Is adjuvant chemotherapy necessary for early gastric cancer?

Objective:To quantify the potential benefit of adjuvant chemotherapy (ACT) with respect to survival, and to identify factors for predicting prognoses in early gastric cancer patients.Methods:Patients with pT1 gastric cancer (GC) who underwent radical resection with D2 lymphadenectomy were retrospectively analyzed. Based on lymph node metastasis (LNM) status and treatment regimens, patients were classified into groups, and clinicopathological variables, overall survival (OS), and disease-specific survival (DSS) were compared.Results:Of 1,050 enrolled patients, 151 patients (14.4%) had a positive LNM status. Submucosal invasion, undifferentiated state, tumor size > 2 cm, ulceration, and lymphovascular invasion were independent risk factors for LNM using multivariate analyses. The 5-year OS of all patients was 96.4%. HER2 positive, perineural invasion, and LNM were independent factors for worse survival. Patients with pT1N3 GC had a worse 5-year OS and DSS than pT1N0, pT1N1, and pT1N2 patients (P < 0.001). The 5-year OS and DSS for pT1N1 patients showed no significant difference between ACT and surgery only patients. For pT1N2 patients, the 5-year OS and DSS showed no significant difference between S-1 and Xelox treatments. For pT1N3 patients, 7 (36.8%) received S-1, while 12 (63.2%) received Xelox treatment. Patients receiving Xelox treatment showed a better 5-year OS (75.0% vs. 14.3%) and DSS (81.8% vs. 20.0%) than patients receiving S-1 (P < 0.05).Conclusions:Curative surgery only was adequate for patients with pT1N0 and pT1N1. Xelox showed no survival benefits for pT1N2 patients. Therefore, S-1 is the optimal choice for pT1N2 patients, when considering adverse effects. Xelox is recommended for pT1N3 patients.     

Is abdominoperineal resection a good option for stage IV adenocarcinoma of the distal rectum?

BACKGROUND AND OBJECTIVES: The management of the primary lesion in patients with stage IV adenocarcinoma of the distal rectum is controversial. An abdominoperineal resection (APR) may be a good option. METHODS: A retrospective analysis of the medical records of 21 patients with stage IV distal rectal adenocarcinoma treated with an APR between January 1991 to December 2000 was performed. RESULTS: All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and normal preoperative alkaline phosphatase and total bilirubin levels. Twelve patients (92%) with liver metastases had less than 25% of total liver volume involvement. Twenty patients (95%) had complete resolution of their symptoms related to the primary rectal cancer. The median follow-up was 19 months (range 3-92 months), with a median survival of 21.6 months and a 2-year overall survival of 34%. CONCLUSIONS: Patients with stage IV distal rectal adenocarcinoma who have a good performance status, normal preoperative liver function tests, and minimal metastatic disease to the liver can be offered resective surgery.     

Is adenocarcinoma/large cell carcinoma the most radiocurable type of cancer of the lung?

Radiation therapy is widely considered the primary treatment for inoperable "non-small" cell carcinoma of the lung. In clinical investigations, distinction has been infrequent among the histopathologic subtypes of non-small cell carcinoma. Studies have shown significant differences between squamous cell carcinoma and adenocarcinoma/large cell carcinoma; adenocarcinoma/large cell carcinoma has a greater propensity for extrathoracic dissemination, especially to the brain, and it is less curable by resection when regional lymph node metastases are present. No differences have been documented between adenocarcinoma and large cell carcinoma. A retrospective study was undertaken to determine the results of definitive radiation therapy by histopathologic subtype of non-small cell carcinoma of the lung. Between July 1977 and April 1983, 134 patients with non-small cell carcinoma of the lung underwent definitive radiation therapy with curative intent. All patients had performance status scores of 80 to 100 (Karnofsky), and received minimum total doses within the tumor of 60 Gy in 6 to 7 weeks, five fractions per week. The median period of observation was 63 months. Ninety patients had squamous cell carcinoma; 44 had adenocarcinoma/large cell carcinoma. The two groups of patients were comparable in respect to age and Stage; there were significantly more women with adenocarcinoma/large cell carcinoma (27%) than with squamous cell carcinoma (13%). The median survival for patients with squamous cell carcinoma was 11.5 months; the 2 and 4 year survival rates were 21 and 7%, respectively. The median survival for patients with adenocarcinoma/large cell carcinoma was 18 months; 2 and 4 year survival rates were 38 and 23%, respectively. Comparison of the overall survival experience did not show a significant difference between the two cell types (p = .12 using Gehan's generalized Wilcoxon test). However, comparison of the proportion of patients with adenocarcinoma/large cell carcinoma surviving 18 months (50%) was significantly higher (p = .02) than that with squamous cell carcinoma (30%). A small body of data from the literature also suggests a better long-term prognosis for adenocarcinoma/large cell carcinoma. This observation requires confirmation from large trials with histopathologic review. If it is confirmed, there are important implications for therapeutic strategies in future clinical investigations of inoperable carcinoma of the lung.     

Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma?

BACKGROUND:

It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival.

METHODS:

Patients with stage II‐III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse‐free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy ≤60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log‐rank test and multivariate analysis by the Cox proportional hazards model.

RESULTS:

Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08‐4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance.

CONCLUSIONS:

Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS. Cancer 2011;. © 2010 American Cancer Society.     

Should adjuvant chemotherapy become standard treatment for patients with stage II colon cancer? For the proposal

Adjuvant chemotherapy is regarded as standard treatment for patients with stage III colon cancer; however, use of chemotherapy after surgery in patients with stage II disease remains controversial because of a lack of level I evidence. In 2005, the Minimum Clinical Recommendations, issued by the European Society for Medical Oncology (ESMO), did not advocate use of chemotherapy in stage II disease, but did state that chemotherapy "may be considered in selected node-negative patients". Similarly, in 2004, treatment recommendations from the American Society of Clinical Oncology (ASCO) for stage II colon cancer proposed that there might be some "patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology". Consequently, use of adjuvant chemotherapy in patients with stage II colon cancer is not universal. In this Debate, Alberto Sobrero from Genoa, Italy, and Claus-Henning K?hne from Oldenburg, Germany, present the arguments for and against the use of this type of treatment.     

Do thymidylate synthase gene promoter polymorphism and the C/G single nucleotide polymorphism predict effectiveness of adjuvant 5-fluorouracil-based chemotherapy in stage III colonic adenocarcinoma?

Since 5-fluorouracil (5-FU)-based chemotherapy has become standard adjuvant treatment for patients with node-positive colonic adenocarcinoma, there has arisen the need for predictive factors. Thymidylate synthase (TS) is a major target of 5-FU's action, and high TS expression in carcinoma cells could reduce its cytostatic effect. Both, a 28-base pair repeat polymorphism and a cytosine vs. guanine single nucleotide polymorphism in the promoter region of the TS gene are known to modulate its expression. All patients with a single, non-metachronous node-positive colonic adenocarcinoma who underwent a potentially curative resection at this institution in the years 1994-2002, and who received adjuvant 5-FU (n=95) were included in this study. Ninety-four of the 95 patients were successfully genotyped: 70 patients were classified as TS gene low-expressors (2R-2R, 2R-3C and 3C-3C), and 24 patients were classified as high-expressors (2R-3G, 3C-3G and 3G-3G). Contrary to the hypothesis, Kaplan-Meier survival analysis did not reveal any differences between the groups (power of 0.8 to detect an absolute survival difference >30%). In a Cox model, venous angioinvasion and the infiltrative pattern of tumour invasion were strong adverse factors. These results argue against a practical role for the TS gene repeat polymorphism or the C/G single nucleotide polymorphism as a predictive factor. However, by careful histopathological examination a high-risk group of node-positive patients can be defined that could be candidates for studies of alternative (more aggressive) adjuvant treatment.     

Is postoperative adjuvant chemoradiotherapy necessary for high-risk oropharyngeal squamous cell carcinoma?

Background

High-risk factors for recurrence of head and neck squamous cell carcinoma after surgical resection include involvement of ≥2 regional lymph nodes, extracapsular spread, and microscopic involvement of resected mucosal margins. Adjuvant chemoradiotherapy is thought to improve postoperative locoregional control and survival. In this paper, we evaluate the efficacy of adjuvant therapy for high-risk oropharyngeal squamous cell carcinoma (OPSCC) (i.e., with ≥2 lymph nodes, positive extracapsular spread, or positive margins).

Methods

This is a retrospective analysis of 45 high-risk OPSCC patients who underwent surgery without adjuvant therapy (n = 19), with radiotherapy (n = 17), or with chemoradiotherapy (n = 9).

Results

The median follow-up period was 41.0 months. Radiotherapy patients showed a trend toward longer overall survival than patients without adjuvant therapy [hazard ratio (HR) = 0.32, p = 0.176]. However, overall survival for the chemoradiotherapy group seemed to be the same as that for the no adjuvant therapy group (HR = 0.79, p = 0.779). Multivariate analysis found that the relative risk of recurrence for patients without adjuvant therapy compared with any adjuvant therapy was 3.02 (p = 0.101). The relative recurrence risk in radiotherapy patients was 0.95 compared with that in chemoradiotherapy patients (p = 0.971). However, pathological T-stage was significantly associated with disease-free survival for high-risk OPSCC.

Conclusions

Although the current study uses data from a small retrospective sample of patients, our results suggest that the addition of chemotherapy to radiotherapy may not be necessary as an adjuvant therapy for all high-risk OPSCC. A novel prognostic factor, such as pathological T-stage, should be considered for selecting those patients with high-risk OPSCC who would benefit from adjuvant therapy.     

Is cognitive dysfunction a complication of adjuvant chemotherapy in the older patient with breast cancer?

For a number of years, patients have anecdotally reported changes in memory and concentration problems after receiving chemotherapy for breast cancer. Neuropsychological studies have been performed to seek objective evidence as to the existence and extent of this phenomenon; however, these studies were primarily performed in younger women and there is sparse data regarding the impact of adjuvant chemotherapy on an older woman’s cognition. The objective of this paper was to evaluate the current literature in order to propose ways to overcome methodological limitations of studies to consider whether chemotherapy-associated cognitive dysfunction exists in older patients and if so, who is at risk. A systematic review of relevant literature was performed including study design, mean age of participants, treatment received, neuropsychological tests employed, timing of assessments, definition of cognitive impairment, and results. The literature primarily consists of small studies, which lack a prospective longitudinal design, vary in design measures, and exclude older patients who are at greatest risk for cognitive impairment. Since aging is the number one risk factor for breast cancer, future studies of the neuropsychological impact of chemotherapy should include older patients.     

Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin?

PURPOSE: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy in improving survival was evaluated by comparison of a matched set of historic control subjects with patients treated in a prospective Phase II study that used synchronous chemotherapy and radiation and adjuvant chemotherapy. PATIENTS AND METHODS: Patients were included in the analysis if they had disease localized to the primary site and nodes, and they were required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, or gross residual disease after surgery. All patients who received chemotherapy were treated in a standardized fashion as part of a Phase II study (Trans-Tasman Radiation Oncology Group TROG 96:07) from 1997 to 2001. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (AUC 4.5) and etoposide, 80 mg/m(2) i.v. on Days 1 to 3, were given in Weeks 1, 4, 7, and 10. The historic group represents a single institution's experience from 1988 to 1996 and was treated with surgery and radiation alone, and patients were included if they fulfilled the eligibility criteria of TROG 96:07. Patients with occult cutaneous disease were not included for the purpose of this analysis. Because of imbalances in the prognostic variables between the two treatment groups, comparisons were made by application of Cox's proportional hazard modeling. Overall survival, disease-specific survival, locoregional control, and distant control were used as endpoints for the study. RESULTS: Of the 102 patients who had high-risk Stage I and II disease, 40 were treated with chemotherapy (TROG 96:07) and 62 were treated without chemotherapy (historic control subjects). When Cox's proportional hazards modeling was applied, the only significant factors for overall survival were recurrent disease, age, and the presence of residual disease. For disease-specific survival, recurrent disease was the only significant factor. Primary site on the lower limb had an adverse effect on locoregional control. For distant control, the only significant factor was residual disease. CONCLUSIONS: The multivariate analysis suggests chemotherapy has no effect on survival, but because of the wide confidence limits, a chemotherapy effect cannot be excluded. A study of this size is inadequately powered to detect small improvements in survival, and a larger randomized study remains the only way to truly confirm whether chemotherapy improves the results in high-risk MCC.     

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial

Introduction

Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction.

Methods

Patients were randomised to receive preoperative CT with cisplatin (80 mg/m²) and infusional 5 fluorouracil (1000 mg/m²/d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m²/d. The radiation dose was 35 Gy in 15 fractions over 3 weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life.

Results

Seventy-five patients were enroled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p = 0.01) and R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively (p = 0.37). The median OS was 29 months for CT compared with 32 months for CRT (p = 0.83).

Conclusions

Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus.