Tithi Biswas

Complications from Stereotactic Body Radiotherapy for Lung Cancer

Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative to other surgical and non-surgical approaches. Given the excellent tumor control rates and increasing utilization of SBRT, recent efforts have focused on limiting toxicity while expanding treatment to increasingly complex patients. We review toxicities from SBRT for lung cancer, including central airway, esophageal, vascular (e.g., aorta), lung parenchyma (e.g., radiation pneumonitis), and chest wall toxicities, as well as radiation-induced neuropathies (e.g., brachial plexus, vagus nerve and recurrent laryngeal nerve). We summarize patient-related, tumor-related, dosimetric characteristics of these toxicities, review published dose constraints, and propose strategies to reduce such complications.

Tumor control probability modeling for stereotactic body radiation therapy of early-stage lung cancer using multiple bio-physical models

This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large α/β ratios of about 20Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1Gy physical dose at isocenters per fraction (⩽5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20Gy. The six models predict that a BED (calculated with α/β of 20) of 90Gy is sufficient to achieve TCP⩾95%. Among the models considered, the regrowth model leads to a better fit to the clinical data.

Race, insurance type, and stage of presentation among lung cancer patients

The purpose of this study was to determine whether African-American lung cancer patients are diagnosed at a later stage than white patients, regardless of insurance type. The relationship between race and stage at diagnosis by insurance type was assessed using a Poisson regression model, with relative risk as the measure of association. The setting of the study was a large tertiary care cancer center located in the southeastern United States. Patients who were diagnosed with lung cancer between 2001 and 2010 were included in the study. A total of 717 (31%) African-American and 1,634 (69%) white lung cancer patients were treated at our facility during the study period. Adjusting for age, sex, and smoking-related histology, African-American patients were diagnosed at a statistically significant later stage (III/IV versus I/II) than whites for all insurance types, with the exception of Medicaid. Our results suggest that equivalent insurance coverage may not ensure equal presentation of stage between African-American and white lung cancer patients. Future research is needed to determine whether other factors such as treatment delays, suboptimal preventive care, inappropriate specialist referral, community segregation, and a lack of patient trust in health care providers may explain the continuing racial disparities observed in the current study.

Emerging applications of stereotactic body radiotherapy

Stereotactic body radiotherapy (SBRT) has been used extensively in patients with lung, liver and spinal tumors, and the treatment outcomes are very favorable. For certain conditions such as medically inoperable stage I non-small-cell lung cancer, liver and lung oligometastases, primary liver cancer and spinal metastases, SBRT is regarded as one of the standard therapies. In the recent years, the use of SBRT has been extended to other disease conditions and sites such as recurrent head and neck cancer, renal cell carcinoma, prostate cancer, adrenal metastasis, pancreatic cancer, gynecological malignancies, spinal cord compression, breast cancer, and stage II-III non-small-cell lung cancer. Preliminary data in the literature show promising results but the follow-up intervals are short for most studies. This paper will provide an overview of these emerging applications.

The survival benefit of neoadjuvant chemotherapy and pCR among patients with advanced stage triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive subtype that accounts for 15-20% of cases, with a higher incidence of relapse/death. Even with adjuvant chemotherapy, the 5 year distant metastasis-free survival rate remains low. A total of 452 tumor registry patients with TNBC and no evidence of metastatic disease were identified over the period of 1996-2011. The median age and follow-up time were 51 (range=21-88) and 3.9 (range=0.14-14) years. Approximately 75% of patients with stage III disease received neoadjuvant chemotherapy (NACT) compared with 47% for stage II. Patients with stage I disease predominantly received adjuvant chemotherapy (ACT). Among those who underwent NACT (n=202), 33% had a pathological complete response (pCR). Overall (OS) and disease-free (DFS) survival were significantly longer among patients achieving pCR (versus residual disease) following NACT (OS: all patients P<0.0001, stage II P<0.0001, stage III P=0.0062; DFS: all patients P<0.0001, stage II P=0.0011, stage III P=0.015). ACT was not associated with improved OS or DFS for stage III disease. Adjustment for age, chemotherapy, health insurance type, lymphovascular invasion, race, radiation, and surgery did not alter our results. These findings suggest that pCR following NACT is associated with improved survival among patients with TNBC, independent of diagnostic stage.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients: PECT Versus POCRT

Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas.

Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine

BACKGROUND AND PURPOSE The anti-folate pemetrexed is a radiosensitizer. In pre-clinical models, pemetrexed is more effective along with the base-excision-repair inhibitor methoxyamine. We tested whether methoxyamine enhances pemetrexed-mediated radiosensitization of lung adenocarcinoma cells and xenografts. MATERIALS AND METHODS A549 and H1299 cells were evaluated for cell cycle distribution by flow cytometry, radiosensitization by clonogenic assay, and DNA repair by neutral comet assay and repair protein activation. H460 cells were included in some studies. Xenografts in nude mice received drug(s) and/or radiation, and tumor growth was monitored by caliper and in vivo toxicity by animal weight. RESULTS Exposure to pemetrexed/methoxyamine for 24 (H1299, H460) or 48 (A549)hours before irradiation resulted in accumulation of cells near the radiosensitive G1/S border; dose-enhancement factors of 1.62±0.19, 1.97±0.25, and 1.67±0.30, respectively; reduction of mean inactivation dose by 32%, 30%, and 46%, respectively; and significant reductions of SF2 and SF4 (p<0.05). Radiosensitization was associated with rapid DNA double-strand-break rejoining and increased levels of DNA-PKcs. Both tumor-growth rate and tumor-growth delay were significantly improved by adding methoxyamine to pemetrexed pre-irradiation (p<0.0001); no mice lost weight during treatment. CONCLUSIONS Addition of methoxyamine to pemetrexed and fractionated radiotherapy may improve outcome for patients with locally advanced non-squamous non-small-cell lung cancer.

Comparison of cisplatin/etoposide versus carboplatin/etoposide concurrent chemoradiation therapy for limited-stage small cell lung cancer (LS-SCLC) in the elderly population (age >65 years) using national SEER-Medicare data

PURPOSE Standard therapy for limited-stage small cell lung cancer (SCLC) (American Joint Committee on Cancer stages I-III) is concurrent chemoradiation therapy (CRT) with cisplatin/etoposide (EP), but carboplatin/etoposide (EC) is often used in clinical practice. Though a growing proportion of this disease is diagnosed in older patients, there are limited studies of older patients comparing cisplatin to carboplatin. This study compared survival outcomes of elderly patients with limited-stage SCLC treated with concurrent EC or EP and radiation. METHODS AND MATERIALS Limited-stage SCLC diagnosed at ages 66 to 80 years during 1992 to 2007 were selected from the Surveillance Epidemiology and End Results-Medicare database to compare EP with EC. Concurrent CRT was defined as starting radiation and cisplatin or carboplatin within 14 days. Study endpoints were overall survival (OS, time from diagnosis until death) and cause-specific survival (CSS, time from diagnosis until death from lung cancer). RESULTS Final analysis included 565 cases: 219 EP (39%) and 346 EC (61%), with median age 72 and gender ratio 1.0. A majority of the cases were stage III (85%). Median and 5-year OS were 13.8 months (95% confidence interval [CI], 11.4-15.0 months) and 10.2% (95% CI, 6.2-15.3%) for EP, versus 13.7 months (95% CI, 12.0-15.6 months) and 10.9% (95% CI, 7.6-14.8%) for EC (P = .51). CSS were also similar (P = .91). OS and CSS were not statistically different in single- or multivariable survival analysis. CONCLUSIONS EC and EP had similar survival outcomes, suggesting EC could be used with (or instead of) EP as the standard of care, at least in the elderly population.

Controversies in the management of stage III non-small-cell lung cancer

Lung cancer remains the leading cause of death in the USA and is the most common cancer both in incidence and in mortality globally (1.35 million deaths annually). Non-small-cell lung cancer accounts for >80% of all lung cancers 1. About 35–45% of non-small-cell lung cancer patients present with locally advanced non-metastatic stage III disease. However, confirmed stage III disease represents a very heterogeneous group ranging from borderline surgical candidate with minimal mediastinal involvement to bulky mediastinal nodes or contralateral nodal involvement with significant controversy regarding optimal management in these various situations. This article specifically addresses the role of surgery, radiotherapy and chemotherapy in multimodal approach to treat stage III patients with N2/N3 involvement and controversies surrounding these recommendations.

Prognostic potential of neutrophil-to-lymphocyte ratio and lymphocyte nadir in stage III non-small-cell lung cancer

AIM Studies have shown increased pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios to be predictive of survival in various cancers. Our aim was to evaluate the prognostic role of such inflammatory markers in non-small-cell lung cancer (NSCLC). METHODS One hundred and sixty-three patients with stage III NSCLC who received definitive treatment were included. Survival analysis was performed using Kaplan-Meier method. Hazard ratios for overall and recurrence-free survival were estimated using Cox proportional hazards model. RESULTS Both neutrophil-to-lymphocyte >Q75 (4.5) and lymphocyte nadir values <Q25 (0.25) and their unified values were associated with 90% increased overall mortality risk (p = 0.040) and a nonsignificant 50% decreased recurrence-free survival risk. CONCLUSION Our exploratory analysis showed markers of systemic inflammation predicted survival outcomes in advanced NSCLC. Future prospective data analyses are needed to confirm this potential.