Damien Urban

What is the best treatment for patients with human papillomavirus–positive and –negative oropharyngeal cancer?

The discovery that the human papilloma virus (HPV) is associated with a high and increasing percentage of oropharyngeal squamous cell carcinomas (SCCs) is among the most significant advances in the field of head and neck oncology. HPV‐positive oropharyngeal cancer (HPVOPC) has clinical, etiologic, pathologic, and molecular features that distinguish it from HPV‐negative disease. Increasingly, HPVOPC is being diagnosed in clinical practice because of the easy availability of p16 immunohistochemistry, a surrogate marker of HPV. The superior prognosis of HPVOPC has led to a reexamination of treatment approaches, and clinical trials are currently investigating strategies to deintensify treatment to reduce acute and late toxicity while preserving efficacy. This is of particular interest in low‐risk patients. Unfortunately, patients with HPV‐negative tumors still have high rates of locoregional failure and more efficacious treatments are required. This review of oropharyngeal SCC focuses on current and investigational treatment strategies in patients with both HPV‐positive and HPV‐negative oropharyngeal SCC. Cancer 2014;120:1462–1470.

Frequency and prognostic significance of p16INK4A protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma

Background:Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed.Methods:We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16INK4A (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes.Results:Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P<0.05). There were no other significant clinical or demographic differences between p16-positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36–1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16-positive and -negative patients, respectively (HR=0.60, 95% CI 0.26–1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23–2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19–2.03, P=0.43).Conclusions:p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes.

Changing prognosis of metastatic colorectal adenocarcinoma: Differential improvement by age and tumor location

Over the past 2 decades, significant progress has been made in the field of metastatic colorectal cancer (mCRC) regarding new imaging techniques, surgical interventions, and systemic therapy. It is not known whether the benefit from these interventions has extended overall survival (OS) within the general mCRC population. A population‐based survival analysis of newly diagnosed patients who presented with mCRC was therefore performed.

Lymph node ratio may predict the benefit of postoperative radiotherapy in non-small-cell lung cancer.

Introduction: The use of postoperative radiotherapy (PORT) after resection of non–small-cell lung cancer (NSCLC) is controversial, with some evidence suggesting a benefit in patients with N2 disease. We assessed lymph node ratio (LNR) as a predictor of PORT benefit. Methods: By using the Surveillance, Epidemiology and End Results database, we analyzed resected, node-positive (N1–N2) NSCLC patients diagnosed between 1998 and 2009. LNR, (number of positive nodes/number of resected nodes) was categorized into four groups: LNR less than 12.5%, 12.5 to 24.9%, 25 to 49.9%, and 50% or more. Results: Of 11,324 node-positive NSCLC patients identified, 6551 (57.9%) had N1 disease. The LNR was prognostic for survival in the entire cohort and within each nodal stage. The median survival in LNR groups 1, 2, 3, and 4 was 43, 40, 30, and 23 months in N1 disease and 40, 32, 27, and 22 months in N2 disease, respectively. PORT was associated with a worse survival on univariate analysis (hazard ratio [HR] =1.09; confidence interval [CI] 1.03–1.15; p = 0.002) but no effect on multivariate analysis (HR = 0.96; CI 0.90–1.02; p = 0.201). When analyzed by nodal stage, the benefit of PORT was limited to N2 disease (HR = 0.9; CI 0.84–0.99; p= 0.026) with no benefit in N1 disease (HR = 1.06; CI 0.97–1.15; p=0.2). After stratifying by LNR, the survival benefit of PORT was limited to those with N2 disease and an LNR of 50% or more. Conclusion: A high LNR is associated with a poorer survival in resected, node-positive NSCLC. The survival benefit associated with PORT in this disease seems to be limited to those with an LNR of 50% or more. This warrants further investigation in other cohorts and prospective studies.

Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities.

Background:Cancer of unknown primary (CUP) is the fourth most common cause of cancer death. With advanced diagnostics and treatments, we investigated the proportion of cancers diagnosed as CUP, treatment outcomes and association with socioeconomic disparities.Methods:We analysed trends in CUP diagnosis and outcome within the Surveillance, Epidemiology, and End Results registry between 1973 and 2008.Results:The percentage of all cancers diagnosed as CUP has decreased over time comprising <2% of cancers since 2007. A higher proportion of CUP was diagnosed in the elderly, females, blacks and residents of less affluent or less educated counties. Median survival of all CUP patients was 3 months, with no improvement over time. The 5-year survival significantly improved in those with squamous histology (squamous cell carcinoma; SCC) but only marginally in non-SCC. Factors associated with a longer survival on multivariate analysis included white race; female; <65 years old; most recent decade at diagnosis; SCC; married; a histological diagnosis; and treatment with radiotherapy (all P<0.001). Despite the improvement in survival with radiotherapy, its use was less frequent in females and blacks.Conclusion:The percentage of cancers diagnosed as CUP is decreasing but prognosis remains poor, particularly in non-SCC CUP. However, significant socioeconomic disparities exist in diagnosis and survival, suggesting inequalities in access to diagnostic investigations and treatment.

High incidence of fistula formation during bevacizumab treatment in rectal cancer patients.

Bevacizumab (Avastin) is a recombinant, humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits tumor angiogenesis. Randomized clinical trials have demonstrated significant improvement in survival for patients with advanced colorectal cancer, when treated with bevacizumab together with a 5-fluorouracil (5-FU) based combination chemotherapy [1 3]. Bevacizumab treatment is associated with a unique side-effect profile, which includes hypertension, proteinuria, thromboembolic events, bleeding and impaired wound healing [4]. In addition, bevacizumab treatment may be associated with severe intestinal complications, including perforations, which have been observed in up to 3% of the patients, colitis and diarrhea [5 7]. We report here, for the first time, on high incidence of another severe intestinal complication, namely fistula formation. Moreover, we suggest an association between fistula formation and active pelvic disease and lack of response to bevacizumab. The charts of all patients with metastatic or locally advanced rectal cancer, treated with bevacizumab at the Sheba Medical Center from the introduction of bevacizumab in January 2005 until this analysis in April 2006 were reviewed. Demographic and clinical data were obtained and stage was defined according to the 2002 American Joint Committee on Cancer Staging System for colon and rectal cancer [8]. Information regarding therapy, including type of surgery, radiation therapy, chemotherapy and bevacizumab therapy were obtained from the patients’ charts and response to bevacizumab therapy and its duration were documented. Between January 2005 and April 2006 13 rectal cancer patients were treated in our institution with bevacizumab together with 5-FU, leucovorin and irinotecan (FOLFIRI) regimen, for metastatic (12 patients) or locally advanced disease (one patient, Table I). Four of these patients developed either recto-cutaneous (three patients) or recto-vaginal fistula (one patient). Fistula formation occurred from 2 to 5 weeks following bevacizumab treatment. Three of the patients who developed fistula had prior operation and two of them received prior radiation therapy. Four of five patients with locally advanced disease suffered from fistula, compared to none of eight with distant metastases but without locally advanced disease. Progressive disease was also noted in all the patients who developed fistula but only in three of those who did not. During the same time period 53 colon cancer patients were treated by the same 5-FU, leucovorin and irinotecan (FOLFIRI) regimen. No fistula formation or perforation was noted among these patients.

Suicide in Lung Cancer: Who Is at Risk?

BACKGROUND Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer. METHODS We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. RESULTS From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, > 50% of suicides occurred in those with locoregional and potentially curable disease. CONCLUSIONS Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.

Lymph node ratio predicts the benefit of post-operative radiotherapy in oral cavity cancer.

BACKGROUND The standard treatment for non-metastatic oral cavity squamous cell carcinoma (OCSCC) is surgical resection followed by post-operative radiotherapy (PORT) with/without chemotherapy in high risk patients. Given the substantial toxicity of PORT we assessed lymph node ratio (LNR) as a predictor of PORT benefit. DESIGN By using the Surveillance, Epidemiology and End Results (SEER) database, we analyzed all node positive OCSCC patients diagnosed between 1988 and 2007 who underwent neck dissection. LNR was categorized into three groups: < 6%, 6-12.5% and > 12.5%. RESULTS In 3091 subjects identified, median survival was 32, 25 and 16 months for LNR Groups 1, 2 and 3, respectively. On multivariate analysis, survival was associated with age, race, grade, tumor size, nodal stage, extra-capsular extension, use of PORT and LNR. When stratified by LNR group, PORT was associated with a survival benefit only in Group 3 (LNR > 12.5%): 2 year survival 25% vs 37%. No benefit to PORT was seen when the LNR ≤ 12.5%: 2 year survival 51% vs 54%. CONCLUSION A low LNR is associated with extended survival in LN positive OCSCC. The survival benefit associated with PORT in this disease appears to be limited to those with a LNR > 12.5%. Validation is required prior to the clinical implementation of our findings.

Original ResearchLung CancerSuicide in Lung Cancer: Who Is at Risk?

BACKGROUND Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer. METHODS We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. RESULTS From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, > 50% of suicides occurred in those with locoregional and potentially curable disease. CONCLUSIONS Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.

Genetic mutation screen in early non-small-cell lung cancer (NSCLC) specimens

BACKGROUND Testing for genetic abnormalities in epithelial growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and potentially additional genes is a critical tool in the care of advanced NSCLC. There is conflicting evidence for the role of such tests in early NSCLC. We report a single-institute Sequenom testing for a wide range of mutations and their clinical correlations in early-resected NSCLC specimens. MATERIALS AND METHODS Early NSCLC paraffin-embedded, formalin-fixed (FFPE) specimens were collected, DNA extracted, and using Sequenom-based matrix-assisted laser desorption/ionization-time of flight analysis, mutations in 22 oncogenes and tumor suppressor genes were evaluated. Clinical data was collected retrospectively. RESULTS The technique was found to be feasible. Thirty-six of 96 patients (37.5%) had any genetic abnormality identified, and 8 (8.3%) had 2 or more mutations. Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR were the most common genes to appear mutated (15.6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) was the gene to be found most commonly in tumors with co-mutations. Transversions were found mostly in KRAS gene mutations and to be nonprognostic. No difference in the spectrum of mutations was found between squamous-cell and non-squamous-cell lung cancers. Ever-smokers showed a trend for worse prognosis, with a similar spectrum of mutations. CONCLUSION Sequenom-based mutation screen is feasible using FFPE samples. More than a third of the patients were found to harbor some genetic abnormality, and 8% were found to have more than a single mutated gene. Wide-range gene screens using large sample depositories are required for further insight into the important genes at play in early NSCLC.