Prognostic value of the epidermal growth factor receptor (EGRF) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction chemotherapy

We measured the expression of the p53 nuclear protein and epidermal growth factor receptor (EGFR) in 46 biopsy samples from patients with advanced head and neck cancer treated with induction combination chemotherapy of 5-fluorouracil, cisplatin, and paclitaxel. Tumour expression of p53 protein was analysed with the monoclonal D07 antibody and EGFR with monoclonal H11 antibody. The overall response, defined as complete (CR) and partial response (PR) rates to treatment, was 88%. p53 positive staining was significantly more frequent in patients who did not respond to the induction treatment. EGFR expression failed to show any correlation with the response rate. Multivariate analysis indicated that a tumour location in the oral cavity together with p53 expression combined with moderate-to-high EGFR staining were independent prognostic factors of a shorter disease-free survival (DFS). Location of the tumour in the oral cavity and EGFR expression had independent prognostic value for overall survival (OS). We conclude that the EGFR status and an oral cavity location of the tumour have independent prognostic value in patients with advanced head and neck carcinoma treated with induction chemotherapy. The p53 status appears to be a determinant of the tumour chemo-sensitivity in advanced head and neck squamous cell carcinoma (HNSCC). The presence in the tumour of a p53-positive stain and moderate-to-high staining of EGFR is associated with a shorter DFS and time to treatment failure (TTF) probably reflecting a more aggressive tumour phenotype.     

Excision repair cross complementation group 1 immunohistochemical expression predicts objective response and cancer-specific survival in patients treated by Cisplatin-based induction chemotherapy for locally advanced head and neck squamous cell carcinoma.

PURPOSE: To assess the correlation of excision repair cross complementation group 1 (ERCC1) immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous cell carcinoma treated with cisplatin-based induction chemotherapy. EXPERIMENTAL DESIGN: The initial cohort was composed of 107 patients who were treated from 1992 to 1996 by an induction chemotherapy regimen for locally advanced head and neck squamous cell carcinoma. p53 mutations had previously been studied. Pretherapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 immunohistochemical expression. RESULTS: Of 96 patients, 68 (71%; 95% confidence interval, 61-79%) had tumors that expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 (29%) patients with tumors expressing ERCC1 at lower levels had a 4-fold greater odds of benefiting from an objective response to chemotherapy (odds ratio, 4.3; 95% confidence interval, 1.4-13.4; P = 0.01) compared with the group of 68 patients with high ERCC1 expression. ERCC1 and p53 status, but not their interaction, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on age, TNM stage, tumor differentiation, and tumor localization, ERCC1 low expression was associated with a lower risk of cancer death (risk ratio, 0.42; 95% confidence interval, 0.20-0.90; P = 0.04) whereas p53 status had no prognostic value. CONCLUSION: Our results suggest that those patients characterized by low ERCC1 expression are more likely to benefit from cisplatin induction chemotherapy compared with patients with high ERCC1 expression.     

Taxanes as radiosensitizers for head and neck cancer.

Combinations of paclitaxel and radiation therapy or paclitaxel with other chemotherapy agents and radiation have been tested with variable results in patient populations. To date, three phase I trials have been conducted using paclitaxel alone in combination with radiotherapy for the treatment of patients with head and neck cancer. Dose-limiting toxicity in the 1-hour infusion was mucositis, whereas in the 24-h/wk infusion, fever was the dose-limiting toxicity. In the long-term infusion (24 h/d, 7 d/wk), no dose-limiting toxicity was seen at the doses of paclitaxel given. In two of the protocols in which biopsies were obtained, a G2/M block was observed. A phase I protocol using paclitaxel in combination with fluorouracil and hydroxyurea with radiation and a phase II protocol using paclitaxel with cisplatin in operable head and neck cancers have been reported. Preliminary results suggest that paclitaxel in combination with radiotherapy is a reasonable experimental treatment that deserves further study in patients with stage III and IV squamous cell carcinomas of the head and neck.     

Revisiting induction chemotherapy for head and neck cancer

Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. However, randomized trials have failed to demonstrate a survival advantage with the addition of induction chemotherapy to locoregional therapy consisting of surgery and/or radiation therapy. Currently, concomitant radiation and chemotherapy has emerged as a standard and has optimized locoregional control in head and neck cancer. In this setting, the addition of induction chemotherapy may further improve outcome by enhancing both locoregional and distant control. As interest in induction regimens is renewed, we elected to conduct a systematic review of trials of induction chemotherapy for locoregionally advanced head and neck cancer. The most studied combination--cisplatin plus fluorouracil (5-FU)--achieves objective response rates of about 80%. In a meta-analysis, induction with platinum/5-FU resulted in a small survival advantage over locoregional therapy alone. The introduction of a taxane into induction chemotherapy regimens has produced promising results. Induction chemotherapy should be the subject of further clinical research in head and neck cancer. Randomized clinical trials in which the control arm is concurrent chemoradiotherapy and the experimental arm is induction chemotherapy followed by concurrent chemoradiotherapy are planned. Platinum/taxane combinations are the preferred regimens for further study in the induction setting and a suitable platform with which to investigate the addition of novel targeted agents.     

Revisiting induction chemotherapy for head and neck cancer. References and reviews

Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. However, randomized trials have failed to demonstrate a survival advantage with the addition of induction chemotherapy to locoregional therapy consisting of surgery and/or radiation therapy. Currently, concomitant radiation and chemotherapy has emerged as a standard and has optimized locoregional control in head and neck cancer. In this setting, the addition of induction chemotherapy may further improve outcome by enhancing both locoregional and distant control. As interest in induction regimens is renewed, we elected to conduct a systematic review of trials of induction chemotherapy for locoregionally advanced head and neck cancer. The most studied combination-cisplatin plus fluorouracil (5-FU)--achieves objective response rates of about 80%. In a meta-analysis, induction with platinum/5-FU resulted in a small survival advantage over locoregional therapy alone. The introduction of a taxane into induction chemotherapy regimens has produced promising results. Induction chemotherapy should be the subject of further clinical research in head and neck cancer. Randomized clinical trials in which the control arm is concurrent chemoradiotherapy and the experimental arm is induction chemotherapy followed by concurrent chemoradiotherapy are planned. Platinum/taxane combinations are the preferred regimens for further study in the induction setting and a suitable platform with which to investigate the addition of novel targeted agents.     

Growth inhibition and apoptosis induction in ovarian cancer cells

Standard therapy for the treatment of ovarian cancer is radical surgery followed by radiation and/or chemotherapy using cisplatin and paclitaxel. Unfortunately, some patients relapse after this first line chemotherapy and some patients become platinum-refractory. Therefore, we analyzed two different ovarian carcinoma cell lines for their sensitivity for gamma-irradiation and treatment with cisplatin, irinotecan, paclitaxel and gemcitabine. We found that both cell lines were rather resistant against gamma-irradiation and treatment with cisplatin and irinotecan whereas paclitaxel and gemcitabine resulted in a considerable reduction of the viability of the cancer cells. Both paclitaxel and gemcitabine treatment resulted in the induction of apoptosis. This sensitivity profile might be due to a particular subset of p53, which reacted with monoclonal antibodies DO-1 and PAb1801 but not with PAb1620 and PAb421. Gemcitabine and paclitaxel are highly efficient in the induction of apoptosis in ovarian cancer cells, which express a particular subset of the growth suppressor protein p53. Thus, a sensitivity profile for each ovarian carcinoma seems to be highly recommended before starting treatment.     

Intensive concurrent chemoradiotherapy for head and neck cancer with 5-Fluorouracil- and hydroxyurea-based regimens: reversing a pattern of failure

Combined modality programs that were developed over the past two decades demonstrated that the nonsurgical therapy of locoregionally advanced head and neck cancer is feasible and produces survival outcomes that are at least comparable with surgery. The systemic therapy of head and neck cancer has gained momentum in recent years. Several randomized studies have shown that the concurrent administration of chemotherapy and radiation therapy is superior to radiation therapy alone. In consecutive clinical studies since 1986, we have developed multiagent chemoradiotherapy regimens based on initial observations with the 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy combination. Three consecutive multicenter phase II trials reported that the combination of 5-FU and hydroxyurea with either cisplatin or paclitaxel along with twice daily radiation therapy administered every other week is a highly effective regimen with local control rates that approach 90% and 3-year survival rates of approximately 60% in patients with stage IV disease. The vast majority of patients in these studies achieved anatomical organ preservation. A reversal of the historical pattern of failure was evident, with distant sites becoming the predominant site of failure in each trial. The paclitaxel-containing regimen was better tolerated than the cisplatin-containing regimen and was advanced to further clinical testing. The incorporation of induction chemotherapy may improve the results of treatment by targeting systemic micrometastatic disease.     

Combination chemotherapy with high-dose methotrexate, bleomycin, and cisplatin in management of head and neck squamous cell carcinoma

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.     

Organ preservation in multimodality therapy of head and neck cancer

Several conclusions can be drawn from the studies that have been done to evaluate induction chemotherapy and organ preservation. These principles can serve as the foundation for the design of future trials for organ preservation. 1. The addition of chemotherapy to surgery/radiation for advanced head and neck cancer has not improved overall patient survival. 2. Surgery and radiation therapy can safely and effectively be given after chemotherapy to patients who have had induction chemotherapy. 3. Neoadjuvant chemotherapy followed by definitive radiation therapy can achieve laryngeal preservation in a high percentage of patients, without compromise of survival. 4. In order to change the standard of care, organ preservation trials must be conducted in a randomized, prospective fashion. 5. Organ preservation trials must be conducted for specific sites and stages of head and neck cancer. 6. All patients with nonlaryngeal head and neck cancer who are treated with induction chemotherapy for organ preservation should be treated within a protocol setting.     

Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): analysis of chemoradiation treatment approaches in the United States

BACKGROUND:

A study was undertaken to examine the patterns of systemic therapy use in conjunction with radiation therapy for patients with locally advanced head and neck squamous cell cancer.

METHODS:

Between December 1, 2005 and May 11, 2009, 2874 patients with newly diagnosed head and neck squamous cell cancer who were scheduled to receive radiotherapy and/or drug therapy were registered in a prospective national database. The database was specifically analyzed to examine patients who received chemotherapy in conjunction with definitive radiotherapy.

RESULTS:

A total of 1144 patients received systemic therapy in conjunction with radiotherapy; 645 (56%) patients received agents concurrent with radiation therapy, 49 (4%) patients received chemotherapy before radiotherapy (induction), 224 (20%) patients received chemotherapy before and during radiotherapy (sequential), and 226 (20%) patients received chemoradiation after surgery. Single‐agent cisplatin, single‐agent cetuximab, and carboplatin plus paclitaxel were, in order, the 3 most commonly prescribed concurrent regimens. Concurrent cisplatin was more frequently used in the academic setting compared with the community setting (P = .0015). Postoperative chemoradiation, rather than radiation alone, was more commonly used in academic centers compared with community practice centers (P = <.0001).

CONCLUSIONS:

The LORHAN (Longitudinal Oncology Registry of Head and Neck Carcinoma) database is a useful barometer of current US practice patterns and can be applied to analyze future trends in the combined modality management of head and neck cancer. Sequential chemotherapy is used frequently, but cisplatin‐based concurrent chemoradiation remains the most commonly used regimen for locally advanced head and neck cancer. Cancer 2011. © 2010 American Cancer Society.     

Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head and neck cancer to cytotoxic and radiation therapy.

Thymidine phosphorylase (TP), an enzyme involved in the thymidine synthesis and degradation, has been shown to promote tumor angiogenesis. Both TP expression and tumor vascularization are putative postoperative prognostic markers of cancer. Because of its bifunctional role, TP may have interactions with cytotoxic drugs or radiation via pathways requiring thymidine or prodrug activation. The microvessel score and TP expression were examined immunohistochemically on paraffin-embedded bioptical material from 94 locally advanced squamous cell head and neck carcinomas. All patients were treated with conventionally fractionated radiotherapy combined with induction (platinum- and 5-fluorouracil-based) or concurrent platinum chemotherapy. The follow-up of patients ranged from 6 to 108 months (median, 48 months). Nuclear TP expression was significantly associated with increased microvessel score (P < 0.0001, r = 0.45). A low percentage of cancer cells with nuclear TP expression in pretreatment biopsies was associated with a high rate of CR after combined chemoradiotherapy (P = 0.006) and induction chemotherapy (0.01). A better local relapse-free and overall survival was also observed in these patients (P = 0.001 and P = 0.0005, respectively). Biospies on the day after the delivery of 20 Gy of conventionally fractionated radiotherapy showed residual cancer cell nests, frequently of high vascularization and of intense nuclear TP reactivity. It is concluded that thymidine phosphorylase is associated with angiogenesis, with resistance to radiotherapy and cytotoxic therapy, and with poorer survival in squamous cell head and neck cancer. A strong rationale is provided for subsequent clinical trials of concurrent radiotherapy and chemotherapy with antiangiogenic agents or with specific TP inhibitors.     

Induction chemotherapy in the management of squamous cell carcinoma of the head and neck

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.     

Role of multimodal treatment in oropharynx, larynx, and hypopharynx cancer

Due to recent advances in radiation fractionation, radiochemotherapy, and conservative surgical techniques, the concept of multimodal therapy in head and neck cancer is currently changing. The recently published RTOG Phase III trial 9003, with 1,113 patients accrued, showed that hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally-advanced head and neck cancer. Acute, but not late, toxicity was also increased. Three meta-analyses have suggested that the impact of chemotherapy in head and neck cancer is small but is highly associated with the timing of therapy. Concomitant administration of radiation therapy and chemotherapy led to an absolute benefit in 5-year survival of about 10%. This finding has been further supported by recently published randomized prospective trials comparing concomitant radiochemotherapy with radiotherapy alone in advanced head and neck cancer. There is now clear evidence that radiochemotherapy provides a substantial and statistically significant improvement in survival and local-regional control, as compared to radiotherapy alone. Radiochemotherapy should be considered an accepted standard of care in cancers of the oropharynx, particularly for patients with locally-advanced disease who have a good performance status. Two randomized studies conducted by the Department of Veterans' Affairs and the EORTC, with a total of 534 patients accrued, showed that induction chemotherapy followed by radiotherapy of responders yields survival rates equal to those of total laryngectomy with postoperative radiotherapy. After 4 years, one-half to two-thirds of survivors of the chemotherapy arm retained a functional larynx. Larynx preservation using induction chemotherapy can now be regarded as feasible but still investigational. Current phase II studies show excellent larynx preservation rates using a primary concomitant radiochemotherapy with an altered fractionation regimen. More clinical and laboratory research is required to further evaluate the different treatment options of the multimodality concept, and to develop prognostic models that will allow individualization of the therapy.     

Paradigm shift in the treatment of head and neck cancer: the role of neoadjuvant chemotherapy

Chemotherapy is an integral component of the management of patients with locally advanced head and neck cancer, though the optimal use of chemotherapy remains to be defined. The combination of a platinum agent and 5-fluorouracil has been used as the standard neoadjuvant treatment and has been shown to permit organ preservation in operable patients and improve long-term survival outcomes in operable and inoperable patients. Recently, the addition of a taxane, docetaxel or paclitaxel, to standard platinum plus 5-fluorouracil induction chemotherapy has been shown to further improve response rates and survival outcomes. Phase III data are emerging to support combinations of docetaxel or paclitaxel with a platinum plus 5-fluorouracil as a new, more effective and less toxic standard for neoadjuvant chemotherapy. Sequential treatment regimens, incorporating a combination of induction chemotherapy and chemoradiation, are also under study in efforts to further improve long-term survival outcomes. Induction regimens incorporating docetaxel or paclitaxel with a platinum plus 5-fluorouracil are under evaluation in this setting. Randomized trials comparing a sequential treatment approach with standard therapies are also being undertaken and will likely define a new treatment paradigm for patients with locally advanced head and neck cancer.     

Larynx preservation using induction chemotherapy plus radiation therapy as an alternative to laryngectomy in advanced head and neck cancer. A long-term follow-up report.

Since 1977, we have used induction chemotherapy (CT) plus radiation therapy (RT) with curative intent in 35 advanced head and neck cancer (Ca) patients who otherwise would have required total laryngectomy. Fourteen patients had advanced Ca of the larynx or supraglottic larynx (SGL); 21 patients had Ca of the hypopharynx. In six patients the Ca was Stage III; in 26 patients it was Stage IV. Three patients had Stage II disease--2 with cancer of the pyriform sinus and one patient with Stage II SGL Ca who refused surgery. Chemotherapy consisted of platinum (P) + bleomycin in 18 patients until 1982, then P + fluorouracil in the next 17 patients. Total response rate was 77%--complete (CR) in 26% and partial (PR) in 51%. There were two toxic deaths. Surgery was limited to tracheostomy in 4 patients prior to CT and to radical neck dissection after CT in 4 others. Two patients required salvage laryngectomy at 11 and 31 months, respectively. One patient underwent partial laryngectomy with voice preservation. Thirty-two patients were evaluable for overall response after RT. Final disease-free status was achieved in 20/34. One long-term survivor was lost to follow-up (44 months) and 8 patients remained alive at 13+ to 109+ months. Median failure-free survival for all patients was no less than 24 months. Not counting 4 early deaths free of disease, 2-year local control using only chemotherapy plus radiation was 52% (16:31). Overall, 33 of 35 patients retained their voices. Sixteen patients (46%) have survived 2 years or longer. Survival of patients who achieved CR after induction chemotherapy was 48 months versus 14 months for those with less than a CR (p = 0.001). Patients with a hypopharyngeal primary had only a 33% 2-year local control rate with chemotherapy and radiation and a median survival of only 12 months versus 77% control and a minimum 39-month survival for those whose tumor arose in the larynx (p = 0.009). Induction chemotherapy plus radiation therapy is an effective strategy which can produce a high rate of larynx preservation, local control, and long-term survival in patients with advanced cancer of the larynx. Patients with hypopharyngeal primaries have a lesser rate of long-term survival and local control, despite similar overall response rates.     

白蛋白结合型紫杉醇在局部晚期/晚期头颈部肿瘤治疗中的研究进展及展望

化疗在局部晚期/晚期头颈部肿瘤的治疗中发挥重要作用,对提高肿瘤局部控制率、延缓肿瘤进展、减少远处转移及延长患者生存时间有重要的意义。TP（紫杉醇类加铂类）和TPF（紫杉醇类、顺铂及5-氟尿嘧啶）方案是头颈部肿瘤的经典有效化疗方案,故紫杉醇类（如紫杉醇和多西他赛）是头颈部肿瘤常用的化疗药物。白蛋白结合型紫杉醇作为一种新型紫杉醇类药物,以其独特剂型优势,已在多个临床试验中显示出良好的疗效及安全性。本文总结了以白蛋白结合型紫杉醇为基础分别联合其他不同化疗药物方案治疗局部晚期/晚期头颈部肿瘤的安全性及有效性,对白蛋白结合型紫杉醇在局部晚期/晚期头颈部肿瘤中应用的最新临床研究作一综述,并对未来该药治疗局部晚期/晚期头颈部肿瘤进行展望。      

DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer

Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also being VP16 resistant. In order to explain the VP16 resistant phenotype several mechanisms where considered. The p53 status, P-glycoprotein, MRP, topoisomerase IIalpha, and Mre11 protein levels, as well as growth kinetics, provided no explanations of the observed VP16 resistance. In contrast, a significant difference in repair of both VP16- and IR-induced DSBs, together with a difference in the levels of the DSB repair proteins DNA-dependent protein kinase (DNA-PK(cs)) and RAD51 was observed. The VP16- and radioresistant 54B subline exhibited a pronounced higher repair rate of DSBs and higher protein levels of both DNA-PK(cs) and RAD51 compared with the sensitive 54A subline. We suggest, that different DSB repair rates among tumor cell subpopulations of individual SCLC tumors may be a major determinant for the variation in clinical treatment effect observed in human SCLC tumors of identical histological subtype.     

Induction chemotherapy in the management of squamous cell carcinoma of the head and neck

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.     

Multimodality therapy for unresectable squamous cell carcinoma of the head and neck

Eighteen patients with unresectable Stage III or IV squamous cell carcinoma of the head and neck were treated with induction therapy consisting of sequential methotrexate and 5-fluorouracil. This was followed by full course radiation therapy and radical neck dissection for those with residual neck disease. Those with local control were then treated with vinblastine, bleomycin, and cisplatin (VBP). Although 79% of patients achieved a partial or complete response to chemotherapy, only 50% of patients achieved local control. Marked mucositis limited the dose and schedule of radiation therapy. The methotrexate and 5-fluorouracil combination appears to be too toxic for multimodality therapy of advanced head and neck cancer.