My personal highlights of ESMO 2016.

Results of several clinically relevant studies were presented at the 2016 Annual Meeting of the European Society of Medical Oncology (ESMO). This article summerizes the personal highlights of three medical oncologists in their respective areas of expertise.

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials.

OBJECTIVES: Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500mg/m(2) plus cisplatin 75mg/m(2) every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression. METHODS: Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. RESULTS: Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p=0.117, HR=1.16; median OS: 14.0 versus 14.2 months, p=0.979, HR=1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p<0.00001, HR=0.66; median OS: 16.9 versus 14.2 months, p=0.003, HR=0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. CONCLUSIONS: The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

Impact of adjuvant chemotherapy in stage IB non-small-cell lung cancer: an analysis of 112 consecutively treated patients.

PURPOSE: The impact of adjuvant chemotherapy (CT) in the management of radically resected stage IB non-small cell lung cancer (NSCLC) is highly debated. The aim of this study was to evaluate the outcome of this category of patients treated at our institution. METHODS: We retrospectively analysed the survival data of patients with pathologic stage IB NSCLC, who received at least 1 cycle of adjuvant CT. CT was planned to be platinum based and to be delivered for 6 cycles. RESULTS: One hundred and twelve consecutively treated patients were evaluated. PATIENT CHARACTERISTICS: median age 60 years, median tumor diameter 4 cm, 87% underwent lobectomy and 13% pneumonectomy, 58% had visceral pleural involvement (VPI). After a median follow up of 46 months, the estimated 5-year disease-free (DFS) and overall survival (OS) rates were 68% and 77%, respectively. The mean number of CT cycles was 5.2 (range 3-6), with 82% of patients receiving ≥ 5 cycles. The median cisplatin dose intensity (DI) was 22 mg/m(2)/week, and the relative DI was 85%. Median total cisplatin (CDDP) dose/patient was 416 mg/m(2). A total of 31 (27.6%) relapses were recorded, of which 81% were distant. Multivariate analysis showed no significant interaction between overall survival and the following variables: gender, type of surgery, histology, tumor volume, VPI. CONCLUSION: Our results compare favorably with the historical data evaluating the outcome of stage IB patients treated by surgery alone in a customary medical setting. Overall, our data support the use of adjuvant CT in stage IB NSCLC patients.

Controversies in the management of advanced non-small cell lung cancer: maintenance therapy.

The majority of patients with non-small cell lung (NSCLC) present with advanced, metastatic disease at the time of diagnosis. The current state of the art for the management of this condition is first- and second-line chemotherapy (CT), along with appropriate supporting care measures, which are supposed to alleviate symptoms and to improve survival. During the last years, maintenance therapy (MT) was included in the therapeutic algorithm for these patients. MT could be defined as continuation of an active treatment until disease progression in patients who demonstrated a non-progressing status following induction chemotherapy. Despite the results of several randomized trials showing a significant benefit by using this approach, the strategy is far from being universally accepted. The internationally recognized guidelines provide different recommendation when it comes to this topic, while some major drawbacks in the design of the positive clinical trials may have distorted the relevance of the communicated data. This paper aimed to review the most contentious aspects which should be considered while contemplating the use of MT in the daily clinical practice.

Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24.

BACKGROUND: Hypertension (HTN), a recognized adverse effect of angiogenesis inhibitors, may be a potential biomarker of activity of these agents. We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib, and the relationship of this adverse event with treatment outcomes. PATIENTS AND METHODS: BR24 was a double-blind placebo-controlled phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo in patients (n = 296) with advanced non-small-cell lung cancer (NSCLC). Exploratory analyses characterized relationships between HTN, baseline variables, and efficacy outcomes. RESULTS: New onset or worsening of preexisting HTN (treatment-emergent HTN) was more frequent in patients receiving cediranib (68 versus 45%, P < 0.0001). Factors associated with HTN in all randomized patients were good performance status and treatment with cediranib. In both arms, treatment-emergent HTN was associated with improved efficacy outcomes, but there was no evidence of a differential treatment effect, with nonsignificant interaction P values. CONCLUSIONS: In advanced NSCLC, HTN is frequent in patients receiving chemotherapy, with or without cediranib. The development of HTN was favorably prognostic in these patients, but not predictive of a differential outcome with cediranib.

Adjuvant therapy with aromatase inhibitors in postmenopausal, estrogen receptor- positive breast cancer patients: upfront or sequential?

For decades tamoxifen (TAM) has been the mainstay hormonal treatment for estrogen receptor positive (ER+) breast cancer patients. Nevertheless, during the last years, for postmenopausal women particularly, the third generation aromatase inhibitors (AI) became the preferred alternative. The results of the randomized trials showed that AI were superior to TAM in terms of efficacy, and were accompanied by a different but fairly convenient side effects profile. Subsequently, all updated guidelines recommend the use of AI in the adjuvant setting for this category of patients, either upfront, following 2-3 years of TAM or as extended adjuvant therapy, after 5 years of TAM. However, no consensus has been reached regarding the best strategy to be used, and the expert opinion is divided, based on the available evidence. The controversial aspect of whether AI should be used upfront or following 2-3 years of TAM is further detailed in this manuscript, and some useful recommendations are provided in order to facilitate the decision-making process during the current clinical practice.

Controversies around the use of monoclonal antibodies in the treatment of advanced non-small cell lung cancer.

First line combination chemotherapy (CT) using platinum-based doublets is established as a standard of care for advanced non-small cell lung cancer (NSCLC). Nevertheless, no significant advances have been recorded during the last years in this field. Therefore, there is a wide consensus among physicians that a plateau has already been reached with this strategy. Targeted therapy using tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies emerged as a new field of development in the NSCLC therapeutics. Recently, the results of the phase III trials testing antibodies against vascular endothelial growth factor-VEGF (bevacizumab) and epidermal growth factor receptor-EGFR (cetuximab) challenged the paradigm of the platinum doublets as a gold standard in advanced NSCLC. Their appearance was enthusiastically commended both by patients and the oncological community. However, all medical oncologists have the responsibility to carefully analyze the real benefits of these new agents, to balance the advantages against the implicit risks of therapy and to make the decision having in mind the best interest of their patients. Last but not least, the associated health economic burden should also be considered. This paper addresses some issues related to the use of cetuximab and bevacizumab in advanced NSCLC. The main controversial aspects regarding patient selection, the real benefit of therapy, the molecular and clinical predictors, and the impact of other independent variables are carefully examined and presented. Due to many unsolved questions, no definite conclusions can be supported. The final decision about the optimal use of these agents is left to the clinical judgment of each treating physician.

Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting.

BACKGROUND: Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response. PATIENTS AND METHODS: A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3). RESULTS: The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14). CONCLUSION: All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.

Compliance with adjuvant chemotherapy in non-small cell lung cancer. The experience of a single institution evaluating a cohort of 356 patients.

PURPOSE: To evaluate the patient compliance with adjuvant chemotherapy (CT) following radical surgery for non-small cell lung cancer (NSCLC), and to identify the potential confounding factors affecting this particular aspect. PATIENTS AND METHODS: We retrospectively evaluated a series of 356 consecutively treated NSCLC patients at a single institution during 1994-2003. All patients had macroscopic and microscopic radical resection of the primary tumor, with or without mediastinal node dissection or sampling, had received at least one adjuvant CT cycle, with or without postoperative irradiation (RT). CT was planned to be believed for 6 cycles. The following schedules were used: cisplatin (CDDP) 60 mg/m(2), cyclophosphamide 600 mg/m(2) and epirubicin 60 mg/m(2) on day 1 every 21 days (16%);etoposide 120 mg/m(2) and CDDP 30 mg/m(2), on days 1-3, every 21 days (68%); other platinum-based doublets (16%). A multivariate analysis, for a target of 4 and 6 cycles was performed in order to evaluate the potential impact on the patient compliance of the following categories: age, sex (male vs. female), extent of surgery (pneumectomy vs. lesser resection), stage (I,II vs. III), RT(delivered or not) and patient residence (local vs. remote). RESULTS: One hundred and seventy-nine (50%) patients completed all 6 cycles, while 299 (84%) received at least 4 cycles. The median number of administered cycles was 5. For a target of 4 cycles none of the investigated variables had any significant impact. A significant impact on compliance for 6 cycles was recorded for age (OR 0.97, 95% CI 0.95-0.99, p=0.01) and extent of surgery (OR 0.54, 95% CI 0.33-0.87, p=0.01) CONCLUSION: Using the above mentioned combinations, the patient compliance with adjuvant CT was good, with 84% receiving at least 4 and 50% all 6 cycles. The median number of cycles was 5. For a target of 4 cycles none of the investigated variables had a significant impact. For a longer CT duration, age and extent of surgery were correlated with a lower compliance.

Anthracycline pretreated patients: who is who in the chemotherapy choice of relapsed breast cancer?

During the last years, a strong trend towards excluding anthracyclines from the first-line chemotherapy (CT) of relapsed breast cancer (RBC) has been noticed. This trend is based on the concept of previous exposure of the tumor on the same drugs in the adjuvant setting. Consequently, some guidelines and experts recommend the avoidance of using these compounds for RBC under those circumstances, while the taxanes became the first treatment option. This article gives detailed references about the lack of correlation between the type of adjuvant chemotherapy (including anthracyclines), and the clinical outcome of patients treated with front-line anthracyclines for RBC. It also addresses the weakness of this rationale based on recent translational research data and comments on the fact that anthracyclines could represent the best treatment option for some subcategories of patients with RBC. Concluding, this new trend seems more empirical than evidence-based, and clarification of this issue is warranted.

Split course radiation with concurrent vinorelbine and cisplatin in locally advanced non-small cell lung cancer. A phase II study.

PURPOSE: Recent results coming from large randomized trials suggest that for locally advanced non-small cell lung cancer (NSCLC), integration of chemotherapy (CT) with irradiation (RT) should be concurrent rather than sequential. This study aimed at evaluating the actually delivered RT and CT dose intensities (DI), along with the toxicity and efficacy of a split course RT program with concurrent CT. PATIENTS AND METHODS: From October 2000 to September 2002, 24 patients with histologically or cytologically documented NSCLC were included. Patients' characteristics were as follows: males/females=22/2, median age=59 years, stage IIIB/IIIA=22/2 patients, ECOG PS 0-1=15 (62%) and PS 2=9 (38%). HISTOLOGY: adenocarcinoma/ squamous cell/large cell/unclassified 10/6/1/7, respectively. Four cycles of vinorelbine (VNB) 25 mg/m(2) and cisplatin (CDDP) 40 mg/m(2) on days 1+8 were administered (days 1,8,22,29,57,64,78,85). Concurrent with the second CT cycle, RT (2 courses of 30 Gy separated by a 2-week break) was delivered, with a plan to achieve a total dose of 60 Gy, with a fractionation schedule of 2 Gy/day/5 days weekly. RESULTS: The intended RT dose was delivered to 21 (88%) patients with a relative DI of 0.93. Nineteen (79%) patients received more than 3 CT cycles. The relative DI for VNB and CDDP were 0.88 and 0.83, respectively. During treatment 3 (13%) patients experienced WHO grade 3-4 hematologic toxicity while ECOG grade 3 esophagitis was recorded also in 3 patients. At the end of treatment 14 (58%) patients achieved an objective response (2 complete - CR and 12 partial response - PR), while 8 (33%) patients had stable disease (SD) and 2 (8%) progressive disease (PD). After a median follow up of 15 months (range 3-26), 15 (62%) patients relapsed. There were 8 (33%) patients with local relapse and 7 (29%) with distant metastases. The median progression free (PFS) and overall survival (OS) were 10 (range 2-24) and 15 (range 5-24) months, respectively, with an estimated 1 and 2-year survival rates of 55% and 10%, respectively. CONCLUSION: Our concurrent schedule allows for good CT and RT DI, with low associated toxicities. The efficacy data are considered promising, taking into account the high proportion of stage IIIB patients evaluated.