Hepatic arterial infusion pump chemotherapy in the management of colorectal liver metastases: expert consensus statement.

Despite significant improvements in systemic therapy for patients with colorectal liver metastases (crlms), response rates in the first-line setting are not optimal, and response rates in the second-line setting remain disappointing. Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms, but it remains infrequently used. We convened an expert panel to discuss the role of haip in the contemporary management of patients with crlm. Using a consensus process, we developed these statements: haip chemotherapy should be given in combination with systemic chemotherapy.haip chemotherapy should be offered in the context of a multidisciplinary program that includes expertise in hepatobiliary surgery, medical oncology, interventional radiology, nursing, and nuclear medicine.haip chemotherapy in combination with systemic therapy should be considered in patients with unresectable crlms who have progressed on first-line systemic treatment. In addition, haip chemotherapy is acceptable as first-line treatment in patients with unresectable colorectal liver metastases.haip chemotherapy is not recommended in the setting of extrahepatic disease outside the context of a clinical trial.haip chemotherapy in combination with systemic therapy is an option for select patients with resected colorectal liver metastases. These consensus statements provide a framework that clinicians who treat patients with crlm can use when considering treatment with haip.

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.

A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer.

BACKGROUND: Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS: Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS: All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 µgPt h/mL, 49.3 ± 30.7 µg h/mL 5-FU (DL1), and 70.5 ± 35.5 µg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS: The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

Clinical results of cytoreduction and HIPEC for malignant peritoneal mesothelioma.

Taken together, these reports provide very provocative and encouraging data that have prompted some to conclude that cytoreduction and HIPEC represents a "new standard of care" for patients with MPM [26]. Certainly, for selected patients who have good performance status (low operative risk) and in whom complete or near complete cytoreduction can be achieved, this form of therapy is associated with a very notable overall survival ranging from 67 to 92 months in 2 larger series. Patient selection remains the central criteria for successful outcome. Patients should be carefully evaluated for co-morbid illnesses that would make them an unacceptable operative risk. Subsequently, CT scan and possibly laparoscopy should be performed to assess resectability with the appreciation that patients with suboptimal resection do very poorly. Pre-operative assessment of disease resectability is difficult to ascertain but some useful information can be obtained from a careful review of the CT scan; some investigators have advocated routine laparoscopy. Technically, details of HIPEC vary from center to center to some degree with respect to type of chemotherapy, dose of chemotherapy, duration of HIPEC, degree of hyperthermia, and method of recirculating the chemotherapy using either the open or closed technique. The use of the HIPEC technique, however, is considered the optimal method of ensuring complete distribution of therapeutic agents to the peritoneal cavity. Hyperthermia is routinely used for its synergistic actions with chemotherapy and its direct tumoricidal activity in experimental models. However, the therapeutic contribution of HIPEC above the effects of successful cytoreduction cannot be determined with available data although palliation of ascites is observed with HIPEC even without cytoreduction. There are no data indicating that one intra-operative chemotherapy regimen is superior to any other. The centers that report use of prolonged induction or post-operative intraperitoneal chemotherapy do not appear to have superior outcomes to those centers that use a more simple treatment regimen. Finally, although the intensity of therapy is considerable, once recovered, the patients appear to enjoy a good HRQOL. Although not specific for patients with MPM, 2 reports have convincingly demonstrated that HRQOL is significantly improved after HIPEC.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperitoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected whenever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P < 0.001), and number of previous operations, which was greater in group II (P < 0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher's exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

Incidental parathyroidectomy during thyroid surgery does not cause transient symptomatic hypocalcemia.

OBJECTIVES: To identify any risk factors for incidental parathyroidectomy and to define its association with symptomatic postoperative hypocalcemia. DESIGN: Retrospective study. SETTING: Tertiary referral cancer center. PATIENTS: Consecutive patients who underwent thyroid surgery between 1991 and 1999. Patients who underwent procedures for locally advanced thyroid cancer requiring laryngectomy, tracheal resection, or esophagectomy were excluded. INTERVENTIONS: All pathology reports were reviewed for the presence of any parathyroid tissue in the resected specimen. Slides were reviewed, and information regarding patient demographics, diagnosis, operative details, and postoperative complications was collected. MAIN OUTCOME MEASURE: Identification of parathyroid tissue in resected specimens and postoperative symptomatic hypocalcemia. RESULTS: A total of 141 thyroid procedures were performed: 69 total thyroidectomies (49%) and 72 total thyroid lobectomies (51%). The findings were benign in 68 cases (48%) and malignant in 73 cases (52%). In the entire series, incidental parathyroidectomy was found in 21 cases (15%). Parathyroid tissue was found in intrathyroidal (50%), extracapsular (31%), and central node compartment (19%) sites. The performance of a concomitant modified radical neck dissection was associated with an increased risk of unplanned parathyroidectomy (P =.05). There was no association of incidental parathyroidectomy with postoperative hypocalcemia (P =.99). Multivariate analysis identified total thyroidectomy as a risk factor for postoperative hypocalcemia (P =.008). In the entire study group, transient symptomatic hypocalcemia occurred in 9 patients (6%), and permanent hypocalcemia occurred in 1 patient who underwent a total thyroidectomy and concomitant neck dissection. CONCLUSIONS: Unintended parathyroidectomy, although not uncommon, is not associated with symptomatic postoperative hypocalcemia. Modified radical neck dissection may increase the risk of incidental parathyroidectomy. Most of the glands removed were intrathyroidal, so changes in surgical technique are unlikely to markedly reduce this risk.

Trimodality therapy for advanced gallbladder cancer.

We conducted a retrospective review of all patients who underwent surgical extirpation for stage III, stage IV, or recurrent carcinoma of the gallbladder. Between 1991 and 1999 ten patients underwent surgical resection for advanced gallbladder cancer. All patients received adjuvant therapy either pre- or postoperatively. Radiotherapy was used in all patients and chemotherapy in 90 per cent of patients. Two patients subsequently underwent resection for locally recurrent disease. An additional patient with stage II disease initially was also treated surgically for a local recurrence. Surgical management involved cholecystectomy and resection of various amounts of liver surrounding the gallbladder bed and regional lymphadenectomy. Contiguously involved structures were resected en bloc. Resection of recurrent disease included excision of all gross tumor. The median overall survival excluding the one 30-day mortality was 53.6 months (range 8-73 months). Four patients have survived 4 or more years, and currently four patients are alive and disease free at 73, 49, 33, and 8 months. Median disease-free interval after each resection of recurrent disease was 13.8 months (range 4-28 months). We conclude that trimodality therapy in selected patients with stage III, IV, or recurrent carcinoma of the gallbladder is possible and may result in prolonged survival.