Journal of Surgical Oncology 2014;110:575–584
Outcomes With Cytoreductive Surgery and HIPEC for Peritoneal Metastasis SHUJA AHMED, MD, JOHN H. STEWART, MD, PERRY SHEN, MD, KONSTANTINOS I. VOTANOPOULOS, MD, PhD, AND EDWARD A. LEVINE, MD* Surgical Oncology Service, Department of General Surgery, Wake Forest Baptist Medical Center, Winston Salem, North Carolina
Peritoneal metastasis (PM) has traditionally been approached with therapeutic nihilism. The evolution of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) over the last two decades, however, has caused a paradigm shift in treatment for PM. This modality is rapidly gaining acceptance as standard of care for PM from various cancers. This article reviews the current literature regarding the use of CRS/HIPEC for PM from the most common intra‐abdominal malignancies.
J. Surg. Oncol. 2014;110:575–584. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: peritoneal metastasis; cytoreductive surgery; hyperthermic intraperitoneal chemotherapy; colorectal cancer
INTRODUCTION PM has traditionally been approached with therapeutic nihilism. Patients typically progress to death due to bowel obstruction in less than a year from the time of diagnosis [1]. PM results from intracavitary dissemination of tumor from a variety of primary pathologic lesions. Such findings are all too common for gastrointestinal cancers including appendiceal and colorectal cancers, as well as ovarian carcinomas, sarcoma, and mesothelioma. Frequently, PM is confined to the peritoneal cavity without extra‐abdominal disease. Thus, a regional approach for selected patients with PM is reasonable. Beginning approximately 30 years ago, aggressive treatment of PM was explored. Centres evaluated treatment options such as peritonectomy procedures [2] supplemented with intraperitoneal adjuvant therapies [3,4]. Over the last two decades, there has been an increasing body of evidence for CRS/HIPEC as a treatment modality for PM. Consequently, more centres have adopted this modality contributing to the exponential rise in popularity of this procedure. The expanding literature has helped us identify not only the primary cancers for which CRS/HIPEC offers survival benefit but also the type of patients who may benefit from this treatment modality given its potentially debilitating complications. This article reviews the outcomes for CRS/HIPEC and its most common indications [5] including appendiceal tumors, diffuse malignant peritoneal mesothelioma, colorectal cancer, gastric cancer, and epithelial ovarian cancer.
CRS/HIPEC FOR APPENDICEAL TUMORS According to NCCN guidelines, epithelial neoplasms of the appendix are categorized under colorectal cancers (CRC) and comprise 1% of the CRC. It is pertinent to mention, however, that the two malignancies have genetic profiles quite distinct from each other [6]. Approximately 10% of patients with an epithelial appendiceal neoplasm develop mucinous ascites, also known as pseudomyxoma peritonei (PMP). Despite its low incidence, PMP from appendiceal tumor remains one of the most common indications for CRS/HIPEC. In addition, its rarity has not precluded an intense debate pertaining to its classification. The pathologic classification has been relevant due to its significant impact on prognosis. Ronnett et al. [7] first proposed a staging system
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with three categories of appendiceal tumor: Diffuse peritoneal adenomucinosis (DPAM) consisting of low‐grade tumors with low numbers of mitotic figures and cytologic atypia; peritoneal mucinous carcinomatosis (PMCA) consisting of high‐grade tumors and characterized by atypia and more prominent mitotic figures; and PMCA‐I/D marked by intermediate or discordant features. They showed that 5 and 10‐year survival for patients with DPAM (75%, 68%) was significantly better than that for PMCA‐I/D (50%, 21%) or PMCA (14%, 3%) [8]. We have published our experience with pathology from 101 patients with diagnosis of mucinous ascites related to primary appendiceal tumors [9]. Based on our data, the 5‐year survival for DPAM and PMCA‐I/D was 68% and 61%, respectively. PMCA, in comparison, had a 5‐year survival of 37% (P ¼ 0.004). We, therefore, proposed a two‐ tiered system. DPAM was categorized as low‐grade mucinous carcinoma peritonei (MCP‐L) and PMCA as high‐grade mucinous carcinoma peritonei (MCP‐H). Significantly, based on similar survival rates, PMCA‐I/D was also categorized under MCP‐L, with the exception that any case with signet‐ring cell component was categorized as PMCA and thus considered MCP‐H. Since the two tiered system is readily reproducible by pathologists who infrequently encounter this diagnosis, and Ronnett’s intermediate subset is a small minority of cases, we and others continue to support the two tier system. The role of cytoreduction in the treatment of PMP has long been recognized. Gough et. al. [10] demonstrated 5 and 10‐year survivals rates of 53% and 32%, respectively with serial debulking. More recently, 10‐year survival of 21% was reported with serial debulking, systemic chemotherapy and delayed intermittent intraperitoneal chemotherapy by
Disclosure Information: Nothing to disclose *Correspondence to: Edward A Levine, MD, Surgical Oncology Service, Medical Center Blvd., Winston‐Salem, North Carolina 27157. Fax: 336‐716‐ 9758. E‐mail: [email protected] Received 18 April 2014; Accepted 16 July 2014 DOI 10.1002/jso.23749 Published online 28 August 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Memorial Sloan Kettering Cancer Center [11]. Since Sugarbaker, an early pioneer in this area, initially championed CRS in combination with HIPEC [12], this technique has been much more popular. Clearly, CRS has benefit over observation or systemic chemotherapy alone. However, the therapeutic role of HIPEC independent of CRS has not been evaluated in randomized trials to date. Further, there have been no randomized trials evaluating the impact of type, dosage, and duration of intraperitoneal chemotherapy on PMP. In addition, the therapeutic benefit of hyperthermia is also yet to be demonstrated. The rarity of the disease makes randomized trials difficult to conduct for appendiceal neoplasms. Despite some limitations in evidence, PMP has been considered the classic indication for CRS/HIPEC. Five year survival rates have ranged from 66% to 97% [13]. A recent consensus statement reviewed the evidence and proposed CRS/HIPEC as standard of care for perforated appendiceal tumor with PSD [14]. Table I summarizes some of the studies that evaluated outcomes of CRS/HIPEC for appendiceal tumor. Wake Forest University published outcomes of 110 patients with PMP who underwent CRS/HIPEC, which is comparable to other centers [15]. Fifty percent of patients had DPAM, while 27% patients had PMCA. Mean age was 52.2 years. Mitomycin C (MMC) was used for intraperitoneal chemotherapy at concentration of >5 mg/ml for 2 hr with inflow temperature maintained at 42.0°C. Forty‐eight patients had complete (R0/1) cytoreduction. Thirty day post‐operative morbidity and mortality was 38% and 4%, respectively. Median follow‐up was 34.8 months. Median OS was 63.6 months. One, 3 and 5‐year survival were 79.9%, 59% and 53.4%, respectively. On subgroup analysis, patients with DPAM had better overall survival. Age at diagnosis, performance status, time between diagnosis and HIPEC, resection status and length of chemoperfusion were independent predictors of survival. The Basingstoke group [16] published their findings for 456 patients with PMP treated with CRS/HIPEC in the United Kingdom. The median age of patients was 56 years. MMC was used for intraperitoneal perfusion for 1 hr. Two hundred‐eighty nine (66%) patients achieved complete cytoreduction (CCR‐0/1). Five and 10‐year OS were 69% and 57%, respectively. However, on subgroup analysis, patients who had complete cytoreduction had 5 and 10‐year survival of 87% and 74%, respectively. Post‐operative mortality was 1.6% with grade3/4 morbidity of 7%. Paul Sugarbaker reported his experience of approximately 900 patients with appendiceal neoplasm at the Washington Cancer Institute [17]. Patients with low‐grade tumor who underwent complete cytoreduction had 80% survival rate after 20 years. However, the survival rate dropped to 45% at 20 years for patients with high‐grade tumor. Extent of disease (PCI score) and completeness
of cytoreduction had prognostic significance. However, lymph node status did not impact survival. A recent multi‐institutional retrospective study (which both Wake Forest and Basingstoke participated in) evaluated both early and long‐ term outcomes associated with CRS/HIPEC for PMP from appendiceal origin [18]. The study involved 2,298 patients from 16 institutions and is the largest retrospective study for appendiceal PMP to date. Median follow‐up was 36 months. Median survival was 16.3 years and progression‐free survival was 8.2 years. Ten and 15‐year survival rates were 63% and 59%, respectively. Post‐operative morbidity was 24% while 30‐day mortality was 2%. On multivariate analysis, prior chemotherapy, higher PCI score, PMCA histopathologic subtype, incomplete debulking (CCR‐2/3) surgery, major (Grade 3/4) post‐ operative complications and not using HIPEC were predictors of worse progression‐free survival. Similarly, older age, prior chemotherapy, PMCA histopathologic subtype, debulking (CCR‐2/3) surgery, and major post‐operative complications were associated with worse overall survival. Significantly, use of HIPEC did not affect overall survival. Based on these findings, the group proposed complete cytoreduction as a predictor of long‐term survival. Oxaliplatin and Mitomycin C (MMC) are the most commonly used chemotherapy drugs for intraperitoneal perfusion during HIPEC (Table I). Use of irinotecan has also been reported by some centers [19]. Both oxaliplation and MMC have large molecular weight and achieve high intraperitoneal concentrations with limited systemic absorption and toxicity. In the absence of prospective randomized‐controlled trials, the use of one drug versus the other is usually based on surgeon and hospital preference. Hompes et al. [20] compared survival and toxicity outcomes with intraperitoneal use between oxaliplatin and MMC, and found no statistically significant differences, although there was a higher tendency of extra‐abdominal complications in patients perfused with MMC. Our group reported a higher platelet (grade 3) and neutrophil (grade 4) toxicity with oxaliplatin only in setting of splenectomy during cytoreduction [21]. Wake Forest University is currently leading a randomized‐controlled trial comparing oxaliplatin versus MMC for use in intraperitoneal chemotherapy for PM from appendiceal cancer. The role of peri‐operative chemotherapy for appendiceal tumor has long been a matter of debate. Sugarbaker [22] reported a 29% histopathologic response rate after 3–6 months of neoadjuvant chemotherapy with FOLFOX in patients with PMCA. However, a follow‐up study by the same group failed to show a survival benefit associated with pre‐operative chemotherapy [23]. Our group reported improved progression‐free survival with post‐operative chemotherapy in patients with MCP‐H. However, no therapeutic benefit was noted with peri‐operative chemotherapy for MCP‐L [24].
TABLE I. Outcomes following CRS‐HIPEC for Appendiceal Tumor
Author
Year
n
Drug
Deraco [89] Stewart [15] Yan [90] Eliasb [75]
2004 2006 2006 2008
33 110 50 105
Baratti[91] Elias[92]
2009 2010
102 301
Chua[17] Arjona‐Sanchez [93]
2012 2013
2298 38
MMC þ CDDP MMC MMC MMC þ oxaliplatin þ CPT‐11 MMC þ cisplatin MMC or oxaliplatin þ EPIC MMC or oxal MMC
Median follow‐up (months)
Median overall survival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
24a 34.8 51.5 48
NR 63.6 Not reached Not reached
97 53 69 80
18 38 48 67.6
3 4 4 7.6
45 88.4
NR Not reached
84.4 72.6
NR 40
1 4.4
36 32
196 36
74 58.7
24 18.4
2 NR
MMC: Mitomycin C; CDDP: cisplatin; NR: not reported. a Mean follow‐up. b 89% patients had appendiceal primary, rest had PMP from other sources.
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Outcomes With Cytoreductive Surgery and HIPEC In summary, CRS/HIPEC is the standard of care for appendiceal mucinous tumors with peritoneal dissemination. Systemic chemotherapy should be reserved for high‐grade disease.
CRS/HIPEC FOR DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA Diffuse malignant peritoneal mesothelioma (DPM) is a rare disease accounting for 10–20% of the 2,500 cases of malignant mesothelioma diagnosed each year in the US [25,26]. Although this disease was first described in 1908 [27], its prognosis, to date, remains dismal. Unlike pleural mesothelioma, the association of DPM with asbestos is not as well‐established. The diagnosis of DPM is often delayed and most patients present with advanced disease [28]. DPM is broadly categorized into three major subtypes: epithelioid, biphasic, and sarcomatoid [29]. The classification clearly impacts prognosis. Epithelioid subtype comprises 75–92% of cases and is associated with the best prognosis. Biphasic and sarcomatoid subtypes are relatively rare, and have significantly worse prognosis. We are unaware of any long‐term survivors for the sarcomatoid subtype and typically do not offer CRS/HIPEC to these patients. Traditionally, DPM was treated using a combination of palliative surgery and systemic chemotherapy, with or without radiation. Despite the multi‐modality treatment, outcomes remained poor with median survival of one year [30]. Recent evidence regarding combination systemic chemotherapy with cisplatin and pemetrexed (the only FDA approved systemic therapy regimen) has shown slightly better median survival of 12–26.8 months [31]. Several studies have evaluated the role of CRS/HIPEC for treatment of DPM (Table II). Our institution initially reported a retrospective study of 12 such patients [32]. MMC was used for intra‐peritoenal chemotherapy. Although R0/R1 resection was achieved in only one patient, we reported a median survival of 34.2 months after a median follow‐up of 45.2 months. A follow‐up of this study was published [33] in which we reported 38 patients with DPM treated with CRS/HIPEC. Nineteen patients were perfused with MMC while 15 patients received cisplatin. We changed the perfusate to cisplatin (250 mg/m2 with thiosulfate protection for nephrotoxicity) in 2004 based from the National Cancer Institute [34]. The median age was 54.9 years. Eighty‐ five percent of patients had epithelioid subtype of peritoneal mesothelioma. Twenty‐two (65%) patients underwent R0/1 or R2a resection. Median follow‐up was 6 years. Median survival was 40.8 months with 3 and 5‐year survival of 56% and 17%, respectively. Although not statistically significant, we found a trend towards better overall survival for patients perfused with cisplatin (40.8 months versus 10.8 months, respectively). Brigand et al. [35] published their outcomes in 15 patients. Median age of patients was 53.6 years. Eleven of whom had CC‐0 or CC‐1
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resection. A combination of cisplatin and mitomycin‐C was used for intraperitoneal perfusion. No peri‐operative deaths were reported, but 6 patients had peri‐operative complications. Median follow‐up was 46.7 months and median survival was noted to be 35.6 months. Three and 5‐ year survival rates were 43.3% and 28.9%, respectively. There was a statistically significant difference noted in median survival between patients with CC‐0/CC‐1 versus those with CC‐2/CC‐3 (37.8 months versus 6.5 months; P < 0.001). The extent of disease (PCI score) was the other significant prognostic indicator noted in the study. Baratti et al [36] reported their long‐term outcomes for 108 patients treated with CRS/HIPEC for DPM. All patients had CCR‐0/1 resection. A majority of the patients (102/108) were perfused with cisplatin and doxorubicin, while the remainder of the 6 patients received cisplatin and mitomycin‐C. Forty‐nine patients received pre‐operative chemotherapy. Peri‐operative morbidity and mortality was 38.9% and 1.9%, respectively. Median overall survival was 63.2 months. Significantly, there were 19 actual survivors of the 39 patients (43.6%) with potential follow‐up of >7 years. On multivariate analysis, epithelioid histology subtype and negative lymph node status correlated with both overall survival and progression‐free survival. The same group [37] had earlier undertaken a controlled study comparing survival outcomes between patients undergoing selective parietal peritonectomy versus completion parietal peritonectomy, regardless of extent of DPM. They showed that completion parietal peritonectomy was associated with better 5‐year survival (63.9% versus 40%; P ¼ 0.02). Yan et al. described their experience with 62 patients who underwent CRS/HIPEC followed by early post‐operative intraperitoneal chemotherapy (EPIC) [38]. A combination of cisplatin and doxorubicin were used for HIPEC followed by early post‐operative intraperitoneal chemotherapy using paclitaxel on post‐operative days 1– 5. Median OS was 79 months with 1, 3 and 5‐year survivals being 84%, 58% and 50%, respectively. A multi‐institutional study [39] showed survival benefit for patients with DPM treated with CRS/HIPEC. This study included 405 patients with a mean age of 50 years. Mean PCI was 20. One hundred forty‐ seven (46%) patients had R0/1 resection. Three hundred seventy‐two patients (92%) had HIPEC. The median follow‐up for patients who were alive was 33 months. Peri‐operative morbidity and mortality was 46% and 2%, respectively. Overall median survival was noted to be 53 months with 3 and 5‐year survivals being 60% and 47%, respectively. Epithelioid subtypes (P < 0.001), absence of lymph node involvement (P < 0.001), completeness of cytoreduction (P < 0.001) and HIPEC (P ¼ .002) were prognostic indicators identified on multivariate analysis. Like appendiceal cancer, the role of peri‐operative chemotherapy for DPM has remained unclear. According to the consensus statement on peritoneal mesothelioma, [40] induction systemic chemotherapy should be considered for patients not deemed suitable for immediate
TABLE II. Outcomes following CRS/HIPEC for DPM
Author
Year
n
Drug
Feldman[94] Brigand [34] Yan[38] Blackham[32] Baratti[95] Deraco[40]
2003 2006 2009 2010 2010 2013
49 14 405 34 83 116
Alexander[96]
2013
211
CDDP CDDP þ MMC Multiple regimens CDDP or MMC CDDP doxorubicin CDDP þ MMC or CDDP þ doxorubicin CDDP or MMC
CDDP: cisplatin; MMC: Mitomycin C; NR: not reported. Patients with >1 complications.
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Median follow‐up (months)
Median overallsurvival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
28.3 46.7 33 72 52 NR
92 35.6 53 40.8 44 NR
59 28.9 47 17 49.5 49
25 40 31 NR 27.7 41.3
NR 0 2 NR 2.4 2.6
NR
38.4
41
30a
2.3
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cytoreduction, while adjuvant systemic chemotherapy may be employed for patients considered high‐risk for post‐operative failure. These proposals were based on evidence of 26% response rate of DPM to combination regimen systemic chemotherapy (cisplatin, pemetrexed). A recent study [41] from an Italian group, however, showed no survival benefit for chemotherapy at the induction or adjuvant stage. Given the survival benefit, DPM should be approached with aggressive cytoreduction and HIPEC. The role of systemic therapy, however, needs to be better defined.
CRS/HIPEC FOR COLORECTAL CANCER Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Over the last decade, effective systemic chemotherapy regimens have significantly improved median survival for patients with metastatic CRC [42]. However, these improved outcomes were primarily achieved in patients with systemic metastases with minimal or no evidence of peritoneal metastases [43]. PM offers a unique challenge for systemic chemotherapy due to unique pharmacokinetic demands of drug entry into the peritoneum. In a sub‐group analysis of 2,095 patients from two prospective randomized control trials (NCCTG‐N9741 and NCCTG‐N9841), Franko et al. [44] demonstrated that with FOLFOX regimen patients with PM had median OS of 15.7 months versus 20.9 months for patients with systemic disease. Approximately 25% patients with CRC will eventually develop recurrence confined only to the peritoneum [45]. Traditionally, these patients had a median survival of 6 months with palliative surgery and chemotherapy [1]. Since the introduction of CRS/HIPEC for PM from colorectal cancer, the outcomes have gradually improved [46]. To date there has only been one randomized trial comparing CRS/ HIPEC with systemic chemotherapy for PM from CRC, which was reported by Verwaal et al. in 2003 and included 105 patients [47]. After a median follow‐up of 21.6 months, patients in the CRS/HIPEC arm had a median survival of 21.6 months versus 12.3 months for patients in the systemic chemotherapy arm. This difference in survival was statistically significant (P ¼ 0.032). A more recent update of the study reported a disease‐specific survival of 12.6 months versus 22.2 months in the HIPEC arm (P ¼ 0.028) with a median follow‐up of 8 years. [48]. Despite the improved outcomes for CRS/HIPEC, it is important to emphasize that CRS/HIPEC (like liver resection for hepatic metastasis) should be used in conjunction with systemic chemotherapy and not in lieu of it. Since that landmark randomized trial, several studies reported their outcomes with CRS/HIPEC for CRC‐related PM (Table III). Our group reported outcome of a Phase II trial in 2004 which included 77 patients [49]. We reported median survival of 16 months after a median follow‐up of 15 months. One, 3, and 5‐year survival rates were 56%,
35%, and 17%, respectively. Glehen et al. [43] reported a multi‐ institutional study involving 28 French institutions which included 506 patients. Median follow‐up was 53 months. Median survival was 19 months and 1, 3, and 5‐year survivals were 87%, 47%, and 31%, respectively. Based on these encouraging results, a multi‐institutional consensus statement was issued proposing guidelines regarding the indication and technique of CRS/HIPEC for metastatic colon cancer with peritoneal involvement in setting of PM from CRC [50]. Over the last decade, progressive experience with this technique has continued to yield improved outcomes. As a result, CRS/HIPEC continues to gain widespread acceptance. Elias et al. [51] reported a multi‐institutional retrospective analysis which included 523 patients over a 17‐year period. Although the study had some limitations, they achieved 84% R0 resection rate and mortality rate of 3.1%, with a median survival of 30.1 months. One, 3, and 5‐year survival were 81%, 41%, and 27%, respectively. A meta‐analysis by Cao et al. [52] also confirmed the superiority of CRS/HIPEC in improving survival over palliative surgery alone (P < 0.0001). An important caveat to the good outcomes associated with CRS/ HIPEC for colorectal cancer is the PCI score. Although PCI score is an important prognostic factor for all peritoneal metastases, its impact on survival outcomes is best documented for colorectal cancer. Elias et al. [53] reported better survival for PCI 2) was prognostic for survival. Subsequently, studies from Kianmanesh [57] and Carmignani et al. [58] have also showed no difference in outcome with synchronous CRS and liver resection. Our group [59] reported respective overall survival of 23 months versus 15.8 months (P ¼ 0.39) in patients undergoing CRS/HIPEC with and without synchronous liver metastasis, respectively. However, most patients
TABLE III. Outcomes following CRS‐HIPEC for Colorectal Cancer
Author
Year
n
Shen[47] Glehen[48]
2004 2004
77 506
Chua[98] Elias[50] Verwaal [46] Elias[98] Franko [99]
2009 2009 2008 2009 2010
55 523 105 48 67
Drug MMC Oxaliplatin or CDDP or 5‐FU or LCV MMC HIPEC þ 5‐FU EPIC Multiple regimens MMC oxaliplatin MMC
Median follow‐up (months)
Median overall survival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
15 53
16 19
17 19
30 22.9
12 4
19 45 96 63 NR
36 30.1 22.2 62.7 34.7
60a 27 20 51 25
30.9 31 NR NR NR
0 3.3 NR NR NR
MMC, mitomycin C; CDDP, cisplatin; 5‐FU, 5‐fluorouracil; LCV, leucovorin; NR, not reported. 3‐yr survival.
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Outcomes With Cytoreductive Surgery and HIPEC had a single small (median size 3cm) liver lesion which was treated with minor hepatic resection. Our most recent (unpublished) data, however, shows that hepatic resection in setting of R0/R1 peritoneal cytoreduction is associated with worse median overall survival (21.2 months versus 33.6 months; P ¼ 0.03). Based on the evidence, CRS/HIPEC should be offered for PM from CRC to only those patients with PCI < 20 and no extra‐abdominal metastases. We also perform liver resection as part of cytroreductive surgery for small lesion(s) in setting of peritoneal metastasis from colorectal cancer. The approach to both the liver lesions and the peritoneal lesions must be complete resection of all gross disease.
CRS/HIPEC FOR GASTRIC CANCER Peritoneal metastasis is the most common type of recurrence and cause of death in gastric cancer. In particular, patients with locally advanced gastric cancer (tumor penetrating deeper to mucosa) at time of diagnosis remain at high risk for peritoneal dissemination despite margin‐negative resection. Serosal tumor invasion is closely correlated with intraperitoneal free cancer cells [60]. Unfortunately, adjuvant therapies do not seem to decrease the risk of peritoneal metastasis in these patients. The role of CRS/HIPEC for gastric cancer has been evaluated both in an adjuvant setting for locally advanced disease with curative resection as well as in setting of peritoneal metastasis. Further, the improving response rate of gastric cancer to systemic chemotherapy makes this an evolving area of therapy.
CRS/HIPEC IN ADJUVANT SETTING The significant risk of PM from locally advanced gastric cancer has led to substantial literature using intraperitoneal adjuvants for resectable (but without proven PM) disease. Several RCTs have shown the survival benefit of intraperitoneal chemotherapy after curative resection for locally advanced gastric cancer [61,62]. A recent meta‐analysis by Yan at al. [63] showed significant survival advantage for resection with adjuvant intraperitoneal therapy (HIPEC with and/or without EPIC) versus surgery alone. The hazard rate for survival was 0.60 with a 95% confidence interval of 0.43 to 0.83 (P ¼ .002). However, no consistent decrease in peritoneal failure was found and patients undergoing HIPEC (or similar type procedures) did have a higher complication rate after surgery. A previous meta‐analysis by Xu at al. [64] had similarly concluded that intraperitoneal chemotherapy after curative resection may benefit patients with locally advanced gastric cancer. Despite the evidence, CRS/HIPEC as an adjuvant therapy is not currently the standard of care and is not recommended under the NCCN guidelines. With proven adjuvant therapies available for gastric cancer only within the last decade, adjuvant HIPEC is best reserved for clinical trials.
CRS/HIPEC FOR PM FROM GASTRIC CANCER Peritoneal metastasis remains the most common type of local recurrence after gastric cancer and is associated with median survival of approximately 4 months [65]. Systemic chemotherapy improves median survival in patients with metastatic gastric cancer to 7–10 months [66]. However, the response rate to systemic chemotherapy for peritoneal metastasis from gastric cancer is low [67], which puts into perspective the role of CRS/HIPEC for these patients. A phase III randomized trial by Yang et al. [68] evaluated outcomes of CRS/HIPEC for PM from gastric cancer. Sixty‐eight patients were randomized into CRS alone (n ¼ 34) versus CRS/HIPEC (n ¼ 34). The median age was 50 years, with a median PCI was 15 in both groups. A combination of cisplatin and MMC was used for HIPEC. Both groups had the same proportion of patients (58.8%) undergoing CC‐0/1 Journal of Surgical Oncology
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resection. At a median follow‐up of 32 months, disease‐specific death occurred in 33 of 34 (97.1%) patients in CRS groups and 29 of 34 patients (85.3%) in the CRS/HIPEC group. Median survival was 6.5 months in the CRS group versus 11 months in CRS þ HIPEC group (P ¼ 0.046). Both groups had similar rates of serious adverse effects (11.7% in CRS versus 14.7% in CRS/HIPEC, P ¼ 0.8). On subgroup analysis, patients with metachronous PM had worse survival than those with synchronous PM. Their results corroborated findings of Glehen et al. [69] who reported an OS of 9.2 months for patients PM from gastric cancer treated with CRS/HIPEC with completeness of cytoreduction being the only prognostic indicator on multivariate analysis. Coccolini et al. [70] performed a meta‐analysis to evaluate the impact of CRS/HIPEC but did not distinguish patients with locally advanced disease from those with peritoneal metastasis. Outcomes of 20 RCTS were evaluated which included 2145 (1152 surgery þ IP chemotherapy; 993 controls) patients with advanced cancer (macroscopic serosal involvement and/or peritoneal metastasis but no distant metastasis) treated with CRS þ IP chemotherapy (HIPEC and/or EPIC). CRS/IPC was shown to increase 1, 2, and 3‐ year survival rates (OR 0.31. 0.27, 0.29, respectively) as well as a decrease in the overall recurrence rate (OR 0.46). It is important to note that despite CRS/HIPEC offering survival benefit both in adjuvant setting as well as in presence of peritoneal metastasis for gastric cancer, these survival outcomes are still significantly worse compared to some other malignancies [71]. Given the aggressive nature of gastric cancer with survival benefit of CRS/HIPEC measured only in terms of a few months, the importance of patient selection for CRS/HIPEC in this setting cannot be stressed enough. We currently offer CRS/HIPEC for gastric cancer only in setting of peritoneal metastasis to a subset of patients with low disease burden (PCI < 6) and with good response to pre‐operative chemotherapy. The role of CRS/HIPEC in adjuvant settings, however, needs to be better defined.
CRS/HIPEC FOR EPITHELIAL OVARIAN CANCER (EOC) The traditional approach for advanced ovarian cancer (stages IIIC and IV) was cytoreduction followed by intravenous platinum based therapy. This approach has been shown to provide a median OS of up to 50 months with a 5‐year OS of 30% .The origin of CRS can be traced to Munnel [72] who proposed the idea of “maximum surgical effort” and showed survival benefit with extensive cytoreduction for ovarian cancer with intra‐peritonaeal metastasis. The role of cytoreduction in EOC has subsequently evolved and current guidelines recommend cytoreduction for residual disease of at least 1 cm followed by systemic chemotherapy for maximum therapeutic benefit. Patients with complete cytoreduction clearly have better outcomes than those who do not. Traditionally, EOC has shown good response rate to systemic chemotherapy. Despite the high response rate of approximately 80% to first‐line chemotherapy, however, approximately 75% patients will relapse within 5 years [73]. Additionally, 20–30% patients of initial responders will develop platinum resistance (relapse within 6 months of treatment). Three randomized trials have shown the superiority of intraperitoneal chemotherapy over systemic chemotherapy following cytoreduction for peritoneal metstasis from EOC.[74–76]. The first of the three randomized controlled trials (RCT) was conducted by Southwest Oncology Group (SWOG) and Gynecologic Oncology Group (GOG1014) [72]. After extensive cytoreduction (residual disease
Outcomes With Cytoreductive Surgery and HIPEC for Peritoneal Metastasis SHUJA AHMED, MD, JOHN H. STEWART, MD, PERRY SHEN, MD, KONSTANTINOS I. VOTANOPOULOS, MD, PhD, AND EDWARD A. LEVINE, MD* Surgical Oncology Service, Department of General Surgery, Wake Forest Baptist Medical Center, Winston Salem, North Carolina
Peritoneal metastasis (PM) has traditionally been approached with therapeutic nihilism. The evolution of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) over the last two decades, however, has caused a paradigm shift in treatment for PM. This modality is rapidly gaining acceptance as standard of care for PM from various cancers. This article reviews the current literature regarding the use of CRS/HIPEC for PM from the most common intra‐abdominal malignancies.
J. Surg. Oncol. 2014;110:575–584. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: peritoneal metastasis; cytoreductive surgery; hyperthermic intraperitoneal chemotherapy; colorectal cancer
INTRODUCTION PM has traditionally been approached with therapeutic nihilism. Patients typically progress to death due to bowel obstruction in less than a year from the time of diagnosis [1]. PM results from intracavitary dissemination of tumor from a variety of primary pathologic lesions. Such findings are all too common for gastrointestinal cancers including appendiceal and colorectal cancers, as well as ovarian carcinomas, sarcoma, and mesothelioma. Frequently, PM is confined to the peritoneal cavity without extra‐abdominal disease. Thus, a regional approach for selected patients with PM is reasonable. Beginning approximately 30 years ago, aggressive treatment of PM was explored. Centres evaluated treatment options such as peritonectomy procedures [2] supplemented with intraperitoneal adjuvant therapies [3,4]. Over the last two decades, there has been an increasing body of evidence for CRS/HIPEC as a treatment modality for PM. Consequently, more centres have adopted this modality contributing to the exponential rise in popularity of this procedure. The expanding literature has helped us identify not only the primary cancers for which CRS/HIPEC offers survival benefit but also the type of patients who may benefit from this treatment modality given its potentially debilitating complications. This article reviews the outcomes for CRS/HIPEC and its most common indications [5] including appendiceal tumors, diffuse malignant peritoneal mesothelioma, colorectal cancer, gastric cancer, and epithelial ovarian cancer.
CRS/HIPEC FOR APPENDICEAL TUMORS According to NCCN guidelines, epithelial neoplasms of the appendix are categorized under colorectal cancers (CRC) and comprise 1% of the CRC. It is pertinent to mention, however, that the two malignancies have genetic profiles quite distinct from each other [6]. Approximately 10% of patients with an epithelial appendiceal neoplasm develop mucinous ascites, also known as pseudomyxoma peritonei (PMP). Despite its low incidence, PMP from appendiceal tumor remains one of the most common indications for CRS/HIPEC. In addition, its rarity has not precluded an intense debate pertaining to its classification. The pathologic classification has been relevant due to its significant impact on prognosis. Ronnett et al. [7] first proposed a staging system
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with three categories of appendiceal tumor: Diffuse peritoneal adenomucinosis (DPAM) consisting of low‐grade tumors with low numbers of mitotic figures and cytologic atypia; peritoneal mucinous carcinomatosis (PMCA) consisting of high‐grade tumors and characterized by atypia and more prominent mitotic figures; and PMCA‐I/D marked by intermediate or discordant features. They showed that 5 and 10‐year survival for patients with DPAM (75%, 68%) was significantly better than that for PMCA‐I/D (50%, 21%) or PMCA (14%, 3%) [8]. We have published our experience with pathology from 101 patients with diagnosis of mucinous ascites related to primary appendiceal tumors [9]. Based on our data, the 5‐year survival for DPAM and PMCA‐I/D was 68% and 61%, respectively. PMCA, in comparison, had a 5‐year survival of 37% (P ¼ 0.004). We, therefore, proposed a two‐ tiered system. DPAM was categorized as low‐grade mucinous carcinoma peritonei (MCP‐L) and PMCA as high‐grade mucinous carcinoma peritonei (MCP‐H). Significantly, based on similar survival rates, PMCA‐I/D was also categorized under MCP‐L, with the exception that any case with signet‐ring cell component was categorized as PMCA and thus considered MCP‐H. Since the two tiered system is readily reproducible by pathologists who infrequently encounter this diagnosis, and Ronnett’s intermediate subset is a small minority of cases, we and others continue to support the two tier system. The role of cytoreduction in the treatment of PMP has long been recognized. Gough et. al. [10] demonstrated 5 and 10‐year survivals rates of 53% and 32%, respectively with serial debulking. More recently, 10‐year survival of 21% was reported with serial debulking, systemic chemotherapy and delayed intermittent intraperitoneal chemotherapy by
Disclosure Information: Nothing to disclose *Correspondence to: Edward A Levine, MD, Surgical Oncology Service, Medical Center Blvd., Winston‐Salem, North Carolina 27157. Fax: 336‐716‐ 9758. E‐mail: [email protected] Received 18 April 2014; Accepted 16 July 2014 DOI 10.1002/jso.23749 Published online 28 August 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Memorial Sloan Kettering Cancer Center [11]. Since Sugarbaker, an early pioneer in this area, initially championed CRS in combination with HIPEC [12], this technique has been much more popular. Clearly, CRS has benefit over observation or systemic chemotherapy alone. However, the therapeutic role of HIPEC independent of CRS has not been evaluated in randomized trials to date. Further, there have been no randomized trials evaluating the impact of type, dosage, and duration of intraperitoneal chemotherapy on PMP. In addition, the therapeutic benefit of hyperthermia is also yet to be demonstrated. The rarity of the disease makes randomized trials difficult to conduct for appendiceal neoplasms. Despite some limitations in evidence, PMP has been considered the classic indication for CRS/HIPEC. Five year survival rates have ranged from 66% to 97% [13]. A recent consensus statement reviewed the evidence and proposed CRS/HIPEC as standard of care for perforated appendiceal tumor with PSD [14]. Table I summarizes some of the studies that evaluated outcomes of CRS/HIPEC for appendiceal tumor. Wake Forest University published outcomes of 110 patients with PMP who underwent CRS/HIPEC, which is comparable to other centers [15]. Fifty percent of patients had DPAM, while 27% patients had PMCA. Mean age was 52.2 years. Mitomycin C (MMC) was used for intraperitoneal chemotherapy at concentration of >5 mg/ml for 2 hr with inflow temperature maintained at 42.0°C. Forty‐eight patients had complete (R0/1) cytoreduction. Thirty day post‐operative morbidity and mortality was 38% and 4%, respectively. Median follow‐up was 34.8 months. Median OS was 63.6 months. One, 3 and 5‐year survival were 79.9%, 59% and 53.4%, respectively. On subgroup analysis, patients with DPAM had better overall survival. Age at diagnosis, performance status, time between diagnosis and HIPEC, resection status and length of chemoperfusion were independent predictors of survival. The Basingstoke group [16] published their findings for 456 patients with PMP treated with CRS/HIPEC in the United Kingdom. The median age of patients was 56 years. MMC was used for intraperitoneal perfusion for 1 hr. Two hundred‐eighty nine (66%) patients achieved complete cytoreduction (CCR‐0/1). Five and 10‐year OS were 69% and 57%, respectively. However, on subgroup analysis, patients who had complete cytoreduction had 5 and 10‐year survival of 87% and 74%, respectively. Post‐operative mortality was 1.6% with grade3/4 morbidity of 7%. Paul Sugarbaker reported his experience of approximately 900 patients with appendiceal neoplasm at the Washington Cancer Institute [17]. Patients with low‐grade tumor who underwent complete cytoreduction had 80% survival rate after 20 years. However, the survival rate dropped to 45% at 20 years for patients with high‐grade tumor. Extent of disease (PCI score) and completeness
of cytoreduction had prognostic significance. However, lymph node status did not impact survival. A recent multi‐institutional retrospective study (which both Wake Forest and Basingstoke participated in) evaluated both early and long‐ term outcomes associated with CRS/HIPEC for PMP from appendiceal origin [18]. The study involved 2,298 patients from 16 institutions and is the largest retrospective study for appendiceal PMP to date. Median follow‐up was 36 months. Median survival was 16.3 years and progression‐free survival was 8.2 years. Ten and 15‐year survival rates were 63% and 59%, respectively. Post‐operative morbidity was 24% while 30‐day mortality was 2%. On multivariate analysis, prior chemotherapy, higher PCI score, PMCA histopathologic subtype, incomplete debulking (CCR‐2/3) surgery, major (Grade 3/4) post‐ operative complications and not using HIPEC were predictors of worse progression‐free survival. Similarly, older age, prior chemotherapy, PMCA histopathologic subtype, debulking (CCR‐2/3) surgery, and major post‐operative complications were associated with worse overall survival. Significantly, use of HIPEC did not affect overall survival. Based on these findings, the group proposed complete cytoreduction as a predictor of long‐term survival. Oxaliplatin and Mitomycin C (MMC) are the most commonly used chemotherapy drugs for intraperitoneal perfusion during HIPEC (Table I). Use of irinotecan has also been reported by some centers [19]. Both oxaliplation and MMC have large molecular weight and achieve high intraperitoneal concentrations with limited systemic absorption and toxicity. In the absence of prospective randomized‐controlled trials, the use of one drug versus the other is usually based on surgeon and hospital preference. Hompes et al. [20] compared survival and toxicity outcomes with intraperitoneal use between oxaliplatin and MMC, and found no statistically significant differences, although there was a higher tendency of extra‐abdominal complications in patients perfused with MMC. Our group reported a higher platelet (grade 3) and neutrophil (grade 4) toxicity with oxaliplatin only in setting of splenectomy during cytoreduction [21]. Wake Forest University is currently leading a randomized‐controlled trial comparing oxaliplatin versus MMC for use in intraperitoneal chemotherapy for PM from appendiceal cancer. The role of peri‐operative chemotherapy for appendiceal tumor has long been a matter of debate. Sugarbaker [22] reported a 29% histopathologic response rate after 3–6 months of neoadjuvant chemotherapy with FOLFOX in patients with PMCA. However, a follow‐up study by the same group failed to show a survival benefit associated with pre‐operative chemotherapy [23]. Our group reported improved progression‐free survival with post‐operative chemotherapy in patients with MCP‐H. However, no therapeutic benefit was noted with peri‐operative chemotherapy for MCP‐L [24].
TABLE I. Outcomes following CRS‐HIPEC for Appendiceal Tumor
Author
Year
n
Drug
Deraco [89] Stewart [15] Yan [90] Eliasb [75]
2004 2006 2006 2008
33 110 50 105
Baratti[91] Elias[92]
2009 2010
102 301
Chua[17] Arjona‐Sanchez [93]
2012 2013
2298 38
MMC þ CDDP MMC MMC MMC þ oxaliplatin þ CPT‐11 MMC þ cisplatin MMC or oxaliplatin þ EPIC MMC or oxal MMC
Median follow‐up (months)
Median overall survival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
24a 34.8 51.5 48
NR 63.6 Not reached Not reached
97 53 69 80
18 38 48 67.6
3 4 4 7.6
45 88.4
NR Not reached
84.4 72.6
NR 40
1 4.4
36 32
196 36
74 58.7
24 18.4
2 NR
MMC: Mitomycin C; CDDP: cisplatin; NR: not reported. a Mean follow‐up. b 89% patients had appendiceal primary, rest had PMP from other sources.
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Outcomes With Cytoreductive Surgery and HIPEC In summary, CRS/HIPEC is the standard of care for appendiceal mucinous tumors with peritoneal dissemination. Systemic chemotherapy should be reserved for high‐grade disease.
CRS/HIPEC FOR DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA Diffuse malignant peritoneal mesothelioma (DPM) is a rare disease accounting for 10–20% of the 2,500 cases of malignant mesothelioma diagnosed each year in the US [25,26]. Although this disease was first described in 1908 [27], its prognosis, to date, remains dismal. Unlike pleural mesothelioma, the association of DPM with asbestos is not as well‐established. The diagnosis of DPM is often delayed and most patients present with advanced disease [28]. DPM is broadly categorized into three major subtypes: epithelioid, biphasic, and sarcomatoid [29]. The classification clearly impacts prognosis. Epithelioid subtype comprises 75–92% of cases and is associated with the best prognosis. Biphasic and sarcomatoid subtypes are relatively rare, and have significantly worse prognosis. We are unaware of any long‐term survivors for the sarcomatoid subtype and typically do not offer CRS/HIPEC to these patients. Traditionally, DPM was treated using a combination of palliative surgery and systemic chemotherapy, with or without radiation. Despite the multi‐modality treatment, outcomes remained poor with median survival of one year [30]. Recent evidence regarding combination systemic chemotherapy with cisplatin and pemetrexed (the only FDA approved systemic therapy regimen) has shown slightly better median survival of 12–26.8 months [31]. Several studies have evaluated the role of CRS/HIPEC for treatment of DPM (Table II). Our institution initially reported a retrospective study of 12 such patients [32]. MMC was used for intra‐peritoenal chemotherapy. Although R0/R1 resection was achieved in only one patient, we reported a median survival of 34.2 months after a median follow‐up of 45.2 months. A follow‐up of this study was published [33] in which we reported 38 patients with DPM treated with CRS/HIPEC. Nineteen patients were perfused with MMC while 15 patients received cisplatin. We changed the perfusate to cisplatin (250 mg/m2 with thiosulfate protection for nephrotoxicity) in 2004 based from the National Cancer Institute [34]. The median age was 54.9 years. Eighty‐ five percent of patients had epithelioid subtype of peritoneal mesothelioma. Twenty‐two (65%) patients underwent R0/1 or R2a resection. Median follow‐up was 6 years. Median survival was 40.8 months with 3 and 5‐year survival of 56% and 17%, respectively. Although not statistically significant, we found a trend towards better overall survival for patients perfused with cisplatin (40.8 months versus 10.8 months, respectively). Brigand et al. [35] published their outcomes in 15 patients. Median age of patients was 53.6 years. Eleven of whom had CC‐0 or CC‐1
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resection. A combination of cisplatin and mitomycin‐C was used for intraperitoneal perfusion. No peri‐operative deaths were reported, but 6 patients had peri‐operative complications. Median follow‐up was 46.7 months and median survival was noted to be 35.6 months. Three and 5‐ year survival rates were 43.3% and 28.9%, respectively. There was a statistically significant difference noted in median survival between patients with CC‐0/CC‐1 versus those with CC‐2/CC‐3 (37.8 months versus 6.5 months; P < 0.001). The extent of disease (PCI score) was the other significant prognostic indicator noted in the study. Baratti et al [36] reported their long‐term outcomes for 108 patients treated with CRS/HIPEC for DPM. All patients had CCR‐0/1 resection. A majority of the patients (102/108) were perfused with cisplatin and doxorubicin, while the remainder of the 6 patients received cisplatin and mitomycin‐C. Forty‐nine patients received pre‐operative chemotherapy. Peri‐operative morbidity and mortality was 38.9% and 1.9%, respectively. Median overall survival was 63.2 months. Significantly, there were 19 actual survivors of the 39 patients (43.6%) with potential follow‐up of >7 years. On multivariate analysis, epithelioid histology subtype and negative lymph node status correlated with both overall survival and progression‐free survival. The same group [37] had earlier undertaken a controlled study comparing survival outcomes between patients undergoing selective parietal peritonectomy versus completion parietal peritonectomy, regardless of extent of DPM. They showed that completion parietal peritonectomy was associated with better 5‐year survival (63.9% versus 40%; P ¼ 0.02). Yan et al. described their experience with 62 patients who underwent CRS/HIPEC followed by early post‐operative intraperitoneal chemotherapy (EPIC) [38]. A combination of cisplatin and doxorubicin were used for HIPEC followed by early post‐operative intraperitoneal chemotherapy using paclitaxel on post‐operative days 1– 5. Median OS was 79 months with 1, 3 and 5‐year survivals being 84%, 58% and 50%, respectively. A multi‐institutional study [39] showed survival benefit for patients with DPM treated with CRS/HIPEC. This study included 405 patients with a mean age of 50 years. Mean PCI was 20. One hundred forty‐ seven (46%) patients had R0/1 resection. Three hundred seventy‐two patients (92%) had HIPEC. The median follow‐up for patients who were alive was 33 months. Peri‐operative morbidity and mortality was 46% and 2%, respectively. Overall median survival was noted to be 53 months with 3 and 5‐year survivals being 60% and 47%, respectively. Epithelioid subtypes (P < 0.001), absence of lymph node involvement (P < 0.001), completeness of cytoreduction (P < 0.001) and HIPEC (P ¼ .002) were prognostic indicators identified on multivariate analysis. Like appendiceal cancer, the role of peri‐operative chemotherapy for DPM has remained unclear. According to the consensus statement on peritoneal mesothelioma, [40] induction systemic chemotherapy should be considered for patients not deemed suitable for immediate
TABLE II. Outcomes following CRS/HIPEC for DPM
Author
Year
n
Drug
Feldman[94] Brigand [34] Yan[38] Blackham[32] Baratti[95] Deraco[40]
2003 2006 2009 2010 2010 2013
49 14 405 34 83 116
Alexander[96]
2013
211
CDDP CDDP þ MMC Multiple regimens CDDP or MMC CDDP doxorubicin CDDP þ MMC or CDDP þ doxorubicin CDDP or MMC
CDDP: cisplatin; MMC: Mitomycin C; NR: not reported. Patients with >1 complications.
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Median follow‐up (months)
Median overallsurvival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
28.3 46.7 33 72 52 NR
92 35.6 53 40.8 44 NR
59 28.9 47 17 49.5 49
25 40 31 NR 27.7 41.3
NR 0 2 NR 2.4 2.6
NR
38.4
41
30a
2.3
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cytoreduction, while adjuvant systemic chemotherapy may be employed for patients considered high‐risk for post‐operative failure. These proposals were based on evidence of 26% response rate of DPM to combination regimen systemic chemotherapy (cisplatin, pemetrexed). A recent study [41] from an Italian group, however, showed no survival benefit for chemotherapy at the induction or adjuvant stage. Given the survival benefit, DPM should be approached with aggressive cytoreduction and HIPEC. The role of systemic therapy, however, needs to be better defined.
CRS/HIPEC FOR COLORECTAL CANCER Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Over the last decade, effective systemic chemotherapy regimens have significantly improved median survival for patients with metastatic CRC [42]. However, these improved outcomes were primarily achieved in patients with systemic metastases with minimal or no evidence of peritoneal metastases [43]. PM offers a unique challenge for systemic chemotherapy due to unique pharmacokinetic demands of drug entry into the peritoneum. In a sub‐group analysis of 2,095 patients from two prospective randomized control trials (NCCTG‐N9741 and NCCTG‐N9841), Franko et al. [44] demonstrated that with FOLFOX regimen patients with PM had median OS of 15.7 months versus 20.9 months for patients with systemic disease. Approximately 25% patients with CRC will eventually develop recurrence confined only to the peritoneum [45]. Traditionally, these patients had a median survival of 6 months with palliative surgery and chemotherapy [1]. Since the introduction of CRS/HIPEC for PM from colorectal cancer, the outcomes have gradually improved [46]. To date there has only been one randomized trial comparing CRS/ HIPEC with systemic chemotherapy for PM from CRC, which was reported by Verwaal et al. in 2003 and included 105 patients [47]. After a median follow‐up of 21.6 months, patients in the CRS/HIPEC arm had a median survival of 21.6 months versus 12.3 months for patients in the systemic chemotherapy arm. This difference in survival was statistically significant (P ¼ 0.032). A more recent update of the study reported a disease‐specific survival of 12.6 months versus 22.2 months in the HIPEC arm (P ¼ 0.028) with a median follow‐up of 8 years. [48]. Despite the improved outcomes for CRS/HIPEC, it is important to emphasize that CRS/HIPEC (like liver resection for hepatic metastasis) should be used in conjunction with systemic chemotherapy and not in lieu of it. Since that landmark randomized trial, several studies reported their outcomes with CRS/HIPEC for CRC‐related PM (Table III). Our group reported outcome of a Phase II trial in 2004 which included 77 patients [49]. We reported median survival of 16 months after a median follow‐up of 15 months. One, 3, and 5‐year survival rates were 56%,
35%, and 17%, respectively. Glehen et al. [43] reported a multi‐ institutional study involving 28 French institutions which included 506 patients. Median follow‐up was 53 months. Median survival was 19 months and 1, 3, and 5‐year survivals were 87%, 47%, and 31%, respectively. Based on these encouraging results, a multi‐institutional consensus statement was issued proposing guidelines regarding the indication and technique of CRS/HIPEC for metastatic colon cancer with peritoneal involvement in setting of PM from CRC [50]. Over the last decade, progressive experience with this technique has continued to yield improved outcomes. As a result, CRS/HIPEC continues to gain widespread acceptance. Elias et al. [51] reported a multi‐institutional retrospective analysis which included 523 patients over a 17‐year period. Although the study had some limitations, they achieved 84% R0 resection rate and mortality rate of 3.1%, with a median survival of 30.1 months. One, 3, and 5‐year survival were 81%, 41%, and 27%, respectively. A meta‐analysis by Cao et al. [52] also confirmed the superiority of CRS/HIPEC in improving survival over palliative surgery alone (P < 0.0001). An important caveat to the good outcomes associated with CRS/ HIPEC for colorectal cancer is the PCI score. Although PCI score is an important prognostic factor for all peritoneal metastases, its impact on survival outcomes is best documented for colorectal cancer. Elias et al. [53] reported better survival for PCI 2) was prognostic for survival. Subsequently, studies from Kianmanesh [57] and Carmignani et al. [58] have also showed no difference in outcome with synchronous CRS and liver resection. Our group [59] reported respective overall survival of 23 months versus 15.8 months (P ¼ 0.39) in patients undergoing CRS/HIPEC with and without synchronous liver metastasis, respectively. However, most patients
TABLE III. Outcomes following CRS‐HIPEC for Colorectal Cancer
Author
Year
n
Shen[47] Glehen[48]
2004 2004
77 506
Chua[98] Elias[50] Verwaal [46] Elias[98] Franko [99]
2009 2009 2008 2009 2010
55 523 105 48 67
Drug MMC Oxaliplatin or CDDP or 5‐FU or LCV MMC HIPEC þ 5‐FU EPIC Multiple regimens MMC oxaliplatin MMC
Median follow‐up (months)
Median overall survival (months)
5‐year Survival (%)
Major Morbidity (%)
Mortality (%)
15 53
16 19
17 19
30 22.9
12 4
19 45 96 63 NR
36 30.1 22.2 62.7 34.7
60a 27 20 51 25
30.9 31 NR NR NR
0 3.3 NR NR NR
MMC, mitomycin C; CDDP, cisplatin; 5‐FU, 5‐fluorouracil; LCV, leucovorin; NR, not reported. 3‐yr survival.
a
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Outcomes With Cytoreductive Surgery and HIPEC had a single small (median size 3cm) liver lesion which was treated with minor hepatic resection. Our most recent (unpublished) data, however, shows that hepatic resection in setting of R0/R1 peritoneal cytoreduction is associated with worse median overall survival (21.2 months versus 33.6 months; P ¼ 0.03). Based on the evidence, CRS/HIPEC should be offered for PM from CRC to only those patients with PCI < 20 and no extra‐abdominal metastases. We also perform liver resection as part of cytroreductive surgery for small lesion(s) in setting of peritoneal metastasis from colorectal cancer. The approach to both the liver lesions and the peritoneal lesions must be complete resection of all gross disease.
CRS/HIPEC FOR GASTRIC CANCER Peritoneal metastasis is the most common type of recurrence and cause of death in gastric cancer. In particular, patients with locally advanced gastric cancer (tumor penetrating deeper to mucosa) at time of diagnosis remain at high risk for peritoneal dissemination despite margin‐negative resection. Serosal tumor invasion is closely correlated with intraperitoneal free cancer cells [60]. Unfortunately, adjuvant therapies do not seem to decrease the risk of peritoneal metastasis in these patients. The role of CRS/HIPEC for gastric cancer has been evaluated both in an adjuvant setting for locally advanced disease with curative resection as well as in setting of peritoneal metastasis. Further, the improving response rate of gastric cancer to systemic chemotherapy makes this an evolving area of therapy.
CRS/HIPEC IN ADJUVANT SETTING The significant risk of PM from locally advanced gastric cancer has led to substantial literature using intraperitoneal adjuvants for resectable (but without proven PM) disease. Several RCTs have shown the survival benefit of intraperitoneal chemotherapy after curative resection for locally advanced gastric cancer [61,62]. A recent meta‐analysis by Yan at al. [63] showed significant survival advantage for resection with adjuvant intraperitoneal therapy (HIPEC with and/or without EPIC) versus surgery alone. The hazard rate for survival was 0.60 with a 95% confidence interval of 0.43 to 0.83 (P ¼ .002). However, no consistent decrease in peritoneal failure was found and patients undergoing HIPEC (or similar type procedures) did have a higher complication rate after surgery. A previous meta‐analysis by Xu at al. [64] had similarly concluded that intraperitoneal chemotherapy after curative resection may benefit patients with locally advanced gastric cancer. Despite the evidence, CRS/HIPEC as an adjuvant therapy is not currently the standard of care and is not recommended under the NCCN guidelines. With proven adjuvant therapies available for gastric cancer only within the last decade, adjuvant HIPEC is best reserved for clinical trials.
CRS/HIPEC FOR PM FROM GASTRIC CANCER Peritoneal metastasis remains the most common type of local recurrence after gastric cancer and is associated with median survival of approximately 4 months [65]. Systemic chemotherapy improves median survival in patients with metastatic gastric cancer to 7–10 months [66]. However, the response rate to systemic chemotherapy for peritoneal metastasis from gastric cancer is low [67], which puts into perspective the role of CRS/HIPEC for these patients. A phase III randomized trial by Yang et al. [68] evaluated outcomes of CRS/HIPEC for PM from gastric cancer. Sixty‐eight patients were randomized into CRS alone (n ¼ 34) versus CRS/HIPEC (n ¼ 34). The median age was 50 years, with a median PCI was 15 in both groups. A combination of cisplatin and MMC was used for HIPEC. Both groups had the same proportion of patients (58.8%) undergoing CC‐0/1 Journal of Surgical Oncology
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resection. At a median follow‐up of 32 months, disease‐specific death occurred in 33 of 34 (97.1%) patients in CRS groups and 29 of 34 patients (85.3%) in the CRS/HIPEC group. Median survival was 6.5 months in the CRS group versus 11 months in CRS þ HIPEC group (P ¼ 0.046). Both groups had similar rates of serious adverse effects (11.7% in CRS versus 14.7% in CRS/HIPEC, P ¼ 0.8). On subgroup analysis, patients with metachronous PM had worse survival than those with synchronous PM. Their results corroborated findings of Glehen et al. [69] who reported an OS of 9.2 months for patients PM from gastric cancer treated with CRS/HIPEC with completeness of cytoreduction being the only prognostic indicator on multivariate analysis. Coccolini et al. [70] performed a meta‐analysis to evaluate the impact of CRS/HIPEC but did not distinguish patients with locally advanced disease from those with peritoneal metastasis. Outcomes of 20 RCTS were evaluated which included 2145 (1152 surgery þ IP chemotherapy; 993 controls) patients with advanced cancer (macroscopic serosal involvement and/or peritoneal metastasis but no distant metastasis) treated with CRS þ IP chemotherapy (HIPEC and/or EPIC). CRS/IPC was shown to increase 1, 2, and 3‐ year survival rates (OR 0.31. 0.27, 0.29, respectively) as well as a decrease in the overall recurrence rate (OR 0.46). It is important to note that despite CRS/HIPEC offering survival benefit both in adjuvant setting as well as in presence of peritoneal metastasis for gastric cancer, these survival outcomes are still significantly worse compared to some other malignancies [71]. Given the aggressive nature of gastric cancer with survival benefit of CRS/HIPEC measured only in terms of a few months, the importance of patient selection for CRS/HIPEC in this setting cannot be stressed enough. We currently offer CRS/HIPEC for gastric cancer only in setting of peritoneal metastasis to a subset of patients with low disease burden (PCI < 6) and with good response to pre‐operative chemotherapy. The role of CRS/HIPEC in adjuvant settings, however, needs to be better defined.
CRS/HIPEC FOR EPITHELIAL OVARIAN CANCER (EOC) The traditional approach for advanced ovarian cancer (stages IIIC and IV) was cytoreduction followed by intravenous platinum based therapy. This approach has been shown to provide a median OS of up to 50 months with a 5‐year OS of 30% .The origin of CRS can be traced to Munnel [72] who proposed the idea of “maximum surgical effort” and showed survival benefit with extensive cytoreduction for ovarian cancer with intra‐peritonaeal metastasis. The role of cytoreduction in EOC has subsequently evolved and current guidelines recommend cytoreduction for residual disease of at least 1 cm followed by systemic chemotherapy for maximum therapeutic benefit. Patients with complete cytoreduction clearly have better outcomes than those who do not. Traditionally, EOC has shown good response rate to systemic chemotherapy. Despite the high response rate of approximately 80% to first‐line chemotherapy, however, approximately 75% patients will relapse within 5 years [73]. Additionally, 20–30% patients of initial responders will develop platinum resistance (relapse within 6 months of treatment). Three randomized trials have shown the superiority of intraperitoneal chemotherapy over systemic chemotherapy following cytoreduction for peritoneal metstasis from EOC.[74–76]. The first of the three randomized controlled trials (RCT) was conducted by Southwest Oncology Group (SWOG) and Gynecologic Oncology Group (GOG1014) [72]. After extensive cytoreduction (residual disease
