Scott Tyldesley

Breast Cancer Subtypes and the Risk of Local and Regional Relapse

PURPOSE The risk of local and regional relapse associated with each breast cancer molecular subtype was determined in a large cohort of patients with breast cancer. Subtype assignment was accomplished using a validated six-marker immunohistochemical panel applied to tissue microarrays. PATIENTS AND METHODS Semiquantitative analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin (CK) 5/6 was performed on tissue microarrays constructed from 2,985 patients with early invasive breast cancer. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype-nonbasal. Multivariable Cox analysis was used to determine the risk of local or regional relapse associated the intrinsic subtypes, adjusting for standard clinicopathologic factors. RESULTS The intrinsic molecular subtype was successfully determined in 2,985 tumors. The median follow-up time was 12 years, and there have been a total of 325 local recurrences and 227 regional lymph node recurrences. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67 < 1%) had the best prognosis and the lowest rate of local or regional relapse. For patients undergoing breast conservation, HER2-enriched and basal subtypes demonstrated an increased risk of regional recurrence, and this was statistically significant on multivariable analysis. After mastectomy, luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis. CONCLUSION Luminal A tumors are associated with a low risk of local or regional recurrence. Molecular subtyping of breast tumors using a six-marker immunohistochemical panel can identify patients at increased risk of local and regional recurrence.

Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer

PURPOSE Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. PATIENTS AND METHODS Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. RESULTS Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. CONCLUSION Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.

ESTIMATING THE NEED FOR RADIOTHERAPY FOR LUNG CANCER: AN EVIDENCE-BASED, EPIDEMIOLOGIC APPROACH

BACKGROUND AND OBJECTIVES Current estimates of the proportion of cancer patients who will require radiotherapy (RT) are based almost entirely on expert opinion. The objective of this study was to use an evidence-based approach to estimate the proportion of incident cases of lung cancer that will require RT at any point in the evolution of the illness. METHODS A systematic review of the literature was undertaken to identify indications for RT for lung cancer, and to ascertain the level of evidence that supported each indication. An epidemiologic approach was then used to estimate the incidence of each indication for RT in a typical North American population of lung cancer patients. The effect of sampling error on the estimated appropriate rate of RT was calculated mathematically, and the effect of systematic error, was estimated by sensitivity analysis. RESULTS It was shown that 53.6% +/- 3.3% of small-cell lung cancer (SCLC) cases develop one or more indications for RT at some point in the course of the illness, 45.4% +/- 4.3% in their initial treatment, and 8.2% +/- 1.5% later for recurrence of progression. Overall, 64.3% +/- 4.7% of non-small-cell lung cancer (NSCLC) cases require RT, 45.9% +/- 4.3% in their initial treatment, and 18.3% +/- 1.8% later in the course of the illness. The proportion of NSCLC cases that ever require RT is stage dependent; 41.0% +/- 5.5% in Stage I; 54.5% +/- 6.5% in Stage II; 83.5% +/- 10.6% in Stage III; and 65.7% +/- 7.6% in Stage IV. In total, 61.0% +/- 3.9% of all patients with lung cancer will develop one or more indications for RT at some point in the illness, 44.6% +/- 3.6% in their initial treatment, and 16.5% +/- 1.5% later for recurrence or progression. CONCLUSION This method provides a rational starting point for the long-term planning of radiation services, and for the audit of access to RT at the population level. We now plan to extend this study to the other major cancer sites to enable us to estimate the appropriate RT treatment rate for the cancer population as a whole.

Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement

PURPOSE To endorse Cancer Care Ontarios guideline on Active Surveillance for the Management of Localized Prostate Cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines developed by other professional organizations. METHODS The Active Surveillance for the Management of Localized Prostate Cancer guideline was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and the recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the Active Surveillance for the Management of Localized Prostate Cancer guideline, published in May 2015, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the Active Surveillance for the Management of Localized Prostate Cancer guideline with added qualifying statements. The Cancer Care Ontario recommendation regarding 5-alpha reductase inhibitors was not endorsed by the ASCO panel. RECOMMENDATIONS For most patients with low-risk (Gleason score ≤ 6) localized prostate cancer, active surveillance is the recommended disease management strategy. Factors including younger age, prostate cancer volume, patient preference, and ethnicity should be taken into account when making management decisions. Select patients with low-volume, intermediate-risk (Gleason 3 + 4 = 7) prostate cancer may be offered active surveillance. Active surveillance protocols should include prostate-specific antigen testing, digital rectal examinations, and serial prostate biopsies. Ancillary radiologic and genomic tests are investigational but may have a role in patients with discordant clinical and/or pathologic findings. Patients who are reclassified to a higher-risk category (Gleason score ≥ 7) or who have significant increases in tumor volume on subsequent biopsies should be offered active therapy.

Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance

PURPOSE To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse. METHODS Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded. RESULTS Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion-positive CSI nonseminoma, lymphovascular invasion-negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy for CSI nonseminoma (90%)/CSI seminoma (92%). Relapses were detected by computed tomography scan/tumor-markers in 87%/3% of seminoma recurrences, in 48%/38% of lymphovascular invasion-negative and 41%/61% of lymphovascular invasion-positive patients, respectively. 90% of CSI-nonseminoma and 99% of CSI-seminoma relapses exhibited International Germ Cell Collaborative Group good-risk features. Three patients with CSI nonseminoma died of disease (0.3%). One patient with CSI seminoma and two patients with CSI nonseminoma died because of treatment-related events. Overall, advanced disease was seen in both early- and late-relapse patients. All late recurrences were cured with standard therapy. Five-year disease-specific survival was 99.7% (95% CI, 99.24% to 99.93%). CONCLUSION Active surveillance for CSI testis cancer leads to excellent outcomes. The vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma. Late and advanced stage relapse are rarely seen. These data may inform further refinement of rationally designed surveillance schedules.

Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias☆

PURPOSE To validate the Houston prostate-specific antigen relapse definition in a mature cohort of men treated with external beam radiotherapy (EBRT) and adjuvant androgen ablation (AA) and men treated with EBRT monotherapy, and to compare these results with the American Society for Therapeutic Radiology and Oncology (ASTRO) and Vancouver prostate-specific antigen relapse (biochemical no evidence of disease) definitions. METHODS AND MATERIALS A prospective database of 1490 men treated with EBRT, with or without AA, was examined. The impact on hazard proportions, as well as the predictive ability, of the Houston, ASTRO, and Vancouver definitions was tested. RESULTS For all patients, the Houston definition was more accurate (79.5%) than the ASTRO (76.7%) or Vancouver (77.2%) definitions in predicting subsequent clinical relapse. The Houston definition was superior to the ASTRO definition in those treated both with and without AA and equivalent to the Vancouver definition in those receiving AA. The Houston definition demonstrated proportional hazards when categorized for the use of AA, unlike the ASTRO and Vancouver definitions. The effect of inadequate follow-up on the projected relapse rates was negligible with the Houston definition. CONCLUSION The Houston relapse definition is favored after EBRT monotherapy or combined EBRT and AA. Use of the Cox proportional hazard multivariate analysis is appropriate with the Houston definition, but not with the ASTRO or Vancouver definitions if AA and non-AA patients are combined.

Active Surveillance Is the Preferred Approach to Clinical Stage I Testicular Cancer

Craig R. Nichols, Virginia Mason Medical Center, Seattle, WA Bruce Roth, Washington University School of Medicine, St Louis, MO Peter Albers, University Hospital Heinrich-Heine, University of Dusseldorf, Dusseldorf, Germany Lawrence H. Einhorn and Richard Foster, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN Siamak Daneshmand, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA Michael Jewett and Padraig Warde, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada Christopher J. Sweeney and Clair Beard, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA Tom Powles, Bart’s Cancer Institute, St Bartholomew’s Hospital, Queen Mary University of London, London, United Kingdom Scott Tyldesley and Alan So, British Columbia Cancer Agency–Vancouver Cancer Centre, University of British Columbia, Vancouver, British Columbia, Canada Christopher Porter and Semra Olgac, Virginia Mason Medical Center, Seattle, WA Karim Fizazi, Institute Gustave Roussy, University of Paris Sud, Paris, France Brandon Hayes-Lattin, Knight Cancer Institute, Oregon Health and Science University, Portland, OR Peter Grimison, Royal Prince Alfred Hospital, Sydney Cancer Centre, University of Sydney, Sydney, New South Wales, Australia Guy Toner, Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Victoria, Australia Richard Cathomas, Kantonsspital Graubuenden, Chur, Switzerland Carsten Bokemeyer, University Medical Centre Eppendorf, Hamburg University, Hamburg, Germany Christian Kollmannsberger, British Columbia Cancer Agency–Vancouver Cancer Centre, University of British Columbia, Vancouver, British Columbia, Canada

Population‐based 10‐year oncologic outcomes after low‐dose‐rate brachytherapy for low‐risk and intermediate‐risk prostate cancer

The objective of this study was to report the rates of disease‐free survival (DFS), cause‐specific survival (CSS), and overall survival after low‐dose‐rate (LDR) prostate brachytherapy (PB).

Dynamic multi-appointment patient scheduling for radiation therapy

Seeking to reduce the potential impact of delays on radiation therapy cancer patients such as psychological distress, deterioration in quality of life and decreased cancer control and survival, and motivated by inefficiencies in the use of expensive resources, we undertook a study of scheduling practices at the British Columbia Cancer Agency (BCCA). As a result, we formulated and solved a discounted infinite-horizon Markov decision process for scheduling cancer treatments in radiation therapy units. The main purpose of this model is to identify good policies for allocating available treatment capacity to incoming demand, while reducing wait times in a cost-effective manner. We use an affine architecture to approximate the value function in our formulation and solve an equivalent linear programming model through column generation to obtain an approximate optimal policy for this problem. The benefits from the proposed method are evaluated by simulating its performance for a practical example based on data provided by the BCCA.

THE USE OF RADIOLOGICALLY PLACED GASTROSTOMY TUBES IN HEAD AND NECK CANCER PATIENTS RECEIVING RADIOTHERAPY

PURPOSE Patients undergoing radiotherapy to the head and neck area frequently experience radiation reactions that can markedly restrict oral intake, require hospitalization, and occasionally cause treatment interruptions. The Vancouver Cancer Center (VCC) has recently employed radiologically placed gastrostomy tubes (G-tubes) in the management of this problem. A review of the patients on whom this procedure had been performed is the subject of this review. METHODS AND MATERIALS Thirty-four patients had gastrostomy tubes inserted under radiologic guidance. This group is compared to a control group matched for age, sex, irradiated volume, and radiation dose, who did not have gastrostomy tubes. Patients with gastrostomy tubes were divided into two categories: (a) patients who had tubes inserted in anticipation of severe reactions, and (b) patients who developed severe radiation reactions necessitating nutritional support. RESULTS The gastrostomy group consisted of 65% males with an average age of 59 years and stage range of II (12%), III (24%), and IV (65%). In both the elective group and the nonelective group, patients maintained their weight at 95 to 97% of the pretreatment weight, at follow-up of 6 weeks and 3 months. This compared with an average weight loss in the control group of 9% at 6 weeks and 12% at 3 months. The length of hospitalization was a mean of 4.9 days in the elective group and 19 days in the nonelective group. Complication were low compared to those documented in the literature, but included two tube migrations, two aspirations, and one gastrointestinal bleed. CONCLUSIONS We believe that gastrostomy tubes contribute significantly to the management of patients with head and neck cancer, particularly in maintanence of nutrition, and they may decrease the need for hospitalization.