Who Undergoes Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Appendiceal Cancer? An Analysis of the National Cancer Database.

BACKGROUND: We sought to identify patterns of care for patients with appendiceal cancer and identify clinical factors associated with patient selection for multimodality treatment, including cytoreductive surgery and perioperative intraperitoneal chemotherapy (CRS/PIC). MATERIALS AND METHODS: National Cancer Database (NCDB) data from 2004 to 2014 of all diagnoses of appendiceal cancers were examined. We examined treatment modalities, as well as demographic, tumor-specific, and survival data. A multivariate logistic regression analysis was performed to determine the patient cohort most likely to receive CRS/PIC. Kaplan-Meier was used to estimate survival for all treatment groups. Significance was evaluated at P ≤ 0.05. RESULTS: We analyzed data on 18,055 patients. Nine thousand nine hundred ninety-two (55.3%) were treated with surgery only, 5848 (32.4%) received surgery and systemic chemotherapy, 1393 (7.71%) received CRS/PIC, 520 (2.88%) received chemotherapy alone, and 302 (1.67%) received neither surgery nor chemotherapy. Significant predictors of receiving CRS/PIC included male sex (OR 1.33, 95% CI: 1.11-1.59), white race (OR 2.00, 95% CI 1.40-2.86), non-Hispanic ethnicity (OR 1.92, 95% CI 1.21-3.05), private insurance (OR 1.52, 95% CI 1.26-1.84), and well-differentiated tumors (OR 4.25, CI: 3.39-5.32) (P < 0.05). Treatment with CRS/PIC was associated with a higher 5-year survival for mucinous malignancies, when compared to surgery alone (65.6% versus 62.4%, P < 0.01). Treatment with CRS/PIC was also associated with higher 5-year survival for well-differentiated malignancies, when compared to all other treatment modalities (74.9% versus 65.4%, P < 0.01). CONCLUSIONS: Patients were more likely to undergo CRS/PIC if they were male, white, privately insured, and with well-differentiated tumors. CRS/PIC was associated with improved survival in patients with mucinous and low-grade tumors.

[Implementation of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Germany]. / Anwendung der hyperthermen intrathorakalen Chemotherapie (HITHOC) in Deutschland.

INTRODUCTION: For several years, hyperthermic intrathoracic chemotherapy (HITHOC) has been performed in a few departments for thoracic surgery in a multimodality treatment regime in addition to surgical cytoreduction. Specific data about HITHOC in Germany are still lacking. METHODS: Survey in written form to all departments of thoracic surgery in Germany. The objective is the evaluation of HITHOC with respect to number, indications, technique, perioperative protection measure and complications. RESULTS: A total of 116 departments of thoracic surgery were contacted, with a return rate of 43% (n = 50). HITHOC was not performed in 33 departments, due to lack of resources or experience (n = 17), missing efficacy of the procedure (n = 8) and fear of excessive complication rates (n = 3). Since 2008, a total of 343 HITHOC procedures have been performed in 17 departments. Eight departments have their own perfusion machine, whereas the remaining departments borrow the perfusion machine. Indications were malignant pleural mesothelioma in all departments (n = 17), thymoma with pleural spread (n = 11) and secondary pleural carcinosis (n = 7). The HITHOC was performed in nearly all departments after closing the chest (n = 16), with a temperature of 42 °C (n = 12) and for 60 minutes (n = 15). Cisplatin was always used, either alone (n = 9) or in combination (n = 8). In all the participating departments, the aims of the HITHOC were improvement in local tumor control and prolonged recurrence-free and overall survival. Relevant HITHOC-associated complications were low. CONCLUSIONS: HITHOC is performed in at least 17 departments of thoracic surgery in Germany, and is widely standardised with protective measures and a low rate of complications. The aims of the HITHOC are improvement in local tumor control in pleural malignancies combined with prolonged overall survival and better quality of life.

Interval between cytoreductions as a marker of tumor biology in selecting patients for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for recurrence of peritoneal surface malignancies is safe and effective. Patient selection and factors associated with a favorable outcome are still evolving. METHODS: A prospectively maintained institutional database consisting of 1314 CRS/HIPEC procedures performed between February 1993 and December 2015 was reviewed. Clinicopathologic data from 103 patients and 112 (8.5%) repeat CRS/HIPEC procedures were retrospectively analyzed. RESULTS: Primary tumors were appendiceal for 60 patients (58.3%), mesothelioma for 14 (13.6%), colorectal for 9 (8.7%), ovarian for 8 (7.8%). R0/R1 resection was achieved in 46 (46.5%) patients. The time interval between the initial and the repeat CRS/HIPEC was <1 year for 21 (20.4%), 1-2 years for 40 (38.8%), and >2 years for 42 patients (40.8%). Overall median survival was 4.3 years and correlated with the time interval (1.3 years for <1 years, 3.7 years for 1-2 years, and 7 years for >2 years; P < 0.001). In multivariate analysis, the R status (P = 0.005) and a time interval of more than 2 years (P = 0.0002) were strongly associated with survival with each additional month between the surgeries conferring a 2.6% reduction in the risk of death. CONCLUSIONS: The current series validates time interval between cytoreductions as a major surrogate of tumor biology in selection of patients with recurrent peritoneal surface malignancies for repeat CRS/HIPEC. Complete repeat cytoreduction more than 2 years from the initial surgery is associated with a favorable outcome.

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis.

INTRODUCTION: Isolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US). METHODS: Retrospective, observational study, using administrative claims data from the MarketScan(®) databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed. RESULTS: One hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (± SD) length of hospital stay was 5.6 (± 3.5) days and the mean (± SD) cost was US$36,758 (± 27,124) per ILP/ILI procedure. CONCLUSIONS: Isolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma. FUNDING: This study was funded by Amgen, Inc.

[HEMIHEPATECTOMY FOR RESECTABLE HEPATIC METASTASIS FROM COLORECTAL CANCER WITH POOR PROGNOSIS].

The current study aimed at improvement of treatment effects for patients with resectable metastases of colorectal cancer in the liver with a poor prognosis. Overall 437 patients were enrolled with metastatic colorectal cancer in the liver exhibiting at least one adverse factor of long-term prognosis: multiple metastases, bilobar liver metastases, large metastases, the presence of extrahepatic metastases, etc. Combined treatment was performed for 339 (78%) patients: combined treatment with adjuvant systemic chemotherapy (163 patients), combined treatment with perioperative systemic chemotherapy (54 patients), or combined treatment of perioperative regional chemotherapy (122 patients). Surgical treatment was performed in 66 (15%) patients. The remaining group of 32 (7%) patients with resectable metastases who received only systemic chemotherapy was considered separately. All liver resections were extensive due to the widespread metastases. The complication rate stood at 56%. Mortality among operated patients was 4%. Postoperative mortality and complications as well as the intraoperative blood loss were not statistically different in two groups. Adding bevacizumab to preoperative chemotherapy did not increase blood loss. After combined treatment with adjuvant chemotherapy a 5-year survival was 26 ± 4% that significantly outperforming a 5-year survival rate after surgery (17 ± 5%), after just drug treatment a 5-year survival has not been reached, and also after combined treatment with perioperative systemic chemotherapy (13 ± 5%) and not statistically significant exceeded a 5-year survival after combined treatment with perioperative regional chemotherapy (20 ±5%). Thus our study demonstrates the benefits of combined treatment with adjuvant systemic chemotherapy for resectable metastases of colorectal cancer in the liver with a poor prognosis. For initially unresectable metastases with extrahepatic manifestations of the disease treatment should be begun with systemic chemotherapy. To liver resection in the latter cases there are resorted only after the transfer of patients in operable condition.

Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety.

BACKGROUND: Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits. METHODS: A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used. RESULTS: Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively. CONCLUSIONS: ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.

Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach.

BACKGROUND: The high complication rates of surgically implanted port catheter systems (SIPCS) represents a major drawback in the treatment of isolated liver neoplasms by hepatic arterial infusion (HAI) of chemotherapy. Interventionally implanted port catheter systems (IIPCS) have evolved into a promising alternative that enable initiation of HAI without laparatomy, but prospective data on this approach are still sparse. Aim of this study was to evaluate the most important technical endpoints associated with the use of IIPCS for the delivery of 5-fluorouracil-based HAI in patients with colorectal liver metastases in a phase 2-study, and to perform a non-randomised comparison with a historical group of patients in which HAI was administered via SIPCS. METHODS: 41 patients with isolated liver metastases of colorectal cancer were enrolled into a phase II-study and provided with IIPCS between 2001 and 2004 (group A). The primary objective of the trial was defined as evaluation of device-related complications and port duration. Results were compared with those observed in a pre-defined historical collective of 40 patients treated with HAI via SIPCS at our institution between 1996 and 2000 (group B). RESULTS: Baseline characteristics were balanced between both groups, except for higher proportions of previous palliative pre-treatment and elevated serum alkaline phosphatase in patients of group A. Implantation of port catheters was successful in all patients of group A, whereas two primary failures were observed in group B. The frequency of device-related complications was similar between both groups, but the secondary failure rate was significantly higher with the use of surgical approach (17% vs. 50%, p < 0.01). Mean port duration was significantly longer in the interventional group (19 vs. 14 months, p = 0.01), with 77 vs. 50% of devices functioning at 12 months (p < 0.01). No unexpected complications were observed in both groups. CONCLUSION: HAI via interventionally implanted port catheters can be safely provided to a collective of patients with colorectal liver metastases, including a relevant proportion of preatreated individuals. It appears to offer technical advantages over the surgical approach.

Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan.

OBJECTIVES: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP. SETTING: University surgical oncology division with an integrated eight-bed intensive care unit. PATIENTS: Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma. INTERVENTIONS: The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel. MEASUREMENTS AND MAIN RESULTS: PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes. CONCLUSIONS: Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.

Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion.

To date, little is known about prognostic factors for limb recurrence-free interval and survival in patients with recurrent melanoma of the limbs treated with regional isolated perfusion. Therefore, 216 such patients treated with normothermic perfusion using melphalan during the period 1978 to 1990 were analyzed for patient and tumor related variables using a Cox proportional hazard model. The five year limb recurrence-free interval was 52 percent. For stage II (n = 67), IIIA (n = 71) and IIIAB and IIIB (n = 78) disease separately, these percentages were 53, 56 and 47 percent. In stage II disease, patients with a local recurrence adjacent to scar or skin graft had a significantly better five year limb recurrence-free interval than patients with satellites (75 versus 33 percent; p = 0.0009). Prognostic factors for limb recurrence-free interval were--in order of importance--tumor tissue left in situ, number of previous limb recurrences and total tumor surface area. The overall five year survival rate was 42 percent. For stages II, IIIA and IIIAB and IIIB disease, these percentages were 57, 45 and 25 percent, respectively. There was no survival benefit for patients with a local recurrence. Prognostic factors for survival were, in order of importance, stage of disease, gender, age, Breslow thickness, Clark level of infiltration of the primary melanoma and the number of lesions forming the indication for perfusion. The results of this study will eventually further delineate indications for perfusion.

Surgical limb perfusion for extremity melanoma.

For over 35 years, various centres throughout the world have surgically perfused extremities afflicted with various stages of melanoma. Throughout these years the true effectiveness of this invasive technique has remained controversial. Herein, an attempt has been made to critically survey this literature, with emphasis on reports from the past few years, to ascertain what role limb perfusion may play in the 1990s.