Predictors of cisplatin-induced ototoxicity and survival in chemoradiation treated head and neck cancer patients.

OBJECTIVES: Cisplatin-induced ototoxicity is a common permanent consequence of curative chemoradiation for locally advanced head and neck squamous cell carcinoma (HNSCC). Predictors of ototoxicity in HNSCC were examined. MATERIALS AND METHODS: In this prospective, observational cohort study, 206 adult HNSCC patients underwent audiometric testing at baseline, during and after treatment with cisplatin-based chemoradiation. Ototoxicity was defined as ≥grade 2 audiometric change from baseline (CTCAE v4.02). Relationships between clinical and pharmacogenetic (TPMT, COMT, ACYP2, CTR1, OCT2, MATE1, ABCC2, ABCC3, and ABCG2) covariates and ototoxicity, progression-free (PFS) and overall survival (OS) were assessed by Cox regression. RESULTS: Weekly cisplatin resulted in lower ototoxicity risk while PFS and OS were similar compared to high dose cisplatin (P = 0.00035; HR = 0.18; 95% CI, 0.07-0.46). COMT (rs9332377) carriers had higher ototoxicity risk (P = 0.00556; HR = 1.72; 95% CI, 1.17-2.52) while MATE1 (rs2289669) A/A carriers were protected from ototoxicity (P = 0.01062; HR = 0.46; 95% CI, 0.26-0.84). Absence of the protective MATE1 allele among those who carry the risk allele in COMT predicted increased ototoxicity risk, (P = 0.00414; HR = 3.22; 95% CI, 1.45-7.17 and P = 0.00022; HR = 4.89; 95% CI, 2.11-11.36). Survival outcomes did not differ between carriers of protective or risk alleles. CONCLUSIONS: Weekly cisplatin dosing, COMT and MATE1 are predictors of ototoxicity without affecting treatment efficacy. COMT and MATE1 genotyping and weekly dosing may be a potential strategy for mitigating cisplatin-induced ototoxicity in HNSCC.

Feasibility of Targeting PIK3CA Mutations in Head and Neck Squamous Cell Carcinoma.

PIK3CA is the only frequently-mutated, directly druggable oncogene in head and neck squamous cell carcinoma (HNSCC). However, it is unclear if a molecularly-driven intervention trial can be launched successfully, particularly within a single-institution setting secondary to the infrastructure necessary for mutation detection, mutation prevalence, and patient willingness to participate. This study aimed to evaluate 1) local frequency of PIK3CA activating mutations in HNSCC, 2) timeliness of our mutation-profiling clinical pathway, and 3) patients' willingness to enroll in a novel neoadjuvant drug trial. Tissue biopsies of 25 consecutive cases of HNSCC were tested for activating PIK3CA mutations at three mutational hotspots by real-time polymerase chain reaction. Mutations prevalence and number of working days accrued in determining PIK3CA mutational status were calculated. In addition, 30 HNSCC patients were surveyed prospectively regarding their willingness to participate in a hypothetical drug trial. Survey data were summarized descriptively. 4 of 25 (16 %) tumors harbored a PIK3CA activating mutation, including one at codon E542K, two at codon E545K/D, and one at codon H1047R. On average, this result was obtained in approximately 15 working days (range, 9-24 working days). The majority of patients surveyed (70 %) indicated their willingness to participate in a targeted PIK3CA trial. This study provides evidence that within a single institution, PIK3CA activating mutations can be detected with expected frequency, with sufficient timeliness and sufficient patient interest to mount a targeted intervention trial that may lead to improved tumor response in selected HNSCC patients.

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.

Evaluation of second-line and subsequent targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first-line cediranib.

INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.

Practice patterns and perceptions of survivorship care in Canadian genitourinary oncology: A multidisciplinary perspective.

INTRODUCTION: There is little knowledge of survivorship care specific to genitourinary (GU) cancers. To improve care delivery to this patient population, we need to clearly define physician perceptions of survivorship care. We therefore conducted a study to determine the challenges to GU cancer survivorship care in Canada. METHODS: A web-based questionnaire was e-mailed to physicians treating GU cancers in Canada, including urologists, radiation oncologists, and medical oncologists. Five domains were assessed: demography, current post-cancer treatment care, perspectives on barriers to survivorship care, accessibility to survivorship resources, and perspectives about advocacy groups. RESULTS: There were 306 responses, with 260 eligible for study. A total of 82% of physicians involve primary care practitioners (PCPs) at some point in survivorship care. Most physicians provide some form of written follow-up plan to PCPs. However, only 25% provided lifestyle recommendations and 53% included persistent and late effects of therapy. Lack of time or resources dedicated to survivorship care was the most commonly reported barrier. There was variation in accessibility to survivorship support programs among different subspecialties and regions. Advocacy groups generally were underutilized, particularly in testis cancer. Low response rate and the potential response bias are the main limitations of this survey. CONCLUSION: To our knowledge this is the first study to address the challenges of GU cancer survivorship care in Canada. The barriers and accessibility of survivorship care quoted in this survey may be used to improve care for this group of patients. Underutilization of advocacy groups may stimulate the advocacy groups and institutions to address its causes and solutions.

New directions for biologic targets in urothelial carcinoma.

Urothelial carcinoma remains an important oncologic problem with significant morbidity and mortality. This article provides an overview of the current status of treatment of urothelial carcinoma, with an update on current trials and recent American Society of Clinical Oncology abstracts. As an alternative to focusing on the metastatic setting, we take a broad look at drug development to date, as it spans from early disease to advanced disease in the context of emerging molecular data. This approach allows us to show that each stage involves key considerations based on emerging evidence regarding molecular biology, stage-specific novel endpoints, and rational patient selection that may help further trial designs in the future. Key issues, such as neoadjuvant versus adjuvant perioperative chemotherapy, approaches to salvage second-line therapy in the metastatic setting, and treatment of elderly and cisplatin-ineligible patients, are discussed. New paradigms in clinical research, including novel endpoints, upfront rational patient selection, biomarkers, and trial design, are also addressed.

Fecal DNA screening in colorectal cancer.

Colorectal cancer (CRC) is the third most common type of cancer diagnosed in Canada, and is the leading cause of cancer-related deaths in nonsmokers. Although CRC is considered to be 90% curable if detected early, the majority of patients present with advanced stage III or IV disease. An effective screening test may significantly decrease disease burden. The present paper examines the rationale and potential of fecal DNA testing as an alternative and adjunct to other CRC screening tests. The most efficacious fecal DNA test developed to date has a sensitivity and specificity of 87.5% and 82%, respectively. The approach has a higher positive predictive value than the currently used fecal occult blood test and offers a noninvasive option to patients. It is not reliant on the presence of bleeding, which may be intermittent or altogether absent. The test is now commercially available and is supported by a number of American insurers. Current challenges include cost reduction and demonstration of mortality benefit in a rigorous clinical trial. Despite current challenges, fecal DNA testing is worth pursuing. Both the American Gastroenterological Society and the American Cancer Society maintain that molecular testing is in its infancy but is promising. Fecal DNA testing has the potential to be an exciting addition to the current armament of CRC screening options.

Effect of patient socioeconomic status on perceptions of first- and second-year medical students.

BACKGROUND: Physician decision-making and perceptions of patients are affected by a patient's socioeconomic status (SES). We sought to determine if the perceptions of first- and second-year medical students are similarly affected. We also wanted to determine whether a student's own SES affects his or her perceptions of patients from a low or high SES background. METHODS: Two similar videos of a physician-patient interview were created. One video featured a patient of apparently high SES and the other featured a patient of apparently low SES. Differences in SES were portrayed by means of clothing, accessories and dialogue. First- and second-year medical students at the University of Western Ontario were recruited to view 1 of the videos and to answer a questionnaire using a 5-point Likert scale. RESULTS: Responses were obtained from 205 (89%) of the 231 medical students invited to participate. Respondents' perceptions of the low SES and high SES patients were significantly different in the following respects. The low SES patient was perceived to be less compliant in taking medications and less likely to return for follow-up visits; was perceived to have a lower level of social support, poorer overall health and a worse prognosis; and was perceived to be more adversely affected in his occupational duties by illness (p < 0.05). Furthermore, second-year students who watched the video with the low SES patient were less inclined to want that patient in their practice than second-year students who watched the video with the high SES patient (p = 0.032). One hundred and six students (52%) were categorized as having high SES and 37 (18%) as having low SES (the remaining students were categorized as having mid-level SES). Among students who watched the video with the low SES patient, the level of agreement with the statement "This person is the kind of patient I would like to have in my practice" was greater among low SES students than among high SES students (p = 0.012). INTERPRETATION: First- and second-year medical students have negative perceptions of low SES patients on several dimensions.

Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma.

Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of RB1 mutations are unique and distributed throughout the RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.