TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG

Abstract

Background

Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined.

Methods

TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates.

Results

The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients.

Conclusions

These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.

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Reconstruction Outcomes of Oncologic Foot Defect Using Well-Contoured Free Perforator Flaps

Abstract

Background

Reconstruction of foot defects following oncologic resection is a crucial element in the treatment of soft tissue malignancy of the foot.

Objective

The present study aimed to comprehensively evaluate outcomes of oncologic foot reconstruction using free perforator flaps.

Methods

Outcomes of patients with soft tissue malignancy of the foot who underwent reconstruction using a free perforator flap following ablative surgery were reviewed, and perioperative and delayed complications (secondary debulking operation and flap instability) were documented. The Foot Function Index (FFI) questionnaire was surveyed to assess functional status.

Results

Overall, 72 patients were analyzed, with a median follow-up period of 28 months. Malignant melanoma was a predominant etiology. Three kinds of perforator flaps were used, with the thoracodorsal artery perforator flap being the most common. Flaps with skin dimensions matching the defect size were inset and the thickness of the flaps was controlled with primary defatting. Flap re-exploration was conducted in 11 (15.2%) cases and total flap loss occurred in 3 (4.2%) cases. Delayed complications developed in an additional 12 cases, therefore 23 (31.9%) cases required a return to the operating room. The average FFI score was 8.86 at postoperative month 36, on average (range 11–128 months). All respondents reported being independently ambulatory and had minimal difficulty in their daily lives. Reconstruction of defects on weight-bearing regions showed a significantly higher FFI score than that on nonweight-bearing regions (mean 11.96 vs. 4.79, p = 0.029), although the scores remained very low for both instances.

Conclusions

Oncologic foot defects can be reliably reconstructed using well-contoured free perforator flaps with minimal functional morbidity.

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Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials

Abstract

Background

Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS.

Methods

A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach.

Results

For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67–0.94; p < 0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76–0.97; p < 0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07–0.72; p = 0.02) and between OS and DCR was 0.74 (95% CI 0.38–0.90; p < 0.001).

Conclusions

First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.

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Peritoneal Metastases from Gastroenteropancreatic Neuroendocrine Tumors: Incidence, Risk Factors and Prognosis

Abstract

Background

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms and data on peritoneal metastases (PM) from these tumors are scarce.

Objective

The aim of this study was to present population-based data on the incidence, risk factors, and survival of synchronous PM in GEP-NETs.

Methods

Data from all patients diagnosed with a GEP-NET during 2007–2013 were collected from the Netherlands Cancer Registry. Age-standardized incidence rates were calculated and risk factors for developing PM were determined using multivariable logistic regression analysis. Survival was investigated using Kaplan–Meier and Cox regression analyses.

Results

A total of 4114 patients were diagnosed with a GEP-NET. PM were diagnosed in 234 patients (19% of patients with metastasized disease, representing 6% of all GEP-NETs). The incidence of patients diagnosed with PM was 1.6:1,000,000 persons per year. Risk factors for developing PM were higher age (odds ratio [OR] 1.4, 95% CI 1.0–2.0) and primary tumor location in the small intestine (OR 3.5, 95% CI 2.1–5.7) or colon (OR 2.5, 95% CI 1.4–4.4). Small intestinal NETs with PM had the best survival, while appendiceal NETs with PM had the poorest survival (5-year survival rates of 67 and 7%, respectively). Multivariate analysis showed that survival in patients with PM was worse compared with patients without metastases; however, the presence of PM among all metastasized patients was not associated with worse survival.

Conclusions

This nationwide population-based study provides relevant insight into the incidence and risk factors of PM in GEP-NETs, and reveals detailed site-specific data on the presence of PM and survival data that may contribute to develop individualized treatment strategies in patients with these heterogeneous neoplasms.

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Poor Adherence to National Clinical Management Guidelines: A Population-Based, Cross-Sectional Study of the Surgical Management of Melanoma in New South Wales, Australia

Abstract

Background

Standardization of the clinical management of melanoma through the formulation of national guidelines, based on interpretation of the existing evidence and consensus expert opinion, seeks to improve quality of care; however, adherence to national guidelines has not been well studied.

Methods

A population-based, cross-sectional study of the clinical management of all patients with newly notified primary melanomas in the state of New South Wales, Australia, during 2006/2007 was conducted using cancer registry identification and questionnaires completed by treating physicians.

Results

Surgical margin guidelines were adhered to in 35% of cases; 45% were over treated and 21% were undertreated. Factors independently associated with non-concordance on multivariate analysis were lower Breslow thickness, lower socio-economic status of the physician's practice location, older physician age, lower physician caseload, and physicians who biopsied the lesion and then referred for definitive management. Complications were not related to over- or under-treatment on multivariate analysis (p = 0.72). Sentinel lymph node biopsy was performed in 17% of patients with invasive melanoma, with the main determinant for selection being a Breslow thickness >0.75 mm.

Conclusions

The low level of concordance with national guidelines for surgical management of melanoma resulted in overtreatment of many patients. However, a fifth of patients were undertreated, which is likely to have resulted in increased locoregional recurrence rates. The better concordance achieved by physicians treating >30 melanomas per year suggests that a minimum caseload threshold for physicians treating melanoma patients would be desirable. High guideline concordance will ensure patients receive optimal care and minimize morbidity and health service costs.

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The Impact of Smoking on Sentinel Node Metastasis of Primary Cutaneous Melanoma

Abstract

Background

Although a well-established causative relationship exists between smoking and several epithelial cancers, the association of smoking with metastatic progression in melanoma is not well studied. We hypothesized that smokers would be at increased risk for melanoma metastasis as assessed by sentinel lymph node (SLN) biopsy.

Methods

Data from the first international Multicenter Selective Lymphadenectomy Trial (MSLT-I) and the screening-phase of the second trial (MSLT-II) were analyzed to determine the association of smoking with clinicopathologic variables and SLN metastasis.

Results

Current smoking was strongly associated with SLN metastasis (p = 0.004), even after adjusting for other predictors of metastasis. Among 4231 patients (1025 in MSLT-I and 3206 in MSLT-II), current or former smoking was also independently associated with ulceration (p < 0.001 and p < 0.001, respectively). Compared with current smoking, never smoking was independently associated with decreased Breslow thickness in multivariate analysis (p = 0.002) and with a 0.25 mm predicted decrease in thickness.

Conclusion

The direct correlation between current smoking and SLN metastasis of primary cutaneous melanoma was independent of its correlation with tumor thickness and ulceration. Smoking cessation should be strongly encouraged among patients with or at risk for melanoma.

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Excellent Long-Term Prognosis and Favorable Postoperative Nutritional Status After Laparoscopic Pylorus-Preserving Gastrectomy

Abstract

Background

Laparoscopic pylorus-preserving gastrectomy (LPPG) has been introduced as a minimally invasive function-preserving operation for early gastric cancer (GC). This study aimed to investigate the surgical and prognostic outcomes after LPPG at the authors' institution.

Methods

This study analyzed 465 patients who underwent LPPG for cT1 N0 GC located in the middle part of the stomach between 2006 and 2012. Short- and long-term surgical outcomes including 5-year survival rates, postoperative nutritional data, and body weight change were retrospectively investigated.

Results

Regarding short-term surgical results, 14 (3%) of the 465 patients had severe complications classified as Clavien–Dindo grade 3a or above, and no mortality occurred (no in-hospital deaths). The median follow-up period was 1829 days (range 226–3197 days), and the 5-year overall survival and relapse-free survival rates were respectively 98% (95% confidence interval [CI] 96.1–99.0%) and 98% (95% CI 96.1–99.0%). Only two cases of postoperative recurrence were confirmed, and their recurrence sites were not in the remnant stomach or regional lymph nodes. The postoperative nutritional status, in terms of serum total protein, albumin, and hemoglobin levels, was well maintained, and the mean relative body weight (postoperative/preoperative) was 93.24 ± 7.29% after LPPG.

Conclusions

For the first time, we have clarified the detailed long-term survival outcomes of LPPG for cT1 N0 GC. LPPG is an acceptable and favorable operative method for clinically diagnosed early-stage GC, in terms of long-term survival and postoperative nutrition.

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