It is clear that in a subset of patients with GI malignancies, particularly the low-grade appendiceal neoplasms, CS + HIPEC can result in improved outcomes and in some cases, long-term remission and occasionally cure.
The review by Drs. Loggie and Thomas addresses the rationale for the specialized surgical approach known as cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS + HIPEC), and it explores the controversy surrounding the use of this procedure in more aggressive gastrointestinal (GI) malignancies. While we agree with the authors that the best outcomes have been documented when CS + HIPEC is used in the more indolent appendiceal neoplasms, we do not recommend HIPEC as a standard-of-care option for other GI tumor types, such as colorectal or gastric cancer. We favor the design of more definitive clinical trials, which we feel are feasible, to better elucidate whether HIPEC, which does carry a certain amount of morbidity, results in improved outcomes compared with more modern and effective chemotherapy regimens.
Complete CS combined with HIPEC is an aggressive surgical approach that has been employed for a variety of GI cancers that develop peritoneal spread. Original studies by Sugarbaker and colleagues reported markedly higher chemotherapy concentrations in peritoneal fluid as opposed to systemic blood with this technique. Heating the chemotherapy is thought to improve drug penetration and possibly increase its cytotoxicity. Pertinent prognostic factors that portend improved survival in nonrandomized case series include a more extensive cytoreduction as well as more indolent tumor biology. Regardless, the procedure results in a high rate of perioperative morbidity, ranging from 19% to 49%, with one study reporting at least grade 3 toxicity in 65% of patients and a high rate of fistula formation. Clearly, the expertise of the surgeon performing this specialized procedure plays a key role in minimizing toxicity, and more recent studies suggest lower morbidity rates-on the order of 10%.
The bulk of the early data surrounding HIPEC involved tumors of the appendix, specifically the more indolent mucinous appendiceal tumors such as the pseudomyxoma peritonei (PMP) variant for which the peritoneum is the primary site of metastatic spread. A case series of PMP patients undergoing CS + HIPEC reported 5-year survival rates of over 75%. However, the studies were comprised of small numbers of patients, were not randomized, and were typically classified as being of poor quality, with a lack of inclusion criteria and no specifics on histology. Appendiceal adenocarcinomas, including mucinous and signet ring varieties, fail to achieve the long-lasting benefit from HIPEC documented in PMP, with 5-year survival rates closer to 50%. The risk of death is substantially higher for more aggressive tumor histologies and for those with more extensive residual disease at the end of the procedure. Given the lack of randomized trials, the absolute benefit of HIPEC for appendiceal tumors is unknown. It is possible that selection bias is driving the improved outcomes in the patients undergoing HIPEC (due to their better performance status and more indolent tumor histologies). That being said, given the lack of benefit of systemic therapy for these patients, CS + HIPEC is considered a standard approach for low-grade appendiceal neoplasms that have metastasized intraperitoneally.
What is less clear is the role of HIPEC in other GI malignancies, specifically colorectal cancer and gastric cancer. Only two randomized controlled trials have been reported to date that have evaluated HIPEC in patients with metastatic colorectal cancer. This partly reflects the rarity of this particular presentation; in a retrospective review of over 2,000 patients with metastatic colorectal cancer, only 2% of patients had peritoneal disease as their only site of metastasis. A systematic review of all relevant studies pertaining to HIPEC in colorectal cancer was conducted by Sugarbaker et al and revealed that patients undergoing complete cytoreduction fared the best, with median overall survival (OS) times of between 28 and 60 months. However, morbidity rates were high, at 23% to 44%. A major critique of the randomized trials included in this review was that the comparator arms used fluorouracil/leucovorin as the systemic chemotherapy option, as opposed to a more aggressive chemotherapy regimen incorporating oxaliplatin or irinotecan.[10,11]
In an attempt to address this weakness, a retrospective analysis compared about 50 colorectal cancer patients with solitary peritoneal carcinomatosis who were treated with more modern chemotherapy regimens (oxaliplatin- and irinotecan-based) against a similar separate group of patients who underwent CS + HIPEC using oxaliplatin. This analysis documented that median survival times with chemotherapy alone vs CS + HIPEC were 24 months vs 63 months, respectively. The authors concluded that in the right patient population, HIPEC may be superior to chemotherapy alone; however, the retrospective nature of this study makes it difficult to draw firm conclusions. Additionally, there is no clear way at present to identify a subset of patients who would have better outcomes with this aggressive approach than they would with chemotherapy alone. Therefore, we would argue that further clinical trials need to be conducted to better establish the role of this modality in colorectal cancer. As Drs. Loggie and Thomas mention in their review, an ongoing French study (PRODIGE 7) may help to bring some clarity to the issue. Until the results of this study are reported, we feel that further research should be conducted to optimize both patient selection and the safety and efficacy of HIPEC.
Gastric cancer also has a propensity to spread to the peritoneum and hence has garnered attention for the use of CS + HIPEC to improve outcomes. In a randomized phase III trial of almost 70 patients that compared CS alone vs CS + HIPEC, the latter increased OS from 6.5 to 11 months. Complication rates were around 20% and were comparable to rates seen in other similar studies. The more recently reported GYMSSA trial investigated the role of CS + HIPEC compared with chemotherapy alone in patients with metastatic gastric cancer involving the peritoneum. Median OS was 11.3 months in the surgery arm compared with 4.3 months in the chemotherapy-alone arm. Those in the surgery arm who survived longer than 1 year all had documented complete cytoreduction. No patient receiving chemotherapy alone lived longer than 11 months. While these results are encouraging, this study enrolled only 17 patients, and the OS rates for those patients who received systemic chemotherapy alone (with FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, and irinotecan]) were lower than the rates in other metastatic gastric cancer trials.
It is clear that in a subset of patients with GI malignancies, particularly the low-grade appendiceal neoplasms, CS + HIPEC can result in improved outcomes and in some cases, long-term remission and occasionally cure. However, the data are limited for the most part to small case series and chemotherapy control arms that are not always in line with more modern effective regimens. Additionally, the available literature likely contains selection bias that has arisen because of the enrollment of patients who have more favorable outcomes a priori. Therefore, the routine incorporation of CS + HIPEC in the treatment of patients with GI cancers such as colorectal cancer and gastric cancer should not be considered standard of care; however, for a select subset of patients, thoughtful consideration can be given to this approach. In our opinion, the focus of the field should remain on conducting definitive clinical trials that evaluate the benefit of CS + HIPEC compared with aggressive chemotherapy.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Loggie BW, Thomas P. Gastrointestinal cancers with peritoneal carcinomatosis: surgery and hyperthermic intraperitoneal chemotherapy. Oncology (Williston Park). 2015;29:515-21.
2. Sugarbaker PH, Graves T, DeBruijn EA, et al. Early postoperative intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies. Cancer Res. 1990;50:5790-4.
3. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol. 2001;27:239-43.
4. Verwaal VJ, van Tinteren H, Ruth SV, Zoetmulder FA. Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. J Surg Oncol. 2004;85:61-7.
5. Yan TD, Links M, Fransi S, et al. Learning curve for cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal surface malignancy-a journey to becoming a Nationally Funded Peritonectomy Center. Ann Surg Oncol. 2007;14:2270-80.
6. Bryant J, Clegg AJ, Sidhu MK, et al. Systematic review of the Sugarbaker procedure for pseudomyxoma peritonei. Br J Surg. 2005;92:153-8.
7. Austin F, Mavanur A, Sathaiah M, et al. Aggressive management of peritoneal carcinomatosis from mucinous appendiceal neoplasms. Ann Surg Oncol. 2012;19:1386-93.
8. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of North Central Cancer Treatment Group phase III trials N9741 and N9841. J Clin Oncol. 2012;30:263-7.
9. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol. 2006;24:4011-9.
10. Elias D, Delperro JR, Sideris L, et al. Treatment of peritoneal carcinomatosis from colorectal cancer: impact of complete cytoreductive surgery and difficulties in conducting randomized trials. Ann Surg Oncol. 2004;11:518-21.
11. Verwaal VJ, van Ruth S, de Bree E, et al. 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;21:3737-43.
12. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2009;27:681-5.
13. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18:1575-81.
14. Rudloff U, Langan RC, Mullinax JE, et al. Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial. J Surg Oncol. 2014;110:275-84.
15. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46.