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.     

The efficacy of long-term oral chemotherapy with 5′-deoxy-5-fluorouridine and cyclophosphamide for recurrent breast cancer

Background 5-Deoxy-5-fluorouridine (5-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity, specifically in tumor cells. The purpose of the present study was to examine the efficacy of long-term administration of 5-DFUR/CPA for patients with recurrent breast cancer.Methods Fifteen breast cancer patients with recurrent tumors entered this study. Ten patients had bone metastasis, five had lung metastasis, and two had liver metastasis. Three patients had multiorgan metastases. All patients had had previous exposure to standard chemotherapy such as CAF (CPA, doxorubicin, and 5-FU) and CMF (CPA, methotrexate, and 5-FU). The patients were orally administered with daily doses of 5-DFUR at 800–1200mg and CPA at 200mg for 2 weeks as induction therapy, followed by 2 weeks rest (one to two cycles). Daily doses of 800mg of 5-DFUR and 100mg of CPA (as maintenance therapy) were continuously administered thereafter. Ten of the 15 patients received the maintenance therapy alone. The treatment was continued for at least 24 months (average, 35.2 months).Results The main findings included a significant decrease in pain in nine patients with bone metastasis, and this effect continued for more than 2 years. As the pain decreased, the patients quality of life (QOL) was improved. Liver metastasis was diminished in two out of two patients. Hematological toxicity of more than grade 3 was recognized in three patients, but only during the induction therapy.Conclusion Oral administration of 5-DFUR/CPA is well tolerated and useful for patients with recurrent breast cancer.     

Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis

BackgroundMicrosatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial.Materials and methodsStudies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI).ResultsA MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not.For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62–1.49); HR OS (6 studies): 0.70 (95% CI: 0.44–1.09; p = 0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67–0.87)).ConclusionWe found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.     

Obesity and colon cancer: Does leptin provide a link?

Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte-derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case-control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C-peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3-fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44-5.12) for top vs. bottom quartile (p(trend) = 0.008). The corresponding OR for C-peptide was 1.81 (95% CI = 0.67-4.86; p(trend) = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C-peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity-induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found.     

Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials

BackgroundThe results of the recently published large European randomised study in rectal cancer (European Organisation for Research and Treatment of Cancer 22921 trial) do not support current guidelines recommending postoperative chemotherapy for patients who have previously undergone preoperative radiochemotherapy or radiotherapy [radio(chemo)therapy]. To evaluate this discrepancy further, a systematic review of relevant randomised trials was undertaken.Materials and methodsA systematic literature search was carried out in order to identify randomised studies exploring adjuvant chemotherapy against observation in patients with rectal cancer previously treated with preoperative radio(chemo)therapy.ResultsA statistically significant benefit of adjuvant chemotherapy was not found in any of the four relevant randomised trials. Non-protocolised subgroup analysis of one study indicated a beneficial effect of adjuvant chemotherapy for high rectal tumours and for patients downstaged to ypT0-2N0 but no effect for low-lying rectal tumours. However, the body of evidence indicates that patients downstaged after radio(chemo)therapy to ypT0-2N0 disease are not candidates for testing adjuvant chemotherapy in future trials due to the considerable over-treatment anticipated by this manoeuvre.ConclusionsTo resolve the issue in question, a meta-analysis of relevant studies is required, and new trials should be launched to explore new drug combinations against observation. Currently, delivery of adjuvant chemotherapy in patients undergoing preoperative radio(chemo)therapy is not evidence based.     

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 postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer?

PURPOSE: This study analyzes the long-term outcome of patients with stage T4 colon cancer who receive postoperative irradiation. The purpose of the study is to define the potential role of this modality with current systemic therapies. PATIENTS AND METHODS: A retrospective analysis was performed of 152 patients undergoing resection of T4 colon cancer followed by moderate- to high-dose postoperative tumor bed irradiation with and without 5-fluorouracil-based chemotherapy. Of the 152 patients, 110 patients (T4N0 or T4N+) were treated adjuvantly, whereas 42 patients received irradiation for the control of gross or microscopic residual local tumor. RESULTS: For 79 adjuvantly treated patients with stage T4N0 or T4N+ cancer with one lymph node metastasis, the 10-year actuarial rates of local control and recurrence-free survival were 88% and 58%, respectively. Results were less satisfactory for patients with more extensive nodal involvement. The 10-year actuarial rates of local control and recurrence-free survival of 39 patients with T4 tumors complicated by perforation or fistulas were 81% and 53%, respectively. For 42 patients with incompletely resected tumors, the 10-year actuarial recurrence-free survival was 19%. CONCLUSIONS: In comparison with historical controls, postoperative tumor bed irradiation improves local control for some subsets of patients. In addition to standard 5-fluorouracil-based chemotherapy, adjuvant tumor bed irradiation should be considered when colon cancers invade adjoining structures, when they are complicated by perforation or fistulas, or when they are incompletely excised at the primary site.     

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.     

Does long-term treatment with Doxil® predispose patients to oral cancer?

We present a possible adverse reaction related to long-term use of Doxil^® in female patients. We believe that long-term use of Doxil^® may predispose female patients to oral squamous cell carcinoma. The patients in this report were not exposed to the common risk factors related to oral cancer formation such as smoking or alcohol consumption. Both patients were 59-year-old females. The first patient was diagnosed in 2001 with stage IIIC ovarian cancer. Seven years following treatment with Doxil^®, she was diagnosed with stage III squamous cell carcinoma of the right maxilla. The second patient was diagnosed with Kaposi’s sarcoma with evidence of spread to the lungs. Four years following treatment with Doxil^® she was diagnosed with stage I squamous cell carcinoma of the left maxilla. A literature review did not reveal any report on Doxil^® and predisposition to oral cancer; however, we found an abstract that was presented at the last annual meeting of the American Society of Clinical Oncology (ASCO) by Cannon et al. When we combine the data from Cannon et al. and the data presented here, a total of six female patients developed an epithelial carcinoma of the oral cavity following long-term treatment with Doxil^®. We believe that a large-scale study should be initiated on patients that were treated with Doxil^® for more than 3 years, since these patients might be at risk for developing secondary cancer of the oral cavity.     

Does postoperative chemotherapy have a survival benefit for patients with pancreatic cancer?

In our study, we investigated whether postoperative chemotherapy improved survival in patients with invasive ductal carcinoma of the pancreas. Between 1987 and 2004, 111 patients underwent pancreatic resection against invasive ductal carcinoma of the pancreas in Wakayama Medical University Hospital. Median survival time (MST) was 19.4 months, 8.6 months, and 7.2 months, in JPS Stage III (UICC Stage IIA and IIB), JPS Stage IVa (UICC Stage IIA and IIB), and JPS Stage IVb (UICC Stage IV), respectively (P < 0.01). The MST of the chemotherapy group was 12 months, and the MST of the non-chemotherapy group was 8.4 months (P < 0.05). Moreover, in JPS Stage IV (UICC Stage IIA, IIB, III, and IV) highly advanced pancreatic cancer, the MST of the chemotherapy group was 10.9 months, and the MST of the group without chemotherapy was 6.6 months (P < 0.01). Since pancreatic cancer is characterized by an aggressive tumor with a high recurrent rate, postoperative chemotherapy is effective for an improvement of survival.     

Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials

BACKGROUND: Several randomised trials have compared interferon-alpha with control as adjuvant therapy for high-risk malignant melanoma. The results of the individual trials have been either inconclusive or even apparently conflicting. To assess all the available evidence we performed a meta-analysis of these trials. METHODS: Standard methods for quantitative meta-analysis based on published data were used. Endpoints evaluated were recurrence-free survival and overall survival. A subgroup analysis by dose of interferon-alpha was performed. FINDINGS: Twelve trials, comprising 14 comparisons of interferon-alpha with control, with results available were identified. Recurrence-free survival was improved with interferon-alpha: hazard ratio 0.83, 95% confidence interval 0.77 to 0.90, p=0.000003. The benefit on overall survival was less clear (0.93, 0.85 to 1.02, p=0.1) and the confidence interval is compatible both with no benefit and with a moderate, but clinically worthwhile, benefit. There was some evidence of a dose response relationship with a significant trend for the benefit of interferon-alpha to increase with increasing dose for recurrence-free survival (test for trend: p=0.02) but not for overall survival (trend: p=0.8). INTERPRETATION: This meta-analysis provides the most reliable synthesis of the data currently available. Adjuvant interferon-alpha produces clear reductions in recurrence of high-risk melanoma, with some evidence of an effect of dose of interferon-alpha, but it is unclear whether this translates into a worthwhile survival benefit or not. Additional and more mature data are needed to resolve these issues and an individual patient data meta-analysis should be performed.     

Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

Introduction

Predictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A copy number can be used to predict benefit from epirubicin (E) containing chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil (CMF) treatment.

Methods

For the purpose of this study, formalin fixed paraffin embedded tumor tissue from women recruited into the BR9601 clinical trial, which randomized patients to E-CMF versus CMF, were analyzed for TIMP-1 immunoreactivity. Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1 immunoreactive and HER2 negative) and anthracycline responsive (all other cases).

Results

In total, 288 tumors were available for TIMP-1 analysis with (183/274) 66.8%, and (181/274) 66.0% being classed as 2T and HT responsive, respectively. TIMP-1 was neither associated with patient prognosis (relapse free survival or overall survival) nor with a differential effect of E-CMF and CMF. Also, TIMP-1 did not add to the predictive value of HER2, TOP2A gene aberrations, or to Ki67 immunoreactivity.

Conclusion

This study could not confirm the predictive value of TIMP-1 immunoreactivity in patients randomized to receive E-CMF versus CMF as adjuvant treatment for primary breast cancer.     

Does chemotherapy regimen matter in the neoadjuvant treatment of esophageal cancer?

BackgroundNeoadjuvant chemoradiotherapy has become the mainstay of treatment for locally advanced esophageal cancer. CALGB 9781 trial established cisplatin and 5-flourouracil (5-Fu) with radiotherapy as superior to surgery alone while the CROSS trial established paclitaxel, carboplatin, and radiotherapy as superior to surgery alone. Previous data has been unclear as to which regimen provides a superior pathologic response. This study aims to look at this. This study aims to look at this.MethodsA retrospective chart review at a single institution of patients who underwent esophagectomies after neoadjuvant chemoradiotherapy with either cisplatin and 5-Fu or carboplatin and paclitaxel between 2012–2020 was performed. Demographics as well as staging, response rates, and modified Ryan scores were collected. Univariate analysis between the two groups was performed.ResultsA total of 82 patients were identified between 2012–2020 who underwent esophagectomy after neoadjuvant chemoradiotherapy. In total, 74 (90.2%) received carboplatin and paclitaxel while 8 (9.8%) received 5-Fu and carboplatin. Both groups included patients with squamous cell carcinoma (SCC) and adenocarcinoma. No significant factors were found in terms of patient comorbidities or pathologic staging. There was no significant difference in modified Ryan score between the two groups (P=0.745).ConclusionsThis study evaluates the degree and presence of pathologic response between the two neoadjuvant chemoradiotherapy modalities used for esophageal cancer. Our results, in contrast to other studies, suggest no significant difference with regards to pathologic response rate. Furthermore, our findings suggest that use of the least toxic regimen would make sense.     

What is the Japanese consensus on adjuvant chemotherapy in breast cancer?

The international conference of adjuvant therapy for primary breast cancer in St. Gallen and the National Institute of Health Consensus Conference for Breast Cancer Treatment have recommended appropriate treatment for individual subgroups by recurrence risk. However, evidence provided by Japanese clinical trials did not contribute to the consensus recommendations. To compare the risk of recurrence in breast cancer patients between Japan and western countries, a database of Japanese breast cancer patients was analyzed. From 1991 to 2001, approximately 12100 articles listed on MEDLINE were reviewed by abstract, and articles were then selected and reviewed by the authors. According to the AHPC (Agency for Health Care Policy and Research), quality assessment and strength for recommendation of the evidence from clinical trials were classified. Even though there are likely some unknown ethnic differences, we should provide Japanese patients with state of the art treatment for breast cancer in accordance with global standard therapies, which have been evaluated by breast cancer specialists in western countries.