Extensive surgical history prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is associated with poor survival outcomes in patients with peritoneal mucinous carcinomatosis of appendiceal origin.

BACKGROUND: Patients with PMCA commonly undergo surgery before CRS/HIPEC. We evaluated the role of extensive surgical treatment before CRS/HIPEC in terms of overall survival (OS). METHODS: 105 patients with PMCA who underwent a CRS/HIPEC procedure were identified from a prospective database. Patients were divided into two groups based on Prior Surgery Score (PSS): PSS ≤ 1 limited surgery group (LSG), PSS >1 extensive surgery group (ESG). Survival of lymph node (LN) negative and positive patients was analyzed separately. RESULTS: 40 patients were in LSG and 65 in ESG. Mean time from diagnosis to CRS/HIPEC was 6 and 17 months for LSG and ESG, respectively (p = 0.004). Groups were well balanced in peritoneal cancer index, complete cytoreduction rate, and LN status. One, 3, and 5-year OS among LN negative patients was 95, 83, and 75% for the LSG (n = 22) group and 87, 55, and 32% for the ESG (n = 35), group respectively (p = 0.026). One, 3, and 5-year OS among LN positive patients was 69, 50, and 17% for the LSG (n = 18) group and 80, 21, and 14% for the ESG (n = 30), group respectively (p = 0.613). For all patients 1, 3, and 5-year OS was 84, 65, and 54% for the LSG (n = 40) group and 86, 43, and 26% for the ESG (n = 65) group, respectively (p = 0.029). CONCLUSION: Extensive surgical treatment before CRS/HIPEC is associated with delay of CRS/HIPEC and poorer OS overall, especially among LN negative patients. We recommend early referral of PMCA patients to a peritoneal surface malignancy center.

Systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in patients with peritoneal mucinous carcinomatosis of appendiceal origin (PMCA).

BACKGROUND: The role of SC before CRS/HIPEC for patients with PMCA is unclear. This study explores the effect of SC prior to CRS/HIPEC on overall survival (OS) in patients with PMCA. METHODS: 72 patients with recently diagnosed PMCA who underwent CRS/HIPEC were identified from a prospective database. Thirty patients had SC before CRS/HIPEC (Group 1) and 42 did not (Group 2). Patients who were referred to our center after multiple lines of SC were excluded from this analysis. OS was estimated. RESULTS: Median follow-up was 3.2 years. Groups were similar regarding lymph node positivity, postoperative SC and rate of complete cytoreduction. Twenty-four (80%) patients in Group 1 and 21 (50%) in Group 2 had high grade histology (HG) (p = 0.01). OS from CRS/HIPEC at 1, 2, and 3 years was 93, 68, 51% in Group 1 and 82, 64, 60% in Group 2, respectively (p = 0.74). Among HG patients 3-year survival was 36% in the SC group vs. 35% in the group without SC (p = 0.67). The 3-year OS for patients with low grade (LG) tumors was 100% in the SC group vs. 79% in the group with no prior SC (p = 0.26). Among patients with signet ring cell (SRC) histology, 1, 2 and 3-year survival was 94, 67 and 22% in the SC group vs. 43, 14, 14% in the group with no SC, respectively (p = 0.028). There were only 6 patients with LG PMCA who received prior SC. CONCLUSIONS: Preoperative SC could improve the prognosis of patients with high-grade PMCA with SRC histology.

Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei.

BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

The role of VEGFR-2 expression in outcomes and survival of patients with peritoneal carcinomatosis from appendiceal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a prognostic factor and target treatment for metastatic colorectal and ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival on peritoneal carcinomatosis (PC) from appendiceal cancer. We hypothesize that tumoral high expression of VEGF receptor 2 (VEGFR-2) is a negative prognostic factor for survival in patients with PC from appendiceal cancer. METHODS: A retrospective study of a prospective database revealed 89 patients with PC from appendiceal cancer who underwent 127 CRS/HIPECs. Surgical specimens from 59 patients were tested to identify high vs. low VEGFR-2 expression. Patient outcomes and survival were analyzed. RESULTS: There were 26 males and 33 females. Mean age was 51 years. Forty-seven VEGFR-2 high expressers and 15 low expressers were identified. Mean follow-up of high and low expressers was 25.1 and 26.6 months, respectively (p = 0.806). At follow-up, 33 (70%) high expressers were alive and 14 (30%) deceased, while 11 (92%) low expressers were alive and 1 (8%) deceased. Recurrence, use of bevacizumab, CC score, PCI, and LN status showed no differences between high and low expressers. OS for high expressers was 90.5%, 59.8%, and 47.1% at 1-, 3-, and 5-years, respectively, while OS for low expressers remained stable at 91.7% at 1-, 3-, and 5-years (p = 0.133). CONCLUSION: There is a trend towards better outcomes and survival in patients with PC from appendiceal cancer who have low expression of VEGFR-2 compared to high expression. More studies are encouraged to confirm this trend.

Repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: analysis of survival outcomes.

BACKGROUND: Cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) is the procedure of choice in patients with peritoneal dissemination from appendiceal cancer. Although recurrence rates are 26%-44% after first CRS/HIPEC, the role of repeated CRS/HIPEC has not been well defined. We hypothesize that patients undergoing multiple CRS/HIPEC's have meaningful long term survival. METHODS: A retrospective study of a prospective database of 294 patients with peritoneal carcinomatosis (PC) was conducted, of these 162 had PC of appendiceal origin. Twenty-six of these patients underwent 56 CRS/HIPEC. Survival and outcomes was analyzed. RESULTS: The percentage of patients with pre-surgical PCI scores ≥ 20 for the first, second, and third CRS/HIPEC was 65, 65, and 25%, respectively. Complete cytoreduction (CC 0-1) at first, second, and, third surgeries was 96, 65 and 75%, respectively. The mean operating time was 10.1 h. There was no 30-day peri-operative mortality. Following the first, second, and third CRS/HIPEC 27, 42, and 50% experienced grade III complications, respectively. Mean follow up was 51, 28, and 16 months from the first, second, and third CRS/HIPEC, respectively. Overall survival rate for the first CRS/HIPEC was 100, 83, 54, and 46% at years 1, 3, 5 and 10, respectively; from the second CRS/HIPEC 91, 53, and 34% at 1, 3, and 5 years, respectively; and from the third CRS/HIPEC was 75% at one year. CONCLUSION: Repeat CRS/HIPEC can lead to meaningful long term survival rates in patients with appendiceal peritoneal carcinomatosis with morbidity and mortality similar to those of the initial CRS/HIPEC.

Clinical utility of elevated tumor markers in patients with disseminated appendiceal malignancies treated by cytoreductive surgery and HIPEC.

BACKGROUND: Appendiceal malignancies with peritoneal spread have been successfully treated with Cytoreductive Surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study is to clarify the utility of common tumor markers in selecting patients for the combined treatment. METHODS: Data on 56 patients with appendiceal neoplasms treated with CRS and HIPEC were prospectively collected. Chi square test was used to analyze a link between common tumor markers and completeness of cytoreduction score (CC score) and preoperative peritoneal cancer index score (PCI score). Cox proportional hazard model was used to perform survival analysis. RESULTS: Forty-two patients were alive after 3 years of follow-up. Hazard ratio of disease related death was 5.6 (95% CI, 1.8-17.2) among patients with high CC score as compared to those with low CC score. Number of abnormal tumor markers (0 vs 1/2/3) correlated with PCI score 16.2 vs 32.5 (p < 0.001) but not with completeness of cytoreduction or survival. The 3-year survival rates in patients with normal vs abnormal CA 125 levels were 83% vs 52%(p = 0.003). CONCLUSIONS: Multiple abnormal tumor markers were not useful as an exclusion criterion for patients undergoing CRS. Elevation in CA 125 was an important indicator of survival in these patients. Complete cytoreduction was crucial for long-term survival.

Multimodality treatment in the management of esophageal cancer: neoadjuvant chemoradiotherapy followed by transhiatal esophagectomy.

Esophageal cancer, although not one of the more common malignancies in the United States, remains a significant problem. Nearly as many patients as are diagnosed die in the same year, regardless of the treatment employed. Surgery is considered the mainstay of therapy. Esophagectomy with the use of the stomach as a substitute is preferred. Radical procedures have not proven more effective in extending survival. Because of the poor five-year survival rate, multimodality therapy with preoperative chemoradiotherapy (neoadjuvant therapy) followed by esophagectomy has shown encouraging results. Two illustrative cases are presented, one with adenocarcinoma and one with a squamous cell carcinoma, that were treated in this manner.

Immunoperoxidase confirmation of ultrasonically guided fine needle aspirates in patients with recurrent hyperparathyroidism.

Fine needle aspiration (FNA) biopsy in conjunction with ultrasonic definition of nonpalpable masses in the neck region is being used more frequently. Currently available preoperative localization tests have failed, in many instances, to delineate adequately the location of missed adenomas of the parathyroid gland. We describe herein the use of ultrasonically guided FNA of parathyroid tissue with immunoperoxidase confirmation for precise localization of the diseased gland. Three patients with persistent hypercalcemia after exploration of the neck were referred to Ochsner Clinic, New Orleans. In two of these patients, a parathyroid adenoma had been removed, while in one patient no adenoma was found. All patients had elevated calcium (range 10.9 to 11.6 milligrams per deciliter), low phosphorous and elevated parathyroid levels. Preoperative ultrasonography to localize the suspected parathyroid glands was performed, with FNA and immunohistochemical confirmation. Smears confirmed adequate cellular material. Alcohol fixed, Papanicolaou stained and air dried, Wright's and Giemsa stained smears were evaluated for the presence of parathyroid cells by conventional cytologic examination. The Papanicolaou-stained slides were then decolorized in 1 percent hydrochloric acid in 70 percent ethanol. After decolorization, the smears were stained for parathyroid hormone (PTH) in an avidin-biotin complex (ABC) system, using a commercially available ABC kit (Vector Laboratories Inc.). The primary antibody is a polyclonal antiserum generated in rabbits against a synthetic human PTH. Negative controls were obtained from normal thyroid glands. In all three patients, the diseased gland was localized by ultrasound with cytologic and immunohistochemical confirmation, one on the right side and two on the left side. At surgical excision, the adenomas weighed 0.8 and 0.75 gram and the carcinoma, 0.75 gram. In two, intraoperative identification of the diseased gland was aided by ultrasound directed methylene blue injection into the adenoma. During a follow-up evaluation of eight to 24 months, serum calcium had remained normal in two patients, and one patient had become hypocalcemic and required calcium supplements. The preoperative localization allowed a direct surgical approach to the side in question in all patients. Ultrasonically guided FNA in an immunoperoxidase system can be a valuable preoperative localization technique for patients with recurrent hyperparathyroidism, thus avoiding extensive exploration of the neck with the subsequent complications.

Radioimmunoguided surgery in primary colon cancer.

Radioimmunoguided surgery (RIGS), the intraoperative use of a hand-held gamma detecting probe (GDP) to identify tissue containing radiolabeled monoclonal antibody (MAb), was performed upon 30 patients with primary colon carcinoma. Each patient received an intravenous injection of MAb B72.3 (1.0 to 0.25 mg) radiolabeled with 125I (5.0 to 1.0 mCi) 8 to 34 days before exploration. The GDP was used to measure radioactivity in colon tissue, tumor bed, nodal drainage areas, and areas of suspected metastases. Antibody localized to histologically documented tumor in 23 of 30 patients (77%). Tumor margins were more clearly defined in 20 of 30 patients (67%). GDP counts led to major alterations in surgical resection in five patients (17%) and changes in adjuvant therapy in four (14%). GDP counts identified occult liver metastases in two patients (7%) and correctly indicated the benign nature of liver masses in three (10%). In four patients (13%), occult nodal metastases were identified. RIGS can precisely delineate tumor margins, define the extent of nodal involvement, and localize occult tumor, providing a method of immediate intraoperative staging that may lessen recurrences and produce higher survival rates.

The use of a hand-held gamma detector improves the safety of isolated limb perfusion.

We used two hand-held gamma-detecting probes (GDP) (Neoprobe 1000 system) capable of detecting small gamma emissions to monitor leakage in patients undergoing hyperthermic isolated limb perfusion (HILP) who received 800 microCi Technetium 99m pentetate through the perfusate. The percentage of gamma-ray leakage was calculated by a simultaneous reading of two probes at 1-minute intervals (one over the precordial area and one over the thigh) and this was compared to results of simultaneous blood sampling from the perfusate and systemic circulation at 15-minute intervals for gamma well counting (GWC). The percentage of leakage recorded by the GDPs was essentially identical to that detected by the GWC (7.3% and 8.2%, respectively at the conclusion of the perfusion). The GDP gives an immediate and accurate indication of the percentage of leakage during HILP, making it a safer procedure.