Ramesh Rengan

Predicting Radiation Pneumonitis After Chemoradiation Therapy for Lung Cancer: An International Individual Patient Data Meta-analysis

BACKGROUNDnRadiation pneumonitis is a dose-limiting toxicity for patients undergoing concurrent chemoradiation therapy (CCRT) for non-small cell lung cancer (NSCLC). We performed an individual patient data meta-analysis to determine factors predictive of clinically significant pneumonitis.nnnMETHODS AND MATERIALSnAfter a systematic review of the literature, data were obtained on 836 patients who underwent CCRT in Europe, North America, and Asia. Patients were randomly divided into training and validation sets (two-thirds vs one-third of patients). Factors predictive of symptomatic pneumonitis (grade ≥2 by 1 of several scoring systems) or fatal pneumonitis were evaluated using logistic regression. Recursive partitioning analysis (RPA) was used to define risk groups.nnnRESULTSnThe median radiation therapy dose was 60 Gy, and the median follow-up time was 2.3 years. Most patients received concurrent cisplatin/etoposide (38%) or carboplatin/paclitaxel (26%). The overall rate of symptomatic pneumonitis was 29.8% (n=249), with fatal pneumonitis in 1.9% (n=16). In the training set, factors predictive of symptomatic pneumonitis were lung volume receiving ≥20 Gy (V(20)) (odds ratio [OR] 1.03 per 1% increase, P=.008), and carboplatin/paclitaxel chemotherapy (OR 3.33, P<.001), with a trend for age (OR 1.24 per decade, P=.09); the model remained predictive in the validation set with good discrimination in both datasets (c-statistic >0.65). On RPA, the highest risk of pneumonitis (>50%) was in patients >65 years of age receiving carboplatin/paclitaxel. Predictors of fatal pneumonitis were daily dose >2 Gy, V(20), and lower-lobe tumor location.nnnCONCLUSIONSnSeveral treatment-related risk factors predict the development of symptomatic pneumonitis, and elderly patients who undergo CCRT with carboplatin-paclitaxel chemotherapy are at highest risk. Fatal pneumonitis, although uncommon, is related to dosimetric factors and tumor location.

Central-Airway Necrosis after Stereotactic Body-Radiation Therapy

Stereotactic body-radiation therapy is a novel technique that aims to deliver higher doses of radiation to cancers in a more focused way. However, adjacent tissues also get higher doses and fatal toxicities can emerge, as in one patient.

Predicting Esophagitis After Chemoradiation Therapy for Non-Small Cell Lung Cancer: An Individual Patient Data Meta-Analysis

PURPOSEnConcurrent chemoradiation therapy (CCRT) improves survival compared with sequential treatment for locally advanced non-small cell lung cancer, but it increases toxicity, particularly radiation esophagitis (RE). Validated predictors of RE for clinical use are lacking. We performed an individual-patient-data meta-analysis to determine factors predictive of clinically significant RE.nnnMETHODS AND MATERIALSnAfter a systematic review of the literature, data were obtained on 1082 patients who underwent CCRT, including patients from Europe, North America, Asia, and Australia. Patients were randomly divided into training and validation sets (2/3 vs 1/3 of patients). Factors predictive of RE (grade≥2 and grade≥3) were assessed using logistic modeling, with the concordance statistic (c statistic) used to evaluate the performance of each model.nnnRESULTSnThe median radiation therapy dose delivered was 65 Gy, and the median follow-up time was 2.1 years. Most patients (91%) received platinum-containing CCRT regimens. The development of RE was common, scored as grade 2 in 348 patients (32.2%), grade 3 in 185 (17.1%), and grade 4 in 10 (0.9%). There were no RE-related deaths. On univariable analysis using the training set, several baseline factors were statistically predictive of RE (P<.05), but only dosimetric factors had good discrimination scores (c>.60). On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade≥2 and grade≥3 RE, with good calibration and discrimination. Recursive partitioning identified 3 risk groups: low (V60<0.07%), intermediate (V60 0.07% to 16.99%), and high (V60≥17%). With use of the validation set, the predictive model performed inferiorly for the grade≥2 endpoint (c=.58) but performed well for the grade≥3 endpoint (c=.66).nnnCONCLUSIONSnClinically significant RE is common, but life-threatening complications occur in <1% of patients. Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability. Efforts to reduce the V60 should be prioritized, with further research needed to identify and validate new predictive factors.

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

BACKGROUNDnElective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT.nnnMETHODSnWe assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy.nnnRESULTSnOf the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT.nnnCONCLUSIONSnNodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.

Disparities in the treatment and outcomes of lung cancer among HIV-infected individuals

Objectives:HIV-infected people have elevated risk for lung cancer and higher mortality following cancer diagnosis than HIV-uninfected individuals. It is unclear whether HIV-infected individuals with lung cancer receive similar cancer treatment as HIV-uninfected individuals. Design/methods:We studied adults more than 18 years of age with lung cancer reported to the Texas Cancer Registry (Nu200a=u200a156u200a930) from 1995 to 2009. HIV status was determined by linkage with the Texas enhanced HIV/AIDS Reporting System. For nonsmall cell lung cancer (NSCLC) cases, we identified predictors of cancer treatment using logistic regression. We used Cox regression to evaluate effects of HIV and cancer treatment on mortality. Results:Compared with HIV-uninfected lung cancer patients (Nu200a=u200a156u200a593), HIV-infected lung cancer patients (Nu200a=u200a337) were more frequently young, non-Hispanic black, men, and with distant stage disease. HIV-infected NSCLC patients less frequently received cancer treatment than HIV-uninfected patients [60.3 vs. 77.5%; odds ratio 0.39, 95% confidence interval (CI) 0.30–0.52, after adjustment for diagnosis year, age, sex, race, stage, and histologic subtype]. HIV infection was associated with higher lung cancer-specific mortality (hazard ratio 1.34, 95% CI 1.15–1.56, adjusted for demographics and tumor characteristics). Inclusion of cancer treatment in adjusted models slightly attenuated the effect of HIV on lung cancer-specific mortality (hazard ratio 1.25; 95% CI 1.06–1.47). Also, there was a suggestion that HIV was more strongly associated with mortality among untreated than among treated patients (adjusted hazard ratio 1.32 vs. 1.16, P-interactionu200a=u200a0.34). Conclusion:HIV-infected NSCLC patients were less frequently treated for lung cancer than HIV-uninfected patients, which may have affected survival.

Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

We investigated the effect of 2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl} propanenitrile (NVP-BEZ235) (Novartis, Basel Switzerland), a dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor currently being tested in phase I clinical trials, in radiosensitization. NVP-BEZ235 radiosensitized a variety of cancer cell lines, including SQ20B head and neck carcinoma cells and U251 glioblastoma cells. NVP-BEZ235 also increased in vivo radiation response in SQ20B xenografts. Knockdown of Akt1, p110α, or mTOR resulted in radiosensitization, but not to the same degree as with NVP-BEZ235. NVP-BEZ235 interfered with DNA damage repair after radiation as measured by the CometAssay and resolution of phosphorylated H2A histone family member X foci. NVP-BEZ235 abrogated the radiation-induced phosphorylation of both DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia telangiectasia mutated. Knockdown of either p110α or mTOR failed to decrease the phosphorylation of DNA-PKcs, suggesting that the effect of the drug was direct rather than mediated via p110α or mTOR. The treatment of cells with NVP-BEZ235 also promoted autophagy. To assess the importance of this process in radiosensitization, we used the autophagy inhibitors 3-methyladenine and chloroquine and found that either drug increased cell killing after NVP-BEZ235 treatment and radiation. Knocking down the essential autophagy proteins autophagy related 5 (ATG5) and beclin1 increased NVP-BEZ235-mediated radiosensitization. Furthermore, NVP-BEZ235 radiosensitized autophagy-deficient ATG5(−/−) fibroblasts to a greater extent than ATG5(+/+) cells. We conclude that NVP-BEZ235 radiosensitizes cells and induces autophagy by apparently distinct mechanisms. Inhibiting autophagy via pharmacologic or genetic means increases radiation killing after NVP-BEZ235 treatment; hence, autophagy seems to be cytoprotective in this situation. Our data offer a rationale for combining NVP-BEZ235 along with an autophagy inhibitor (i.e., chloroquine) and radiation in future clinical trials.

Stereotactic Body Radiation Therapy for Lung Cancer

Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed.

A Phase I Trial of the HIV Protease Inhibitor Nelfinavir with Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer A Report of Toxicities and Clinical Response

Background: The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). Methods: Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis. Results: Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%). Conclusion: Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.

Effect of HIV on survival in patients with non-small-cell lung cancer in the era of highly active antiretroviral therapy: a population-based study.

BACKGROUNDnHIV-infected patients with lung cancer have been reported to have poorer survival than uninfected patients. Whether this outcome holds true in the era of highly active antiretroviral therapy (HAART) is unclear. We examined the effect of HIV infection on clinical outcome in patients with lung cancer who are also receiving HAART.nnnMETHODSnPatients diagnosed with non-small-cell lung cancer (NSCLC) from Jan 1, 2000, to Dec 31, 2005, with or without HIV infection were identified by querying the Surveillance, Epidemiology, and End Results registry and the Medicare lung cancer database. Survival analysis by stage and treatment delivered comparing the HIV-infected patients with uninfected controls was done with Kaplan-Meier and Cox models with propensity score adjustments.nnnFINDINGSn71,976 patients with NSCLC were identified as uninfected controls and 322 patients with NSCLC were identified in the HIV group; median age was 75 years for both groups. Median overall survival for all stages was 7·0 months (95% CI 7·0-7·0) for uninfected controls versus 8·0 months (6·0-10·0) for the HIV group (p=0·16); for those with stage I/II disease it was 37·0 months (36·0-39·0) versus 43·0 months (26·0-58·0; p=0·37); for those with stage IIIA/IIIB disease it was 7·0 months (7·0-7·0) versus 3·0 months (2·0-8·0; p=0·051); and for those with stage IV disease it was 3·0 months for both groups (95% CI 3·0-3·0 for controls; 2·0-5·0 for HIV group; p=0·77). After propensity score adjustment, the survival difference in stage IIIA/IIIB was no longer seen (hazard ratio 0·88; 95% CI 0·71-1·09). The median survival for HIV infected patients with stage I or II NSCLC who underwent surgical resection was 58·0 months (95% CI 57·0-60·0) for uninfected controls versus 50·0 months (42·0 to unestimable) for the HIV group (p=0·88).nnnINTERPRETATIONnWe noted no significant difference in clinical outcome between patients with HIV and uninfected controls with NSCLC. Survival after curative surgical resection in early-stage patients was similar in HIV-infected individuals and uninfected controls. These data suggest that HIV status should not affect therapeutic decision making in NSCLC.nnnFUNDINGnUS National Cancer Institute (award number UC2CA148310).

The Role of Radiation Therapy in Malignant Thymoma: A Surveillance, Epidemiology, and End Results Database Analysis

Introduction: The potential benefits and long-term complications of radiotherapy treatment for malignant thymoma are unclear. This is a retrospective analysis of outcome in patients with malignant thymoma from the Surveillance, Epidemiology, and End Results database between 1973 and 2005. Methods: Of the 1987 patients identified, 1334 were analyzed. Patients were categorized according to the Masaoka staging system as stage I to IIA, IIB or III to IV. The primary end points were overall survival, cardiac mortality, and the development of secondary malignancies. Results: Patients received surgery and radiation (50%), surgery alone (26%), radiation alone (12%), or no treatment (12%). The median follow-up time for survivors was 65 months (range, 1–361 months). There was no significant increase in the 12-year cumulative incidence rate of death from heart disease (10.2% radiation versus 7.5% no radiation, p = 0.83) or incidence of secondary malignancies (11.7% versus 12.4%, p = 0.70) with radiation. Compared with surgery alone, adjuvant radiation significantly improved overall survival in patients with stage III to IV disease (p = 0.04) and demonstrated a nonsignificant trend in patients with stage IIB disease (p = 0.09). However, after excluding patients surviving less than 4 months to account for surgical mortality, the benefit with radiation was no longer significant (stage IIB: p = 0.45, stage III–IV: p = 0.44). Conclusions: Radiation does not seem to increase the risk of cardiac mortality or secondary malignancy in patients with malignant thymoma. Although the routine use of postoperative radiotherapy in malignant thymoma does not appear warranted, high-risk patients may benefit from adjuvant radiation. This study can help to design prospective trials to further establish the role of radiotherapy in malignant thymoma.