Akash Mehta

Clinical presentation, diagnosis, classification and management of peritoneal mesothelioma: a review

Peritoneal mesothelioma (PM) is an uncommon but a serious, and often, fatal primary peritoneal tumour, with increasing incidence worldwide. Conventional systemic chemotherapy, generally based on experience with pleural mesothelioma, usually has disappointing results considering PM as a terminal condition. Patients usually present with non-specific symptoms of abdominal distension and pain making the diagnosis challenging. As PM is confined to the abdomen for all, or much, of its clinical course, a multimodality treatment combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a new standard of care, and has been reported to achieve promising survival outcomes and local disease control in selected patients with PM. This review updates the presentation, diagnosis, classification and treatment strategies for PM.

Preserving fertility in pseudomyxoma peritonei, a novel approach

Abstract Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is the gold standard treatment for patients with pseudomyxoma peritonei (PMP) but involves routine bilateral salpingo-oophorectomy. Young women wishing to maintain fertility may be reluctant to pursue this. An alternative strategy in women with low-grade PMP has been explored in the form of laparoscopic evacuation of pelvic and ovarian mucin with resection of the appendiceal tumour. Methods Between January 2012 and January 2015, four young women (aged 28–35 years) with PMP seeking to maintain fertility underwent laparoscopy, appendicectomy and pelvic mucinous evacuation and washout. Data regarding intra-operative and histopathological findings were collected. Endpoints were fertility-related outcomes and oncological follow-up. Results Infertility was a presenting symptom in three of the four women. All four had significant pelvic mucinous disease on radiological imaging and were offered CRS and HIPEC as definitive treatment, but chose laparoscopy with appendicectomy and copious irrigation and washout of the pelvis with stripping of mucinous disease off the ovarian surfaces. Postoperative histology demonstrated a low-grade appendiceal mucinous neoplasm (LAMN) in all patients with acellular mucin or low-grade mucinous carcinoma peritonei in the peritoneal cavity. All patients successfully conceived subsequently and gave birth to healthy babies. After 12–29 months follow-up, all women are well with no radiological or laparoscopic evidence of disease recurrence. Conclusions In patients with low-grade PMP, initial therapeutic laparoscopy can restore fertility, whilst providing short- to medium-term disease control. This modality in young women wishing to have children appears to be a feasible alternative to immediate CRS and HIPEC.

Risk of Ovarian Involvement in Advanced Colorectal or Appendiceal Tumors Involving the Peritoneum

BACKGROUND: Ovarian metastases of GI tumors grow rapidly and are relatively resistant to systemic chemotherapy. They may be unilateral or bilateral and macroscopic or occult. The risk of macroscopic ovarian involvement or occult involvement of macroscopically normal ovaries is unquantified. OBJECTIVE: This study aims to quantify the risks of ovarian involvement in patients with peritoneal malignancy undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. DESIGN: This was a retrospective analysis of a dedicated prospective malignancy database. SETTINGS: This study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Female patients with at least 1 remaining ovary, undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal tumors or colorectal peritoneal metastases between January 2010 and March 2015 were included. OUTCOME MEASURES: Data regarding ovarian involvement was extracted from surgical and histological records. RESULTS: Two hundred fifty-eight female patients with at least 1 ovary underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy during the study period. In total, 141 of 258 (54.7%) patients had ovarian tumor involvement, and 80% with at least 1 macroscopically abnormal ovary had bilateral involvement. Of 40 patients with 1 macroscopic ovarian metastasis, microscopic involvement of the contralateral ovary was found in 18 of 40 (45.0%). Of 141 patients in whom both ovaries were macroscopically normal, 24 of 141 (17.0%) patients had microscopic ovarian involvement. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Occult malignancy was present in 17% when both ovaries looked macroscopically normal and in 45% of contralateral normal-looking ovaries if the other ovary was macroscopically involved. These results help to inform preoperative consent and intraoperative decision making in patients with advanced appendiceal and colorectal malignancy, and are of benefit in managing advanced lower GI tract malignancy.

Management of Complications of CRS and HIPEC

The potential clinical benefits of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have for long been overshadowed by its relatively high morbidity and mortality compared to other surgical procedures. It takes 3–12 months on an average for the quality of life to return to normal. With standardization of indications, better patient selection, development and implementation of perioperative care pathways and institution of formal teaching programs, there has been a reduction in the overall morbidity and mortality from the procedure, and it is now similar to that of other major gastrointestinal surgeries when performed in specialized centres. Morbidity has a negative impact on the overall survival in certain cancers (including colorectal cancer) and can delay the administration of systemic therapy which is equally important in other cancers like ovarian cancer which further emphasizes the importance of patient selection. It may result in a significant additional financial burden where such procedures are not under ‘insurance cover’ and are ‘out-of-pocket’ spending for patients. The 90-day morbidity and mortality capture the overall complication rate more accurately and should be recorded and reported instead of the 30-day morbidity and mortality. Early recognition and management of complications by multidisciplinary teams are needed to ‘rescue’ patients who develop complications.

New Treatment Modalities for the Management of Peritoneal Metastases

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a therapeutic option for a small subset of patients with peritoneal metastases arising from various primary sites. Locoregional therapies for effective management of patients who are not candidates for this procedure are needed. Recurrence after CRS and HIPEC is common. Strategies for improving the efficacy of CRS and HIPEC are being studied. New treatments that overcome the limitations of CRS and HIPEC are being evaluated in clinical and preclinical studies. New drugs for intraperitoneal use and new intraperitoneal therapies have been developed and investigated in both experimental and clinical studies. The results of some of these studies are encouraging, and these therapies may find a place in routine clinical practice in the future. An overview of the rationale, methodology, and preliminary results of experimental and clinical studies evaluating these new locoregional therapies for the management of PM is provided here.

Role of HIPEC in the Prevention of Peritoneal Metastasis from Colorectal, Gastric and Appendiceal Cancer

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have offered new hope for patients with peritoneal metastasis from colorectal and gastric cancers. However, this treatment can be offered only to a small, select group of patients, and even in this select group, only a small proportion can be cured. Hence, prevention of peritoneal metastasis assumes importance. Currently, three approaches are being evaluated to prevent colorectal peritoneal metastasis using HIPEC: a proactive approach, in patients considered to be at high risk of microscopic peritoneal dissemination; an adjuvant approach, in the immediate or delayed postoperative period after primary resection; and a second-look approach, during a systematic second-look operation approximately 1 year after primary resection. The effectiveness of HIPEC in preventing gastric peritoneal metastasis has already been shown in a number of randomised studies from Asia and is also currently being evaluated in Western patients. The results of ongoing trials could well be a game changer in the prevention of colorectal and gastric cancer-associated peritoneal metastasis. Unlike colorectal and gastric cancer, mucinous appendiceal neoplasms, which are the commonest cause of pseudomyxoma peritonei, pursue a more indolent course, and even patients with extensive disease are amenable to curative resection. However, early diagnosis can lead to a prolongation in survival, and strategies to prevent peritoneal dissemination are recommended during surgery for mucinous appendiceal neoplasms.

Diagnostic and therapeutic laparoscopy in assessment and management of patients with appendiceal neoplasms.

Abstract Introduction: Radiological imaging often underestimates the extent of low volume peritoneal disease. The benefit of laparoscopy in assessing peritoneal metastases from colorectal and gastric cancer is accepted, but is inconclusive for appendiceal malignancy. We report our experience of diagnostic (DL) and therapeutic laparoscopy (TL) in patients with appendiceal tumours to determine indications and role in assessment and management. Methods: A retrospective review of a National Peritoneal Malignancy Centre’s prospectively maintained database was performed. All patients with appendiceal neoplasms who underwent DL or TL between September 2011 and January 2016 were included. The indications and outcomes of the laparoscopy, complications and interval to laparotomy were evaluated. Results: Six hundred and eighty-five patients underwent surgery for appendiceal neoplasms during the study period, of which 73 (10.6%) underwent laparoscopy (50 DL, 23 TL). The main indications for DL were to clarify imaging and stage patients with high-risk histology. Indications for TL were an abnormal appendix without gross pseudomyxoma peritonei (PMP) or with low volume PMP, and concerns for fertility in the presence of PMP. DL resulted in 16 patients (32%) avoiding laparotomy because of extensive disease or no tumour found. Overall, 28 patients were assessed to have resectable disease and at laparotomy, 25/28 had complete cytoreduction with three patients unresectable. In the TL group, appendicectomy and peritoneal lavage was achieved in all four women with fertility concerns, allowing them to conceive thereafter. There were no complications. Conclusions: Patients with high-risk appendiceal neoplasm may benefit from DL, and potentially avoid unnecessary laparotomy. TL is useful in patients with low volume PMP and may aid fertility in selected patients.

Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival

Abstract Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) benefits selected patients with peritoneal mesothelioma. We present the outcomes of this treatment strategy in a UK peritoneal malignancy national referral centre. Methods: Observational retrospective analysis of data prospectively collected in a dedicated peritoneal malignancy database between March 1998 and January 2016. Results: Of 1586 patients treated for peritoneal malignancy, 76 (4.8%) underwent surgery for peritoneal mesothelioma. Median age was 49 years (range 21–73 years). 34 patients (45%) were female. Of the 76 patients, 39 (51%) had low grade histological subtypes (mostly multicystic mesothelioma), and 37 (49%) had diffuse malignant peritoneal mesothelioma (DMPM; mostly epithelioid mesothelioma). Complete cytoreduction was achieved in 52 patients (68%) and maximal tumour debulking (MTD) was performed in 20 patients (26%); the remaining 4 patients (5%) underwent a laparotomy with biopsy only. HIPEC was administered in 67 patients (88%). Median overall (OS) and disease-free survival (DFS) after CRS was 97.8 (80.2–115.4) and 58.8 (47.4–70.3) months, respectively. After complete cytoreduction, 100% overall survival was observed amongst patients with low-grade disease. Ki-67 proliferation index was significantly associated with survival outcomes after complete cytoreduction for DMPM and was an independent predictor of decreased survival. Conclusion: With adequate patient selection (guided by histological classification and Ki-67 proliferation index) and complete cytoreduction with HIPEC, satisfactory outcomes can be achieved in selected patients with peritoneal mesothelioma.

Peritoneal Involvement Is More Common Than Nodal Involvement in Patients With High-grade Appendix Tumors Who Are Undergoing Prophylactic Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BACKGROUND: Right hemicolectomy is routinely recommended in patients with histologic findings of high-grade appendix tumors after appendicectomy. Undetected peritoneal disease may be encountered at surgery. In high-grade appendix tumors with disease detected radiologically, complete cytoreduction may not be possible and outcomes poor. For these reasons, we adopted a policy of prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. OBJECTIVE: The purpose of this study was to quantify the rates of peritoneal and nodal metastatic disease in patients with high-grade appendix tumors without obvious metastatic disease and to report the long-term outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in these patients. DESIGN: Data regarding peritoneal and nodal metastatic disease were extracted from surgical and histologic records. SETTINGS: The study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Patients referred with histologically high-grade appendix tumors at appendicectomy, without detectable metastatic spread, between January 1994 and September 2016 were included MAIN OUTCOME MEASURES: A total of 62 patients with high-grade pathology at appendicectomy, without clinical or radiological peritoneal disease, underwent complete cytoreduction with hyperthermic intraperitoneal chemotherapy. RESULTS: Thirty-five (57%) of 62 patients had peritoneal disease (median peritoneal cancer index 5 (range, 1–28)). Eleven (31%) of 35 had microscopic peritoneal disease. Overall, 23 (37%) of 62 had peritoneal disease beyond the confines of a standard right hemicolectomy. Nine (15%) of 62 had nodal involvement. Mean overall and disease-free survival were 110.9 (95% CI, 94.8–127.0 mo) and 102.1 months (95% CI, 84.3–119.9 mo), with 5-year overall and disease-free survival of 83.2% and 76.0%. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Complete cytoreduction was achieved in all of the patients, with excellent long-term survival. The incidence of peritoneal spread (57%) compared with nodal involvement (15%) supports cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as definitive treatment rather than prophylaxis in patients with high-grade appendix tumors, even without radiologically detectable disease. High-grade appendix tumors benefit from early aggressive operative management to deal with potential peritoneal and nodal spread and should be considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. See Video Abstract at http://links.lww.com/DCR/A360.