Terence C. Chua

Early- and Long-Term Outcome Data of Patients With Pseudomyxoma Peritonei From Appendiceal Origin Treated by a Strategy of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

PURPOSE Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: Multi-Institutional Experience

PURPOSE This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival. RESULTS Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002). CONCLUSION The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.

Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure? A systematic review of morbidity and mortality

Background:Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been offered in many institutions worldwide since the 1990s. Despite its existence of more than 10 years, this treatment has received heavy criticism for its morbidity and mortality rates. This consequentially resulted in a lack of randomized trials being conducted and translates into a lack of the most reliable form of scientific evidence in clinical research, hence limiting its general acceptance. Objective:To report the morbidity and mortality outcomes of CRS and HIPEC from all institutions performing this treatment as a prelude toward establishing the safety of this treatment for peritoneal carcinomatosis. Methods:A systematic review of relevant studies before August 2008 was performed. Each study was appraised using a predetermined protocol. The quality of studies was assessed. The morbidity and mortality of the treatment were synthesized through a narrative review with full tabulation of results of all included studies. Conclusions:The morbidity and mortality outcomes of CRS and HIPEC are similar to a major gastrointestinal surgery, such as a Whipples procedure. To derive the maximal benefit of this treatment, careful patient selection with an optimal level of postoperative care must be advocated to avoid undesirable complications of this treatment.

Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases.

Background:Yttrium-90 (90Y) radioembolization is a promising treatment option for unresectable neuroendocrine tumor liver metastases (NETLM). This study is the first to evaluate the prognostic variables that influenced radiologic response and survival in patients with unresectable NETLM who were treated with 90Y radioembolization. As a secondary outcome, the impact of this treatment on serologic toxicity was assessed. Methods:Forty-eight patients underwent resin-based 90Y radioembolization for unresectable NETLM at a single institution between December 2003 and May 2009. Patients were assessed radiologically and serologically at 1 month and then at 3 month intervals after treatment. Prognostic variables that affected response and survival were determined. The impact of this treatment on serologic toxicity over a 6-month period was assessed. Discussion:No patient was lost to follow-up. The median follow-up for the patients who were alive was 41 months. The median survival was 35 months (range: 5–63). On imaging follow-up, 7 patients (15%) had a complete response and 19 patients (40%) had a partial response to treatment. Eleven patients (23%) had stable disease and 11 patients (23%) had progressive disease. Five prognostic factors were associated with an improved survival: complete/partial response (P = 0.003), low hepatic tumor burden (P = 0.022), female gender (P = 0.022), well-differentiated tumor (P = 0.001), and absence of extra—hepatic metastasis (P < 0.001). Three factors were associated with a complete/partial response: female gender (P = 0.040), well-differentiated tumor (P < 0.001) and low hepatic tumor burden (P = 0.041). There was a significant increase in the level of alkaline phosphatase over the 6-month period (P < 0.001). Conclusions:90Y radioembolization is a promising treatment option for unresectable NETLM. Patients with low hepatic tumor burden, well-differentiated tumor, female gender, and no extrahepatic disease benefit most from treatment.

Systematic Review of Randomized and Nonrandomized Trials of the Clinical Response and Outcomes of Neoadjuvant Systemic Chemotherapy for Resectable Colorectal Liver Metastases

BackgroundNeoadjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases (CLM) may facilitate the resectability of the liver lesions and treat occult metastasis but may also lead to hepatic parenchyma damage. There is argument over the oncologic benefit of this practice in patients who would already be suitable for a curative hepatectomy.MethodsExtensive literature search of databases (MEDLINE and PubMed) to identify published studies of preoperative systemic chemotherapy for resectable CLM was undertaken with clinical response to treatment and survival outcomes as the endpoints.ResultsTwenty-three studies were reviewed: 1 phase III randomized control trial, 3 phase II studies, and 19 observational studies, comprising 3,278 patients. Objective (complete/partial) radiological response was observed in 64% (range 44–100%) [complete 4% (range 0–38%), partial 52% (range 10–90%)] of patients after neoadjuvant chemotherapy. Pathologically, a median of 9% (range 2–24%) and 36% (range 20–60%) had complete and partial response, respectively. Of patients, 41% (range 0–65%) had stable or progressive disease whilst on neoadjuvant chemotherapy. Median disease-free survival (DFS) was 21 (range 11–40) months. Median overall survival (OS) was 46 (range 20–67) months.ConclusionCurrent evidence suggests that objective response to neoadjuvant chemotherapy may be achieved with improvement in DFS in patients with resectable CLM. A prospective randomized trial of neoadjuvant therapy versus adjuvant therapy after liver resection is required to determine the optimal perisurgical treatment regimen.Neoadjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases (CLM) may facilitate the resectability of the liver lesions and treat occult metastasis but may also lead to hepatic parenchyma damage. There is argument over the oncologic benefit of this practice in patients who would already be suitable for a curative hepatectomy. Extensive literature search of databases (MEDLINE and PubMed) to identify published studies of preoperative systemic chemotherapy for resectable CLM was undertaken with clinical response to treatment and survival outcomes as the endpoints. Twenty-three studies were reviewed: 1 phase III randomized control trial, 3 phase II studies, and 19 observational studies, comprising 3,278 patients. Objective (complete/partial) radiological response was observed in 64% (range 44–100%) [complete 4% (range 0–38%), partial 52% (range 10–90%)] of patients after neoadjuvant chemotherapy. Pathologically, a median of 9% (range 2–24%) and 36% (range 20–60%) had complete and partial response, respectively. Of patients, 41% (range 0–65%) had stable or progressive disease whilst on neoadjuvant chemotherapy. Median disease-free survival (DFS) was 21 (range 11–40) months. Median overall survival (OS) was 46 (range 20–67) months. Current evidence suggests that objective response to neoadjuvant chemotherapy may be achieved with improvement in DFS in patients with resectable CLM. A prospective randomized trial of neoadjuvant therapy versus adjuvant therapy after liver resection is required to determine the optimal perisurgical treatment regimen.

Radioembolization versus Standard Care of Hepatic Metastases: Comparative Retrospective Cohort Study of Survival Outcomes and Adverse Events in Salvage Patients

PURPOSE To retrospectively evaluate the safety and survival of patients with chemotherapy-refractory liver metastases treated with yttrium-90 ((90)Y) resin microspheres, and to compare survival in this patient group versus survival after standard/supportive care to assess whether radioembolization contributes to survival gains in the salvage setting. MATERIALS AND METHODS While 339 patients with chemotherapy-refractory liver metastases underwent (90)Y microspheres radioembolization at a single institution between 2006 and 2011, 51 patients were referred back to their treating physician for conservative treatment or best supportive care. Adverse events were assessed at the time of treatment and at 1 and 3 months after treatment. Overall survival (OS) was calculated by the Kaplan-Meier method for the radioembolization cohort (as a whole and according to two subcohorts: patients with colorectal primary cancer and patients with all other primary cancers, eg, breast or neuroendocrine) and the standard-care cohort. RESULTS The median OS after (90)Y radioembolization (339 patients) was 12.0 months, versus 6.3 months for the standard-care cohort (51 patients; P < .001). The median OS times for the two subcohorts were 11.9 months and 12.7 months, respectively. At the 3-month follow-up, the incidence of more serious adverse events was low, with 11 cases (3%) of ulceration, 10 cases (2.9%) of radiation-induced liver disease, and six complications (1.8%) involving the gallbladder (eg, cholecystitis). CONCLUSIONS The present study suggests that radioembolization shows promise as an effective and safe treatment for patients with chemotherapy-refractory hepatic metastases and improves overall survival in a select population of patients in a salvage setting compared with best supportive care alone.

A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database*.

Currently, no tumor‐node‐metastasis (TNM) staging system exists for patients with diffuse malignant peritoneal mesothelioma (DMPM). The primary objective was to formulate a clinicopathological staging system through the identification of significant prognostic parameters.

Evaluation of Best Supportive Care and Systemic Chemotherapy as Treatment Stratified according to the retrospective Peritoneal Surface Disease Severity Score (PSDSS) for Peritoneal Carcinomatosis of Colorectal Origin

BackgroundWe evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes.MethodsOne hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test.ResultsMedian survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001].ConclusionA trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.

Hepatic resection for metastatic breast cancer: A systematic review

BACKGROUND Systemic chemotherapy is the mainstay of treatment for metastatic breast cancer with the role of surgery being strictly limited for palliation of metastatic complications or locoregional relapse. An increasing number of studies examining the role of therapeutic hepatic metastasectomy show encouraging survival results. A systematic review was undertaken to define its safety, efficacy and to identify prognostic factors associated with survival. METHODS Electronic search of the MEDLINE and PubMed databases (January 2000-January 2011) to identify studies reporting outcomes of hepatectomy for breast cancer liver metastases (BCLM) with hepatectomy was undertaken. Two reviewers independently appraised each study using a predetermined protocol. Safety and clinical efficacy was synthesised through a narrative review with full tabulation of results of all included studies. RESULTS Nineteen studies were examined. This comprised of 553 patients. Hepatectomy for BCLM was performed at a rate of 1.8 (range, 0.7-7.7) cases per year in reported series. The median time to liver metastases occurred at a median of 40 (range, 23-77) months. The median mortality and complication rate were 0% (range, 0-6%) and 21% (range, 0-44%), respectively. The median overall survival was 40 (range, 15-74) months and median 5-year survival rate was 40% (range, 21-80%). Potential prognostic factors associated with a poorer overall survival include a positive liver surgical margin and hormone refractory disease. CONCLUSION Hepatectomy is rarely performed for BCLM but the studies described in this review indicate consistent results with superior 5-year survival for selected patients with isolated liver metastases and in those with well controlled minimal extrahepatic disease. To evaluate its efficacy and control for selection bias, a randomised trial of standard chemotherapy with or without hepatectomy for BCLM is warranted.

Pelvic exenteration for rectal cancer: a systematic review.

BACKGROUND: Pelvic exenteration is a potentially curative treatment for locally advanced primary or recurrent rectal cancer. OBJECTIVE: This systematic review examines the current evidence regarding clinical and oncological outcomes in patients with locally advanced primary and recurrent rectal cancer who undergo pelvic exenteration. DATA SOURCES: A literature search of PubMed, Medline, and the Cochrane library was undertaken, and studies published in the English language from January 2000 to August 2012 were identified. STUDY SELECTION: Prospective and retrospective studies that report outcomes of pelvic exenteration for primary advanced and locally recurrent rectal cancer with or without subgroup evaluation were included for examination. MAIN OUTCOME MEASURES: Oncological outcomes included 5-year survival, median survival, and local recurrence rates. Clinical outcomes included complication rates and perioperative mortality rates. RESULTS: A total of 23 studies with 1049 patients were reviewed. The complication rates ranged from 37% to 100% (median, 57%) and the perioperative mortality rate ranged from 0% to 25% (median, 2.2%). The rate of local recurrence ranged from 4.8% to 61% (median, 22%). The median survival for primary advanced rectal cancers was 14 to 93 months (median, 35.5 months) and 8 to 38 months (median, 24 months) for locally recurrent rectal cancer. LIMITATIONS: Our review was limited by the small sample sizes from single-institutional studies reporting outcomes over long periods of time with heterogeneity in both the disease and treatments reported. CONCLUSIONS: Although the human costs and risks are significant, the potentially favorable survival outcomes make this acceptable in the absence of other effective treatment modalities that would otherwise result in debilitating symptoms that afflict patients who have advanced pelvic malignancy.