Do patients with metastatic urothelial carcinoma benefit from docetaxel as second-line chemotherapy?

Purpose

To evaluate the efficacy and toxicity of docetaxel regimen as second-line after failure of a platinum-based chemotherapy.

Methods

Between May 2005 and June 2008, we retrospectively analyzed the data of 22 patients who had evidence of disease progression after one prior platinum-based regimen for metastatic urothelial carcinoma. Patients were treated with two different docetaxel dose schedules: (1) docetaxel 60 mg/m² every 21 days for unfit patients or (2) docetaxel 75 mg/m² every 21 days for fit patients.

Results

Median number of docetaxel cycles was three. Overall disease control rate was 18 %. Of the 22 patients, no patient achieved complete or partial response and four patients had stable disease. Median progression-free survival was 1.67 months and median overall survival was 3.12 months. Neutropenia was the most common adverse event.

Conclusions

This study identifies that docetaxel as second-line chemotherapy has low activity and was associated with significant toxicity.

     

Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data

Background

After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far.

Methods

We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings.

Results

A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months).

Conclusions

The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

     

Medikamentöse Therapie des metastasierten oder rezidivierten mutationsnegativen NSCLC

Background

The introduction of immune checkpoint inhibitors (ICI) has led to rapid changes in the treatment of metastatic non-small cell lung cancer (NSCLC) without treatable driver mutations over the last few years.

Objective

A brief historical outline of treatment before and a summary of changes after the arrival of ICI is given.

Material and methods

A selective Pubmed search was performed employing the keywords NSCLC stage IV, checkpoint inhibitors and chemotherapy.

Conclusion

The ICIs were initially introduced as second line treatment of metastatic NSCLC as several large phase III trials were able to show a clinically significant improvement compared to the standard docetaxel treatment. Meanwhile, pembrolizumab is the standard first-line treatment of NSCLC with high PD-L1 expression (TPS?>?50%). Recently, several phase III trials could show superior efficacy of the combination of an ICI with standard platinum-based doublet chemotherapy compared to chemotherapy alone. Some of the investigated combinations have already been approved for nonsquamous NSCLC and further approvals can be expected. Since the introduction of ICI long-term survival of 3 or more years has been achieved in some patients with metastatic NSCLC.

     

Efficacy and cost-effectiveness of second-line chemotherapy in elderly patients with advanced gastric cancer

Purpose

Second-line chemotherapy has been shown to benefit patients with advanced gastric cancer (AGC), extending the overall survival (OS) and progression-free survival (PFS). This study aimed to assess the efficacy and cost-effectiveness of second-line treatment for elderly patients with AGC.

Methods

Medical records and follow-up information of elderly patients (≥70 years) with AGC who received second-line chemotherapy were collected. A Markov model comprising three health states PFS, progressive disease and death was developed to simulate the process of AGC. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables.

Results

Forty-three elderly patients with AGC receiving second-line chemotherapy were included in our study. The median OS was 6.0 months (95% confidence interval (CI) 3.90–8.10) and PFS was 3.1 months (95% CI 1.38–4.82). No treatment-related death occurred. The most frequently drug-related grade 3/4 AEs were diarrhea (2.3%), leukopenia (16.3%) and nausea (7.0%). The incremental cost-effective ratio was $18,223.75/QALY for second-line chemotherapy versus BSC, which was below the threshold of 3× the per capita GDP of China, $23,970.00.

Conclusion

Second-line chemotherapy was an optimal strategy for elderly AGC patients in China from the efficacy and cost-effectiveness perspective.

     

Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review

Background

There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting.

Methods

A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review.

Results

Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies.

Conclusion

The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.

     

A retrospective analysis of 5-fluorouracil plus cisplatin as first-line chemotherapy in the recent treatment strategy for patients with metastatic or recurrent esophageal squamous cell carcinoma

Background

Patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) have a poor prognosis. For decades, the most widely used first-line chemotherapy regimen for these patients has been the combination of 5-fluorouracil + cisplatin (CF). However, prognostic factors of CF as first-line chemotherapy for ESCC have not been clarified.

Methods

A total of 187 patients with metastatic or recurrent esophageal ESCC treated with CF at the National Cancer Center Hospital between January 2001 and December 2012 were enrolled in the study. The CF regimen comprised cisplatin (80 mg/m²) administered on day 1 and 5-fluorouracil (800 mg/m²) administered continuously on days 1–5, every 4 weeks. Multivariate Cox regression analysis was used to determine the potential prognostic factors.

Results

The median age of the patients was 62 (range 34–84) years. Metastasis and recurrence occurred in 116 and 71 of these patients, respectively. The overall response rate was 37.2%, with median progression-free and overall survival times of 4.8 and 10.4 months, respectively. In the multivariate analysis, higher serum C-reactive protein level and lower serum albumin level at the time of CF treatment initiation and number of metastatic sites were identified as independent prognostic factors for survival.

Conclusions

The results of this study corroborate previous findings on the efficacy of CF and will aid physicians in clinical decision-making and individual patient risk stratification, as well as in the further development of chemotherapy regimens.

     

Metastasis of breast cancer prior to invasion

Purpose

The landscape of HER2+ metastatic breast cancer (mBC) treatment is changing due to the availability of new anti-HER2 drugs. The purpose of this study was to assess the current treatment patterns and sequences used in HER2+ mBC in the real-world setting. Secondary objectives were to describe the factors that influence the decision to prescribe a first and second-line antitumour treatment.

Methods

Retrospective chart review of 3068 cases in Spain, Italy, the Netherlands and the UK.

Results

First and second-line treatments and regimens are consistent with the clinical guidelines, especially for recently initiated treatments. Age and performance status (PS) of patients impact treatment patterns: younger patients received more innovative treatments than elderly patients. In addition, while most patients received a first antitumor treatment, the rate of patients who continue to subsequent lines of therapy is low (55% transitioning from 1st to 2nd line; 58% from 2nd to 3rd line). Age and PS are key factors in the decision to prescribe further antitumor treatment.

Conclusion

Fewer HER2+ mBC patients than expected receive a second and third line therapy. Guidelines should make specific recommendations for older patients or those with a poor PS.

     

Efficacy of intrathecal chemotherapy in patients with central nervous system involvement of hematological malignancies: a retrospective analysis

Introduction

Central nervous system (CNS) involvement, especially involvement of the cerebrospinal fluid (CSF), is common in several haematological malignancies. Intrathecal (IT) chemotherapy can be used to manage CSF involvement.

Methods

Here we evaluated the effectiveness of IT chemotherapy among 80 patients with haematological malignancies and CSF localization who were treated with IT chemotherapy from 2001 to 2012.

Results

The majority of patients was diagnosed with diffuse large B-cell lymphoma (26%) or acute lymphoblastic leukaemia/lymphoblastic lymphoma (19%). After first-line IT chemotherapy, which mainly consisted of methotrexate (MTX) and corticosteroids, CSF complete response (CSF CR) was achieved in 76% of patients. 91% reached CSF CR when including second-line IT-chemotherapy. Clinical response was documented in 75%. Although most patients were additionally treated with systemic chemotherapy, response rate did not differ between patients treated with CNS-penetrating and CNS-non-penetrating drugs. CNS progression/relapse occurred in 40% of patients with median progression-free survival of 12.2 months. The median overall survival was 18.3 months; 55% of the patients died during follow-up.

Conclusions

Our analysis shows a high response rate after first-line IT chemotherapy, but also a relatively high progression/relapse percentage.

     

Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis

Background

The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results.

Objective

To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens.

Patients and Methods

Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n?=?401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n?=?71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n?=?101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle.

Results

Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9–13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6–39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5–14.3) and 30.6 months (95% CI 25.2–36.1) for cohort A, 9.7 (95% CI 9.1–10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8–13.2) and 37.9 months (95% CI 28.6–47.3) for cohort C, respectively.

Conclusions

Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

     

Kleinzelliges Lungenkarzinom

Background

Prognostic improvements for patients with small cell lung cancer (SCLC) have been achieved within the last decade especially due to the use of radiotherapeutic treatment options.

Methods

In this article, an overview of the approved and current therapeutic approaches for the treatment of SCLC is presented.

Results

Given the high potential for proliferation and metastatic spread in SCLC, systemic chemotherapy, preferably with a platinum/etoposide combination, is still the therapeutic basis. In limited stage disease this is performed, if possible, simultaneously with thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI). In extended stage disease (ED), TRT also has therapeutic value for those patients who respond to chemotherapy. PCI generally shows a reduction in the risk for cerebral metastases, but is with regard to the improvement of overall survival in ED controversial.

Conclusion

Chemotherapy together with radiooncology is of substantial relevance for survival of SCLC patients.

     

Periphere Neurotoxizität

Background

Peripheral nerve dysfunction is a common and frequently dose-limiting side effect in the course of tumor treatment with neurotoxic drugs. The severity of chemotherapy-induced peripheral neuropathy (CIPN) is related to the cumulative dose and dose intensity of the causative agent. Neither medical prophylaxis nor specific treatment of CIPN is available.

Objective

This article describes the incidence and clinical presentation of CIPN and discusses evidence-based dosage modification of chemotherapy regimens using agents associated with a high neurotoxic risk.

Material and methods

A systematic literature search in PubMed and Medline was performed to review relevant articles published up to October 2014.

Results

Quantitative and qualitative evaluation of CIPN requires a combined assessment of clinical parameters and patient-reported outcome measures by means of validated scales. Following discontinuation of platinum-based chemotherapy, CIPN can progress for up to 6 months (coasting). Advanced stages of thalidomide-induced CIPN are fully reversible in only 25?% of patients. Adherence to a specific dosage modification strategy validated in a phase III trial improves the outcome of bortezomib-associated peripheral neuropathy without adversely affecting the efficacy of antineoplastic therapy.

Conclusion

Currently, prevention of advanced CIPN by early dosage adjustment at the onset of neurotoxic signs is the only effective approach in the management of CIPN.

     

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial

Backgrounds

In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294).

Methods

HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m² bid for 14 days plus cisplatin 80 mg/m² on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety.

Results

Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6–5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0–17.7) and ORR was 8/30 (26.7%) (95% CI 14.2–44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%).

Conclusions

XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1.

Trial registration

NCT01412294.

     

Second-Line Therapy for Advanced Colorectal Cancer: EGFR vs. Continuation of VEGF Inhibition

Purpose of Review

We review second-line biological therapies for metastatic colorectal cancer (mCRC), including their mechanisms of action, adverse events, survival outcomes, optimal chemotherapy combinations, and sequencing of agents.

Recent Findings

The advent of biological therapeutics targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways has enhanced the benefits afforded by the plethora of chemotherapeutic agents for patients with mCRC over the past 10 years, nearly tripling the median OS. Individual biomarkers predicting prognosis and response to VEGF vs. EGFR therapy have been identified. For patients who progress on first-line VEGF therapy, evidence suggests that continued VEGF inhibition may be as efficacious as changing to EGFR therapy with less adverse effects. However, for patients who progress after first-line EGFR therapy, early studies suggest changing to agents targeting the VEGF pathway.

Summary

Biological options for patients with mCRC who progressed on first-line concomitant chemotherapy and biologic therapy depend on individual tumor characteristics and choice of first-line therapy. Future research should focus on prognostic and predictive biomarkers to better inform choice of first-line and sequential therapy beyond progression.

     

Capecitabine and oxaliplatin in combination as first- or second-line therapy for metastatic breast cancer: a Wisconsin Oncology Network trial

Purpose

Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first- or second-line setting.

Methods

Patients received oxaliplatin 85 mg/m² on days 1 and 15, and capecitabine 1,500 mg/m² twice daily on days 1–7 and 15–21 of a 28-day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks.

Results

Ten patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95 % lower confidence bound [LCB]: 5.75 months), median progression-free survival (PFS) was 14.2 months (95 % LCB: 6.14 months), and median overall survival (OS) was 19 months (95 % LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea.

Conclusions

XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.

     

Emerging Therapies in Metastatic Prostate Cancer

Purpose of Review

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy.

Recent Findings

Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals.

Summary

Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

     

Gemcitabine in the management of metastatic breast cancer: a systematic review

Background

A systematic review of the evidence for gemcitabine chemotherapy, alone or in combination, in women with metastatic/advanced breast cancer was undertaken in order to determine gemcitabine’s role in the first-line and/or second-line or greater setting.

Methods

MEDLINE, EMBASE, the American Society of Clinical Oncologists, San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched through September 2006 for randomized controlled trials and non-randomized phase two trials.

Results

Eighty-three trials were identified, including four randomized phase III trials. All of the phase III trials included first-line patients. Two of the phase III trails demonstrated clinical benefit with gemcitabine-based chemotherapy in terms of superior efficacy or less toxicity while two phase III trials found no clinical benefit based on less efficacy or increased toxicity. Although 78 phase II trials of gemcitabine alone or in combination with other chemotherapy agents were identified, few combinations showed results compelling enough to warrant randomized trials.

Conclusion

Available data do not support the acceptance of gemcitabine as a standard therapeutic option in women with metastatic breast cancer in the third-line or greater setting, nor should it be considered as first-line therapy in anthracycline naïve women. Gemcitabine appears to be most effective when administered with a taxane (docetaxel/paclitaxel) in the first- or second-line setting, with gemcitabine/taxane combinations representing a viable alternative to currently accepted taxane combinations such as capecitabine/docetaxel. There is no evidence at this time to support the use of gemcitabine triplets, given the equal efficacy to anthracycline triplets and the added toxicity.

     

MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression

Background

The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate.

Patients and methods

We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression.

Results

We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis.

Conclusion

The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

     

A Bayesian network meta-analysis on second-line systemic therapy in advanced gastric cancer

Background

It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits.

Methods

We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously.

Results

Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30–0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68–0.96), docetaxel (OS HR 0.56, 95 % CR 0.33–0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52–0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care.

Conclusions

This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials.

     

What Is the Best Systemic Therapy for Left-sided <Emphasis Type="Italic">RAS</Emphasis> Wild-type Metastatic Colorectal Cancer?

Purpose of Review

There is a significant difference in embryological origin, gene expression, gene mutation profile, and microbiome between the right-sided and left-sided colon. It has been shown that the sidedness of primary colorectal cancer is a significant prognostic factor and predictive to the clinical benefit of anti-epidermal growth factor receptor (EGFR) antibody-containing chemotherapy in patients with metastatic CRC. Herein, current clinical recommendations for the treatment of patients with left-sided RAS wild-type mCRC are reviewed.

Recent Findings

Retrospective analyses of prior randomized trials (CRYSTAL, PRIME, FIRE-3, CALGB 80405, and PEAK trials) showed that primary tumor sidedness is predictive to anti-EGFR antibody therapy in the first-line treatment of patients with RAS wild-type mCRC, and patients with left-sided RAS wild-type mCRC had a significantly better survival benefit with anti-EGFR antibody plus chemotherapy when compared with anti-VEGF treatment plus chemotherapy.

Summary

The primary tumor sidedness is a significant prognostic factor and predictive to anti-EGFR antibody-containing chemotherapy in patients with metastatic CRC. Based on the currently available data, chemotherapy plus anti-EGFR antibody is recommended for the first-line treatment of patients with left-sided RAS wild-type mCRC. Chemotherapy plus bevacizumab or anti-EGFR antibody is recommended for the second-line therapy of RAS wild-type mCRC regardless of sidedness. However, these recommendations are based on the limited data from the retrospective analyses of prior trials, warranting further prospective randomized trials.

     

The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Background

Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations.

Methods

A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study. Human tissue taken at surgical biopsy under general anaesthetic was divided between two arms of the trial. Subsections of the tumour were used for WES and the remainder was implanted subcutaneously in immunodeficient mice (PDX). Results of WES were analysed using a bioinformatics pipeline to identify mutations conferring susceptibility to kinase inhibitors and common chemotherapeutic agents. PDX models exhibiting successful growth underwent WES of the tumour and subsequent chemosensitivity testing.

Results

WES was successful in all 12 patients, with successful establishment PDX tumours models in seven patients. WES identified potential actionable therapeutics in all patients. Significant variation in predicted therapeutics was demonstrated between three PDX samples and their matched tumour samples.

Conclusion

Analysis of WES of fresh tumour specimens via a bioinformatics pipeline may identify potential actionable chemotherapy agents. Further research into this field may lead to the development of personalized cancer therapy for sarcoma.