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Background: A randomised trial was carried out comparing chemo-radiation (CTRT) vs. radiotherapy (RT) in patients of carcinoma cervix and showed similar rates of pelvic disease control, disease free survival and overall survival. Late toxicity is presented., Methods: Between December 2000 and July 2006, 180 patients of carcinoma cervix were randomly assigned to RT + weekly cisplatin (n = 94) or RT alone (n = 86). Late toxicity was prospectively scored using RTOG criteria in 156 evaluable patients, 79 and 77 respectively and is presented as crude incidence for rectum, bladder, small intestine, vagina, skin and bone and also as actuarial incidence for rectum and bladder., Results: The median follow up of surviving patients was 10.4 years (minimum - 6.5 years). Crude incidence, CTRT vs. RT, of late toxicities were: rectal (7.5% vs. 5%, p = 0.22), bladder (15% vs. 10.4%, p = 0.76), small bowel (3% vs. 1.2%, p = 0.51), vagina (25% vs. 35%, p = 0.35) while the actuarial risk of grades 3-5 rectal and bladder toxicities by 5 years were 13% vs. 10% (p = 0.698) and 16% vs. 14.8% (p = 0.783) respectively. Bladder toxicity appeared later then rectal toxicity (median 49.4 vs. 21.4 months). Severe bone toxicity (fractures) were higher in the CTRT arm, 5% vs. 0%, p = 0.018. On multivariate analysis vaginal involvement (p = 0.016) and bulky tumor (p = 0.020) were associated with severe vaginal morbidity while rectal point dose > 80% (p = 0.040) was associated with a higher incidence of rectal toxicity., Conclusion: Bone toxicity was significantly increased by addition of CT to RT and patients continued to experience toxicity at longer periods of follow up albeit disease free., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Cyclophosphamide (CP), an alkylating chemotherapeutic drug, is catalyzed by the Phase I cytochrome P450 (CYPs) isozymes - CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19. Hence this study aimed to elucidate the influence of genetic variants in CYP450 metabolizing enzymes on breast cancer treatment outcomes, using multi-analytical approaches., Methods: Treatment response was noticed in 111 patients whereas 234 patients were followed for myelo-toxicity. Eight known functional single nucleotide polymorphisms (SNPs) in six CYP450 genes were selected for the study on the basis of CP metabolizing enzyme polymorphisms. The possible functional effects of CYP450 polymorphisms were determined by online Web servers F-SNP. Multifactor dimensionality reductions (MDR), haplotype analysis were combined with logistic regression to characterize gene-gene interaction model with treatment outcomes., Results: Haplotype analysis revealed significant association of G(rs10509681)-*1(rs1799853)-*3(rs1057910)-G(rs4244285) on chromosome 10 with overall toxicity (P=0.024) and grade 2-4 leucopenia (P=0.03). On MDR analysis, CYP3A5*3, CYP2C19*2, CYP2B6*5 yielded the highest testing accuracy for treatment response (0.60) and CYP2C8*3, CYP2C9*2 for overall toxicity (0.50)., Conclusion: Multi-analytical approaches may provide a better clinical prediction of pharmacogenetic based treatment outcomes in breast cancer patients., (Copyright © 2014. Published by Elsevier B.V.)

Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene-gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (Pcorr=0.0465, Pcorr=0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (Pcorr=0.0465). Haplotype analysis further revealed ACYP3A4-ACYP3A5 haplotype to be significantly associated with responders (Pcorr=0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with 'grade 1 or no leucopenia' (Pcorr=0.0465, Pcorr=0.048). On evaluating higher order gene-gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2-4 anemia and dose delay/reduction due to neutropenia (P=0.024, P=0.004, P=0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Objective: Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione-S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients., Method: Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile105Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene-gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis., Results: In single-locus analysis, Ile/Val and Ile/Val+Val/Val genotypes of the GSTP1 Ile105Val (rs1695) polymorphism reached statistical significance with grade 2-4 anemia (P=0.019, P=0.027). On performing gene-gene interaction analysis, GSTM1 null-GSTP1 Ile/Val was significantly associated with response to NACT (P=0.032). On evaluating higher order gene-gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile105Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile105Val showed significant association with treatment response, grade 2-4 anemia, and dose delay/reduction due to neutropenia (P=0.046, P=0.027, P=0.026), respectively., Conclusion: Multi-analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes.

Aim: Chemo-radiotherapy (CRT) is the standard of care for treating almost all cervical carcinoma patients on the basis of the National Cancer Institute (NCI) alert. The disease burden in developing countries is more advanced with poor general condition than in patients in the trials prompting the NCI alert. Therefore, practicing CRT as standard of care should be tested in these patients., Methods: A randomized controlled trial was conducted comparing radiotherapy (RT) alone with CRT (cisplatin 40 mg/m(2) weekly × 5) in patients with localized stage Ib to IVa cervical carcinoma between September 2006 and December 2008. External beam RT was delivered using a telecobalt unit. This was followed by 12-18 Gy of brachytherapy., Results: In total, 305 patients were recruited: RT alone (150) and CRT (155). The median follow up was 34 months. Locoregional relapse-free survival (LRFS) at 2 years was 55 and 54% for the RT and CRT group, respectively, with a median LRFS time of 27 and 30 months for the RT and CRT group, respectively, (P = 0.624). Overall survival (OS) at 2 years was 58 and 60%, with a median OS of 31 and 34 months for the RT and CRT group, respectively; (P = 0.9). The toxicity profile, both acute and late, were comparable in both groups;, Conclusion: No improvement in outcome was seen with addition of cisplatin. In the Indian subcontinent where patients present at late stages with poor general condition and limited access to good supportive care, RT alone still remains a valid option., (© 2013 Wiley Publishing Asia Pty Ltd.)

Background and Purpose: Following our phase II experience, a randomised trial was undertaken to evaluate the efficacy of adding chemotherapy to radiotherapy in patients with unresectable squamous cell cancer of the esophagus., Patients and Methods: Patients randomised to the RT group received 50 Gy/25 fx/5 weeks of teletherapy followed 1-2 weeks later with 12 Gy/2 fx of high-dose-rate intra-lumenal brachytherapy spaced a week apart. Following the first 3 years of recruitment, due to unexpected late morbidity, brachytherapy was excluded and the protocol modified to 66 Gy/33 fx/6.5 weeks. The CRT group received identical radiotherapy with concurrent weekly cisplatin at 35 mg/m(2) for 6-7 cycles., Results: Between April 1999 and December 2005, 125 patients were randomised to a RT (n=60) or CRT group (n=65). Radiotherapy treatment was completed in 78% (47/60) of the RT group and 89% (58/65) of the CRT group (P=0.10). Six or more cycles of cisplatin could be delivered in 63% (41/65), which resulted in RTOG grade 3 neutropenia of 3%. Late morbidity in the form of ulcers (5% vs. 15% odds ratio 0.29, 95% CI 0.08-1.11, P=0.08) and strictures (13% vs. 28%, odds ratio 0.40, 95% CI 0.16-1.01, P=0.05) was observed in the RT and CRT groups, respectively. At a median follow up of 23 months of all patients alive (range 6-82 months) and with 95/125 events, the median, 1, 2 and 5 year projected survival was 7.1 months, 32.3%, 22.8% and 13.7% vs. 13.4 months, 57.6%, 38.9% and 24.8% for the RT and CRT groups, respectively (hazard ratio 0.65, 95% CI 0.44-0.98, P=0.038)., Conclusions: The addition of concurrent cisplatin to radiotherapy resulted in a modest improvement in survival and was associated with manageable additional acute and late morbidity.

Purpose: To ascertain factors that could influence the development of ulcers and strictures in the definitive management of squamous cell carcinoma (SCC) of esophagus treated with external beam radiotherapy (EBRT), high-dose-rate (HDR) intralumenal radiotherapy (ILRT) with or without concurrent weekly cisplatin (CDDP @ 35 mg/m2) chemotherapy (CT)., Materials and Methods: Between 1990-2005, 244 patients with inoperable SCC of esophagus were identified from our database and grouped into one of the following: those receiving at least 60 Gy EBRT (Gp E, n=44); EBRT followed by HDR-ILRT (Gp E+I, n=98); at least 50 Gy EBRT with CT (Gp E+C, n=68); EBRT+HDR-ILRT + CT (Gp E+I+C, n=34). Ulcers (discovered on endoscopy) and strictures evident on a barium swallow (which needed dilatations) were scored as treatment induced, if the biopsy was negative. Factors likely to influence their outcome were analyzed., Results: The groups were matched for all patient and disease characteristics except pretreatment hemoglobin and Karnofsky performance score (KPS), which were lower in Gp E. The incidence of ulcers was 7%, 8%, 6% and 21% (P=0.08) while that of strictures was 14%, 9%, 21% and 41% (P=0.00) for the groups E, E+I, E+C and E+I+C respectively. On univariate analysis, patients with better KPS (P=0.03), treated with narrow applicators (6 mm vs. 10 mm, P=0.00), received CT (P=0.00) or assigned to Gp E+I+C (P =0.00) were more likely to develop strictures, with a trend for development of ulcers in Gp. E+I+C (P=0.08). Logistic regression retained only Gp E+I+C for development of ulcers (OR 10.36, 95% CI 1.2-89.1, P=0.03) and strictures (OR 4.2, 95% CI 1.4-12.6, P=0.00)., Conclusion: Treatment intensification as in Gp E+I+C results in about a three-fold increase in treatment induced late morbidity which can adversely impact on swallowing function and therefore emphasizes the need for optimisation of HDR-ILRT when used in a CT+RT protocol.

Background and Purpose: To determine the safety and efficacy of concomitant boost radiotherapy (CBRT) with concurrent cisplatin chemotherapy (CT) in advanced head and neck cancers., Patients and Methods: Between February 2000 and June 2001, 95 previously untreated patients of advanced head and neck cancers were treated with CBRT and concurrent cisplatin CT. CBRT consisted of: phase I--44 Gy/22fx/4.5 weeks, phase IIa--16 Gy/8fx/1.5 weeks and phase IIb--10 Gy/8fx (delivered as a second daily fraction after a gap of 6h along with phase IIa). CT (cisplatin 35 mg/m(2)) was administered weekly usually preceding CBRT by an hour., Results: The median follow-up was 39 months (range 8-50 months). CBRT compliance (70 Gy in 40-44 days) was seen in 66% (63/95). Six cycles of CT was delivered in 73% (69/95). Acute grade III/IV mucosal toxicity was seen in 79% and resulted, on average, in a total weight loss of 7.9 kg from a mean pretreatment weight of 51 kg. Nasogastric tube placements were required in 26% (25/95) for an average duration of 19.3 days. Grade III leucopenia was seen in 2%. Mortality during and within 30 days of treatment was seen in 14% (13/95). Crude incidence of late subcutaneous fibrosis (grade III) was 21% (12/57) and a case of mandibular necrosis and thyroid cartilage necrosis each were seen. Initial loco regional disease clearance was seen in 59% (56/95) and the Kaplan-Meier estimates of 3-year loco-regional control rate and overall survival were 25% (median 7 months, 95% C.I. 3-11) and 27% (median 12 months, 95% C.I. 8-16), respectively., Conclusions: On present evidence, in the settings of a developing country, CBRT with concurrent cisplatin cannot be recommended as primary therapy in advanced head and neck cancers without formal comparison with other treatment modalities.

Between August 1996 and May 1999, 50 consecutive, previously untreated patients with carcinoma of the esophagus and who were inoperable for various reasons were treated with weekly doses of cisplatin (35 mg/m2, maximum 7 cycles) concurrent with either 66 Gy/33 fractions external beam radiotherapy (EBRT) (n = 42) or 50 Gy/25 fractions EBRT and two insertions of high-dose-rate intraluminal radiotherapy of 6 Gy each, spaced a week apart (n = 8). Eighty-two percent (41/50) of the patients received the stipulated radiotherapy (RT) dose. Seventy-six percent (38/50) received at least 6 cycles of chemotherapy. Neutropenia in the form of WHO grade 11-12%, (6/50) and grade III-2% (1/50) was observed. Grade III emesis was seen in 8% (4/50). Improvement in the swallowing status was seen in 84% (42/50). Median duration of dysphagia relief was 6 months. The median overall survival was 9 months with 17% estimated to be alive after 4 years. Combined treatment with single agent cisplatin and definitive radiotherapy for inoperable cancer of the esophagus is safe, well tolerated and reasonably efficacious.

Purpose: The study aimed to apply the atlas of complication incidence (ACI) method to patients receiving radical treatment for head and neck squamous cell carcinomas (HNSCC), to generate constraints based on dose-volume histograms (DVHs), and to identify clinical and dosimetric parameters that predict the risk of grade 3 oral mucositis (g3OM) and pharyngeal dysphagia (g3PD).Methods and Materials: Oral and pharyngeal mucosal DVHs were generated for 253 patients who received radiation (RT) or chemoradiation (CRT). They were used to produce ACI for g3OM and g3PD. Multivariate analysis (MVA) of the effect of dosimetry, clinical, and patient-related variables was performed using logistic regression and bootstrapping. Receiver operating curve (ROC) analysis was also performed, and the Youden index was used to find volume constraints that discriminated between volumes that predicted for toxicity.Results: We derived statistically significant dose-volume constraints for g3OM over the range v28 to v70. Only 3 statistically significant constraints were derived for g3PD v67, v68, and v69. On MVA, mean dose to the oral mucosa predicted for g3OM and concomitant chemotherapy and mean dose to the inferior constrictor (IC) predicted for g3PD.Conclusions: We have used the ACI method to evaluate incidences of g3OM and g3PD and ROC analysis to generate constraints to predict g3OM and g3PD derived from entire individual patient DVHs. On MVA, the strongest predictors were radiation dose (for g3OM) and concomitant chemotherapy (for g3PD). [ABSTRACT FROM AUTHOR]