Low Expression Of Excision Repair Cross-complementation Group-1Protein Predicts Better Outcome In Patients With Locally Advanced Nasopharyngeal Cancer Treated With Concurrent Chemoradiotherapy

Part ⅠThe expression and significance of ERCCl in the tissue of local advanced nasopharyngealcancerBackground and Purpose Nasopharyngeal carcinoma is a common head and neck tumor in China, radiation therapy is the first choice in the treatment of nasopharyngeal carcinoma.In clinical work, we notice that nasopharyngeal carcinoma patients with the same clinical stages and pathological types, even the dose and treatment of radiotherapy are exactly the same, but the effect of radiotherapy and side reaction were more differences for nasopharyngeal carcinoma patients. An important reason of which is because the difference of tumor radiosensitivity effect. The relevant factors of the radiosensitivity of tumor patients in many aspects, in addition to the inherent sensitivity of tumor cells, whether hypoxia, hypoxia and the proportion of outside, is mainly attributed to the inter individual DNA repair ability of different.Excision repair cross complementing gene1(ERCCl) is a specific nucleotide enzyme, is a nucleotide excision repair system (NER), the rate limiting enzyme of DNA, mainly involved in nucleotide excision repair process, the maintenance of the body tissues of normal breeding, maintains genomic stability. In the nucleotide excision repair process, identify the damage of DNA chain and resection. About the relationship between the expression of ERCCl on chemotherapy and radiotherapy of nasopharyngeal carcinoma synchronous is less, in this study we detect the the expression of ERCCl in locally advanced nasopharyngeal carcinoma tissue by immunohistochemical method, and to investigate its expression level with locally advanced nasopharyngeal carcinoma synchronous chemotherapy efficacy.Methods A retrospective analysis of66cases with locally advanced nasopharyngeal carcinoma patients in2003July to2007July treated in Oingdao Municipal Hospital, were obtained by low differentiated squamous cell carcinoma. Male44cases, female22cases, aged19to84years (mean53years). According to the2002UICC/AJCC staging are as follows:T12cases, T232cases, T320cases, T412cases; NO2cases, N116cases, N230cases, N318cases.37cases of patients with stage Ⅲ,29cases of IV patients. Immunohistochemistry was used to detect the expression of66cases with locally advanced nasopharyngeal carcinoma tissue ERCCl, and compared with chronic inflammatory nasopharyngeal mucosa biopsy specimens of50cases as control.Results1.Expression of ERCCl in nasopharyngeal carcinoma and nasopharyngeal mucosa of chronic inflammatory tissue:66cases of nasopharyngeal carcinoma tissues, high expression of ERCCl in34cases (51.52%), low expression in32cases (48.48%); nasopharyngeal mucosa of chronic inflammatory tissues with high expression in35cases (70%), low expression in15cases (30%). High expression of ERCCl in nasopharyngeal carcinoma tissues was significantly lower than the nasopharyngeal mucosa of chronic inflammatory tissue (2=8.037, P<0.05).2.Relationship between ERCCl expression and clinical pathological features of nasopharyngeal carcinoma:ERCCl high expression group and low expression group in gender, age, T stage, N stage, clinical stage and treatment modality, no statistically significant difference between the two groups (2=0.486,0.670,0.990,0.959,0.641,0.976, P>0.05). 3.The relationship between ERCCl expression and pathological type:10cases of keratinizing high expression of ERCCl in9cases,56cases of non keratinizing expression in25cases, there was significant difference between the two groups (2=5.29, P<0.05).Conclusions1.High expression of ERCCl in nasopharyngeal carcinoma tissues was significantly lower than the nasopharyngeal mucosa of chronic inflammatory tissue. Prompt in nasopharyngeal carcinoma DNA repair function is abate, DNA damage can not get timely repair, tumor cells which cause spontaneous mutation, may be related to the occurrence and development of nasopharyngeal carcinoma.2.Differential expression of ERCCl in nasopharyngeal carcinoma and mucosa of chronic inflammatory tissue, high expression of tumor tissue rate is lower than the normal tissue, suggesting that radiotherapy tumor tissue repair capacity is lower than that in the normal group, the difference in time for the repair of radiation in radiation biology repair provides theory basis.3.In nasopharyngeal carcinoma, ERCCl expression level was down regulated significantly, ERCCl has the potential to become one of the biological index to predict the prognosis of nasopharyngeal carcinoma patients. Part IIThe relationship between ERCCl expression and curative effect in patients with locally advanced nasopharyngeal cancer with concurrent chemoradiotherapyBackground and Purpose Nasopharyngeal carcinoma is a common head and neck tumor in China, radiation therapy is the first choice in the treatment of nasopharyngeal carcinoma. In daily work, we found that although the pathological types and clinical stages of the same, and were treated with the same dose and mode, the effect of radiotherapy in patients with nasopharyngeal carcinoma has obvious difference, and one important reason is due to the different sensitivity of tumor cells to radiation effect. Factors associated with radiosensitivity are in many aspects, in addition to the stage sooner or later, the patient’s age, general condition and cell radiation damage, repair after damage, proliferation, apoptosis, necrosis, but this is mainly attributed to the differences between DNA damage repair ability. Both DNA damage caused by endogenous or exogenous carcinogens, DNA repair gene and genome stability maintenance process plays an important role in the repair of injury. The DNA repair genes in maintaining genomic functional integrity of the repair of carcinogenic, plays an important role in damage and cancer caused by factors in the process.Nucleotide excision repair system is the most powerful genome damage identification. Excision repair cross complementing gene1(ERCCl) is a specific nucleotide enzyme, mainly involved in the DNA nucleotide excision repair pathway, in maintaining normal growth and development, plays an important role in genomic stability. Excision repair cross complementing gene1is the rate limiting enzyme in NER, in the process of NER damage recognition in DNA chain and cutting, plays a key role in DNA damage repair, and tumor cell resistance to platinum compounds closely related. The relationship between the expression of ERCCl of nasopharyngeal carcinoma radiotherapy and chemotherapy of patients is less. we detect the expression of ERCCl in patients with locally advanced nasopharyngeal carcinoma by the method of immunohistochemistry,and to explore the relationship of concurrent chemotherapy efficacy and its expression level.Methods1.A retrospective analysis of66cases with locally advanced nasopharyngeal carcinoma patients in our hospital in2003July to2007July for concurrent chemoradiotherapy, were obtained by low differentiated squamous cell carcinoma, including10cases of keratinizing type,56cases of non keratinizing. Male44cases, female22cases, aged19to84years (mean53years). According to the2002 UICC/AJCC staging are as follows:T12cases, T232cases, T320cases, T412cases; NO2cases, Nl16cases, N230cases, N318cases.37cases of patients with stage Ⅲ,29cases of IV patients.66patients with locally advanced nasopharyngeal carcinoma patients,29cases were treated with conventional radiotherapy,37cases were treated with intensity modulated radiotherapy.2.Treatment of patients with tumor2.1Intensity modulated radiotherapy (IMRT)(1) position and fixed by the supine position, select the head pillow suitable (B or C pillow), fixed cover for neck shoulder heat surface, hands holding body side, and the patient’s name, the number of hospitalized, the head pillow type record on the mask.(2) CT simulation in machine center CT simulation to determine the scanning, and in three dimensional laser light, projection will center on the skin (a front, sides) labeled with a metal point, in order to be able to identify the image on CT scan.(3) CT scan directly with enhanced continuous scanning, slice thickness3mm, scan range from the top of the head to the subclavian3cm range, and will get the influence of information through the network system to plan system workstation for patient information registration, data for image reconstruction in workstation and confirm.(4)The delineation of target and organs at risk target delineation preferably with MRI image data, in order to minimize the error in the position of target delineation.(5)Dose prescription and requirements stated in the radiotherapy planning for single selection, treatment indications and complications of radiotherapy treatment, target area, endanger the organ dose prescription dose.(6) Design, field calculation and optimization meet the prescribed dose requirements and minimize the segment number, shorten the time of irradiation.(7) Treatment plan verification shall not execute untested treatment plan.(8)Confirm the treatment plan requires two physical person sign and competent physician signature recognition.(9)Treatment and treatment verification First treatment requirements of physical teacher and doctor in charge in position, and other inspection and simulation of perturbation center positioning CT as center image alignment, began treatment is correct when. For the first3times a day taken verification like once, then once a week, to ensure that the error of IMRT treatment remained in an acceptable range.2.2Conventional radiotherapy (conventional radiation therapy CRT)(1) posture and position fixingSupine position, flat rack, the head is placed in the appropriate pillow, using3D laser light position, so that the patient horizontal plane parallel to the bed, the body of the sagittal plane perpendicular to the surface of bed, special attention should be paid to the midline neck and body in a straight line, when necessary, can adjust the position in the simulated machine until to meet the conditions. Immobilization by U type thermoplastic mask can be fixed.(2) The conventional radiotherapy simulation locationThe faciocervical portals on the both sides of the horizontal isocenter irradiation, determine the irradiation field before and after, the upper, lower bounds and field center perspective. Method:first in perspective will field center moved to the body midline, and then the frame to90degrees, will be moved to the position of the center of the nasopharyngeal cavity, will be "well" word line open to the desired size of irradiation field. The lower bound is generally hyoid level or lower bound adjustment according to lymph node, shoot positioning sheet (GA=90degrees, HA=0degrees, center unchanged), shooting the other side of the positioning piece of wild, also on the mask mark field center, recording the field depth. Finally, the frame back to zero, mark field center on the mask, record lift bed height.The neck clavicle using source skin distance vertical irradiation technology, the upper bound and lower bound of lower face and neck wild collinear, along the lower edge of clavicle walking, both sides located in the medial margin of the acromioclavicular joint to avoid the acromioclavicular joint, will shoot nodal line and1/2is arranged in the center of the body center of wild wild long, shooting a positioning sheet (GA=0degrees, HA=0degrees), and mark the field center. The amplification coefficient of radiography best fixed, in order to reach a tacit understanding with the die chamber.2.3All patients at the same time give cisplatin40mg/m2weekly in radiotherapy concurrent chemotherapy. After the end of radiotherapy to3～4cycles of systemic chemotherapy (cisplatin+fluorouracil75mg/m2d1500mg/m2d1-d5, a period of28days).2.4Nasopharynx and neck CT or MRI and nasopharyngoscopy efficacy evaluation.After the end of radiotherapy, analysis the relationship of status of expression ERCCl in nasopharyngeal carcinoma and treating efficacy of5years progression free survival (PFS) and survival time (OS).Results1.Relationship between ERCCl of expression and the effect of treatment:66patients with locally advanced nasopharyngeal carcinoma patients, clinical remission rate (CR+PR) was100%, including58cases of patients achieved complete remission (87.88%),8cases of partial remission (12.12%). ERCCl high expression in30cases were CR,4cases PR; ERCCl low expression in28cases were CR,4cases PR. Two complete remission rate was88.24%and87.5%respectively, the two groups was not statistically significant (p=0.775,>0.05).2. compare the efficacy of IMRT group and conventional radiotherapy group:2.1After the end of radiotherapy, efficacy evaluation conducted recently within a month. Journal of Clinical Oncology lesions:IMRT group36cases in37cases of CR,1case PR, complete remission rate of97.30%; conventional radiotherapy group,22cases in29cases of CR,7cases PR, complete remission rate of75.86percent, two completely remission rate was statistically significant (P<0.05). Two clinical remission rate (CR+PR) were100%, no significant difference (P<0.05).2.2Side reaction of IMRT group and conventional radiotherapy groupAcute skin reactions dry mouth, limited mouth opening, the symptoms of dental caries in IMRT group of patients were significantly lower than conventional radiotherapy group. Oral mucosa acute reaction, hematologic toxicity had no significant difference in conventional radiotherapy group and IMRT group.3.ERCC1expression and survival:66cases of NPC patients followed up for30to120months, with an average82months, no patients lost to follow.14people relapse during follow-up (8cases were local recurrence,6cases distant metastasis), ERCC1expression in34cases,10patients relapsed (29.41%), while32cases of low expression of ERCC14patients relapsed (12.5%), the local recurrence rate between the two groups was statistically significant (P=0.041).4.5-year progression-free survival (PFS):ERCC1expression of34(22)64.70%, ERCC1low expression of32(22)68.75%, two5-year progression free survival was not statistically significant (p=0.728).5.5-year overall survival (OS):ERCC1expression34(20) cases58.82%, ERCC1low expression32(27) cases84.37%, the5-year OS in two groups was statistically significant (p=0.022).6Multivariate analysis showed that ERCC1expression status can become an independent prognostic factor in affecting the5-year overall survival in locally advanced nasopharyngeal cancer patients with concurrent chemoradiotherapy (p=0.026).Conclusion1.Recent curative effect The complete remission rate (CR) of high ERCC1expression group and low expression ERCC1group has no difference, the clinical remission rate (CR+PR) has no difference too.2. The complete remission rate of IMRT group was higher than that of conventional radiotherapy group, but the clinical remission rate has no difference between two groups. Acute skin reaction, dry mouth, limitation of mouth opening, dental caries symptoms in IMRT group significantly were lower than the conventional radiotherapy group.3. The high expression of ERCC1group of patients with nasopharyngeal carcinoma recurrence rate is higher than the low ERCC1expression group.4.5years of progression free survival with low ERCC1expression and high expression of ERCC1had no difference.5. The5years OS of concurrent radiotherapy and chemotherapy in patients with locally advanced nasopharyngeal carcinoma patients, ERCC1low expression group is better than ERCC1high expression group. 6. ERCCl state can become a molecular marker to predict the curative effect in the treatment of patients with synchronous radiotherapy and chemotherapy in locally advanced nasopharyngeal carcinoma.