Association of genetic variability in enzymes metabolizing chemotherapeutic agents with treatment response in head and neck cancer cases.

AIM: The prevalence of genetic variants of thiopurine S-methyltransferse (TPMT) and dihydropyrimidine dehydrogenase (DPD) in healthy controls (500) and the treatment response in 500 cases of head and neck cancer of north Indian origin was studied. METHODS: Blood collected from all the subjects was used for isolation of DNA followed by genotyping studies. The cases received cisplatin and 5-fluorouracil (5-FU) or chemo-radiotherapy and treatment response was measured using WHO criteria. RESULTS: Low frequency of heterozygous mutant genotypes of TPMT*2 (2%), TPMT*3B (2.2%), TPMT*3C (4.6%), DPD IVS14+1G>A (3.6%) and G1601A (3%) was observed, although no homozygous mutants could be identified. Treatment response studies in cases receiving cisplatin and 5-FU or chemo-radiotherapy revealed that the number of nonresponders was higher in cases who carried variant genotypes of TPMT*3B (62.50%) or TPMT*3C (59.26%) or DPD IVS14+1G>A (61.90%). Likewise, the number of nonresponders was still higher in cases carrying combination of these genetic variants. Furthermore, the frequency of nonresponders was higher in cases who carried the variant genotypes of TPMT or DPD and were also tobacco users. CONCLUSIONS: Our data clearly show that TPMT and DPD genes are polymorphic in the north Indian population and may be important in determining the treatment response in cases. The data have also suggest tobacco may play an important role in determining the outcome of cancer therapy and there is an urgent need for assessment of drugs for their efficacy/toxicity in smokers compared to nonsmokers.

Clinical Management of Head and Neck Cancer Cases: Role of Pharmacogenetics of CYP2 and GSTs.

Head and neck squamous cell carcinoma (HNSCC) describes a wide range of malignant tumors which originate in the upper aerodigestive tract and have a multifactorial origin involving both genetic and lifestyle risk factors. The clinical management of head and neck cancer involves surgery, radiotherapy, and chemotherapy. With the advances in treatment strategies for HNSCC, newer targeted therapies are adding to the progress already achieved in the multimodality management of patients although the problems of differences in drug response and adverse drug reactions are still grave concerns. Cancer pharmacogenomics has fast emerged as a new and promising field for the early identification of genetic markers that can predict drug response or toxicity. This could greatly help in identifying genetic markers useful for the selection of optimal drugs, dose, and treatment duration on an individual basis resulting in improved drug efficacy and decreased toxicity. This review focuses on the various treatment modalities available for the clinical management of HNSCC followed by a description of the contribution of genetic variations to chemotherapeutic toxicity and response. Furthermore, studies addressing the association of genetic variants of drug-metabolizing enzymes with treatment response in head and neck cancer are also discussed.

Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.

Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx.

Polymorphisms in drug-metabolizing enzymes and risk to head and neck cancer: evidence for gene-gene and gene-environment interaction.

A case-control study involving 750 cases with squamous-cell carcinoma of the head and neck (HNSCC) and an equal number of healthy controls was initiated to investigate the association of polymorphisms in the drug metabolizing genes cytochrome P450 1A1 (CYP1A1), CYP1B1, CYP2E1 and glutathione S-transferase M1 (GSTM1) with the risk of developing cancer. Attempts were also made to identify the role and nature of gene-gene and gene-environment interactions in modifying the susceptibility to HNSCC. Polymorphisms in drug metabolizing CYPs or GSTM1 showed modest associations with cancer risk. However, cases carrying haplotypes with variant alleles of both CYP1A1*2A and *2C or CYP1B1*2 and *3 or CYP2E1*5B and *6 were at significant risk of developing HNSCC. Likewise, cases carrying a combination of variant genotypes of CYPs and GSM1 (null) were at higher risk (up to 5-fold) of developing HNSCC. HNSCC risk also increased several-fold in cases carrying variant genotypes of CYPs who were regular tobacco smokers (8-18-fold), tobacco chewers (3-7-fold), or alcohol users (2-4-fold). Statistical analysis revealed a more than multiplicative interaction between combinations of the variant genotypes of CYPs and GSTM1 (null) and between variant genotypes and tobacco smoking or chewing or alcohol consumption, in both case-control and case-only designs. The data thus suggest that although polymorphisms in carcinogen-metabolizing CYPs may be a modest risk factor for developing HNSCC, gene-gene, and gene-environment interactions play a significant role in modifying the susceptibility to HNSCC.

Association of polymorphism in cytochrome P450 2C9 with susceptibility to head and neck cancer and treatment outcome.

The present case-control study involving 750 cases and equal number of healthy controls investigates the association of polymorphism in cytochrome P450 2C9 (CYP2C9) with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving chemotherapy or combination of radio-chemotherapy. The frequency of heterozygous or homozygous genotypes of CYP2C9*2 & CYP2C9*3, which leads to the poor metabolizer (PM) genotype was significantly higher in HNSCC cases when compared to the healthy controls resulting in significantly increased risk in the cases. Tobacco use in the form of tobacco smoking or tobacco chewing was found to increase the risk several fold in cases when compared to the non-tobacco users. Likewise, alcohol intake in cases with variant genotypes of CYP2C9*2 or CYP2C9*3 also significantly increased the HNSCC risk in cases when compared to non-alcohol users. Further, majority of the cases carrying variant alleles of both CYP2C9*2 or CYP2C9*3 were found to respond poorly to the chemotherapy or combination of radio-chemotherapy. The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome.

Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma.

BACKGROUND: Mucositis, a radiotherapy-associated toxicity, is an important factor determining morbidity and treatment compliance. Gastrointestinal mucositis in patients undergoing radiotherapy may also depend on time of administration of radiation in addition to several other factors. The presence of any correlation between the severity of acute gastrointestinal mucositis in cervical carcinoma patients and the time of irradiation was prospectively evaluated. METHODS: A total of 229 patients with cervical carcinoma were randomized to morning (8:00-10:00 AM) and evening (6:00-8:00 PM) arms. The incidence of mucositis in the 2 arms was assessed and reported in terms of various grades of diarrhea. RESULTS: Overall (grade I-IV) as well as higher grade (III and IV) diarrhea was found to be significantly increased in the morning arm as compared with the evening arm (overall: 87.39 % vs 68.18 %, P < .01; higher grade: 14.29% vs 5.45%, P < .05). Other radiation-induced toxicity was also higher in the morning arm, but its occurrence in the 2 arms did not differ significantly (13.45% vs 12.73%, P > .05). After completion of treatment, patients' response to radiation in the 2 arms was similar (P > .05). CONCLUSIONS: The significant difference in the incidence of higher grade diarrhea between the morning and evening arms is indirect evidence of the influence of circadian rhythm on the intestinal mucosa of the human intestine. This knowledge may facilitate treating patients with decreased toxicity to the intestinal mucosa.

Oral mucositis in morning vs. evening irradiated patients: a randomised prospective study.

PURPOSE: Patients of head and neck cancer undergoing radiotherapy develop oral mucositis. The severity of mucositis may also depend on the time of administration of radiation apart from patient-related factors. The most radiosensitive phase of the cell cycle (G2-M) occurs in the late afternoon and evening in human oral mucosa; therefore, it is more vulnerable to radiation injury in the evening. The present study evaluated prospectively the severity of acute oral mucositis in head and neck carcinoma patients irradiated in the morning (08:00-11:00 h) versus late afternoon/evening (15:00-18:00 h). METHOD: A total of 212 patients of head and neck carcinoma were randomised to morning (08:00-11:00 h) and evening (15:00-18:00 h) groups. The grades of oral mucosa ulceration were compared in the two groups. RESULTS: The grades of mucositis were marginally higher in the evening-irradiated group than in the morning-irradiated group 38% vs. 26% (p = 0.08). CONCLUSION: The observed incidence of grade III/IV mucositis in morning vs. evening irradiated patients may be because of the existence of circadian rhythm in the cell cycle of normal mucosa. This knowledge may provide a possibility of treating the patients with decreased toxicity to oral mucosa.

A prospective comparision of sequential chemoradiation vs concurrent chemoradiation in locally advanced oropharyngeal carcinomas.

PURPOSE: Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer. The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated. Present study evaluates the same prospectively. RESULTS: The response rate and acute toxicity (primary end points) in both the arms were found to be similar (p > 0.05) The points disease free survival and overall survival (secondary end points) were significantly (p < 0.05) better in treatment arm as compared to control arm. METHOD: Out of 135 patients of locally advanced oropharyngeal carcinoma, 105 patients were found eligible and randomized to treat either with induction chemotherapy consisting of 2-3 cycles of cisplatin and 5-Florouracil followed by low dose weekly cisplatin based chemoradiotherapy (treatment arm: n = 48) or chemoradiotherapy only (control arm: n = 57). The primary tumor and regional lymph drainage areas received 66-70 Gy in 6.5 to 7 weeks by fractionated dose schedule. CONCLUSION: Patients receiving chemoradiation following induction chemotherapy showed better response rates both in terms of complete response and disease free survival at two years than those receiving only concurrent chemoradiation but at the cost of manageable increase in toxicity.

Comparitive study of efficacy, tolerability of four field box technique vs. two field anterior posterior technique in locally advanced carcinoma cervix--a prospective analysis.

PURPOSE: The pelvic failure rate decreases with increase in the radiation dose but the complications increase. The four field pelvic technique has a theoretical advantage of providing a higher tumor dose with less dose to the surrounding normal tissue thus reducing the complications. RESULT: Eighty-three patients completed treatment, 42 in Arm A and 41 in Arm B. The complete response achieved in the two groups was 85.75% and 87.8% (p = 0.67). Skin reactions were more in Arm B (p < 0.05). Grade II GIT symptoms were more common in both the groups (p = 0.75). Grade I GUT toxicity was the most common toxicity in both the arms (p = 0.38). The most common hematological toxicity in the two arms was of grade II (p = 0.78). MATERIAL AND METHOD: After satisfying the eligibility criteria histo-pathologically proven locally advanced carcinoma cancer cervix patients were randomized to four (Arm A) or two (Arm B) field techniques. CONCLUSIONS: Both two and four field box techniques are equally effective and feasible as statistically insignificant difference in the response rate and acute toxicities was observed in the two arms.