Susan A. McCloskey

Delivering affordable cancer care in high-income countries

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US

Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Radiation Treatment Interruptions Greater Than One Week and Low Hemoglobin Levels (12 g/dL) are Predictors of Local Regional Failure After Definitive Concurrent Chemotherapy and Intensity- Modulated Radiation Therapy for Squamous Cell Carcinoma of the Head and Neck

PURPOSE To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). METHODS AND MATERIALS Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. RESULTS Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having ≤ 10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. CONCLUSIONS In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within the University of California Athena Breast Health Network.

Increasing age and treatment modality are predictors for subsequent diagnosis of bladder cancer following prostate cancer diagnosis.

Purpose:To determine whether baseline hemoglobin level and radiation treatment interruptions predict for loco-regional failure after intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy for definitive treatment of squamous cell carcinoma of the head and neck (SCCHN). Methods:This retrospective review identified 78 consecutive patients treated with definitive concurrent chemoradiation for SCCHN. Patients were treated with IMRT to 70 Gy in 35 daily fractions to the high-dose target volume and 56 Gy to the elective target volume. Results:Median age of the cohort was 62 (37–81). Median follow-up was 12 months. Tumor sites included: oropharynx (54%), larynx (36%), oral cavity (5%), and hypopharynx (5%). Fifteen of 78 patients (19%) experienced loco-regional failure. These included: 6 primary site failures, 5 regional failures, and 4 failures in both the primary site and regional lymph nodes. All but one failure occurred in the high-dose target volume. Only duration of radiation treatment and baseline hemoglobin levels were significant predictors of local control. Loco-regional failure occurred in 6 of 13 patients (46%) with radiation treatment interruptions (>1 week) versus 9 of 65 patients (14%) completing radiation therapy without interruption (P = 0.0148). Loco-regional failure occurred in 7 of 19 patients (37%) whose pretreatment hemoglobin level was <12 g/dL compared with 8 of 59 patients (14%) with hemoglobin levels ≥12 (P = 0.042). Conclusion:Overall radiation treatment time and pretreatment hemoglobin level were significant predictors for loco-regional failure after definitive concurrent chemotherapy and IMRT for SCCHN.

Value: A Framework for Radiation Oncology

PURPOSE To determine the effect of prostate cancer therapy (surgery or external beam irradiation, or both or none) on the actuarial incidence of subsequent bladder cancer. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results registry from 1973 to 2005 was analyzed. Treatment was stratified as radiotherapy, surgery, both surgery and adjuvant radiation, and neither modality. Brachytherapy was excluded. RESULTS In all, 555,337 prostate carcinoma patients were identified; 124,141 patients were irradiated; 235,341 patients were treated surgically; 32,744 patients had both surgery and radiation; and 163,111 patients received neither modality. Bladder cancers were diagnosed in: 1,836 (1.48%) men who were irradiated (mean age, 69.4 years), 2,753 (1.09%) men who were treated surgically (mean age, 66.9 years); 683 (2.09%) men who received both modalities (mean age, 67.4 years), and 1,603 (0.98%) men who were treated with neither modality (mean age, 71.8 years). In each treatment cohort, Kaplan-Meier analyses showed that increasing age (by decade) was a significant predictor of developing bladder cancer (p < 0.0001). Incidence of bladder cancer was significantly different for either radiation or surgery alone versus no treatment, radiation versus surgery alone, and both surgery and radiation versus either modality alone (p < 0.0001). On multivariate analysis, age and irradiation were highly significant predictors of being diagnosed with bladder cancer. CONCLUSIONS Following prostate cancer, increasing age and irradiation were highly significant predictors of being diagnosed with bladder cancer. While use of radiation increased the risk of bladder cancer compared to surgery alone or no treatment, the overall incidence of subsequent bladder cancer remained low. Routine bladder cancer surveillance is not warranted.

Quantification of the effect of treatment duration on local-regional failure after definitive concurrent chemotherapy and intensity-modulated radiation therapy for squamous cell carcinoma of the head and neck

In the current health care system, high costs without proportional improvements in quality or outcome have prompted widespread calls for change in how we deliver and pay for care. Value-based health care delivery models have been proposed. Multiple impediments exist to achieving value, including misaligned patient and provider incentives, information asymmetries, convoluted and opaque cost structures, and cultural attitudes toward cancer treatment. Radiation oncology as a specialty has recently become a focus of the value discussion. Escalating costs secondary to rapidly evolving technologies, safety breaches, and variable, nonstandardized structures and processes of delivering care have garnered attention. In response, we present a framework for the value discussion in radiation oncology and identify approaches for attaining value, including economic and structural models, process improvements, outcome measurement, and cost assessment.

Renal Atrophy Secondary to Chemoradiotherapy of Abdominal Malignancies

The purpose of this study was to quantify the effect of treatment duration on locoregional progression after definitive concurrent chemoradiation (CCRT) for squamous cell carcinoma of the head and neck (SCCHN).

Treatment of early-stage uterine papillary serous carcinoma at Roswell Park Cancer Institute, 1992–2006

PURPOSE To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies. METHODS AND MATERIALS Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy. RESULTS Of 130 patients, median age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving ≥10 Gy (V(10)), 15 Gy (V(15)), and 20 Gy (V(20)) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V(10), V(15), and V(20) to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively. CONCLUSIONS Significant detriments in PK size and renal function were seen after abdominal RT. The V(10), V(15), and V(20) were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy.

Radioresistance of the breast tumor is highly correlated to its level of cancer stem cell and its clinical implication for breast irradiation

OBJECTIVE Optimal management of early-stage uterine papillary serous carcinoma (UPSC) remains controversial. We reviewed our outcomes in this patient population. METHODS The Roswell Park Cancer Institute (RPCI) tumor registry identified all patients with Stages I and IIA UPSC treated between January 1992 and June 2006. The Fishers exact test was used to compare recurrence rates by adjuvant therapy received. Overall survival (OS) estimates were made using the Kaplan-Meier method. RESULTS Fifty-eight patients with Stage I or IIA UPSC underwent surgery. Thirty-four patients (59%) were surgically staged. Among 21 patients with Stage IA disease, 15 received adjuvant therapy. With a median follow-up of 44.7 months, only one recurrence was observed in a patient who received adjuvant brachytherapy. The 5-year OS was 66%. Among 37 patients with Stages IB-IIA, 30 patients received adjuvant therapy. With a median follow-up of 29 months, there were 7 recurrences. The 5-year OS was 60%. Although there were no significant differences in recurrence by adjuvant therapy received, a significant OS benefit was found in those who received radiation. There was no significant difference in OS distributions of those patients who received Carboplatin/Paclitaxel chemotherapy. CONCLUSIONS Despite the limitations of our retrospective study, we have shown that even comprehensively staged early-stage UPSC patients are still at risk for recurrence despite adjuvant therapy received. Hence, all patients with this histologic diagnosis should be considered at high risk for recurrence and counseled appropriately regarding the risks and benefits of adjuvant therapy.

Practice Patterns in the Delivery of Radiation Therapy After Mastectomy Among the University of California Athena Breast Health Network

BACKGROUND AND PURPOSE Growing evidence suggested the coexistence of cancer stem cells (CSCs) within solid tumors. We aimed to study radiosensitivity parameters for the CSCs and differentiated tumor cells (TCs) and the correlation of the fractions of CSCs to the overall tumor radioresistance. MATERIAL AND METHODS Surviving fractions of breast cancer cell lines were analyzed using a dual-compartment Linear-quadratic model with independent fitting parameters: radiosensitive αTC, βTC, αCSC, βCSC, and fraction of CSCs f. The overall tumor radio-resistance, the biological effective doses and tumor control probability were estimated as a function of CSC fraction for different fractionation regimens. The pooled clinical outcome data were fitted to the single- and dual-compartment linear-quadric models. RESULTS CSCs were more radioresistant characterized by smaller α compared to TCs: αTC=0.1±0.2, αCSC=0.04±0.07 for MCF-7 (f=0.1%), αTC=0.08±0.25, αCSC=0.04±0.18 for SUM159PT (f=2.46%). Higher f values were correlated with increasing radioresistance in cell lines. Analysis of clinical outcome data is in accordance of a dual-compartment CSC model prediction. Higher percentage of BCSCs resulted in more overall tumor radioresistance and less biological effectiveness. CONCLUSIONS Percentage of CSCs strongly correlated to overall tumor radioresistance. This observation suggested potential individualized radiotherapy to account for heterogeneous population of CSCs and their distinct radiosensitivity for breast cancer.