Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature.

PURPOSE: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making. METHODS: In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2- patients with 0-3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan-Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups. RESULTS: A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively. CONCLUSION: These survival analyses indicate that the postmenopausal node-negative ER+HER2- patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients.

Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy.

Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-ß signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

Background: The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens. Design: We nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017. Results: TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further. Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial.

BACKGROUND: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. METHODS: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. RESULTS: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. CONCLUSIONS: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study.

BACKGROUND: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. PATIENTS AND METHODS: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. RESULTS: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118). CONCLUSIONS: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status.

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor.

Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

Best practice guidelines in the psychosocial management of HPV-related head and neck cancer: recommendations from the European Head and Neck Cancer Society's Make Sense Campaign.

Over the past three decades, oral human papillomavirus (HPV) has been associated with an increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in several countries. Specialist oncologists in head and neck cancer are observing a wider range of demographics, sexual behaviours, and survival outcomes with their patients. Additionally, there are fewer smokers, consumers of alcohol, or people of lower socioeconomic status than in previous decades. In order to support patients, the European Head and Neck Society's Make Sense Campaign aims to promote best practice in the management of head and neck cancer through the delivery of counselling, psychological assessment, support with the patient experience following HPV-related cancer diagnosis, sexual impact (in terms of communication, behaviour and prevention), facilitating access to educational resources about HPV in head and neck squamous cell carcinoma and OPSCC, and early referral if necessary. New concerns about psychosocial distress and unmet psychosocial needs following diagnosis, therefore, exist throughout the disease and treatment periods. Oncologists treating patients with HPV-related head and neck cancer must integrate new parameters focused on infection risk transmission and sexual topics. The development and dissemination of best practice guidelines through The European Head and Neck Cancer Society Make Sense Campaign will help healthcare professionals to be more confident and resourceful in supporting patients with HPV-related head and neck cancer.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).

The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck.

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) was traditionally associated with smoking and alcohol use; however, human papillomavirus (HPV) infection has recently been implicated as a novel risk factor for oropharyngeal tumors. Furthermore, HPV-associated oropharyngeal carcinoma (OPC) appears to be a distinct entity with different epidemiology, biology, and clinical outcomes. METHODS: Here, we comprehensively review the existing data regarding HPV status and prognostic or predictive outcomes in both the locoregionally advanced (LA) and recurrent/metastatic (RM) disease setting and discuss ongoing trials that may eventually impact the treatment of patients with HPV-positive (HPV+) SCCHN. RESULTS: A body of retrospective and prospective data established an association between HPV+ OPC and better survival, particularly for LA disease. Current data on RM disease are limited, but they also suggest prognostic significance for HPV. CONCLUSIONS: Better outcomes in HPV+ LA disease may allow for less aggressive treatment in the future, and several trials are evaluating deintensified regimens in patients with HPV+, LA OPC; it should be emphasized that deintensification strategies are appropriate only in a clinical research setting and only for selected subgroups of HPV+ patients. In addition, HPV-targeted strategies, such as vaccines, are currently undergoing clinical evaluation. On the other hand, the prognostic impact of HPV in RM disease requires further validation before any modifications in treatment can be made. Likewise, the predictive significance of HPV status in both disease settings remains to be defined. CLINICAL TRIAL NUMBERS: NCT00226239, NCT00301028, NCT00387127, NCT00410826, NCT00503997, NCT00514943, NCT00544414, NCT00768664, NCT00939627, NCT01084083, NCT01302834, NCT01687413, NCT01706939.

Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial.

BACKGROUND: Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status. PATIENTS AND METHODS: Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays. RESULTS: Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients. CONCLUSION: The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.

Best practices in the management of the psycho-oncologic aspects of head and neck cancer patients: recommendations from the European Head and Neck Cancer Society Make Sense Campaign.

Squamous cell carcinoma of the head and neck (SCCHN) is considered a worldwide health care problem. The majority of patients have a history of alcohol abuse and high-level tobacco consumption; however, SCCHN is also associated with exposure to viruses including human papillomavirus (HPV) and Epstein-Barr virus. A major problem facing SCCHN patients is that their disease is often diagnosed at an advanced stage where treatment options may not be curative, or can have severe post-treatment consequences. Confronted with their diagnosis and treatment options, the patient can express a range of emotional reactions which may lead to maladaptive coping. During the SCCHN patient journey, there are a number of stages where emotional support could be offered. A point of contact should be allocated to help patients navigate these stages and deliver practical emotive support (such as encouraging attendance at hospital appointments, compliance with lifestyle modifications and treatment adherence), and to identify if or when more advanced emotive support, in the form of a mental health professional, might be needed. This role might be carried out by a representative within the multidisciplinary health care team (e.g. a nurse). While optimal care is provided by specialist health care professionals, each with specific roles and responsibilities during the patient journey, all are important in screening for emotional distress and providing referral to the mental health team. This article reviews the key points for delivering emotional support to SCCHN patients at each stage of their care. Emotional problems cannot be ignored in SCCHN patients if optimal outcomes are to be achieved, particularly as therapeutic options extend overall survival for many patients. Health care professionals must be able to implement efficient screening for psychological distress to support patient's compliance to their care and treatment. They must also be able to recognize when to refer patients at risk for pharmacological and/or psychotherapeutic interventions.

Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study.

BACKGROUND: Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. PATIENTS AND METHODS: A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. RESULTS: The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. CONCLUSIONS: Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors.

BACKGROUND: In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m(2)/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m(2) (regimen A) or cisplatin 75-100 mg/m(2)/5-fluorouracil 750-1000 mg/m(2) (regimen B) in patients with advanced solid tumors. PATIENTS AND METHODS: The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). RESULTS: The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. CONCLUSIONS: The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.

CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment.

Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.

Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost-utility analysis.

BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of €11,822/QALY for TAX 323 and €6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of €50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.

Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part.

BACKGROUND: Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil. RESULTS: Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%. CONCLUSION: Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study.

BACKGROUND: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. PATIENTS AND METHODS: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. RESULTS: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. CONCLUSION: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.