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.

     

Treatment of Refractory Colorectal Cancer: Regorafenib vs. TAS-102

Purpose of Review

This paper reviews the development, mechanism of action, clinical efficacy, and safety of regorafenib and TAS-102. Through this review, we aimed to help clinicians make an appropriate choice in patients who progressed after standard therapies.

Recent Findings

Regorafenib and TAS-102 have shown superior survival results compared with placebo in refractory metastatic colorectal cancer (mCRC). In the phase III CORRECT study, regorafenib showed significant improvement in overall survival (OS) and progression-free survival (PFS). TAS-102 was associated with OS and PFS benefit as well in the phase III RECOURSE study. However, the toxicity profiles were quite different between the two agents.

Summary

Regorafenib and TAS-102 are approved for the management of refractory mCRC. Optimal treatment sequence for using these two novel agents is not defined yet. Safety profiles and patient’s condition should be considered before using these two agents in clinical settings. Further investigation is needed to identify the predictive biomarkers of both agents. These results will allow patients to benefit more from regorafenib and TAS-102.

     

The Role of HER2 Testing in Advanced Colorectal Cancer

Purpose of Review

About 1/3 of all metastatic colorectal cancer (mCRC) patients may harbor a mutation in the KRAS or NRAS gene suggesting inefficacy of EGFR inhibitors cetuximab and panitumumab. In spite of tailoring treatment in RAS wild-type patients to receive EGFR inhibitors, not all show response.

Recent Findings

Studies have shown that HER2-neu amplification/alteration in addition to alteration in BRAF and PI3KA may explain resistance to EGFR inhibitors. Several pre-clinical studies have identified that HER2-neu amplification can result in both de novo and acquired resistance to EGFR inhibitors. Recently, several clinical studies have highlighted the use of single or combination HER2-neu directed therapies in HER2-neu amplified/overexpressed mCRC.

Summary

About 5% mCRC patients will demonstrate HER2-neu overexpression and response to HER2-neu-directed therapies can be in the range of 30–38%. Patients not responding to EGFR-inhibitors warrant testing for HER2-neu testing to explain resistance. In the near future, HER2-neu testing is likely to be integrated into our routine clinical practice for management of metastatic colorectal cancer patients.

     

Left Versus Right: Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials?

Purpose

Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies.

Methods

A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log-rank test.

Results

One hundred thirty-nine patients with a median age 59 (33–81). 73.9% received 3+ lines of therapy. All KRAS wild-type patients had received prior EGFR-I. Location: right 20.9%, left 61.9%, and transverse 4.3%. For survival analysis, transverse CRC were included with right. Of the 112 patients, mOS was left (N = 80) 6.6 months versus right (N = 32) 5.9 months, P = 0.18. mPFS was left (n = 86) 2.0 months versus right (N = 35) 2.0 months, P = 0.76. In subgroup analysis, survival was significant for KRAS wild-type patients with left-sided mCRC had mOS of 6.2 months with other agents versus 9.4 months with EGFR-I (P = 0.03).

Conclusions

In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated patients, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR-I, left-sided KRAS wild mCRC patients should be considered for phase 1 studies of agents targeting growth factor pathways.

     

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.

     

Chronische lymphatische Leukämie beim alten Patienten

Background

The majority of patients with chronic lymphocytic leukemia (CLL) are of advanced age and over 70 years old when the disease is diagnosed or requires therapy. Recently, new treatment options have emerged.

Objective

This article gives a review of current diagnostics and therapy of CLL in elderly patients.

Methods

A literature search was carried out in PubMed and in congress abstracts.

Results

The development and approval of new CD20 antibodies (e.g. ofatumumab, and obinutuzumab) as well as kinase inhibitors (e.g. ibrutinib and idelalisib) have broadened the therapeutic arsenal for elderly patients with CLL. Benefits from these advances have been mainly demonstrated for elderly patients with increased comorbidities and for elderly patients with high risk features (e.g. 17p deletion, p53 mutation and early relapse).

Conclusion

For the former group of patients immunochemotherapy and no longer chemotherapy alone is the standard first-line treatment. In the latter group of patients early use of kinase inhibitors which block B-cell receptor signaling and can be taken orally are indicated. Studies are currently being carried out with further agents for targeted therapy (e.g. venetoclax, lenalidomide) as well as with tools for assessing patient fitness in elderly patients with CLL.

     

Combination Immunotherapy in Non-small Cell Lung Cancer

Purpose of Review

Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach.

Recent Findings

Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results. Additional studies targeting other immune pathways like TIGIT, LAG-3, and cellular therapies are ongoing.

Summary

Combination immunotherapy has the potential to improve outcomes in NSCLC. Data from early clinical trials is promising and reveals that these agents can be administered together safely without a significant increase in toxicity. Further studies are needed to evaluate their long-term safety and efficacy and to determine appropriate patient selection.

     

Regorafenib in the Real-Life Clinical Practice: Data from the Czech Registry

Objective

To describe the use of regorafenib for the treatment of metastatic colorectal cancer (mCRC) in clinical practice in the Czech Republic, and to describe the clinical outcomes of patients in terms of safety and survival.

Patients and Methods

The data of patients treated with regorafenib were extracted from the national CORECT registry. The CORECT registry is a non-interventional post-marketing database, gathering information about patients with CRC and treated with targeted agents. Twenty oncology centres in the Czech Republic contributed to this registry. Collected data included patients’ characteristics, disease history, cancer treatments, response to treatments and safety.

Results

A total of 148 patients treated with regorafenib in clinical practice were analysed. At regorafenib initiation, almost all patients were fully active or slightly restricted in physical activity. Regorafenib was not administered as first-line treatment in any patient. Median progression-free survival was 3.5 months and median overall survival was 9.3 months. One-year survival rate was 44.6 %. Four partial responses were observed and 51 stable diseases. Progression was observed in 66 patients (44.6 %). The main reported adverse events were skin toxicity (5.4 %) and fatigue (2.0 %).

Conclusions

Regorafenib is a well-established treatment for pretreated patients with mCRC, however real-life data are scarce. Our results demonstrated slightly better efficacy of regorafenib and better safety profile in patients with mCRC compared to the randomised trials.

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Emerging Role of Immunotherapy in Advanced Urothelial Carcinoma

Purpose of Review

Advanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape.

Recent Findings

Since May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting. Clinical outcomes and safety profiles of these agents appear relatively comparable across separate trials; however, only pembrolizumab is supported by level I evidence from a large randomized phase III trial showing overall survival benefit over conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.

Summary

Pembrolizumab has the highest level of evidence in platinum-refractory aUC, whereas pembrolizumab and atezolizumab have comparable level of evidence in the frontline setting in cisplatin-ineligible patients. Ongoing research is evaluating novel agents, various rational combinations, and sequences, as well as predictive and prognostic biomarkers.

     

Phase I study of primary treatment with 5-FU,oxaliplatin, irinotecan,levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type <Emphasis Type="Italic">RAS</Emphasis> gene: the JACCRO CC-14 study

Background

FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC).

Methods

Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m², and folinate (LV) 200 mg/m²] on day 1, followed by fluorouracil (5-FU) 3200 mg/m² infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m²).

Results

Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9–100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4–7.3) months.

Conclusion

The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

     

Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer

Purpose

The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy.

Methods

In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients’ demographic, lifestyle, clinical tumor characteristics, as well as bone health history.

Results

The presence of bone metastases, prior bisphosphonate (BP) treatment, and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, several factors, including age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy, were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics were not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated.

Conclusions

Our findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer.

     

Analysis of blood markers for early breast cancer diagnosis

Purpose

Breast cancer is the most common neoplasm in women and has the highest associated mortality rate. Rapid detection programmes can provide early diagnosis and increase the chances of survival. There are no specific tumor biomarkers for the early phase of the disease. The primary aim of this study was to search a blood biomarker with levels that exceeded the normal range established in the general population that could be used to screen breast cancer.

Methods/patients

Case–control study. Conventional as well as research (NGAL, EGFR and 8-OHdG) tumor biomarkers were analyzed.

Results

A total of 126 women were enrolled (cases: 63 patients with local breast cancer; Controls: 63 healthy women). Significant differences were found in patients with higher levels of the conventional markers, Ca15.3, CEA, Cyfra 21.1 and NSE. However, when commercial cut-off values were used, only Ca 15.13 was significant. In the group of research biomarkers, significantly higher levels of EGFR were found in the control group, and of 8-OHdG in the case group. Using logistic regression analysis and a ROC curve, an equation composed of five markers, Ca 15.3, NSE, NGAL, EGFR and 8-OHdG, which yielded a correct diagnostic probability of breast cancer of 91.8% was obtained.

Conclusions

8-OHdG has been identified as a new potential marker for screening early stage breast cancer. In addition, a model that combines five blood markers that can be used as a diagnostic test in certain groups of patients has been developed. New studies with a larger sample size are needed to verify the results obtained.

     

The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells

Background

Epidermal growth factor receptor (EGFR) is often overexpressed in triple-negative breast cancer (TNBC). However, clinical studies have shown that therapies against EGFR are not effective in patients with TNBC. Recently, it has been reported that arginine 198/200 in EGFR extracellular domain is methylated by PRMT1 and that the methylation confers resistance to EGFR monoclonal antibody cetuximab in colorectal cancer cells. To explore a potential mechanism underlying intrinsic resistance to anti-EGFR therapy in TNBC, we investigated the role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 (468) TNBC cells.

Methods

We knocked down PRMT1 in 468 cells by shRNA, and subjected the cell lysates to Western blot analysis to examine EGFR activation and its downstream molecules. We also evaluated cell proliferation and sphere formation of PRMT1-knockdown cells. Finally, we examined the effects of pan-PRMT inhibitor, AMI-1, on cetuximab by colony formation and soft agar assays.

Results

EGFR methylation and activity was significantly reduced in PRMT1-knockdown cells compared to the parental cells. Knockdown of PRMT1 also reduced cell proliferation and sphere formation. Moreover, AMI-1 sensitized 468 cells to cetuximab.

Conclusion

The results indicate that PRMT1 is critical for EGFR activity in 468 cells. Our data also suggest that inhibition of PRMT1 sensitizes TNBC cells to cetuximab. Thus, inhibition of PRMT1 may be an effective therapeutic strategy to overcome intrinsic resistance to cetuximab in TNBC.

     

Application of EGFR inhibitor reduces circulating tumor cells during transcatheter arterial embolization

Purpose

Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR).

Methods

Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed.

Results

Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug.

Conclusion

EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.

     

Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials

Background

The strategy of dual inhibiting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has been extensively investigated in advanced non-small-cell lung cancer (NSCLC), but the benefit-to-risk ratio of dual-targeted regimen versus EGFR-tyrosine kinase inhibitors (TKIs) alone is still unclear. We thus perform this meta-analysis to assess the efficacy and safety of this regimen versus EGFR-TKIs alone in those patients.

Methods

Databases from PubMed, Web of Science and the Cochrane Library up to March 31, 2015 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in advanced NSCLC. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3 or 4 adverse events. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies.

Results

A total of 1918 patients with advanced NSCLC from 4 RCTs were identified for the analysis. The pooled results demonstrated that dual inhibiting EGFR and VEGF pathways significantly improved the PFS (HR 0.71, 95 % CI 0.58–0.86, p < 0.001) and ORR (OR 1.54, 95 % CI 1.14–2.08, p = 0.005) in unselected NSCLC when compared to EGFR-TKIs alone, but it did not translate into OS benefit (HR 0.94, 95 % CI 0.84–1.05, p = 0.24). No evidence of publication bias was observed.

Conclusions

Our study suggests that dual inhibition of EGFR and VEGF pathways significantly improves PFS and ORR, but it does not translate into survival benefit in unselected NSCLC patients. Prospective clinical trials investigating the role of this regimen in EGFR mutation-positive NSCLC are still warranted.

     

RETRACTED ARTICLE: The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials

Objective

To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis.

Method

Randomized trials of EGFR-TKIs as treatment for advanced NSCLC were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs in the selected patients by EGFR-mutation status were calculated.

Results

Out of 2134 retrieved articles, 30 randomized controlled trials (RCTs) enrolling more than 4053 patients with wild-type EGFR tumors and 1592 patients with mutant EGFR tumors were identified. For EGFR mutant patients, EGFR-TKIs treatment improved progression-free survival (PFS) compared with chemotherapy: the summary HRs were 0.41 (p?<?0.00001) for the first-line setting and 0.46 (p?=?0.02) for second/third-line setting, respectively. Also, the same superior trend was found with TKIs maintenance over placebo (HR?=?0.14, p?<?0.00001) and with TKIs combined with chemotherapy over chemotherapy (HR?=?0.49, p?=?.002) in both the first-line and maintenance therapy settings. For EGFR wild-type patients, EGFR-TKIs have fared worse than chemotherapy in the first-line setting (HR?=?1.65, p?=?.03) and in the second/third-line setting (HR?=?1.27, p?=?.005). However, EGFR-TKIs maintenance still produced a reduction of 19 % in the risk of progression over placebo (HR?=?0.81, p?=?.02). Furthermore, EGFR-TKIs added to chemotherapy as first-line treatment resulted in an improvement of PFS over chemotherapy alone in such wild-type EGFR patients (HR?=?0.82, p?=?.03). In overall survival (OS) analysis, only EGFR-TKIs single agent was inferior to chemotherapy in EGFR wild-type patients (HR?=?1.13, p?=?.02). No statistically significant difference in terms of OS was observed in any other subgroup analysis.

Conclusions

For EGFR mutant patients, EGFR-TKIs therapy produced a prominent PFS benefit in all settings. Among EGFR wild-type patients, EGFR-TKIs were inferior to chemotherapy both for first-line treatment and for second/third-line treatment. However, EGFR-TKIs maintenance and addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such EGFR wild-type patients.

     

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.

     

Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma

Purpose of Review

Prognosis of advanced oral squamous cell carcinoma remains a challenge for clinicians despite progress in its diagnosis and treatment over the past decades. In this review, we assessed clinicopathological factors and potential biomarkers along with their prognostic relevance in an attempt to develop optimal treatment strategies for these patients.

Recent Findings

In addition to several pathologic factors that have been proposed to improve prognostic stratification and treatment planning in the eighth edition of the American Joint Committee staging manual on cancer, we reviewed some other imaging and clinicopathological parameters demonstrated to be closely associated with patient prognosis, along with the biomarkers related to novel target or immune therapy.

Summary

Evaluation of current literature regarding the prognostic stratification used in contemporary clinicopathological studies and progress in the development of targeted or immune therapy may help these patients benefit from tailored and personalized treatment and obtain better oncological results.

     

Changes in Renal Function of Patients with Metastatic Renal Cell Carcinoma During Treatment with Molecular-Targeted Agents

Background

Impairment of renal function is a serious issue that should be considered in patients undergoing treatment with molecular-targeted agents for metastatic renal cell carcinoma (mRCC).

Aims

The objective of this study was to assess the impact of molecular-targeted therapy on changes in renal function among patients with mRCC.

Patients and Methods

The study included 408 mRCC patients treated with sunitinib, sorafenib, axitinib, everolimus and/or temsirolimus. Among these, 185, 128 and 95 received molecular-targeted agents as first-line (group 1), second-line (group 2) and third-line (group 3) therapy, respectively.

Results

No significant differences between the estimated glomerular filtration rate (eGFR) at baseline and that at the end of molecular-targeted therapy were noted among the three groups of patients. In addition, there were no significant differences between eGFR prior to the introduction of molecular-targeted therapy and that at the end of therapy across agents and lines of targeted therapy, with the exception of patients treated with axitinib and everolimus in second-line and third-line therapy, respectively. In group 1, a reduction in eGFR of >10 % from baseline was independently associated with performance status, hypertension and treatment duration, while in groups 2 and 3, only treatment duration was independently related to a reduction in eGFR of >10 %.

Conclusions

It appears that renal function in patients with mRCC is not markedly impaired by molecular-targeted therapies, irrespective of the specific agents introduced; however, it may be necessary to pay special attention to deterioration in renal function when molecular-targeted therapy is continued for longer periods.

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Incidence,Diagnosis, and Treatment of Cardiac Toxicity From Trastuzumab in Patients With Breast Cancer

Purpose of Review

Treatment with trastuzumab is a cornerstone of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer treatment, but carries an unfortunate risk of toxicity to the cardiovascular system. Here, we review recent findings on trastuzumab-associated cardiotoxicity, focusing on its incidence, diagnosis, and treatment.

Recent Findings

Screening with multigated acquisition scan (MUGA) or echocardiogram (ECHO) is recommended to assess cardiac function prior to and during trastuzumab therapy. Because trastuzumab-induced cardiotoxicity is typically reversible, cessation of trastuzumab and/or administration of first-line heart failure agents effectively restores cardiac function in most cases. Severe trastuzumab-induced cardiotoxicity is rare enough that the risk-benefit ratio still weighs in favor of its use in the vast majority of patients with HER2+ breast cancer.

Summary

An improved understanding of the pathophysiology underlying trastuzumab-induced cardiotoxicity and the identification of patients at highest risk will allow us to continue to safely administer trastuzumab in patients with breast cancer.