Hirnmetastasen des Melanoms

Context

Brain metastases occur in the majority of patients with metastatic melanoma and are the most common cause of death. Until recently, local therapy (neurosurgery, radiosurgery and whole brain radiotherapy) was the only option for a chance of disease control in the brain. Systemic treatment options are now available.

Objective

The aim of this study is to discuss the treatment options for brain metastases from melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma and recent publications (Pubmed and manual search).

Results

In limited brain metastases, neurosurgery and radiosurgery are established treatments that can prolong survival. Immunotherapy with ipilimumab appears to have activity in patients with brain metastases, particularly when metastases are small and asymptomatic (response rate 16?% and median overall survival 7 months). The BRAF inhibitor dabrafenib achieved response rates of 30–40?% and a median overall survival of 7–8 months in patients with asymptomatic BRAF mutation brain metastases. The intracranial disease control rate was 80–90?%. In patients with symptomatic BRAF mutation brain metastases, the BRAF inhibitor vemurafenib showed activity with a disease control rate of >?80?% and a median overall survival of 5 months. In symptomatic multiple brain metastases, palliative whole brain radiotherapy is an established treatment even though it has failed to show an overall survival benefit. Corticosteroids and antiepileptic drugs are indicated for patients presenting with intracranial hypertension and epileptic seizures. Treatment of patients with metastatic melanoma and brain metastases should be discussed in a multidisciplinary team.

Conclusion

The therapeutic options for patients with brain metastases from melanoma have improved in recent years. Presently, there are several effective local and systemic treatments available.     

The novel chemokine receptor CXCR7 regulates trans-endothelial migration of cancer cells

Background

The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAF^V600E expressing WM793 melanoma cells to derive data aimed at investigating the molecular determinant of cell invasion following treatment with clinical BRAF inhibitors.

Findings

Small-molecule inhibitors targeting BRAF reduced MEK1/2-ERK1/2 pathway activation and cell survival; yet, viable cell subpopulations persisted. The residual cells exhibited an elongated cell shape, prominent actin stress fibers and retained the ability to invade 3-D dermal-like microenvironments. BRAF inhibitor treatments were associated with reduced expression of RND3, an antagonist of RHOA activation, and elevated RHOA-dependent signaling. Restoration of RND3 expression or RHOA knockdown attenuated the migratory ability of residual cells without affecting overall cell survival. The invasive ability of BRAF inhibitor treated cells embedded in collagen gels was diminished following RND3 re-expression or RHOA depletion. Conversely, melanoma cell movement in the absence of BRAF inhibition was unaffected by RND3 expression or RHOA depletion.

Conclusion

These data reveal a novel switch in the requirement for RND3 and RHOA in coordinating the movement of residual WM793 cells that are initially refractive to BRAF inhibitor therapy. These results have important clinical implications because they suggest that combining BRAF inhibitors with therapies that target the invasion of drug-resistant cells could aid in controlling disease relapse.     

Medikamentöse Systemtherapie des Melanoms

Context

Around 3000 melanoma patients are diagnosed with metastatic disease each year in Germany. For more than three decades no substantial therapeutic progress in the treatment of advanced melanoma was made; however, the use of targeted agents and immune modulating antibodies has changed the perception of melanoma as treatment-resistant tumor.

Objective

The aim of this article is to discuss the systemic treatment options for advanced metastatic melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma published in 2013 and other recent publications (PubMed and manual search).

Results

The CTLA-4 blocking antibody, ipilimumab, was the first medication to demonstrate an overall survival benefit in a prospective randomized clinical study of metastatic melanoma. Subsequently selective BRAF as well as MEK inhibitors were also shown to prolong overall survival leading to drug registration. Currently additional agents and antibodies, such as MEK inhibitors for NRAS mutations in melanoma and PD1 blocking antibodies are being tested in clinical phase III studies. Over the next years the combination and sequence of these new agents will further improve the treatment and prognosis of advanced melanoma. Treatment of metastatic melanoma always requires a multidisciplinary approach.

Conclusion

Therapy options for patients suffering from advanced metastatic melanoma have improved in recent years. Nevertheless, clinical studies still remain the best option to improve melanoma treatment and to offer patients innovative and promising treatment options despite the recently achieved progress.     

Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations

Background:

The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ∼48%. Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases. As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.

Methods:

A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing. Equivocal results were confirmed by capillary sequencing. Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2–13 per patient).

Results:

BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively. In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient. Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.

Conclusion:

As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible. The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated.     

Correlation of BRAF and NRAS mutation status with outcome,site of distant metastasis and response to chemotherapy in metastatic melanoma

Background:

The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.

Methods:

Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.

Results:

In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF^V600K/R versus BRAF^V600E melanoma in univariate and multivariate analyses.

Conclusions:

BRAF and NRAS mutation status does not influence survival in metastatic melanoma.     

Serum concentrations of pegylated interferon α-2b in patients with resected stage III melanoma receiving adjuvant pegylated interferon α-2b in a randomized phase III trial (EORTC 18991)

Purpose

The EORTC 18991 trial assessed the effect of long-term adjuvant pegylated interferon (Peg-IFN) α-2b administered weekly in patients with lymph node-positive melanoma. Serum concentrations were analyzed to determine exposure to Peg-IFN α-2b.

Methods

After surgery, patients were randomized to receive Peg-IFN α-2b or to observation only. The treatment group received 6 μg/kg/week Peg-IFN α-2b subcutaneously for 8 weeks, followed by a maintenance dose of 3 μg/kg/week for up to 5 years. Blood samples were collected between months 3 and 60.

Results

A total of 208 Peg-IFN α-2b concentrations from 48 patients were available. Serum trough concentrations increased in a dose-related manner. Mean dose-normalized serum concentrations and intersubject variability over the 5-year study period in patients with melanoma were similar to those observed in patients with chronic hepatitis.

Conclusion

Data suggest that the exposure to Peg-IFN α-2b was sustained during long-term adjuvant treatment with Peg-IFN α-2b in patients with melanoma, consistent with the EORTC 18991 trial’s conclusion of a significant, sustained, and relapse-free survival benefit.     

Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies

Purpose of Review

Uveal melanoma is a distinct subset of melanoma with a biology and treatment approach that is unique from that of cutaneous melanoma. Here we will review the current data evaluating immunotherapies in both the adjuvant and metastatic settings in uveal melanoma.

Recent Findings

In the adjuvant setting, interferon demonstrated no survival benefit in uveal melanoma, and studies evaluating immune-based strategies such as vaccine therapy are ongoing. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in uveal melanoma have been evaluated in several small prospective and/or retrospective studies with rare responses and no overall survival benefit demonstrated. Ongoing studies evaluating combination checkpoint inhibition and other antibody-based therapies are ongoing.

Summary

Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited. Clinical trial participation should be prioritized in patients with uveal melanoma.

     

Management of Anorectal Melanoma: Report of 17 Cases and Literature Review

Background

Primary anorectal melanoma is a rare and aggressive disease. It accounts for 0.5% of all rectal tumors. They are very agressive tumors with poor prognosis. The aim of this study is to report the clinical and evolutionary profile and therapeutical approach of these tumors.

Patients and Methods

A retrospective study of 17 patients with anorectal melanoma diagnosed between January 1998 and December 2007 was performed. The signs and symptoms, diagnostic study, and surgical and medical treatments were analyzed.

Results

The average age was 58?years. Sex ratio was 12 men per five women. Patients had symptoms present for an average of 6?months. The most common symptom was rectal bleeding. According to Slingluff classification, five patients had stage I (localized tumor), four cases had stage II (regional nodes metastasis), and eight cases had stage III (distant metastasis). Seven patients have radical surgery. Only two patients received adjuvant immunotherapy. Eight patients received palliative chemotherapy based on dacarbazine or cisplatinum. The median survival was 8?months.

Conclusion

Prognosis of anorectal melanoma is still very poor. However, some patients when treated by radical resection may experience long-term survival. The use of adjuvant immunotherapy needs large collaborative studies in view of the rarity of the tumor.     

Primary amelanotic melanoma of the breast: combating a rare cancer

Background

Malignant melanoma is the foremost cause of metastasis to the breast from extramammary solid neoplasm. However primary melanoma of the breast is a distinct rarity. Primary melanoma involves the skin and less commonly the glandular parenchyma of the breast.

Method

We herein describe a case of primary amelanotic melanoma of the breast parenchyma in a 32-year-old female managed with a combination of surgery, adjuvant radiotherapy and immunotherapy.

Conclusion

This case report aims to increase awareness of unusual neoplasms of the breast which might require a different surgical and adjuvant therapeutic approach.     

Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy

Background:

Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required.

Methods:

The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture.

Results:

BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance.

Conclusion:

Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.     

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

Background

Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs.

Methods

SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patient’s tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively. SCD1, YAP/TAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence.

Results

We first observed that SCD1 expression increases during melanoma progression. BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors. We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors.

Conclusions

Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.

     

TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival

 

After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation.

Design

The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrolment.

Discussion

The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers.     

Phase II study of adjuvant vinorelbine and cisplatin in Japanese patients with completely resected stage II and III non-small cell lung cancer

Purpose

Adjuvant vinorelbine and cisplatin chemotherapy is recognized as a standard regimen for patients with completely resected stage II and III non-small cell lung cancer (NSCLC). However, efficacy of adjuvant chemotherapy in Japanese phase III trials with cisplatin-containing regimen has been controversial, and data are limited on the long-term outcome of adjuvant vinorelbine and cisplatin chemotherapy for NSCLC patients.

Methods

This was a single-arm phase II study in patients with completely resected pathological stage II or III NSCLC, who had not received prior chemotherapy or radiotherapy. Patients received 4 cycles of vinorelbine [25 mg/m² of body surface area (BSA)] and cisplatin (40 mg/m² of BSA) on days 1 and 8, every 4 weeks. Primary end point was the 3-year relapse-free survival; secondary end points were overall survival and safety.

Results

Between December 2006 and January 2011, 60 patients (40 men and 20 women, median age 64 years) were enrolled; all patients were evaluable for survival and safety. Three-year relapse-free survival rate was 55.0 % (95 % confidence interval 42.4–67.6 %). Three- and five-year overall survival rates were 83.3 and 77.8 %, respectively. There were no chemotherapy-related deaths, and adverse effects were acceptable.

Conclusions

Adjuvant vinorelbine and cisplatin chemotherapy was safe and showed a valid relapse-free survival rate. This regimen could be used as a standard regimen and deserves to be a control arm of trials on adjuvant chemotherapy in the Japanese NSCLC patient population.     

Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups

Background

The current standard treatment, at least in Europe, for patients with primarily resectable tumors, consists of surgery followed by adjuvant chemotherapy. But even in this prognostic favourable group, long term survival is disappointing because of high local and distant failure rates. Postoperative chemoradiation has shown improved local control and overalls survival compared to surgery alone but the value of additional radiation has been questioned in case of adjuvant chemotherapy. However, there remains a strong rationale for the addition of radiation therapy considering the high rates of microscopically incomplete resections after surgery. As postoperative administration of radiation therapy has some general disadvantages, neoadjuvant and intraoperative approaches theoretically offer benefits in terms of dose escalation, reduction of toxicity and patients comfort especially if hypofractionated regimens with highly conformal techniques like intensity-modulated radiation therapy are considered.

Methods/Design

The NEOPANC trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant short course intensity-modulated radiation therapy (5 × 5 Gy) in combination with surgery and intraoperative radiation therapy (15 Gy), followed by adjuvant chemotherapy according to the german treatment guidelines, in patients with primarily resectable pancreatic cancer. The aim of accrual is 46 patients.

Discussion

The primary objectives of the NEOPANC trial are to evaluate the general feasibility of this approach and the local recurrence rate after one year. Secondary endpoints are progression-free survival, overall survival, acute and late toxicity, postoperative morbidity and mortality and quality of life.

Trial registration

NCT01372735.     

Soft tissue sarcomas and therapeutic management: is there a place for systemic chemotherapy in an adjuvant setting?

Introduction

Extremity soft tissue sarcomas (STS) represent a rare, heterogeneous malignancy. Surgery is the primary treatment for patients with no evidence of metastatic disease but 50% of patients with high-risk tumors will relapse and develop metastatic disease. Adjuvant chemotherapy aims to lessen the recurrence of cancer after surgery with or without radiotherapy. The objective of this review was to assess the effect of adjuvant chemotherapy in adults with resectable soft tissue sarcoma after such local treatment.

Materials and methods

Pub Med searches were done to identify all randomized controlled phase III trials (RCTs) published, and presented in various international conferences, comparing surgery plus adjuvant systemic chemotherapy to surgery alone (S) for resectable soft tissue sarcoma. The following keywords: adjuvant therapy, chemotherapy, soft tissue sarcoma were used to access the principal phase III study and meta-analysis based on individual and published data.

Results

Three randomized phase III trials and three meta-analyses were identified, comparing adjuvant chemotherapy to observation after curative resection. The majority of studies indicate some benefit with chemotherapy, particularly in the relapse-free survival rate, but no survival benefit was observed in the chemotherapy group relative to the control group. Quality of initial surgery is the most important prognostic and predictive factor for Relapse Free Survival (RFS) and Overall Survival (OS).

Conclusion

Compared to surgery alone, the role and value of adjuvant chemotherapy have not yet been established and cannot be recommended outside the context of a clinical trial.     

Optimal Use of BRAF Targeting Therapy in the Immunotherapy Era

Purpose of Review

The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma.

Recent Findings

Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted. Simultaneously, developments in immunotherapy have suggested long-lasting survival for some patients.

Summary

In advanced BRAF-mutated melanoma, both BRAF/MEK inhibition and immunotherapy agents show improved overall survival and, in a small population of patients, prolonged and long-term benefit as compared to standard chemotherapy. Trials are currently underway evaluating sequencing of these therapies and the safety of targeted therapy plus immunotherapy combinations.

     

Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring

Introduction

In adjuvant treatment for breast cancer there is no tool available with which to measure the efficacy of the therapy. In contrast, in neoadjuvant therapy reduction in tumour size is used as an indicator of the sensitivity of tumour cells to the agents applied. If circulating epithelial (tumour) cells can be shown to react to therapy in the same way as the primary tumour, then this response may be exploited to monitor the effect of therapy in the adjuvant setting.

Method

We used MAINTRAC^® analysis to monitor the reduction in circulating epithelial cells during the first three to four cycles of neoadjuvant therapy in 30 breast cancer patients.

Results

MAINTRAC^® analysis revealed a patient-specific response. Comparison of this response with the decline in size of the primary tumour showed that the reduction in number of circulating epithelial cells accurately predicted final tumour reduction at surgery if the entire neoadjuvant regimen consisted of chemotherapy. However, the response of the circulating tumour cells was unable to predict the response to additional antibody therapy.

Conclusion

The response of circulating epithelial cells faithfully reflects the response of the whole tumour to adjuvant therapy, indicating that these cells may be considered part of the tumour and can be used for therapy monitoring.     

Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy

Background

We have previously reported the superior feasibility and safety of adjuvant S-1 plus docetaxel in patients with stage III gastric cancer during a prospective phase II study. We report 3-year follow-up data on patients enrolled in this study.

Patients and methods

Fifty-three patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled into this study. They received oral S-1 (80 mg/m²/day) for 2 consecutive weeks and intravenous docetaxel (40 mg/m²) on day 1, repeated every 3 weeks (one cycle). Treatment was initiated within 45 days after surgery and repeated for four cycles, followed by S-1 monotherapy (4 weeks on, 2 weeks off) until 1 year after surgery. Three-year overall survival (OS) and disease-free survival (DFS) were evaluated.

Results

The OS rate at 3 years was 78.4 % [95 % confidence interval (CI), 67.9–90.6 %] and the DFS rate at 3 years was 66.2 % (95 % CI, 54.4–80.7 %). Subgroup analyses according to disease stage showed a 3-year OS and DFS rate of 85.7 % (95 % CI, 74.9–98.1 %) and 70.8 % (95 % CI, 57.1–87.8 %) for stage IIIA, and 62.5 % (95 % CI, 42.8–91.4 %) and 56.2 % (95 % CI, 36.5–86.7 %) for stage IIIB, respectively.

Conclusions

On the basis of 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel yielded promising OS and DFS in stage IIIA gastric cancer patients who had undergone D2 gastrectomy. We believe that this regimen is a candidate for future phase III trials studying the optimal adjuvant chemotherapy regimen for stage III gastric cancer.     

Time to Adjuvant Therapy and Other Variables in Localized Gastric and Gastroesophageal Junction (GEJ) Cancer (IJGC-D-13-00162)

Background

Adjuvant chemotherapy with or without radiation in patients with completely resected gastric and gastroesophageal (GE) junction cancer has been associated with better outcomes. In practice, however, there are often delays in commencing adjuvant therapy. The study aims to determine the prognostic importance of timing of adjuvant therapy in such patients.

Methods

A cohort of patients with early stage (IB–IVM0) gastric and GE junction cancer diagnosed between 2002 and 2007 in the province of Saskatchewan was assessed. Cox proportional hazard analysis was used to identify various clinic-pathological factors that correlate with disease-free survival (DFS).

Results

One hundred seventy-four eligible patients with a median age of 71 years (range 36–93) and M/F ratio of 113:61 were identified. Of 174 patients, 60 (35 %) received adjuvant therapy. Median follow-up was 18 months (interquartile range 9–37). Twenty-eight percent received adjuvant therapy within 56 days. Median DFS of patients who received adjuvant therapy within 56 days was 37 months (95 % CI 6.6–67.3) versus 33 months (95 % CI 18.3–47.7) if adjuvant therapy was administered beyond 56 days (p?=?0.67). On multivariate analysis, state III–IVM0 disease, hazard ratio (HR) 2.4 (95%CI 1.6–3.5), and age ≥65 years, HR 2.2 (95 % CI 1.4–3.5), were significantly correlated with inferior disease-free survival.

Conclusions

Only about one third of patients who received adjuvant therapy were treated within 56 days of surgery. Although stages III and IVM0 and older age were associated with inferior outcome, delay in adjuvant therapy was not associated with inferior survival.     

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients

Aim

Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy.

Patients and methods

251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5′untranslated region of the TS gene were genotyped.

Results

There was a positive association between tumor T stage and the VNTR genotypes (p?=?0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes.

Conclusion

We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.