Predictors of toxicity after neoadjuvant chemoradiotherapy for locally advanced gall bladder cancer

Background: The present study evaluated the correlation of hepatobiliary toxicity and radiation dose received in patients undergoing neoadjuvant chemoradiotherapy (NACRT) for locally advanced unresectable gall bladder cancers (LAGBC). Methods: Twenty-six patients with LAGBC, treated with NACRT (55–57 Gy/25 fractions/5 weeks and weekly gemcitabine 300 mg/m2) within a phase II study, were included. Whenever feasible, surgery was performed after NACRT. Acute and late hepatobiliary toxicity was recorded. Treatment scans were retrieved to delineate central porto-hepatobiliary system (CPHBS), resected liver surface, segment IV B and V, and duodenum. The doses received by these structures were recorded and correlated with toxicity. Results: Of 26 patients, 20 (77%) had partial or complete response and 12 (46%) had R0 resection. At the median follow-up of 38 months, overall survival was 38%. Eight (30%) patients had post-treatment toxicity, of which most common was biliary toxicity (30%). A correlation was observed between the biliary leak and V45Gy CPHBS >50 cm3 (P = 0.070). Higher toxicity was observed in those with metallic stents (P = 0.072). Conclusion: The incidence of the biliary leak was 46%. CPHBS dose was found to correlate with biliary leaks. Restricting V45Gy CPHBS <50 cm3 and using plastic stent may facilitate a reduction in hepatobiliary toxicity in patients undergoing NACRT and surgery.

A comparative analysis of quality of life after postoperative intensity-modulated radiotherapy or three-dimensional conformal radiotherapy for cervical cancer

AIMS: The aim of this study is to compare the quality of life (QOL) between adjuvant three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) for cervical cancer. MATERIALS AND METHODS: QOL assessment was done at the baseline and then longitudinally after completing (chemo) radiation. All patients completed EORTC QLQ-C30 and EORTC QLQ Cx-24 modules. Independent-sample t-test was used to compare the mean scores between the two groups. Analysis of variance was used to compare differences in QOL measures over the six time points (baseline, post-RT, 3, 6, 9, and 12 months after treatment) and between treatment groups (3DCRT vs. IMRT). Linear mixed model was also performed to account for attrition. RESULTS: Overall, 64 patients (image-guided IMRT, n = 40 and 3DCRT, n = 24) completed QOL assessment. The median age and follow-up period were 48 years and 15.5 months, respectively. General QOL domains such as emotional (at 12 months, P = 0.04) and social (at 3 months, P = 0.02 and 12 months, P = 0.03) were better with IMRT. Pain (12 months, P = 0.03); fatigue (12 months, P = 0.05); nausea and vomiting (12 months, P = 0.03); insomnia (post-RT, P = 0.05 and 12 months, P = 0.03); appetite loss (post-RT and 12 months, P = 0.04); and diarrhea (6 months, P = 0.02 and 12 months, P = 0.003) scores were significantly better with IMRT. On linear mixed model analysis, there was a significant interaction between treatment cohort and assessment intervals for physical, emotional, and social functioning, appetite loss, diarrhea, lymphedema, and menopausal symptom scores were significantly better with IMRT. CONCLUSIONS: Treatment technique (IMRT vs. 3DCRT) impacts early QOL in undergoing adjuvant radiation for cervical cancer.

Locally advanced cervical cancer: A study of 5-year outcomes

Background: Cervical cancer is the second most common cancer among Indian women. This present retrospective study was conducted to report patient outcomes with locally advanced cervical cancer treated in the year 2010. Materials and Methods: Case records of cervical cancer patients registered from January 1, 2010, to December 31, 2010 were retrieved. A total of 1200 patients were registered, of which 583 received either definitive or adjuvant radiotherapy (RT). Of these, 345 patients who received complete treatment at our hospital were included for outcome analysis. Descriptive statistics were used to summarize patient- and treatment-related variables, and Kaplan–Meier analysis was performed for survival analysis. Results: The median age was 56 years (range: 33–90). Squamous carcinoma was the most common histology (91.4%) and the majority were FIGO Stage III (45.4%). Median follow-up of the cohort was 44 months (1–85 months). The 5-year disease-free survival (DFS) across stages was 50%. Most important predictor of DFS was FIGO staging (Stage II vs. Stage III: 62% vs. 45%) and use of concurrent chemoradiotherapy (CTRT) l (RT vs. CTRT: 32% vs. 57%, respectively). Patients aged >70 years had a significantly poor DFS at 5 years; however, did not have any effect on survival. Grade 3 or more late toxicity was seen in only 5% of the patients. Conclusion: Five-year DFS of 62% and 45% of Stage II and III patients treated under routine care represents comparable stage-matched results to the rest of the world, respectively.

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

Darier's disease following radiotherapy for carcinoma of cervix.

Darier-White disease is due to a defect in the ATP2A2 gene encoding the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2b). We report a case of carcinoma cervix in whom Darier's disease manifested after the initiation of radiation therapy. Conventional cytogenetics on peripheral blood revealed non-clonal constitutional autosomal and X chromosome abnormalities suggesting radiation induced gene toxicity. Occurrence of Darier's disease in our case could be due to treatment induced sustained differentiation in the Darier's affected skin by an unknown mechanism. Late onset or sporadic Darier's disease is the other possibility.