Journal of Surgical Oncology 2013;108:385–386
GUEST EDITORIAL Management of Peritoneal Metastasis from Neuroendocrine Tumors JOYCE T. AU, MD,1 JASON LEVINE, MD,1 AYSE AYTAMAN, MD,2 THOMAS WEBER, FRANCESCO SERAFINI, MD1,4* 2
MD,
3
AND
1 Department of Surgery, SUNY Downstate, Brooklyn, New York Department of Medicine, VA NY Harbor Healthcare System, Brooklyn, New York 3 Department of Surgery, VA NY Harbor Healthcare System, Brooklyn, New York 4 Department of Surgery, Kings County Hospital Center, Brooklyn, New York
Peritoneal metastasis from neuroendocrine tumors (NET) is not uncommon with a range in incidence from 10% to 33% [1,2]. Carcinomatosis can be asymptomatic with incidental discovery during preoperative imaging or resection of the primary tumor, but may also occasionally cause significant morbidity with bowel obstruction and bleeding. The frequent association of peritoneal and liver metastases makes the management of patients with NET more complicated [3]. While Vasseur et al. did not find any change in survival due to carcinomatosis per se from NET, Elias et al. found that peritoneal carcinomatosis was the direct cause of death in 40% patients with NET if left untreated [1,2]. As there is a paucity of research on the management of carcinomatosis from NET, we surveyed the expert opinions of participants from the Regional Cancer Therapies meeting in 2011 on well‐differentiated NET of gastrointestinal or unknown origin. With a response rate of 23% (21/ 91) on a pool of 273 patients, the survey found that the preferred modality for preoperative imaging was computed tomography, followed by colonoscopy, chromogranin A levels, and somatostatin‐analog receptor scintigraphy (100%, 85.7%, 76.2%, and 71.4%, respectively); MRI and PET were used by only 23.8% and 19.0%, respectively, while laparoscopy was reported by only 38.1%. Of the expert opinions, 80.9% used the peritoneal cancer index (PCI) system for staging, with a maximum threshold to still attempt cytoreduction at 20.5 5.47. All responders treated the patients with cytoreduction, and HIPEC after cytoreduction was performed by 85.7%, with mitomycin C as the intraperitoneal agent of choice, followed by cisplatin, doxorubicin, and carboplatin. Neoadjuvant and adjuvant chemotherapy was recommended by only 42.8% and 47.6%, respectively. None of the surveyed institutions had any clinical trials for this disease. Although PET and MRI, especially diffusion‐weighted MRI, have been shown in previous literature to be more reliable imaging modalities than CT to screen for early peritoneal disease [4], other factors such as cost, timing, and convenience may still favor the use of CT. While laparoscopy is traditionally important in staging peritoneal surface malignancies like that in mesothelioma and ovarian cancer, there are also limitations to its use, such as the development of dense adhesions from previous surgery for small bowel obstruction, initial exploration and resection, and tumor recurrence. Nonetheless, when possible, staging laparoscopy is advantageous in allowing the detection of disseminated small nodules not apparent on conventional imaging and preventing non‐therapeutic open surgical interventions. The threshold to proceed with cytoreduction rests on the PCI score. In colorectal cancer, PCI is the most powerful prognostic indicator for
ß 2013 Wiley Periodicals, Inc.
completeness of cytoreduction and for survival, and a score above 16 is a strong predictor for failure to accomplish complete cytoreduction [5]. In our survey on carcinomatosis from well‐differentiated NET, the threshold PCI score is much higher at over 20. As well‐differentiated NET may have a more indolent nature giving way to pursuit of more aggressive cytoreduction, this raises the question of whether different threshold PCI scores are acceptable and reasonable for different types of cancer. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) have been successful in treating other peritoneal surface malignancies of ovarian, gastric, colorectal, mesothelioma, and pseudomyxoma origins, but evidence is lacking with regards to carcinomatosis from NET. While cytoreductive surgery serves to remove macroscopic disease and prevent complications from peritoneal metastasis such as bowel obstruction and hemorrhage, HIPEC is a locoregional approach that utilizes hyperthermia and the timing before adhesion formation for chemotherapeutic drugs to better penetrate tumor cells and treat residual microscopic disease. Our survey revealed that the preferred treatment, based on expert opinions, of carcinomatosis from well‐differentiated NET was cytoreduction and HIPEC. Cytoreduction carries a survival benefit compared to palliative bypass or incomplete tumor removal and should be sought out in patients with good performance status and resectable tumors. Conversely, cytoreductive surgery with HIPEC may incur a 10–60% risk of morbidity with major complications such as bowel perforation and fistula formation [3]. Anticipation of incomplete cytoreduction should discourage “heroic” and futile surgical attempts that may incur morbidity. The utter lack of any clinical trials in the surveyed participant institutions on the management of peritoneal metastasis from NET emphasizes the need of a randomized prospective trial on this disease. Given that this disease is not often encountered, a multi‐institutional
The authors have no conflicts of interest to disclose. *Correspondence to: Francesco Serafini, MD, Department of Surgery, Kings County Hospital Center, 451 Clarkson Avenue, Room C‐3213, Brooklyn, NY 11203. Fax: þ1‐718‐245‐4055. E‐mail: francesco.serafi[email protected] Received 28 June 2013; Accepted 15 July 2013 DOI 10.1002/jso.23399 Published online 20 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
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study would be essential to power the study. Carcinomatosis from NET may be more indolent, and cytoreductive surgery and HIPEC carry both curative benefits as well as the risk of toxicity and complications. While our survey may guide clinicians as to how carcinomatosis from NET is treated based on expert opinions, a level 1 study from a clinical trial is critical to take into account the natural history of the disease and objectively evaluate the safety and efficacy of cytoreduction and HIPEC for treating peritoneal metastasis from NET.
REFERENCES 1. Elias D, Sideris L, Liberale G, et al.: Surgical treatment of peritoneal carcinomatosis from well‐differentiated digestive endocrine carcinomas. Surgery 2005;137:411–416.
Journal of Surgical Oncology
2. Vasseur B, Cadiot G, Zins M, et al.: Peritoneal carcinomatosis in patients with digestive endocrine tumors. Cancer 1996;78:1686– 1692. 3. Kianmanesh R, Ruszniewski P, Rindi G, et al.: ENETS consensus guidelines for the management of peritoneal carcinomatosis from neuroendocrine tumors. Neuroendocrinology 2010;91:333– 340. 4. Satoh Y, Ichikawa T, Motosugi U, et al.: Diagnosis of peritoneal dissemination: Comparison of 18F‐FDG PET/CT, diffusion‐weighted MRI, and contrast‐enhanced MDCT. AJR Am J Roentgenol 2011;196:447–453. 5. Swellengrebel HA, Zoetmulder FA, Smeenk RM, et al.: Quantitative intra‐operative assessment of peritoneal carcinomatosis—A comparison of three prognostic tools. Eur J Surg Oncol 2009;35:1078– 1084.
GUEST EDITORIAL Management of Peritoneal Metastasis from Neuroendocrine Tumors JOYCE T. AU, MD,1 JASON LEVINE, MD,1 AYSE AYTAMAN, MD,2 THOMAS WEBER, FRANCESCO SERAFINI, MD1,4* 2
MD,
3
AND
1 Department of Surgery, SUNY Downstate, Brooklyn, New York Department of Medicine, VA NY Harbor Healthcare System, Brooklyn, New York 3 Department of Surgery, VA NY Harbor Healthcare System, Brooklyn, New York 4 Department of Surgery, Kings County Hospital Center, Brooklyn, New York
Peritoneal metastasis from neuroendocrine tumors (NET) is not uncommon with a range in incidence from 10% to 33% [1,2]. Carcinomatosis can be asymptomatic with incidental discovery during preoperative imaging or resection of the primary tumor, but may also occasionally cause significant morbidity with bowel obstruction and bleeding. The frequent association of peritoneal and liver metastases makes the management of patients with NET more complicated [3]. While Vasseur et al. did not find any change in survival due to carcinomatosis per se from NET, Elias et al. found that peritoneal carcinomatosis was the direct cause of death in 40% patients with NET if left untreated [1,2]. As there is a paucity of research on the management of carcinomatosis from NET, we surveyed the expert opinions of participants from the Regional Cancer Therapies meeting in 2011 on well‐differentiated NET of gastrointestinal or unknown origin. With a response rate of 23% (21/ 91) on a pool of 273 patients, the survey found that the preferred modality for preoperative imaging was computed tomography, followed by colonoscopy, chromogranin A levels, and somatostatin‐analog receptor scintigraphy (100%, 85.7%, 76.2%, and 71.4%, respectively); MRI and PET were used by only 23.8% and 19.0%, respectively, while laparoscopy was reported by only 38.1%. Of the expert opinions, 80.9% used the peritoneal cancer index (PCI) system for staging, with a maximum threshold to still attempt cytoreduction at 20.5 5.47. All responders treated the patients with cytoreduction, and HIPEC after cytoreduction was performed by 85.7%, with mitomycin C as the intraperitoneal agent of choice, followed by cisplatin, doxorubicin, and carboplatin. Neoadjuvant and adjuvant chemotherapy was recommended by only 42.8% and 47.6%, respectively. None of the surveyed institutions had any clinical trials for this disease. Although PET and MRI, especially diffusion‐weighted MRI, have been shown in previous literature to be more reliable imaging modalities than CT to screen for early peritoneal disease [4], other factors such as cost, timing, and convenience may still favor the use of CT. While laparoscopy is traditionally important in staging peritoneal surface malignancies like that in mesothelioma and ovarian cancer, there are also limitations to its use, such as the development of dense adhesions from previous surgery for small bowel obstruction, initial exploration and resection, and tumor recurrence. Nonetheless, when possible, staging laparoscopy is advantageous in allowing the detection of disseminated small nodules not apparent on conventional imaging and preventing non‐therapeutic open surgical interventions. The threshold to proceed with cytoreduction rests on the PCI score. In colorectal cancer, PCI is the most powerful prognostic indicator for
ß 2013 Wiley Periodicals, Inc.
completeness of cytoreduction and for survival, and a score above 16 is a strong predictor for failure to accomplish complete cytoreduction [5]. In our survey on carcinomatosis from well‐differentiated NET, the threshold PCI score is much higher at over 20. As well‐differentiated NET may have a more indolent nature giving way to pursuit of more aggressive cytoreduction, this raises the question of whether different threshold PCI scores are acceptable and reasonable for different types of cancer. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) have been successful in treating other peritoneal surface malignancies of ovarian, gastric, colorectal, mesothelioma, and pseudomyxoma origins, but evidence is lacking with regards to carcinomatosis from NET. While cytoreductive surgery serves to remove macroscopic disease and prevent complications from peritoneal metastasis such as bowel obstruction and hemorrhage, HIPEC is a locoregional approach that utilizes hyperthermia and the timing before adhesion formation for chemotherapeutic drugs to better penetrate tumor cells and treat residual microscopic disease. Our survey revealed that the preferred treatment, based on expert opinions, of carcinomatosis from well‐differentiated NET was cytoreduction and HIPEC. Cytoreduction carries a survival benefit compared to palliative bypass or incomplete tumor removal and should be sought out in patients with good performance status and resectable tumors. Conversely, cytoreductive surgery with HIPEC may incur a 10–60% risk of morbidity with major complications such as bowel perforation and fistula formation [3]. Anticipation of incomplete cytoreduction should discourage “heroic” and futile surgical attempts that may incur morbidity. The utter lack of any clinical trials in the surveyed participant institutions on the management of peritoneal metastasis from NET emphasizes the need of a randomized prospective trial on this disease. Given that this disease is not often encountered, a multi‐institutional
The authors have no conflicts of interest to disclose. *Correspondence to: Francesco Serafini, MD, Department of Surgery, Kings County Hospital Center, 451 Clarkson Avenue, Room C‐3213, Brooklyn, NY 11203. Fax: þ1‐718‐245‐4055. E‐mail: francesco.serafi[email protected] Received 28 June 2013; Accepted 15 July 2013 DOI 10.1002/jso.23399 Published online 20 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
386
Au et al.
study would be essential to power the study. Carcinomatosis from NET may be more indolent, and cytoreductive surgery and HIPEC carry both curative benefits as well as the risk of toxicity and complications. While our survey may guide clinicians as to how carcinomatosis from NET is treated based on expert opinions, a level 1 study from a clinical trial is critical to take into account the natural history of the disease and objectively evaluate the safety and efficacy of cytoreduction and HIPEC for treating peritoneal metastasis from NET.
REFERENCES 1. Elias D, Sideris L, Liberale G, et al.: Surgical treatment of peritoneal carcinomatosis from well‐differentiated digestive endocrine carcinomas. Surgery 2005;137:411–416.
Journal of Surgical Oncology
2. Vasseur B, Cadiot G, Zins M, et al.: Peritoneal carcinomatosis in patients with digestive endocrine tumors. Cancer 1996;78:1686– 1692. 3. Kianmanesh R, Ruszniewski P, Rindi G, et al.: ENETS consensus guidelines for the management of peritoneal carcinomatosis from neuroendocrine tumors. Neuroendocrinology 2010;91:333– 340. 4. Satoh Y, Ichikawa T, Motosugi U, et al.: Diagnosis of peritoneal dissemination: Comparison of 18F‐FDG PET/CT, diffusion‐weighted MRI, and contrast‐enhanced MDCT. AJR Am J Roentgenol 2011;196:447–453. 5. Swellengrebel HA, Zoetmulder FA, Smeenk RM, et al.: Quantitative intra‐operative assessment of peritoneal carcinomatosis—A comparison of three prognostic tools. Eur J Surg Oncol 2009;35:1078– 1084.
