean length of hospitalization of 29 days suggest that this aggressive surgical approach has a significant impact on quality of life. Quality of life was addressed in a separate case series of 64 patients undergoing cytoreductive surgery and intraperitoneal chemotherapy (McQuellon, 2001). The Functional Assessment of Cancer Therapy focusing on colon cancer (FACT-C), activities of daily living, the brief pain inventory, and depression scales composed the quality of life instruments used. A total of 48 patients completed the assessment prior to and at a mean of 12 days after surgery; 16 of the original 64 patients did not complete the survey either due to death (n=11) or missed appointments. By 6 months follow-up, only 39 patients were available, either due to death or continuing dropout. Among the respondents, the overall quality of life decreased significantly from baseline to postsurgery, but improved to greater than baseline at 3 months. However, these data are difficult to interpret without a control group, and owing to the large number of dropouts due to death. European investigators reported on results of treating 120 patients with peritoneal carcinomatosis from colorectal cancer with this technique (Cavaliere, 2006). Most received cisplatin and mitomycin-c. Three-year survival was 25.8%, but was 33.5% in those who could be cytoreduced. Some studies have evaluated factors that may help to predict better prognosis for patients who have this procedure. da Silva and colleagues (2006) reported that a limited volume of carcinomatosis observed at cytoreduction and negative lymph nodes at the time of primary operation were associated with a favorable long-term result. However, none of the studies address the concerns discussed previously. In a study somewhat similar to this approach, European investigators (Nordinger, 2005) concluded that adjuvant fluorouracil-based regional chemotherapy (intraperitoneal or intraportal) did not add further benefit to that obtained with systemic chemotherapy alone in patients with stage II-III colorectal cancer. In this study, overall 5-year survival was 72.3% for those who received regional and systemic chemotherapy compared with 72.0% for those who received only systemic chemotherapy. van Leeuwen (2008) reported on the experience in a Swedish series of 103 patients treated from between 2003 and This study was to explore factors associated with postoperative morbidity and survival. While postoperative mortality in this center was less than 1%, postoperative morbidity was 56%. Tumor type and optimal cytoreduction influenced survival. In this uncontrolled series, at 2 years overall survival was estimated at 72% and disease-free survival was 34%. Gusani (2008) reported results for a series of 122 patients who underwent this treatment for peritoneal carcinomatosis between 2002 and Patients had a number of malignancies, including ovarian cancer (13%) and peritoneal mesothelioma (12%). Overall morbidity was 56%, major morbidity was 30%, and 30-day mortality was 1.6%. Abdominal complications were the most common major morbidity; this included abscess, fistula, and anastomotic leak. The most favorable diagnosis was appendiceal cancer with a reported 2-year survival of 67%. The authors note that controlled studies are needed to help define the role of this procedure in patients with peritoneal carcinomatosis. Page 4 of 10

5 The randomized study by Verwaal (2008) reported an 8-year follow-up of all patients still alive until This update was with a minimum follow-up of 6 years for all patients (median 94 months; range months). During the follow-up, 1 patient crossed over from the standard arm to the hyperthermic intraperitoneal chemotherapy (referred to in this study as HIPEC ) arm after recurrent disease at 30 months after randomization (the standard arm being systemic chemotherapy only and the HIPEC arm systemic chemotherapy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy). At the time of this long-term follow-up, in the standard arm, 4 patients were still alive, 2 with disease and 2 without, and in the HIPEC arm, 5 patients were still alive, 2 with disease and 3 without. Disease-specific survival was reported as 12.6 months in the standard arm and 22.2 months in the HIPEC arm (p=0.028), and progression-free survival was 7.7 months in the standard arm and 12.6 months in the HIPEC arm (p=0.02). An editorial addressing this randomized trial commented that while this study shows that cytoreductive surgery and HIPEC with systemic chemotherapy nearly doubles survival compared to systemic chemotherapy alone, it does not show how much of this benefit is derived from the surgery and how much from the HIPEC (Levine, 2008). Cao and colleagues (2009) published a systematic review and meta-analysis of cytoreductive surgery (CRS) with perioperative intraperitoneal chemotherapy (PIC) for peritoneal carcinomatosis of colorectal origin. They identified only 2 RCTs, 2 controlled observational studies, 3 multi-institutional studies and 40 case-series studies. Primary sites other that colorectal were included in the patient population. PIC might include hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC) which might consist of normothermic intraperitoneal chemotherapy of various regimens. They concluded that there was a significant improvement in survival associated with CRS and HIPEC compared with a palliative approach. They expressed a need for further evaluation of the prognostic significance of lymph node and liver involvement. Despite the encouraging data for CRS and PIC, caution for widespread use is advised: characteristics of patients differed across treatment centers and individual trials; exclusion criteria differed in age limitations, liver involvement and node metastasis; mortality rates ranged from 0% to 12%; perioperative morbidity ranged from 14.8% to 57% but grading of morbidities varied in detail between studies. Glehen et al, 2010, published results of a retrospective, 25 French-speaking centers, review of 1290 patients with nongynecologic peritoneal carcinomatosis. Fifty-two percent had received previous neoadjuvant or palliative systemic chemotherapy. Eightysix percent of patients received HIPEC and 17% received EPIC (3% received EPIC and HIPEC). HIPEC procedures had variations in exposure techniques, drugs, duration, intraperitoneal temperatures, type of perfusate and flow rates. In the postoperative period (30 days) there was a 4.1% mortality and major complications in 33.6% with 14% requiring reoperation. Factors significantly increasing morbidity/mortality risk included increasing age, extent of the carcinomatosis assessed by the Peritoneal Cancer Index, and the experience of the institution where the procedure was performed. Median follow-up was 45.3 months with 1-year, 3-year, and 5-year overall survival rates of 77%, 49% and 37% respectively, with corresponding disease-free survival rates of 55%, 28% and 22% respectively. Overall median survival was 34 months but much higher for Page 5 of 10

6 those with pseudomyxoma peritonei (not reached) and appendiceal adenocarcinoma (77 months), and slightly higher for peritoneal mesothelioma (44 months). Elias, 2010, reported on a subset of patients from the report by Glehen This subset consisted of 523 patients abdominal carcinomatosis arising from colorectal cancer. All had best surgical effort at cytoreduction surgery: 443 had HIPEC, 84 and EPIC and 9 had both. Seventy per cent of all patients had previously been treated with systemic chemotherapy that did not include new, targeted molecules. Median survival for this group was 30.1 months. For this group the overall 1-year, 3-year and 5-year survival rates were 81%, 41% and 27% respectively, while disease free survival rates were 47%, 15% and 10% respectively. While the authors of this report suggested this technique should be considered "the current gold standard therapy, when feasible" and editorial (Khatri, 2010) proposed reservations about an article reporting results in a large group of patients treated with a collection of miscellaneous and nonstandardized techniques. He emphasized this report, as well as previous reports, are unclear about the extent to which each of the components, surgery, HIPEC, EPIC, contributes to the outcome. A trial of patients with peritoneal carcinomatosis randomized to aggressive surgical cytoreduction with or without HIPEC would provide more definitive evidence as to whether the survival advantage seen in the Verwaal trial was due to the extensive surgery rather than the regional chemotherapy. Such a trial is currently underway, NCT This trial is still recruiting patients as of Sep There are other ongoing clinical trials of cytoreduction surgery with hyperthermic intraperitoneal/intrathoracic chemotherapy for gynecologic cancers and mesothelioma in addition to other abdominal malignancies. References: Alexander HR, Hanna N, Pingpank JF.(2007) Clinical results of cytoreduction and HIPEC for malignant peritoneal mesothelioma. Cancer Treat Res, 2007; 134: Bijelic L, Yan TD, Sugarbaker PH.(2007) Failure analysis of recurrent disease following complete cytoreduction and perioperative intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer. Ann Surg Oncol, 2007; 14: Cao C, Tristan D, et al.(2009) A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol, 2009; 16: Cavaliere F, Valle M, et al.(2006) 120 peritoneal carcinomatoses from colorectal cancer treated with peritonectomy and intra-abdominal chemohyperthermia: a S.I.T.I.L.O. multicentric study. In Vivo, 2006; 20(6A): da Silva RG, Sugarbaker PH.(2006) Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer. J Am Coll Surg, 2006; 203(6): Page 6 of 10

7 Elias D, Gilly F, et al.(2010) Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol, 2010; 28(1):63-8. Esquivel J, Sticca R, Sugarbaker P, et al.(2007) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement. Ann Surgi Oncol, 2007; 14: Fagotti A, Paris I, et al.(2009) Secondary cytoreduction plus oxaliplatin-based HIPEC in platinum-sensitive recurrent ovarian cancer patients: a pilot study. Gynecol Oncol, 2009; 113(3): Fujimoto S, Takahashi M, et al.(1996) Survival time and prevention of side effects of intraperitoneal hyperthermic perfusion with mitomycin C combined with surgery for patients with advanced gastric cancer. Cancer Treat Res, 1996; 81: Fujimoto S, Takahashi M, et al.(1997) Improved mortality rate of gastric carcinoma with peritoneal carcinomatosis treated with intraperitoneal hyperthermic chemoperfusion combined with surgery. Cancer, 1997, 79(5): Fujimura T, Yonemura Y, et al.(1994) Continuous hyperthermic peritoneal perfusion for the prevention of peritoneal recurrence of gastric cancer: randomized controlled study. World J Surg. 1994; 18(1): Glehen O, Gilly FN, et al.(2010) Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1290 patients. Cancer, 2010 Aug [Epub ahead of print]. Glehen O, Kwiatkowski F, et al.(2004) Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol, 2004; 22(16): Gusani NJ, Cho SW, et al.(2008) Aggressive surgical management of peritoneal carcinomatosis with low mortality in a high-volume tertiary cancer center. Ann Surg Oncol, 2008; 15(3): Hayes, Inc.(2009) Intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis resulting from cancer of the lower gastrointestinal tract. Hayes Directory, May Hayes, Inc.(2009) Intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis resulting from cancers of the lower gastrointestinal tract. Hayes Directory, May Hayes, Inc.(2009) Intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis resulting from gastric cancer. Hayes Directory, April Page 7 of 10

8 Hayes, Inc.(2009) Intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis resulting from ovarian cancer, peritoneal mesothelioma, or abdominal sarcoma. Hayes Directory, May Hayes, Inc.(2009) Intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis resulting from ovarian cancer, peritoneal mesothelioma, or abdominal sarcoma. Hayes Directory, May Helm CW, Bristow RE, et al.(2008) Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol, 2008; 98: Helm CW, Toler CR, Martin III RS, et al.(2007) Cytoreduction and intraperitoneal hated chemotherapy for the treatment of endometrial carcinoma recurrent within the peritoneal cavity. Int J Gynecol Cancer, 2007; 17: Hildebrandt B, Rau B, et al.(2004) Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinosis. Letter to editor. J Clin Oncol, 2004; 22(8): Khatri VP.(2010) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a panacea or just an obstacle course for the patient? Editorial. J Clin Oncol, 2010; 28(1):5-8. Levine EA.(2008) The randomized trial of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion: what it does and does not tell us. Ann Surg Oncol, 2008; 15(10): Markman, M.(2004) Intraperitoneal hyperthermic chemotherapy as treatment of peritoneal carcinomatosis of colorectal cancer. J Clin Oncol, 2004; 22(8): McQuellon RP, Loggie BW, et al.(2001) Quality of life after intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal carcinomatosis Eur J Surg Oncol, 2001; 27(1): Nordlinger B, Rougier P, et al.(2005) Adjuvant regional chemotherapy and systemic chemotherapy versus systemic chemotherapy alone in patients with stage II-III colorectal cancer: a multicenter randomised controlled phase III trial. Lancet Oncol, 2005; 6(7): Smith HO, Moon J, et al.(2009) Southwest Oncology Group Trial S9912: intraperitoneal cisplatin and paclitaxel plus intravenous paclitaxel and pegylated liposomal doxorubicin as primary chemotherapy of small-volume residual stage III ovarian cancer. Gynecol Oncol, 2009; 114(2): Stewart JH, Shen P, Levine EA.(2005) Intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: Current status and future directions. Ann Surg Onc, 2005; 12: Page 8 of 10

9 van Leeuwen BL, Graf W, et al.(2008) Swedish experience with peritonectomy and HIPEC. HIPEC in peritoneal carcinomatosis. Ann Surg Oncol, 2008; 15(3): Varban O, Levine EA, et al.(2009) Outcomes associated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in colorectal cancer patients with peritoneal surface disease and hepatic metastases. Cancer, 2009; 115(15): Verwaal VJ, Burin S, et al.(2008) 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol, 2008; 15(9): Verwaal VJ, van Ruth S, de Bree E, et al.(2003) Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol, 2003; 21: Yan TD, Black D, Savady R, Sugarbaker PH.(2006) Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol, 2006; 20: Yan TD, Deraco M, et al.(2009) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant mesothelioma: a multi-institurional experience. J Clin Oncol, 2009; 27(36): Yan TD, Morris DL.(2008) Cytoreductive surgery and perioperative intraperitoneal chemotherapy for isolated colorectal peritoneal carcinomatosis: experimental therapy or standard of care? Ann Surg, 2008; 248(5): Yan TS, Black D, et al.(2007) A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol, 2007; 14(10): Yonemura Y, Fujimura T, et al.(1996) Effects of intraoperative chemohyperthermia in patients with gastric cancer with peritoneal dissemination. Surgery, 1996; 119(4): Physician Request for Reconsideration: This coverage policy is the result of the clinical data, peer-reviewed material, documented trials, and other non-member specific clinical data available to and reviewed by the ARBenefits Health Plan Coverage Policy review panel. In the event that the treating physician has additional clinical data, peer-reviewed material, documented trials, or non-member specific clinical data, it should be provided to the Employee Benefits Division, P.O. Box 15610, Little Rock, AR 72231, Attn: Coverage Policy Review panel c/o Chief Health Services Officer. Page 9 of 10

10 Application to Products This policy applies to ARBenefits. Consult ARBenefits Summary Plan Description (SPD) for additional information. Page 10 of 10