Originally published as JCO Early Release 10.1200/JCO.2006.05.8768 on August 8 2006

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DNA-Repair Gene Polymorphisms Predict Favorable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy

Miguel Quintela-Fandino, Ricardo Hitt, Pedro P. Medina, Soledad Gamarra, Luis Manso, Hernan Cortes-Funes, Montserrat Sanchez-Cespedes

Medical Oncology Department. University Hospital 12 de Octubre. Madrid, Spain
Lung Cancer Group. Molecular Pathology Programme. Spanish National Cancer Centre (CNIO), Madrid, Spain
Molecular Biology Division, Hematology Department. University Hospital 12 de Octubre, Madrid, Spain

Address reprint requests to Miguel Quintela-Fandino, MD, PhD, The Ontario Cancer Institute, University Institute for Breast Cancer Research. 620 University Ave, Toronto M5G2M9, Canada; e-mail: quintelamiguel2000{at}yahoo.es

	ABSTRACT

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Purpose: Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. We studied whether single nucleotide polymorphisms (SNPs) of DNA repair genes predict the response to cisplatin or prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN).

Methods: A polymerase chain reaction–restriction fragment length polymorphism (RFLP) approach was used to determine the frequency of the SNPs: XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and XRCC1-Arg399Gln in DNA from peripheral lymphocytes of 103 stage IV SCCHN patients.

Results: The frequencies of the distinct genotypes were, respectively, for the homozygous common allele, heterozygous and homozygous polymorphic variant: 53%, 40%, and 7% for ERCC1; 50%, 42%, and 8% for XPD-312; 35%, 57%, and 8% for XPD751; and 35%, 51%, and 13% for XRCC1. Patients with only common alleles at all the SNPs tested had a median overall survival of 5.1 months (range, 4.3 to 6.0 months) as compared with not reached for patients with at least one polymorphic variant (P < .001). Estimates from Cox's multivariate analysis suggest that the accumulation of each polymorphic variant decreases the probability of dying by a factor of 2.1 (P < .001; the presence of seven polymorphic variants confers a 175-fold protection). The accumulation of polymorphic variants increases by 2.94-fold the probability of achieving a complete response to treatment (P = .041).

Conclusion: Using a multivariate model, the presence of polymorphic variants in DNA-repair genes are powerful prognosis factors and response to cisplatin predictors among SCCHN patients.

	INTRODUCTION

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Squamous cell carcinoma of the head and neck (SCCHN) represents 5% of newly diagnosed cancers in adult patients, with a worldwide incidence of 500,000 yearly cases.¹ Despite being a potentially curable malignancy in its early stages, the majority of patients present with locally advanced disease (stages III-IV). Approximately 55% of these patients will die within 2 years of diagnosis after treatment with standard approaches.² Neoadjuvant chemotherapy before chemoradiotherapy or surgery is considered an alternative treatment to classical chemoradiotherapy.^3-6 for those patients with nonoperable stage IV disease.^7-17 However, even the induction triplets with taxanes^17-24 lack efficacy in 10% to 40% of cases. The identification of the biologic mechanisms that confer sensitivity to these chemotherapeutic agents should allow the correct selection of the patients to avoid toxicity among nonresponders.

Cisplatin is the backbone of chemotherapy regimens used to treat several malignancies. Its main cytotoxic activity is based on the formation of mono-/bifunctional adducts in the DNA, which cause inter-/intrastrand cross linking. Proposed mechanisms of resistance include decreased intracellular accumulation, increased detoxification through its conjugation with glutathione, and increased tolerance to DNA damage resulting from a highly efficient DNA-repair capacity.²⁵

Nucleotide excision repair (NER) and Base excision repair (BER) systems are multistep enzymatic complexes involved in the repair of nonspecific DNA damage, including gamma and ultraviolet radiation, cross linking, and chemical intra-/interstrand adduct formation. Key and rate-limiting enzymes are ERCC1, XPD (NER) and XRCC1 (BER). It has been hypothesized that in tumor cells treated with cisplatin, the impaired function of NER/BER lead to greater induced-DNA damage and thus to tumor cell death.^26,27 Single nucleotide polymorphisms (SNPs) in a given gene may affect the function of the encoded protein. Preclinical data suggest that one polymorphism at the ERCC1 gene (C8092A) may affect its mRNA stability, resulting in impaired DNA repair capacity.²⁸ Two SNPs in the XPD gene (Asp312Asn and Lys751Gln) and one in the XRCC1 (Arg399Gln) have been associated with suboptimal DNA repair capacity.^29,30 Theoretically, a larger number of favorable alleles should confer a poorer DNA-repair ability and an increased sensitivity to cisplatin or any DNA-damaging therapy. The available clinical studies, most of them performed in lung cancer patients, revealed an association between the presence of functional polymorphic variants in DNA-repair genes and a worse clinical outcome when treated with platinum compounds and radiotherapy (RT).^31-35 Because most lung tumors are caused by tobacco-related DNA damage, a proposed explanation is that SNPs at NER/BER genes lead to more aggressive tumors and to a decreased response to chemotherapy that cannot be overcome by an impaired NER/BER performance. Therefore, no predictive assay of clinical response to cisplatin has been described to date.

To test the ability of DNA-repair gene polymorphisms to predict response to chemotherapy in SCCHN patients, we prospectively assessed the status of the ERCC1-C8092A, XPD-Asp312Asn/Lys751Gln, and XRCC1-Arg399Gln gene polymorphisms in peripheral blood mononuclear cells of stage-IV SCHNC patients. We aimed to understand whether the status of the different SNPs can predict the response to cisplatin-based regimens and their prognostic role in advanced SCCHN patients.

	PATIENTS AND METHODS

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Patients, Treatment, and Clinical Response Assessment
The study comprised 103 patients diagnosed with SCCHN and treated at University Hospital 12 de Octubre (Madrid, Spain) between 1998 and 2005. Their main characteristics are shown in Table 1. After signed informed consent, 5-mL blood samples were collected from each patient and frozen (–80°C) until the assay was performed. To avoid the confounding effect of differences in outcome resulting from clinical stage, only stage IV patients (0% M1) were included in the analysis. Relapsed patients with a previous history of SCCHN (19 patients; 18%) were allowed to enter the study if at least 6 months had passed since they had received their last therapeutic procedure. No previous chemotherapy was allowed.

Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria³⁶ with head and neck computed tomography scan performed before treatment ( 4 weeks), after every three cycles, and after ( 4 weeks) the last induction cycle treatment.

DNA Extraction and Genotyping
Genomic DNA was obtained from peripheral blood using a MagNA PureC DNA Isolation Kit-Large Volume (Roche Applied Science, Penzberg, Germany).

The genotyping procedure involved a polymerase chain reaction (PCR) restriction fragment length polymorphism approach, performed following previously described protocols for ERCC1-C8092A, XPD Lys751Gln, and XRCC1 Arg399Gln.^29,30,33 For XPD Asp312Asn, a PCR product of 165 base pairs (bp), was obtained with the following primers (forward/reverse): 5'-CCCAGCTCATCTCTCCGCAGGATCAAAGAG-3'; 5'-TAATATCGGGGCTCACCCTGCAGCACTTCCT-3'. PCR reactions were carried out in a total volume of 25 µL containing 20 ng of genomic DNA. PCR amplifications consisted of an initial denaturation step of 94°C for 2 minutes and 35 cycles of denaturation at 94°C (30 seconds), annealing (55°C, 30 seconds), and extension (72°C, 30 seconds). A final extension at 72°C (7 minutes) was also included. The PCR products were digested overnight with the restriction enzymes MBOII (TaKaRa, Shiga, Japan) for the ERCC1 and XPD-751 gene polymorphisms, StyI (New England BioLabs, Ipswich, MA) for the XPD-312 gene polymorphism, and MSPI (Fermentas, Hanover, MD) for the XRCC1 gene polymorphism. The resulting digested products have previously been described for ERCC1, XPD-751, and XRCC1.^29,30,33 Regarding the XPD312 gene 165 bp/165, 138, and 27 bp/138 and 27 bp corresponded to the wild-type/heterozygous/homozygous phenotypes, respectively. Products were resolved on 2% agarose gels and stained with ethidium bromide. All the samples were genotyped twice for quality control purposes.

Statistical Methods
Follow-up began on the first day of induction treatment. All statistical tests are two-sided. All analyses were performed with SPSS (version 12.0, SPSS Inc, Chicago, IL).

The main statistical methods used were the Kaplan-Meier method, the Cox hazard regression model, and multinomial logistic regression. Only two of the censored times in the Kaplan-Meier plots presented were caused by patients being lost to follow-up; none of them was secondary to death from another cause.

The main outcome variable analyzed was the presence of polymorphisms at genes implicated in NER/BER systems. Theoretically, the more polymorphic variants in the maximum number of genes should be associated with poorer DNA repair ability. Therefore, in the Cox regression model, we avoided dividing the series into different groups according to a specific gene polymorphism. Considering each gene individually in the Cox analysis would have added 12 variables to the model, so the number of altered alleles (zero to eight) was considered as a single variable. In contrast, in the Kaplan-Meier analysis, gene-by-gene comparisons can be made; the clinical outcomes compare patients with only common variants with those with either one or two polymorphic variants.

We performed multivariate analyses of contributing factors for response (multinomial logistic regression) and death (Cox regression). Sex, age (years), induction regimen (one of the four previously described), number of polymorphic variants, smoking history (never, former [ 12 months ago], current), alcohol intake (never, former [12 months ago], current) and total cisplatin dose in the induction regimen (mg/m²) were included in the analysis. Concerning response, the hazards for stable disease (SD), partial response (PR), and complete response (CR) according to RECIST criteria versus progressive disease (PD) attributable to each variable were also included. The multinomial procedure was used as no quantitative-ordinal relation could be established between PD/SD/PR/CR. For the Cox hazard regression model, we included all the variables to test the independence and impact of the polymorphic variants. Categoric variables with more than two categories were automatically decomposed in dummy variables by SPSS for the Cox analysis. The global significance of the model and the goodness of fit are offered both for the multinomial and Cox regression model.

	RESULTS

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Allele Frequencies
The frequencies of the different gene polymorphisms are shown in Table 2. Nine (9%), 17 (16.5%), 23 (22%), 21 (20%), 25 (24%), 6 (6%), 1 (1%), and 1 (1%) patients harbored from 0 to 7 polymorphic variants at any of the genes evaluated, respectively. Nine patients harbored only common variants, whereas 93 patients had at least one polymorphic variant. No statistically significant association was observed between the presence of simultaneous gene polymorphisms except for XPD-751 and XPD-312 (²₃ = 74.9; P < .001).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier plots and log-rank tests for overall survival in relation to the presence of common or polymorphic alleles in patients with advanced squamous cell carcinoma of the head and neck. Analysis for (A) XPD-751, (B) XPD-312, (C) XRCC1, (D) ERCC1, (E) the presence of distinct number of polymorphic (pol) alleles at any gene, and (F) the presence of only common (com) alleles versus polymorphic alleles at any gene.

Figure 1E shows the survival plots for patients with no, one, two, three, four, five, six, and seven polymorphic variants. Median survival times cannot be estimated because all patients with five, six, or seven variants were still alive (censored observations). The log-rank test estimate for this survival analysis is 68.77 (P < .001). Figure 1F depicts the differences in median OS for all patients with at least one polymorphic variant (not reached) compared with those patients carrying only common alleles: 5.1 months (range, 4.3 to 6.0 months); mean times 61.3 months (range, 52.8 to 69.8 months) versus 6.2 months (range, 4.0 to 8.4 months), respectively (log-rank test = 63.68; P < .001).

Multivariate Analysis: Response to Treatment and OS
The analysis of response to treatment reveals that there was a 3.14-fold greater probability of having SD than PD per additional polymorphic variant (P = .038); PR was 3.28- and 1.025-fold more likely than PD per additional variant (P = .026) and per milligram of extra cisplatin in the induction regimen (P = .020), respectively. Finally, CR was 2.94- and 1.026-fold more likely than PD per additional polymorphic variant and per milligram of extra cisplatin in the induction regimen (P = .041 and P = .013), respectively. As an example, CR is 1,898-fold more likely in a patient with seven polymorphic variants than in a patient who carries only common alleles.

A descriptive Cox proportional hazard model was performed to estimate the independent impact of each variable on OS. Statistical significance and hazard ratios of each variable are represented in Table 4. According to the model, each year of age worsens the prognosis, whereas receiving cisplatin + fluoropyrimidines + taxanes, each extra milligram of cisplatin, and each extra polymorphic variant improves OS. A patient with seven variants has a 175.4-fold lower time-dependent hazard ratio of dying than a patient with only common alleles (P < .001). Receiving a regimen containing taxanes confers a 5.1-fold protection of dying (P = .011); time-dependent probability of dying decreases to 0.49 per 100 mg/m² of cisplatin (P = .029). The partial likelihood ratio analysis for global statistical significance of the model gave an estimate of Rao ² of 44.04 (P < .001). The Cox-Snell R² goodness of fit, a measure of the proportion of the total variance among outcomes explained by the model, was 0.62.

	DISCUSSION

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Polymorphisms in several DNA repair genes have been identified, but their biologic significance is not yet fully understood. Duell et al observed that the rate of sister chromatid exchange (an indicator of DNA damage) after exposure to ionizing radiation in human lymphocytes was greater in individuals with the XRCC1-Gln399Gln genotype, than in those with only common variants XRCC1-Arg399Arg. In addition, the amount of polyphenol-induced DNA adducts was associated with the XRCC1-Gln399Gln, with the current smoking status and the age of the blood donors. Similar observations were also reported for the XPD-Gln751Gln compared with XPD-Lys751Lys carriers, although the effect was evident only in smokers.³⁰ Such findings were not confirmed by others, probably because of the low number of patients tested.²⁹ Moreover, a change from C to A in the nucleotide position 8092 at the 3'-untranslated region of the ERCC1 gene affects its mRNA stability,²⁸ which has been linked to a predisposition to astrocytomas.³⁷ Whereas germ-line-inactivating mutations at NER genes lead to genetic syndromes such as xeroderma pigmentosum (from XP-AXP-G genes) or Cockayne syndrome, polymorphisms may influence an individual's risk of cancer associated with DNA-damaging carcinogens, such as that of the lung or SCCHN.^38,39 Several studies have investigated the role of SNPs in genes involved in NER/BER in response to cisplatin-based chemotherapy. Gurubhagavatula et al concluded that the polymorphic variants at XRCC1/XPD312 in stage IIIA-IV lung cancer patients treated with platinum-based doublets conferred poorer survival.³² It was also reported that the ERCC1C8092A variant, but not the ERCC1-Asn118Asn, was associated with a worse clinical outcome in stages IIIA-IV lung cancer patients treated with platinum-based combinations.³³ Others found no such association with the XPD312 and XPD751 gene polymorphisms but detected an association between the common variant at ERCC1-Asn118Asn and a better clinical outcome in stage IIIB/IV lung cancer patients treated with platinum combinations.^34,35 To our knowledge, the present study is the first to report an association of some DNA-repair gene polymorphisms with a better clinical outcome and an increased sensitivity to cisplatin in SHNCC patients.

Several hypotheses may explain the distinct impact of these DNA-repair SNPs on the clinical outcome of SCCHN and lung cancer patients. The DNA-repair efficacy of the variants may be different for DNA damage caused by carboplatin (which is the most widely used drug in the lung cancer studies) than for cisplatin. Cisplatin causes mainly d(GpG)Pt adducts whereas carboplatin mainly produces d(GpNpG)Pt.⁴⁰ Alternatively, there may be other biologic or tissue-specific factors that account for chemoresistance in lung cancer, a tumor that is traditionally more resistant to therapy than SCCHN, which is a more chemosensitive disease. In addition, our analysis includes a highly homogeneous cohort of SCCHN patients (only stage IV) that may have contributed to highlight the relevance of these variants in the response to cisplatin. Whereas the relevance of other factors involved in the response to chemotherapy in other tumors⁴¹ remains to be evaluated in SHNCC, our findings clearly suggest that the polymorphic variants in the XPD and XRCC1 genes confer a better prognosis and response to chemotherapy in these patients.

Furthermore, these SNPs have proven to be predictive factors in our analysis. These observations are in agreement with the preclinical data. Prognostic factors for SCCHN have been reported, such as TNM, Karnofsky status, tumor location, grade, and age.⁴² According to our results, the polymorphic variants in the XPD and XRCC1 genes are among the most reliable in cisplatin-treated patients. Each polymorphic variant confers respectively a three- and 2.1- fold probability of achieving a complete response and of surviving. This provides a reason to test its potential relevance as predictors of response to cisplatin in other tumor types.

A concern about the heterogeneity of induction treatment could be raised in our study, but we demonstrated that the SNPs influence remains statistically independent in two multivariate models for survival and response regardless of the given regimen, which it is not surprising because the SNPs are involved in the repair to DNA damage induced by other agents such as RT.

In conclusion, a predictive assay for the response to a conventional widely used cytotoxic drug such as cisplatin has not been described before for SCCHN patients. Although prospective and multi-institutional studies are needed, our present findings reveal powerful candidate markers for predicting the response and clinical outcome of advanced SCCHN with a single blood test.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Miguel Quintela-Fandino, Ricardo Hitt, Pedro Medina, Montserrat Sanchez-Cespedes Financial support: Montserrat Sanchez-Cespedes Administrative support: Ricardo Hitt, Hernan Cortes Funes, Montserrat Sanchez-Cespedes Provision of study materials or patients: Miguel Quintela-Fandino, Ricardo Hitt, Soledad Gamarra, Luis Manso, Montserrat Sanchez-Cespedes Collection and assembly of data: Miguel Quintela-Fandino, Ricardo Hitt Data analysis and interpretation: Miguel Quintela-Fandino, Montserrat Sanchez-Cespedes Manuscript writing: Miguel Quintela-Fandino, Montserrat Sanchez-Cespedes Final approval of manuscript: Miguel Quintela-Fandino, Ricardo Hitt, Pedro Medina, Soledad Gamarra, Luis Manso, Hernan Cortes Funes, Montserrat Sanchez-Cespedes

 

	GLOSSARY

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Adduct:

An adduct is a substance formed by chemical union of two or more elements or ingredients in definite proportion by weight.

SNP (single nucleotide polymorphism):

Genetic polymorphisms are natural variations in the genomic DNA sequence present in greater than 1% of the population, with SNP representing DNA variations in a single nucleotide. SNPs are being widely used to better understand disease processes, thereby paving the way for genetic-based diagnostics and therapeutics.

Polymerase chain reaction restriction fragment length polymorphism approach:

A procedure to determine single nucleotide polymorphisms (SNPs) on the basis of the different DNA sequence. The small genetic change of variation in the genetic code for a given SNP makes that the concrete DNA region becomes a target for a given restriction enzyme; that restriction enzyme does not recognize the sequence in the absence of the change, or vice-versa. When digesting the amplified DNA fragment with the given restriction enzyme, different size DNA fragments are obtained depending on the SNP presence or absence.

Ethidium bromide:

Ethidium bromide is a compound that binds to DNA and is visible under ultraviolet light. It is used to stain different DNA fragments dissolved in an agarose gel.

Goodness of fit:

This is a coefficient, termed R², with values between 0 and 1. A value of 1 means that all the interpatient outcome variation is perfectly explained by the multivariate model. A value of 0 means that the model does not explain the differences between individual patients at all.

	NOTES

 
published online ahead of print at www.jco.org on August 7, 2006.

Supported by a fellowship from the Comunidad Autonoma de Madrid (P.P.M.).

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Globocan 2000. Database Version 1.0. http://www-dep.iarc.fr/globocan/downloads.htm

2. Forastiere A, Koch W, Trotti A, et al: Head and neck cancer. N Engl J Med 345:1890-1900, 2001[Free Full Text]

3. Merlano M, Benasso M, Corvo R, et al: Five year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583-589, 1996[Abstract/Free Full Text]

4. Adelstein DJ, Adams GL, Li Y, et al: A phase III comparison of standard radiation therapy (RT) versus RT plus concurrent cisplatin (DDP) versus split-course RT plus concurrent DDP and 5-fluorouracil (5FU) in patients with unresectable squamous cell head and neck cancer (SCHNC): An Intergroup study. Prog Proc Am Soc Clin Oncol 19:411a, 2000 (abstr 1624)

5. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318-1324, 1998[Abstract/Free Full Text]

6. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998[Abstract/Free Full Text]

7. Paccagnella A, Orlando A, Marchiori C, et al: Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 86:265-272, 1994[Abstract/Free Full Text]

8. Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685-1690, 1991[Abstract]

9. Domenge C, Hill C, Lefebvre JL, et al: Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC). Br J Cancer 83:1594-1598, 2000[CrossRef][Medline]

10. Monnerat C, Faivre S, Temam S, et al: End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol 13:995-1006, 2002[Abstract/Free Full Text]

11. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996[Abstract/Free Full Text]

12. Kies MS, Haraf DJ, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16:2715-2721, 1998[Abstract]

13. Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320-326, 2003[Abstract/Free Full Text]

14. Machtay M, Rosenthal DI, Hershock D, et al: Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: A University of Pennsylvania Phase II Trial. J Clin Oncol 20:3964-3971, 2002;[Abstract/Free Full Text]

15. Hainsworth JD, Meluch AA, McClurkan S, et al: Induction paclitaxel, carboplatin, and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: A phase II trial of the Minnie Pearl Cancer Res Network. Cancer J 8:311-321, 2002[Medline]

16. Cmelak A, Murphy BA, Burkey B, et al: Induction chemotherapy (IC) followed by concurrent chemoradiation (CCR) for organ preservation (OP) in locally advanced squamous head and neck cancer (SHNC): Results of a Phase II trial. Proc Am Soc Clin Oncol 22:501, 2003 (abstr 2016)

17. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23:8636-8645, 2005[Abstract/Free Full Text]

18. Hitt R, Paz-Ares L, Brandariz A, et al: Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: Long-term results of a phase II trial. Ann Oncol 13:1665-1673, 2002[Abstract/Free Full Text]

19. Benasso M, Numico G, Rosso R, et al: Chemotherapy for relapsed head and neck cancer: Paclitaxel, cisplatin, and 5-fluorouracil in chemotherapy-naive patients—A dose-finding study. Semin Oncol 24:46-50, 1997 (suppl)

20. Janinis J, Papadakou M, Xidakis E, et al: Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: A phase II feasibility study. Am J Clin Oncol 23:128-131, 2000[CrossRef][Medline]

21. Schrijvers D, Van Herpen C, Kerger J, et al: Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: A phase I-II feasibility study. Ann Oncol 15:638-645, 2004[Abstract/Free Full Text]

22. Fonseca E, Grau JJ, Sastre J, et al: Induction chemotherapy with cisplatin/docetaxel versus cisplatin/5-fluorouracil for locally advanced squamous cell carcinoma of the head and neck: A randomised phase II study. Eur J Cancer 41:1254-1260, 2005[CrossRef][Medline]

23. Gibson MK, Li Y, Murphy B, et al: Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23:3562-3567, 2005[Abstract/Free Full Text]

24. Vermorken JB, Remenar E, Van Herpen C, et al: Standard cisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF (TPF) as neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): A phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971). J Clin Oncol 23:488, 2004 (suppl; abstr 5508)

25. Johnson SW, Stevenson JP, O'Dwyer PJ: Cisplatin and its analogues, in DeVita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology. Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 380-382

26. Shellard SA, Fichtinger-Schepman AM, Lazo JS, et al: Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. Anticancer Drugs 4:491-500, 1993[Medline]

27. Bosken CH, Wei Q, Amos CI, et al: An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst 94:1091-1099, 2002[Abstract/Free Full Text]

28. Shen MR, Jones IM, Mohrenweiser H: Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 58:604-608, 1998[Abstract/Free Full Text]

29. Lunn RM, Helzlsouer KJ, Parshad R, et al: XPD polymorphisms: Effects on DNA repair proficiency. Carcinogenesis 21:551-555, 2000[Abstract/Free Full Text]

30. Duell EJ, Wiencke JK, Cheng TJ, et al, et al: Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 21:965-971, 2000[Abstract/Free Full Text]

31. Mort R, Mo L, McEwan C, et al: Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer. Br J Cancer 89:333-337, 2003[CrossRef][Medline]

32. Gurubhagavatula S, Liu G, Park S, et al: XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 22:2594-2601, 2004[Abstract/Free Full Text]

33. Zhou W, Gurubhagavatula S, Liu G, et al: Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 10:4939-4943, 2004[Abstract/Free Full Text]

34. Isla D, Sarries C, Rosell R, et al: Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 15:1194-1203, 2004[Abstract/Free Full Text]

35. Ryu JS, Hong YC, Han HS, et al: Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 44:311-316, 2004[CrossRef][Medline]

36. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

37. Chen P, Wiencke J, Aldape K, et al: Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol Biomarkers Prev 9:843-847, 2000[Abstract/Free Full Text]

38. Butkiewicz D, Rusin M, Enewold L, et al: Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 22:593-597, 2001[Abstract/Free Full Text]

39. Huang WY, Olshan AF, Schwartz SM, et al: Selected genetic polymorphisms in MGMT, XRCC1, XPD, and XRCC3 and risk of head and neck cancer: A pooled analysis. Cancer Epidemiol Biomarkers Prev 14:1747-1753, 2005[Abstract/Free Full Text]

40. Blommaert FA, van Dijk-Knijnenburg HC, Dijt FJ, et al: Formation of DNA adducts by the anticancer drug carboplatin: Different nucleotide sequence preferences in vitro and in cells. Biochemistry 34:8474-8480, 1995[CrossRef][Medline]

41. Rosell R, Taron M, Ariza A, et al: Molecular predictors of response to chemotherapy in lung cancer. Semin Oncol 31:20-27, 2004[Medline]

42. Clavel M, Maged Mansour AR: Head and neck cancer: Prognostic factors for response to chemotherapy. Eur J Cancer 27:349-356, 1991[Medline]

Submitted January 27, 2006; accepted May 16, 2006.

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