Does multicenter care impact the outcomes of surgical patients with gastrointestinal malignancies requiring complex multimodality therapy?

BACKGROUND: Regionalization of oncologic care has increased, but less is known whether patient outcomes are influenced by receipt of multimodality care through multicenter care (MCC) or single-center care (SCC). METHODS: Patients from 2004 to 2015 National Cancer Data Base diagnosed with stage II-III esophageal (EA), stage II-III pancreatic (PA), and stage II-IV rectal (RA) adenocarcinoma who underwent resection at a high volume center (HVC) and required radiation and/or chemotherapy were included. MCC (care at 2+ facilities) and SCC patients were propensity-score matched 1:2 and Cox proportional hazards regression used to analyze survival. RESULTS: On multivariable regression analysis, MCC in RA patients (N = 325/2097, 15.5%) was more associated with residing ≥40 miles from the HVC (odds ratio [OR] = 2.37; P = .044) and receipt of neoadjuvant chemotherapy (1.42, P = .040). In PA patients (N = 75/380, 19.7%), residing ≥40 miles from the HVC (OR = 3.22; P = .001), and in EA patients (N = 88/534, 16.5%), younger patients (<50 years: OR = 2.96; P = .011) were associated with MCC. Following propensity score matching, EA (N = 147), PA (N = 133), and RA (N = 661) patients had no difference in 1-year and 3-year overall survival when comparing MCC to SCC. CONCLUSIONS: The use of MCC appears safe without a difference in survival and may offer significant advantages in convenience to patients as they undergo their complex oncologic care.

Obesity is not associated with increased morbidity in patients undergoing cytoreductive surgery with intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: Recent single-institutional series have examined the relationship of body mass index (BMI) in patients undergoing cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) generally without significant increase in serious complications with increasing BMI. This study evaluates the impact of BMI on complication rates using a national cohort. METHODS: The ACS NSQIP database was queried for patients undergoing concurrent CRS with IPC (2005-2012). Death and serious morbidity (DSM) was the primary outcome. Statistical analyses were performed to determine significant associations between peri-operative factors and DSM. RESULTS: Of 1,085 patients, there were 30.4% (n = 330) obese (BMI >30) and 32.1% (n = 348) normal weight (BMI 18.5-24.9) patients. DSM rates did not differ between these groups (P = 0.853). Obese patients were more likely to experience post-operative wound (P = 0.017) and renal (P = 0.002) complications. Hypoalbuminemia (OR 7.34; 95% CI 2.27-23.73), prolonged operative time (OR 3.02; 95% CI 1.83-4.97) and concomitant liver resection (OR 3.29; 95% CI 1.31-8.28) were independent risk factors for DSM among obese patients. CONCLUSIONS: Obesity is not significantly associated with DSM in patients undergoing CRS/IPC, and should not be a major deterrence for surgery. However, obese patients are more likely to experience wound and renal complications and hypoalbuminemia is a strong preoperative risk factor. J. Surg. Oncol. 2016;114:619-624. © 2016 Wiley Periodicals, Inc.

Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer.

PURPOSE: Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. METHODS AND MATERIALS: The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network--recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. RESULTS: Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non-academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. CONCLUSIONS: Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered.

Morbidity and mortality of cytoreduction with intraperitoneal chemotherapy: outcomes from the ACS NSQIP database.

BACKGROUND: Cytoreduction with intraperitoneal chemotherapy (IPC) for treatment of peritoneal surface malignancies is increasingly utilized. However, the described morbidity and mortality rates are based predominantly on the experience at high-volume centers. We analyzed the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for a nationwide perspective on morbidity and mortality associated with IPC. METHODS: The NSQIP database was queried for all patients undergoing IPC and cytoreduction from 2005 to 2011. Univariate and forward stepwise multivariate regression identified factors associated with 30-day death and morbidity. RESULTS: A total of 795 patients underwent IPC. Patients underwent a median of seven operative procedures (range 2-13). Median hospital stay was 9 days (range 2-79 days). A total of 521 complications occurred in 249 (31 %) patients, and there were 19 (2.3 %) mortalities. The most common complications were bleeding (15.1 %) and sepsis (14.6 %). Univariate analysis identified age ≥60 years, ascites, weight loss, recent prior operation, albumin <3 g/dl, bilirubin ≥2 mg/dl, hematocrit ≤30 %, colon, spleen, small bowel, liver, kidney, diaphragm, and gastric resections, wound classification, operative time, and intraoperative transfusion requirement as significantly associated with death and morbidity. By multivariate analysis, age ≥60 years, preoperative albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement remained significantly associated with death and morbidity. Particularly high death and morbidity rates were associated with preoperative albumin <3 g/dl (58 %), gastrectomy (62 %), and operative time of >500 min (46 %). CONCLUSIONS: In this nationwide cohort, the death and morbidity rate associated with cytoreduction and IPC is consistent with other large series. Age ≥60 years, albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement were associated with 30-day death and morbidity. These factors may help guide patient selection, counseling, and preoperative optimization before IPC.

Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol.

BACKGROUND: Unresectable colorectal liver metastases have a 1- and 2-year survival of 55% and 33% with current systemic therapies. The authors evaluated response and survival after transarterial chemoembolization. METHODS: Chemoembolization with cisplatin, doxorubicin, mitomycin C, ethiodized oil, and polyvinyl alcohol particles was performed at monthly intervals for 1 to 4 sessions. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle was performed for intrahepatic recurrence. Toxicity was assessed using National Cancer Institute's Common Toxicity Criteria version 3.0. Response was evaluated using Response Evaluation Criteria in Solid Tumors criteria. Progression and survival were estimated with Kaplan-Meier analysis. RESULTS: A total of 245 treatments were performed over 141 cycles on 121 patients. Ninety-five of 141 treatment cycles were evaluable for response: 2 (2%) partial response, 39 (41%) stable disease, and 54 (57%) progression. Median time to disease progression (TTP) in the treated liver was 5 months, and median TTP anywhere was 3 months. Median survival was 33 months from diagnosis of the primary colon cancer, 27 months from development of liver metastases, and 9 months from chemoembolization. Survival was significantly better when chemoembolization was performed after first- or second-line systemic therapy (11-12 months) than after third- to fifth-line therapies (6 months) (P = .03). Presence of extrahepatic metastases did not adversely affect survival (P = .48). CONCLUSIONS: Chemoembolization provided local disease control of hepatic metastases after 43% of treatment cycles. Median survival was 27 months overall, and 11 months when initiated for salvage after failure of second-line systemic therapy.

Analysis of factors associated with outcome in patients undergoing isolated hepatic perfusion for unresectable liver metastases from colorectal center.

AIM: To define the indications for hyperthermic isolated hepatic perfusion (IHP) in patients with unresectable liver metastases (LM) from colorectal cancer (CRC) with particular focus on IHP's utility as a second-line option for patients whose tumors have progressed following combination systemic chemotherapy treatment. METHODS: From June 1994 through July 2005, 120 patients with unresectable CRC LM underwent IHP with melphalan (n = 69), tumor necrosis factor (TNF) (n = 10) or both (n = 41). Hepatic arterial infusion (HAI) with floxuridine started 6-8 weeks post IHP in 46 (38%). Patients were followed for toxicity, radiographic response, and overall survival (OS). Wilcoxon rank-sum and Fisher's exact tests were used to compare parameters by response category; survival and hepatic progression-free survival were calculated by the Kaplan-Meier method. RESULTS: Of 79 males and 41 females, 96 (80%) received prior chemotherapy. There were five (4%) operative/treatment mortalities. There were 69 responses in 114 evaluable patients (61%). Total melphalan dose and combination melphalan/TNF were each associated with response; age, preoperative carcinoembryonic antigen (CEA), prior chemotherapy for established LM, tumor burden, and post-IHP HAI therapy were not. Median overall survival was 17.4 months and 2-year survival was 34%. Factors found to be independently related to survival were preoperative CEA <30 ng/mL and use of post-IHP HAI (P < 0.015). CONCLUSIONS: IHP results in marked tumor regression and prolonged survival in patients with CRC LM. Continued development of IHP in this clinical setting is warranted.

Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020.

PURPOSE: To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. PATIENTS AND METHODS: Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. RESULTS: The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). CONCLUSION: In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.

Management of in-transit melanoma of the extremity with isolated limb perfusion.

In-transit metastases for melanoma are a type of stage III regional metastatic disease that are intradermal or subcutaneous nodules growing within lymphatics and not in nodal basins. If the initial diagnosis is a limited number of in-transit metastases (1-3 nodules), the optimal management is simple surgical excision with minimal negative margins and primary closures and appropriate staging to look for any distant metastases. There is no role for wide excision of in-transit lesions as there is for primary melanoma because the entire extremity or that region of the body is at risk for recurrence. Patients who are diagnosed with additional lesions in a short period of time or patients who at initial diagnosis have large numbers of nodules are candidates for isolated limb perfusion (ILP). ILP is a regional administration of high-dose chemotherapeutics within an extremity using a cardiopulmonary bypass machine similar to cardiac surgery. Once isolation is obtained surgically, the limb is heated to what is considered mild hyperthermia (38.5 degrees -40 degrees C), then chemotherapeutics are administered at very high concentrations for a 60- to 90-minute treatment. The drug recirculates and, at the end of the treatment period, it is flushed from the extremity and the circulation is re-established. The optimal regimen is melphalan dosed per limb volume (10 mg/L limb volume for lower extremities and 13 mg/L limb volume for upper extremities) with mild hyperthermia for 60 minutes. Using this regimen, overall response rates between 80% and 90% and complete response rates between 55% and 65% can be obtained. The duration of response is typically 9 to 12 months and a subgroup of complete responders, which is 20% to 25% of the total patient population, typically have sustained complete responses. The major toxicities are skin erythema, myopathy, and peripheral neuropathy. There have been several studies adding high-dose tumor necrosis factor to ILP, but there is no clear benefit in the treatment of melanoma. Other new approaches include isolated limb infusion as a percutaneous procedure to avoid the surgical toxicity.

Patterns of recurrence in patients treated with photodynamic therapy for intraperitoneal carcinomatosis and sarcomatosis.

The purpose of this study was to evaluate the patterns of recurrence in patients treated with Photofrin-mediated intraperitoneal photodynamic therapy (IP PDT). Sixty-six patients with gastrointestinal cancers, ovarian cancers, and sarcomas have been enrolled to date and 51 patients underwent IP PDT. Photofrin, 2.5 mg/kg, was administered intravenously 48 h prior to surgical debulking and intraoperative light treatment. Forty-five, and 49 patients were evaluable for response rates, and patterns of recurrence, respectively. Response to treatment was evaluated by CT or MRI scans of the abdomen and pelvis every 3 months. Patterns of recurrence were determined by evaluating the abdomen as a combination of different treatment regions. Of the 51 patients enrolled and treated with IP PDT two are alive without evidence of recurrence. Eleven of 45 patients showed no evidence of recurrence 3 months after treatment. No evidence of recurrence was noted in 7/17 sarcoma patients, 2 of 13 ovarian cancer patients, and 2 of 15 gastrointestinal cancer patients. The most common site of recurrence as determined by radiographs was the pelvis, which was noted in 19 of 49 (39%) patients. The presence of gross residual disease before light treatment (as determined by the attending surgeon) did not affect the site of recurrence. When studying those patients who had only locoregional recurrence, 9 of 33 evaluated radiographically and 10 of 24 evaluated operatively recurred only in peritoneal areas not previously involved with gross disease. The pelvis was the site with the highest rate of recurrence after IP PDT. A significant minority of patients recurred only in sites not previously involved with gross disease. Patients with gross residual disease before light therapy had similar recurrence rates to those without gross residual disease. Since sites involved with gross residual tumor often received boost doses of light, this could suggest a dose-response relationship for IP PDT.

Intraperitoneal photodynamic therapy causes a capillary-leak syndrome.

BACKGROUND: In patients undergoing intraperitoneal (IP) photodynamic therapy (PDT), the combination of aggressive surgical debulking and light therapy causes an apparent systemic capillary-leak syndrome that necessitates significant intensive care unit (ICU) management after surgery. METHODS: From May 1997 to May 2001, 65 patients underwent surgical debulking and PDT as part of an ongoing phase II trial for disseminated IP cancer. Perioperative data were reviewed retrospectively, and statistical analyses were performed to determine whether any identifiable factors were associated with the need for mechanical ventilation for longer than 1 day and with the occurrence of postoperative complications. RESULTS: Forty-three women and 22 men (mean age, 49 years) were treated. Operative time averaged 9.8 hours, and mean estimated blood loss was 1450 mL. The mean crystalloid requirement for the first 48 hours after surgery was 29.3 L, and 49 patients required blood products. Twenty-four patients were intubated for longer than 24 hours, with a mean of 8.3 days for those intubated longer than 1 day. The median ICU stay was 4 days. Overall, 110 complications developed in 45 (69%) of the 65 patients. Significant complications included 6 patients with acute respiratory distress syndrome, 28 patients with infectious complications, and 4 patients with anastomotic complications. Statistical analyses revealed that surgery-related factors were significantly associated with these complication outcomes. CONCLUSIONS: Patients who undergo surgical debulking and IP PDT develop a significant capillary-leak syndrome after surgery that necessitates massive volume resuscitation, careful ICU monitoring, and, frequently, prolonged ventilatory support.