Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases.

Mounting evidence suggests that radiation stimulates the immune system and this contributes to the abscopal effect, which is defined as "response at a distance from the irradiated volume." Though identified more than 50 years ago, the abscopal effect is revisited today. One rationale is that the abscopal effect is often observed with efficient immunotherapy. Here, we give an overview of the clinical data on the abscopal effect, generated by a combination of immunotherapy and radiotherapy (RT). Only papers that included RT in combination with immunotherapy were evaluated according to four main categories including RT parameters, sequencing of therapies, the definition of the abscopal effect, and patient selection. Twenty-four cases in 15 reports were reviewed. The results varied. Patient ages ranged from 24 to 74. RT dose (median total dose 18-58 Gy) varied. Biologically effective dose (BED) 10 was calculated to be a median 49.65 Gy (28-151 Gy). The time to a documented abscopal response ranged from less than a month to 12 months. The large variation concerning fractionation and sequencing of therapies indicates that these conflicting points need to be resolved, to generate for the abscopal effect to be clinically significant.

Can Hyperpolarized Helium MRI add to radiation planning and follow-up in lung cancer?

Locally advanced non-small-cell lung cancer (NSCLC) is a common disease with a low overall survival even with aggressive treatments. Standard imaging (CT and PET/CT) provide no information about normal lung function. We therefore, sought to pilot HeMRI in patients with non-small-cell lung cancer before and after definitive radiotherapy (RT). Five patients with NSCLC receiving RT were enrolled on a prospective IRB approved study. Patients underwent CT, FDG-PET and HeMRI before and (within 10 days) following RT. All images (CT, FDG-PET and HeMRI) were co-registered. The CT and PET GTVs were contoured, as well as the ventilation defects on HeMRI caused by the tumor. Patients also underwent pulmonary function tests (PFTs). Correlations between the images and PFTs were evaluated by linear regression. CT and FDG-PET tumor volumes were highly correlated (r² = 0.91 before treatment and 0.99 following RT). There was less correlation between HeMRI and CT or PET (r² = 0.67 (CT) and 0.38 (PET)) prior to treatment and 0.27 following RT). However, HeMRI volumes correlated very well with FEV1, both prior to and following RT. (r² = 0.89 and 0.83, respectively). ³Helium MRI scanning is feasible in NSCLC before and after treatment. HeMRI provides important functional information in addition to CT and CT/PET scanning.

Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma.

The current standard therapy for newly diagnosed glioblastoma is multimodal, comprising surgical resection plus radiotherapy and concurrent temozolomide, then adjuvant temozolomide for 6 months. This has been shown to provide survival benefits; however, the prognosis for these patients remains poor, and most relapse. The objective of this prospective Phase II study was to evaluate the efficacy and tolerability of protracted, dose-dense temozolomide therapy (100 mg/m(2) for 21 consecutive days of a 28-day cycle) in patients with recurrent glioblastoma or grade 3 gliomas who had previously received standard therapy. Of the 25 patients included (median age 50 years), 20 were evaluable for radiologic response. Two patients had partial responses and 10 had stable disease (60% overall clinical benefit); 8 patients (40%) progressed after the first treatment cycle. Five patients were not assessed for radiologic response due to early clinical progression but were included in the progression-free survival (PFS) and overall survival (OS) analyses. The median follow-up time was 7 months (range, 1-14 months). The median PFS was 3 months (95% confidence interval, CI, 1.8-4.2) and the median OS was 7 months (95% CI 5.1-8.9). The 6-month PFS rate (primary endpoint) was 17.3% (95% CI 1.7-32.2) and the 1-year OS rate was 12% (95% CI -1-25). This regimen was well tolerated. The most frequent adverse event was lymphopenia (grade 3-4 in 20 patients); no opportunistic infections were reported. Treatment was discontinued due to toxicity in 2 patients (grade 4 hepatic toxicity and thrombocytopenia). These data suggest that protracted, dose-dense temozolomide had modest activity with manageable toxicity in patients with recurrent high-grade glioma previously treated with temozolomide.

Clinical outcome of breast cancer patients with N3a (≥10 positive lymph nodes) disease: has it changed over years?

It has been shown that breast cancer patients with N3a (10 positive lymph nodes) had a poor prognosis. We planned to investigate the clinical outcome BC patients who presented with N3a disease and had no evidence of systemic metastasis at the time of diagnosis. We made a retrospective chart review of breast cancer patients who had ≥10 positive lymph nodes and received adjuvant systemic therapy in Marmara University Hospital between 1998 and 2008. We recorded clinical, pathologic and treatment characteristics of the patients and analyzed the survival outcome. We identified 73 patients with N3a disease who were treated in Marmara University Hospital between 1998 and 2008. The median age was 52. Most (75%) of the patients had invasive ductal histology, 75% had T2/T3 tumors, 36% had grade 3 tumors. The median number of metastatic lymph nodes was 15. Estrogen and progesterone receptors were both positive in 61% and both negative in 16+ tumors. Her-2/neu status was assessed in 68% of the tumors; 18% of patients had 3+ and 50% had negative scores. Six patients had triple negative tumors. All patients except one received adjuvant chemotherapy and radiotherapy. Seventy-four percent of patients received anthracycline/taxane-based chemotherapy. Fifty-nine patients received adjuvant endocrine therapy, 42% them received aromatase inhibitors. Five of the 13 Her-2 positive patients received adjuvant trastuzumab. With a median follow-up of 47 months, 5-year disease and overall survival rates were 66 and 81%, respectively. Twenty-four patients had relapsed and 14 patients died. Her-2 status and the number of lymph nodes (<20 vs. ≥20) had significant impact on disease-free survival in the univariate analysis (P=0.03 and 0.05, respectively) and Her-2 retained its significant impact on disease-free survival in the multivariate analysis (P=0.05). The prognosis of BC patients with N3a disease has changed favorably in the past decade with the current standards of care.

Tumor volume is a prognostic factor in non-small-cell lung cancer treated with chemoradiotherapy.

PURPOSE: To investigate whether primary tumor and nodal volumes defined on radiotherapy planning scans are correlated with outcome (survival and recurrence) after combined-modality treatment. METHODS AND MATERIALS: A retrospective review of patients with Stage III non-small-cell lung cancer treated with chemoradiation at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2000 to 2006 was performed. Tumor and nodal volume measurements, as computed by Eclipse (Varian, Palo Alto, CA), were used as independent variables, along with existing clinical factors, in univariate and multivariate analyses for association with outcomes. RESULTS: For patients treated with definitive chemoradiotherapy, both nodal volume (hazard ratio [HR], 1.09; p < 0.01) and tumor volume (HR, 1.03; p < 0.01) were associated with overall survival on multivariate analysis. Both nodal volume (HR, 1.10; p < 0.01) and tumor volume (HR, 1.04; p < 0.01) were also associated with local control but not distant metastases. CONCLUSIONS: In addition to traditional surgical staging variables, disease burden, measured by primary tumor and nodal metastases volume, provides information that may be helpful in determining prognosis and identifying groups of patients for which more aggressive local therapy is warranted.

Esophagus in-field: a new predictor for esophagitis.

PURPOSE: To define optimization parameters for limiting esophageal toxicity with concurrent chemoradiation (CRT) for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective analysis of patients treated with concurrent chemoradiation at the Dana-Farber/Brigham and Women's Hospital Cancer Center was done with IRB approval. All patients were treated with concurrent CRT. All patients underwent 3-D conformal radiotherapy planned with ECLIPSE (Varian, Palo Alto, CA) treatment planning system. Patients had their esophagus contoured in two ways: the entire esophagus (Esoph) and esophagus in-field (Esoph(in)). Together with clinical variables, dose volume metrics including mean dose, V5-V60 of both structures (Esoph and Esoph(in)) were analyzed for correlation with acute esophagitis (≥ grade 3) and late esophageal stricture. The analyses and graphics were completed using R (R Development Core Team, 2006). Logistic regression analysis was used to assess the relationships between dosimetric factors and swallowing complications while controlling for non-dosimetric variables. RESULTS: 109 patients were studied between 2000 and 2006. 25% of patients had grade 3 or greater acute esophagitis. 5/109 (5.5%) had late esophageal stricture with a six-month actuarial risk of stricture of 6.5% (95% CI=1-11%). Mean dose and V45-V60 for both Esoph and Esoph(in) significantly correlated with development of acute esophagitis. V55 and V60 for both Esoph and Esoph(in) significantly correlated with development of stricture. On Multivariate analysis V55 of the Esoph and Esoph(in) was most predictive of toxicity. Limiting the V55 Esoph(in) to 50% was the best cut-point for acute esophagitis. CONCLUSIONS: In the setting of concurrent CRT, V55 of the Esoph or Esoph(in) is the best predictor of acute esophagitis.

Outcomes of patients with stage III nonsmall cell lung cancer treated with chemotherapy and radiation with and without surgery.

BACKGROUND: The objective of this study was to identify the factors associated with improved outcome after treatment for stage III nonsmall cell lung cancer (NSCLC). METHODS: A retrospective review of stage III NSCLC patients treated at who were treated at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center was done with institutional review board approval. Patients were followed for toxicity, local and distant failure, and overall survival. Multivariate Cox logistic regression analysis was used to determine the factors associated with treatment outcome. RESULTS: Between August 2000 and November 2006, 144 patients received concurrent chemoradiation (CRT) for stage III NSCLC. Eighty of 144 patients were men (56%), and the median age was 61 years (range, 33-81 years). Sixty-two patients (43%) had stage IIIA NSCLC, and 82 patients (57%) had stage IIIB NSCLC. Radiotherapy (RT) was given concurrently with chemotherapy to all patients; 100 patients (69%) received CRT without surgery, and 44 patients (31%) received with neoadjuvant CRT followed by surgical resection. The median RT dose was 60 grays (Gy) (range, 46-70 Gy). The median follow-up was 15 months (range, 3-64 months), the median potential follow-up was 37 months (range, 12-84 months), and the median overall survival was 22 months (95% confidence interval, 15-28 months). The 1-year and 2-year survival rates were 68% and 47%, respectively. Among the 44 patients who underwent resection, the median survival was 61 months, and the 2-year survival rate was 73%. On multivariate analysis, stage at the time of treatment (stage IIIA vs stage IIIB) and use of surgery were the only factors associated with improved outcome (P=.01 and P=.001, respectively). CONCLUSIONS: In this retrospective series, those patients who were able to undergo resection appeared to have improved outcome after induction CRT.

Analysis of p53 gene polymorphisms and protein over-expression in patients with breast cancer.

p53 polymorphic variants play an important role in the determination of tumor phenotype and characteristics in breast cancer. In this study, we examined three common polymorphisms in p53 gene and their haplotype combinations to assess their potential association with inherited predisposition to breast cancer development, in relations with the protein over-expression and patients' demographic data. A total of 99 patients with breast cancer and 107 age-matched healthy controls were included in the study. Genotypes were determined using PCR-RFLP and DNA sequencing techniques. Evaluation of p53 protein over-expression was also examined by immunohistochemistry. Among three polymorphisms, increased codon 72 Pro allele frequency (p = 0.0067) and the presence of Pro allele were found to be significantly associated with breast cancer (p = 0.013). A significant risk was also found in subjects with combinations of specific haplotypes and genotypes. Most of breast cancer women especially younger than 50 years carry at least one p53 polymorphism (p = 0.001). There was no any association between these three p53 polymorphisms and the protein over-expression, separately or in interaction, with breast cancer. In conclusion, presence of proline allele at codon 72 alone, and its special combinations with other two polymorphisms appear to be a significant risk factor for breast cancer. Determination of well-known p53 polymorphisms might be a good predictor for breast cancer development especially in women younger than 50 years.

Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy.

PURPOSE: To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. METHODS AND MATERIALS: Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Women's Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. RESULTS: A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose-volume metrics, including the volume of the larynx receiving >or=50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving >or=50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. CONCLUSION: Aspiration and stricture are common side effects after intensity-modulated radiotherapy for head-and-neck squamous cell carcinoma. The dose given to the larynx and inferior constrictors correlated with these side effects.

Intensity-modulated radiotherapy for head and neck cancer.

Intensity-modulated radiation therapy (IMRT) is a new radiation delivery technique that allows more precise delivery of radiation and optimization of the dose intensity to specific volumes while sparing the dose to critical normal structures. Using IMRT in head and neck cancers is attractive because of close proximity of the tumor targets to critical normal structures such as the spine, eyes, and parotid glands. IMRT has been shown in a number of clinical sites to improve local control and decrease side effects. Specifically, IMRT has shown the ability to preserve salivary function through sparing of the parotid glands. At the same time, there remain some uncertainties in terms of target delineation, secondary cancers, and side effects to swallowing function that may be increased with IMRT. Multi-institutional studies of IMRT are under way, and these studies, combined with refinements of the technique, should lead to continued improvement in the radiotherapeutic management of head and neck cancer.