Radiochemotherapy in head and neck cancer

The present paper is based on a talk given, during the meeting of the EORTC Radiotherapy Group, held in Arona (Italy) on April 19-20, 2002. This review analyses many still open questions on combined chemotherapy and radiotherapy in head and neck cancer, on the basis of the available data.The paper may help to point out future directions for novel clinical researches on combined chemotherapy and radiotherapy in head and neck cancer.     

Radiochemotherapy for oesophageal cancer: a locoregional failure history

Esophageal cancer is characterized by various degrees of lymph node invasion and metastasis, both of which are associated with a poor prognosis. Exclusive concomitant radiochemotherapy (RCT) at a dose of 50 Gy delivered over 25 sessions, according to the RTOG 85-01 protocol, has led to improved five-year survival in 25% of patients, whereas no patients survive for five years using radiotherapy alone. Surgery, even when combined with preoperative RCT, also gives disappointing results for locally advanced tumors, which casts serious doubts on the usefulness of preoperative radiotherapy. By varying the fractionation schedule, the length of treatment or the radiotherapy volumes, it has become possible to obtain levels of locoregional relapse of around 35 to 45%. The increasing incidence of adenocarcinoma, which differs from epidermoid cancer with regard to the degree of lymph node invasion, has revived discussion on radiotherapy volumes. Given this difference between these two histological forms, we propose here a number of recommendations concerning radiotherapy volumes for patients presenting with cancer of the esophagus. Finally, analysis of the results for locoregional relapse according to the dose of radiation and the recommended radiotherapy volumes, has led us to investigate why increasing the dose of radiation has no impact in esophageal cancers.     

MicroRNA in rectal cancer

In rectal cancer, one of the most common cancers worldwide, the proper staging of the disease determines the subsequent therapy. For those with locally advanced rectal cancer, a neoadjuvant chemoradiotherapy (CRT) is recommended before any surgery. However, response to CRT ranges from complete response (responders) to complete resistance (non-responders). To date we are not able to separate in advance the first group from the second, due to the absence of a valid biomarker. Therefore all patients receive the same therapy regardless of whether they reap benefits. On the other hand almost all patients receive a surgical resection after the CRT, although a watch-and-wait procedure or an endoscopic resection might be sufficient for those who responded well to the CRT. Being highly conserved regulators of gene expression, microRNAs (miRNAs) seem to be promising candidates for biomarkers. Many studies have been analyzing the miRNAs expressed in rectal cancer tissue to determine a specific miRNA profile for the ailment. Unfortunately, there is only a small overlap of identified miRNAs between different studies, posing the question as to whether different methods or differences in tissue storage may contribute to that fact or if the results simply are not reproducible, due to unknown factors with undetected influences on miRNA expression. Other studies sought to find miRNAs which correlate to clinical parameters (tumor grade, nodal stage, metastasis, survival) and therapy response. Although several miRNAs seem to have an impact on the response to CRT or might predict nodal stage, there is still only little overlap between different studies. We here aimed to summarize the current literature on rectal cancer and miRNA expression with respect to the different relevant clinical parameters.     

Prediction in rectal cancer

The treatment of rectal cancer largely depends on disease stage at diagnosis, based on which patients can be classified as low, intermediate, or high risk. Prognostic and predictive markers, specific to each risk category, can be applied for optimal risk classification and subsequent treatment allocation. These markers are either histopathological, determined with imaging, or have a biomolecular background. This review provides an overview of the current status of treatment options and the use of prognostic and predictive markers in each risk category. An effort was made to identify those markers that are currently lacking in, but have the potential to improve, the clinical decision process by discussing the data from recent studies aimed at the development of new prognostic and predictive markers. At this moment, none of the markers studied has been proven to be of significant, independent value, justifying implementation in daily clinical practice. However, recent developments in imaging techniques and biomolecular research do show great potential.     

IGRT in rectal cancer

To date, no great interest has been shown in the clinical implementation of recent Image-guided radiation therapy (IGRT) modalities in rectal cancer since only a few studies have been published on this issue. This may be explained by the fact that with current treatment modalities locoregional recurrences are already very low (around 10%). However, there is still room for improvement in treatment of high risk patients (cT3 CRM+, cT4, N+). In these patients better results may be obtained improving radiation technique from 2D to 3D, which showed to be more reliable in terms of target coverage. Also, when higher doses are delivered, Intensity Modulated Radiation Therapy (IMRT) may be used to spare small bowel. But before employing 3D irradiation or IMRT, a proper definition of our clinical target volume (CTV) and planning target volume (PTV) is needed. The CTV should encompass the tumour site, the mesorectum and the lateral nodes, recognized as the most likely sites of local recurrence, with different incidence according to tumour stage. Recent studies discussed the correct delineation of these target volumes in respect of tumour site and stage. From the preliminary results of a study conducted in Rome University 2D planning seemed insufficient to cover the different target volumes especially in T4 patients compared to 3D planning. Also an appropriate PTV margin is necessary in order to manage set-up errors and organ motion. Particularly in these patients, the knowledge of mesorectal movement is required to avoid target missing. Large mesorectal displacements were observed in a study carried out in Leuven University in collaboration with Rome University. A systematic review of the literature together with the data from these first experiences led to the awareness that IGRT could help us to follow the target volume and organs at risk during the treatment, allowing adjustments to improve accuracy in dose delivery, especially when dose escalation studies are planned in the treatment of rectal cancer.     

Perioperative radiotherapy in rectal cancer

Local failure of rectal cancer is one of the principal causes of morbidity and mortality. In order to lower unacceptably high local failure rates, pre- or postoperative radiotherapy has been extensively investigated. The collected information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than half when radiotherapy up to moderately high doses is given preoperatively. This reduction is smaller after postoperative radiotherapy, even if higher doses are used. In addition, there is a positive influence on survival from preoperative radiotherapy. Improved survival has also been seen in trials using postoperative radiotherapy, but only when combined with chemotherapy. With proper radiation techniques, sufficiently high doses can be given preoperatively with little, if any, increase in postoperative mortality and morbidity. Furthermore, late toxicity can be anticipated to be low provided the technique is optimal. The beneficial effects noted so far have been achieved in trials where 'standard' surgery has been used, followed by a local recurrence rate of more than 20% (average 29%, range 23-46%) of the patients. It is, however, possible that the reduction in local failure rates is proportionally even greater added to 'optimal' surgery, although the absolute number of failures prevented is lower.     

Sphincter preservation in rectal cancer

Opinion statement Distal rectal cancer poses two challenges to the oncologist: local tumor control and sphincter preservation. The abdominoperineal resection (APR), long considered the standard treatment of tumors with a distal edge located up to 6 cm from the anal verge, provides local control in many patients but results in sphincter loss with a permanent colostomy. This is a critical limitation. Consequently, there has been significant interest in sphincter-conserving approaches, frequently combining chemoradiation with surgery. These approaches have evolved along two fronts. For patients with small rectal cancers confined to the rectal wall, local excision techniques with and without chemoradiation may offer comparable local control and survival rates as an APR and preserve sphincter function. For patients with larger and more invasive tumors of the distal rectum where local excision is inappropriate, preoperative chemoradiation promotes tumor regression and may facilitate a resection sparing the sphincter with a coloanal anastomosis. Preliminary results from single institution studies appear promising. In both these settings (favorable and more invasive rectal cancer), chemoradiation is employed to compensate for the limitations of the sphincter-preserving surgical technique. In local excision procedures, the excision margins are invariably small, and the mesorectum (lymphatics, soft tissue) surrounding the tumor is not excised. For patients undergoing resection with coloanal anastomosis, there are narrow radial and distal surgical margins. With these approaches of chemoradiation and sphinctersparing surgery, satisfactory local control and survival with avoidance of colostomy are possible for many patients with distal rectal cancer.     

Multidisciplinary management in rectal cancer

The treatment of rectal cancer has evolved over the last few decades from surgery alone to treatments with trimodal therapy for high-risk patients. The involvement of a multidisciplinary team of radiologists, pathologists, surgeons, radiotherapists and medical oncologists is now fundamental for decision-making and outcomes. The evolution of different diagnostic and therapeutic techniques has optimised the therapeutic rate. Future studies will determine the optimal regimen for inducing complete responses in locally advanced disease and whether the intensification of local treatments could enable the use of more conservative treatments, as for other tumour locations. The study of biomarkers will be essential in this respect.     

Improving chemoradiotherapy in rectal cancer

The optimal management of rectal cancer remains a major challenge for oncologists. The treatment of stage II/III rectal cancer has historically been associated with a high risk of local recurrence and poor survival, which led to the development of adjuvant treatments in the hope of improving outcomes. The approach to adjuvant therapy for rectal cancer currently varies widely between Europe and the U.S. Postoperative adjuvant chemoradiation is the standard of care in the U.S. In contrast, in Europe, because there is a greater emphasis placed on preoperative imaging, meticulous surgical technique, and accurate pathologic reporting of the circumferential or radial margin, preoperative treatment (radiotherapy and chemoradiation) is used widely. The aims of preoperative radiotherapy and chemoradiation are to facilitate a curative resection (R0) and to increase the chance of performing sphincter-sparing procedures, and, therefore, to improve both survival and quality of life. This article reviews the clinical trials that led to these diverging standards of care. An interesting new approach in chemoradiation is the use of the oral fluoropyrimidine capecitabine as a combination partner for radiotherapy. Preclinical studies have demonstrated that the combination of capecitabine and radiotherapy has highly enhanced antitumor activity. This is most likely attributable to the upregulation of thymidine phosphorylase (the rate-limiting enzyme needed to convert capecitabine to 5-fluorouracil [5-FU]) in tumor cells following radiotherapy. A phase I study has consequently been performed to establish a feasible chemoradiotherapy combination. Capecitabine has the potential to replace bolus or continuous infusion 5-FU as the standard treatment for rectal cancer and offers a potentially enhanced therapeutic ratio. Oral chemotherapy has the additional advantage of simplifying chemoradiation and providing a treatment that is more appealing to patients.     

Function-preserving operation in rectal cancer

Function preservation in rectal cancer surgery consists of preservation of the anal function, the urinary function and the male sexual function. Low anterior resection (manual or instrumental), invagination technique and pull-through are selected as the sphincter saving operation for cancer of the upper and middle rectum. It is reported that more than 60% of rectal cancers are treated by these operations and that a favorable function are obtained. Autonomic nerves such as hypogastric, pelvic and pudendal nerves are anatomically preserved in Dukes A cancer to prevent the urinary and male sexual dysfunction. The post-operative disturbances of urination and male sexual potency decreased to 10% or less by the autonomic nerves preservation.     

Sphincter preservation in rectal cancer

Sphincter preservation is a major goal in the treatment of rectal cancer. For selected patients with T1–2 disease, local excision followed by postoperative combined modality therapy is a reasonable alternative to an abdominoperineal resection. However, for patients with T3 disease, the local recurrence with this approach is approximately 25% and they are treated more effectively with preoperative combined modality therapy. In patients who undergo a prospective clinical assessment and are declared to require an abdominoperineal resection, preoperative radiation therapy, either alone or when combined with chemotherapy, allows approximately 80% to undergo a low anterior resection/coloanal anastomosis. The majority have good-to-excellent sphincter function. These conservative approaches may be an alternative to an abdominoperineal resection in selected patients. Received: August 7, 1998     

Targeted therapy in rectal cancer

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.     

同步放化疗与序贯放化疗对食管癌预后影响的Meta分析

目的 评价同步放化疗(CCRT)与序贯放化疗(SCRT)治疗食管癌的远期疗效.方法 计算机检索The Cochrane Library、Pubmed、Embase、中国生物医学文献数据库(CBM)、中国期刊全文数据库(CNKI)、维普中文科技期全文数据库(VIP)和万方数据库,对符合纳入标准的随机对照试验进行方法学质量评价,采用RevMan 5.3进行Meta分析.结果 共纳入22个研究1933例患者,结果显示,同步放化疗组1年生存率、2年生存率、3年生存率、1年疾病局部控制率、2年疾病局部控制率、3年疾病局部控制率[OR=2.41,95%CI(1.48,3.91),P=0.0004]优于序贯放化疗组,在远处转移方面,两组无差别.结论 同步放化疗治疗食管癌的1、2、3年生存率,1、2、3、年局部局部控制率优于序贯放化疗,但受纳入研究的质量的影响,上述结论尚需更多高质量的临床试验来进一步证实.