Concurrent chemotherapy and radiation therapy as the standard of care for cervical cancer

From 1999-2000, each of five randomized trials demonstrated improved rates of survival and local control when concurrent cisplatin-based chemotherapy was added to radiation therapy in patients with loco-regionally advanced cervical cancer. These studies demonstrated that addition of chemotherapy to radiation therapy improved the outcome of patients treated with radiation therapy and hysterectomy or radiation therapy alone. Although concurrent chemotherapy increases the severity of acute side effects, it does not appear to increase the risk of late side effects of radiation therapy. A sixth randomized trial, published in 2002, failed to demonstrate improved outcome with concurrent weekly cisplatin over radiation therapy alone; however, the earlier trials demonstrated benefit with this chemoradiation regimen. In addition, three of the earlier randomized trials demonstrated improved outcome with combinations of cisplatin and 5-fluorouracil compared with radiation therapy alone. Although cisplatin-based chemoradiation is the most accepted standard, individual trials have suggested that other drugs, including mitomycin and epirubicin, might be beneficial. Randomized trials that investigated the administration of neoadjuvant chemotherapy before radiation therapy have failed to demonstrate a benefit of this approach. Although the evidence for benefit of concurrent chemotherapy is strong for otherwise healthy patients with newly diagnosed, loco-regionally advanced cervical cancers confined to the pelvis, the relative benefits and risks are not well understood for patients who are infirm or who require larger fields of radiation therapy. In such patients, the theoretical benefits and potential risks should be considered carefully before a treatment plan is prescribed.     

Modern management of locally advanced cervical carcinoma

Radiation was until recently the key and only modality for the routine treatment of locally advanced cervical carcinoma. However after years of studying multi-modality treatments as an alternative to radiation alone in randomized phase III trials, the standard treatment has changed to chemo-radiation based on cisplatin. Three recent meta-analyses have confirmed that cisplatin-based chemo-radiation adds an absolute 12% benefit in five-year survival over radiation therapy alone. Neoadjuvant chemotherapy followed by radiation has not been of proven benefit, but when neoadjuvant chemotherapy is followed by surgery, an absolute increase of 15% in five-year survival over radiation alone is seen. This benefit in survival is comparable to that obtained with the current chemo-radiation schedules based on cisplatin. Despite these encouraging results there remains room for improvement as the five-year survival of patients treated with chemo-radiation ranges from nearly 80% in bulky IB tumours to only 25% in stage IVA disease. Other therapeutic approaches need to be fully evaluated including the use of chemo-radiation after neoadjuvant chemotherapy; the use of new drug combinations and the multi-modality combination of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemo-radiation. Likewise, the addition of radiosensitizers to cisplatin, preoperative chemo-radiation and/or adjuvant chemotherapy may eventually improve the currents results of cisplatin-based chemo-radiation. Nevertheless, it is hard to foresee a dramatic increase in cure rate, even with the most optimal combination of cytotoxic drugs, surgery and radiation, and thus the testing of molecular targeted therapies against cervical cancer is a logical step to follow.     

Recent developments in chemoradiotherapy for locally advanced cancer of the cervix

Patients with locally advanced cervical cancer comprise a significant proportion of the total population with cervical cancer, particularly in developing countries. The inability to control pelvic tumors is still a significant concern. Although neoadjuvant chemotherapy is associated with a high response rate, data from randomized trials clearly do not support the use of neoadjuvant chemotherapy prior to definitive irradiation. However, the results of concurrent cisplatin (Platinol)-based chemotherapy and radiotherapy are highly promising for locally advanced cancer of the cervix and should be considered as a treatment option. To decrease the risk of distant metastasis and improve survival, more effective drugs or drug combinations need to be developed.     

Role of ifosfamide in cervical cancer: an overview

Ifosfamide, a cyclophosphamide analogue, has demonstrated a wide spectrum of activity against numerous neoplasms in different oncologic areas, including paediatric, haematological, breast, lung and testicular cancers, soft tissue sarcomas and gynaecological cancer. In gynaecologic cancers in particular, evidence suggests activity in the treatment of epithelial ovarian cancer, cervical carcinoma, germ cell carcinoma of the ovary. Cervical cancer has long been considered a poorly chemosensitive tumour and for several years the role of chemotherapy in the treatment of this tumour was confined to persistent or recurrent disease after failure of surgery and/or radiotherapy. In the management of cervical cancer, chemotherapy has received increasing attention in the last two decades and is currently used in neoadjuvant regimens, as salvage treatment in patients with disseminated or recurrent disease, or as a radiosensitizer. Over the past 30 years, several agents have been tested but cisplatin and ifosfamide are the agents that have attracted the greater attention. Cisplatin represents the cornerstone of chemotherapy for cervical cancer. Ifosfamide has been studied as a single agent or in combination with other drugs in different studies. In this paper we reviewed the approach with systemic therapy and, in particular, the role of ifosfamide in advanced or recurrent, and less advanced cervical cancer.     

Concurrent chemotherapy and radiation therapy in primary cancer of the cervix

Radiation therapy has been the most active agent for the treatment of patients with locally advanced cervical cancer for many years. Chemotherapy has shown some activity, but data has been lacking to support its routine use. Recently, data from five prospective, randomized trials evaluating this difficult population have matured. Reports from these trials are startlingly similar, leading to the common conclusion that concurrent cisplatin chemotherapy and radiation therapy substantially decrease the risk of relapse and increase the overall survival. These results are compelling evidence for the inclusion of cisplatin with irradiation as a new standard of care for patients with locally advanced cervical cancer.     

Radiation Therapy With 5-fluorouracil in Head and Neck Cancer

5-Fluorouracil (5-FU) alone or combined with other drugs, most frequently cisplatin, has been used concurrently or as induction or adjuvant therapy with radiotherapy with or without surgery in the treatment of head and neck cancer. Improved local-regional control and disease-free survival or overall survival have been shown in several randomized trials using a concurrent approach. However, acute mucositis is usually increased with simultaneous 5-FU and radiation administration, especially when other drugs are used in addition to 5-FU. Alternating radiotherapy with 5-FU and cisplatin was shown to improve the local-regional relapse-free, progression-free, and overall survival of unresectable squamous cell carcinoma of the head and neck compared with radiotherapy alone in one randomized trial. Further evaluation of the alternating chemotherapy and radiotherapy approach is needed, however, before one can accept this as a standard of practice. Induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in the chemotherapy responders in an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hypopharynx who wish to preserve organ function. Induction or adjuvant chemotherapy with 5-FU infusion and cisplatin may also decrease or delay the occurrence of distant metastasis. Induction chemotherapy, however, has not been shown to improve local-regional control or overall survival. Further clinical trials combining 5-FU and its biochemical modulators using innovative radiation and drug dose schedules and other treatment modifiers are needed to improve the therapeutic ratio.     

Chemotherapy for cervical carcinoma

Although cisplatin-based chemotherapy is standard regime for cervical cancer, the major question remains as to what kind of drug is the best candidate for combination with cisplatin. According to recent reports, platinum+taxane is supposed to be a promising combination for not only squamous cell carcinoma but also adenocarcinoma of cervix. Studies of neoadjuvant chemotherapy followed by radiotherapy demonstrate no advantage for overall survival of locally advanced cervical carcinoma. Otherwise, neoadjuvant chemotherapy followed by radical surgery was confirmed to offer a survival advantage in a few prospective randomized trials but its statistical power was low due to small number of patient cases. The platinum+taxane combination is good and its effects should be evaluated on overall survival in the same modality. Concurrent radiotherapy with weekly cisplatin is standard therapy for primary and adjuvant setting for squamous cell carcinoma and adenocarcinoma of cervix.     

Non-small-cell lung cancer (NSCLC): chemotherapy in advanced disease. Our experience in ten years.

This is a review of the therapeutic schedules used in our service during the past 10 years for the therapy of advanced non-small-cell lung cancer. During the first years, nonrandomized trials were conducted and several combinations were tested: MACC (methotrexate, doxorubicin, cyclophosphamide, and CCNU), cisplatin-etoposide, and cisplatin-vindesine. The results of these trials were invariably discouraging: objective responses hardly reached 30%, while the survival was around 15 months in the best case. On December 1985 a new randomized trial, based on the combination MIP (mytomicin, ifosfamide, cisplatin) was designed; 60.7% of objective responses were achieved, with 9 complete remissions (17.6%) and 22 partial remissions (43.1%). Median survival was 15 months. In order to reduce the toxicity of this combination, carboplatin was substituted for cisplatin. Unfortunately, results were very poor. No complete remission, and only 5 partial responses (20%) were achieved. At the present time, a new randomized trial is being conducted. In it, MIP combination is compared with VIP (vindesine, ifosfamide, cisplatin). Preliminary results have shown no differences between both arms in response, toxicity, or survival. New therapeutic approaches, as neoadjuvant therapy, are being explored.     

Have the changes in treatment of rectal cancer made a significant difference to our patients?

The treatment for patients with locally advanced, resectable rectal cancer has evolved over the years. Various combinations and sequences of chemotherapy, radiation therapy, and total mesorectal excision (TME)-based surgery are the mainstay of current therapy. Preoperative combined chemoradiation, followed by surgery, is now the preferred treatment strategy, with the majority of patients receiving either infusion fluorouracil (5-FU) or capecitabine (Xeloda) with radiation. Clinical trials with oxaliplatin (Eloxatin)-based neoadjuvant chemoradiation have not shown improvement in the pathologic complete response rate (pCR) compared with 5-FU; however, final data addressing local recurrence rates and disease-free survival are pending.The use of adjuvant chemotherapy following preoperative chemoradiation and surgery has not been optimally defined. Some studies have shown that patients who obtained significant pathologic downstaging after chemoradiation and surgery have improved survival with the use of adjuvant chemotherapy. Since FOLFOX (folinic acid, 5-FU, and oxaliplatin) is the preferred adjuvant chemotherapy regimen for stage III colon cancer based on randomized clinical trial results, FOLFOX is also recommended for rectal cancer patients as an adjuvant therapy approach.     

Chemotherapeutic advances in pancreatic cancer

Advances in chemotherapy for pancreatic cancer have been limited. In the past decade, the standard therapy for metastatic disease has switched from 5-fluorouracil (5-FU) to gemcitabine. However, several other cytotoxic agents have shown limited but promising efficacy in pancreatic cancer, and many of these appear to be well suited for combination chemotherapy. Although 5-FU and cisplatin have not demonstrated substantial survival benefits when combined with gemcitabine, results of several phase III trials with other agents are still pending. For locally advanced disease, most recent studies have incorporated gemcitabine into combined-modality therapy. Similarly, in surgically resectable disease, current trials are incorporating gemcitabine into adjuvant therapy. Other trials are using neoadjuvant therapy as a possible means to improve upon current surgical results. However, much hope comes from the development of newer “targeted” therapies for this disease. Although matrix metalloproteinase inhibitors and farnesyl transferase inhibitors did not appear to be effective in initial studies, other targeted therapies are beginning to enter clinical trials.     

Paclitaxel in the treatment of advanced urothelial cancer

Median survival in patients with advanced urothelial carcinoma continues to be approximately 1 year following treatment with traditional cisplatin (Platinol)-based regimens, which have substantial toxicity. Thus, research is focusing on newer chemotherapeutic agents and novel combination regimens to improve outcomes and tolerability. Paclitaxel (Taxol) demonstrated one of the highest single-agent response rates (42%) in patients with advanced urothelial tumors, prompting extensive evaluation of combination regimens, including paclitaxel/platinum-based doublets or triplets. In many trials, carboplatin (Paraplatin) has been substituted for cisplatin to produce a more convenient, less toxic regimen. These trials have demonstrated that paclitaxel/platinum-based combinations are similar in efficacy to traditional cisplatin-based regimens and are generally better tolerated. Consequently, paclitaxel-based combinations (e.g., paclitaxel/carboplatin) are now considered alternative treatment options for patients with advanced disease, particularly those who are ineligible for clinical trials or are unable to tolerate standard cisplatin-based regimens. Paclitaxel/ifosfamide (Ifex)/cisplatin is another promising alternative regimen for patients who can tolerate cisplatin-based regimens. An ongoing phase III trial comparing paclitaxel/carboplatin and MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin) should clarify the role of paclitaxel-based combinations. Paclitaxel-based combinations are also under evaluation in the adjuvant setting, and future trials may assess their potential role as neoadjuvant therapy or in combination with radiation therapy.     

Capecitabine for locally advanced and metastatic colorectal cancer: A review

Capecitabine (Xeloda^®) is an oral fluoropyrimidine which is produced as a pro-drug of fluorouracil, and shows improved tolerability and intratumor drug concentrations following its tumor-specific conversion to the active drug. We have searched the Pubmed and Cochrane databases from 1980 to 2009 with the purpose of reviewing all available information on Capecitabine, focusing on its clinical effectiveness against colorectal cancer. Special attention has been paid to trials that compared Capecitabine with standard folinic acid (leucovorin, LV)-modulated intravenous 5-fluorouracil (5-FU) bolus regimens in patients with metastatic colorectal cancer. Moreover the efficacy of Capecitabine on metastatic colorectal cancer, either alone or in various combinations with other active drugs such as Irinotecan and Oxaliplatin was also assessed. Finally, neoadjuvant therapy consisting of Capecitabine plus radiation therapy, for locally advanced rectal cancer was analysed. This combination of chemotherapy and radiotherapy has a special role in tumor down staging and in sphincter preservation for lower rectal tumors. Comparative trials have shown that Capecitabine is at least equivalent to the standard LV-5-FU combination in relation to progression-free and overall survival whilst showing a better tolerability profile with a much lower incidence of stomatitis. It is now known that Capecitabine can be combined with other active drugs such as Irinotecan and Oxaliplatin. The combination of Oxaliplatin with Capecitabine represents a new standard of care for metastatic colorectal cancer. Combinating the Capecitabine-Oxaliplatin regimen with promising new biological drugs such as Bevacizumab seems to give a realistic prospect of further improvement in time to progression of metastatic disease. Moreover, preoperative chemo-radiation using oral capecitabine is better tolerated than bolus 5-FU and is more effective in the promotion of both down-staging and sphincter preservation in patients with locally advanced rectal cancer. Finally, the outcomes of recently published trials suggest that capecitabine seems to be more cost effective than other standard treatments for the management of patients with colorectal cancer.     

A retrospective review of 15 years of radical radiotherapy with or without concurrent cisplatin and/or 5-fluorouracil for the treatment of locally advanced cervical cancer

Radiation therapy is the standard of care treatment for locally advanced cervical cancer in the United States. In 1999 the addition of concomitant chemotherapy to radical radiotherapy became standard. The addition of cisplatin (CDDP) with or without 5-fluorouracil (5-FU) chemotherapy to radiation therapy was based on the near simultaneous reporting of five randomized, controlled clinical trials which all showed an improvement in survival with a magnitude of approximately 35%. The purpose of our study was to test the hypothesis that the addition of chemotherapy improved survival in our patients. We identified 291 patients treated with primary 'intent-to-cure' radiation therapy for locally advanced carcinoma of the cervix between 1985 and 2000. We analyzed patients using a stepwise Cox regression, including as possible predictors: clinical stage, age at diagnosis, use of concurrent chemotherapy with radiation and method of teletherapy delivery. We also examined survival as a function of CRT with a CDDP and/or 5-FU containing regimen using the Kaplan-Meier estimates of overall survival. The use of concurrent CDDP and/or 5-FU chemotherapy with radiation (CRT) was not associated with an increase in disease free survival (p=0.734) or overall survival (p=0.989). In this retrospective study there was no disease free or overall survival benefit from the addition of CDDP and/or 5-FU chemotherapy to radical radiotherapy for the treatment of locally advanced cervical carcinoma, although there was a trend favoring CRT.     

Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients

Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and vascular endothelial growth factor (VEGF) are associated with the effect of 5-fluorouracil (5-FU) based adjuvant chemotherapy. However, very few studies have investigated the relationship between these factors and 5-FU neoadjuvant chemotherapy for primary gastric cancer patients. In this study, we studied the correlation between these markers and the histological chemotherapeutic effect in advanced gastric cancer with neoadjuvant chemotherapy. METHODS: Sixty-two primary advanced gastric cancer patients were recruited into the study. One cycle of continuous infusion of 5-FU (300 mg/m2/day, 14 days) plus drip infusion of cisplatin (15 mg/m2/day, Day one and Day two) was performed as neoadjuvant chemotherapy. Histological chemotherapeutic responses of the resected specimens were classified into responders and nonresponders. TS, DPD, VEGF expressions both before and after neoadjuvant chemotherapy were examined immunohistochemically. RESULTS: There was an association between the TS-low group and the responders (p < 0.05); the DPD-low group and the responders in both biopsy and surgical specimens (p < 0.01). A combination of the low-TS and low-DPD group was further associated with responders (p < 0.01). The immunoexpressions of biopsied and surgical specimens were significantly associated with each other. CONCLUSION: Neoadjuvant chemotherapy for primary gastric cancer with one cycle of 5-FU and cisplatin was associated with histological findings in patients with low baseline TS and DPD. This dual determination may predict for efficacy of neoadjuvant treatment with these drugs.     

A phase-ii trial of neoadjuvant chemotherapy and concomitant chemoradiotherapy for the treatment of locally advanced nonsmall cell lung-cancer

Treatment strategies for locally advanced nonsmall cell lung cancer have failed to significantly alter the survival of most patients. Treatment strategies utilizing, neoadjuvant chemotherapy and concurrent chemotherapy/radiation therapy have shown promise in some reports. Twenty-six consecutive patients with stage III, non-small cell lung cancer were treated over a 3 year period according to a strategy involving neoadjuvant chemotherapy (mitomycin, vinblastine, cisplatin [MVP]) followed by reassessment for surgical resection, followed by treatment with concomitant radiation therapy and chemotherapy (hydroxyurea [HU], 5-fluorouracil [5-FU]). Staging revealed stage IIIa disease in 15 patients and stage IIIb disease in 11 patients. Nine of 18 evaluable patients responded to MVP (50%) with 1 CR and 8 PRs. Only one of nine responders underwent surgical resection. Eleven of 19 patients receiving concomitant 5-FU, HU, and radiation therapy were evaluable for response. Two of 11 patients were converted to clinical CRs, and the remaining 9 patients had stable disease. Myelosuppression, mucositis and hand-foot syndrome were observed with 5-FU/HU/RT. Median survival for all patients is 10.5 months. One and 2-year survival is estimated at 36% and 27%, respectively. This clinical trial combining neoadjuvant chemotherapy with concurrent chemotherapy/radiation therapy is feasible. Select patients appeared to have a survival benefit however most patients failed to derive an improvement in clinical endpoints.     

Induction chemotherapy for head and neck cancer: will history repeat itself?

Locally advanced squamous cell head and neck cancer remains a therapeutic challenge for multidisciplinary teams. Despite high objective response rates, induction chemotherapy has not resulted in tangible benefit in multiple randomized trials. In recent years, as most evidence solidified the role of concurrent chemotherapy and radiation as either primary or postoperative therapy for locally advanced head and neck cancer, induction chemotherapy fell out of scope and practice. The failure of older randomized trials to show a survival benefit from induction chemotherapy can be attributed to several factors. It is possible that the predominance of locoregional failure did not allow any added benefit from better systemic control to translate into a survival advantage. Alternatively, seemingly active chemotherapy regimens may have been suboptimal. Nevertheless, recent developments have altered our perception of head and neck cancer and its treatment. Locoregional control has dramatically improved with concurrent chemoradiotherapy. Of note is that none of the previously conducted randomized trials of induction chemotherapy used concurrent chemoradiotherapy in the control arm. Moreover, we witnessed the development of better combination regimens that improved efficacy in the induction setting. The previously standard cisplatin/5-fluoruracil (5-FU) combination is being replaced by the triple combination of taxane/ cisplatin/5-FU. Randomized trials showed that increased activity with the triplet regimen resulted in improved long-term disease control and survival. Finally, cetuximab, an active epidermal growth factor receptor inhibitor, is entering clinical practice and is expected to change the standard of therapy. With the emergence of more efficacious systemic therapies, the role of induction therapy warrants reevaluation. A number of randomized trials are planned or currently ongoing to investigate concurrent chemoradiotherapy with or without induction. These trials are anticipated to redefine the role of induction chemotherapy for head and neck cancer.     

Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer

To increase the complete response (CR) rate of patients with locally advanced head and neck cancer after three cycles of neoadjuvant chemotherapy, we added sequential methotrexate to the combination of cisplatin and continuous infusion fluorouracil (5-FU). We also evaluated the feasibility of administering three additional cycles of the same regimen as adjuvant chemotherapy. Thirty-eight patients were treated; the median age was 53 years and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/m2 followed 24 hours later by cisplatin 100 mg/m2 and a five-day continuous infusion of 5-FU at 1,000 mg/m2/d. Of 34 patients evaluable for response to neoadjuvant chemotherapy, nine had a CR, 21 a partial response (PR), two a minimal response (MR), and one patient each stable disease (SD) and no response (NR). Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only ten received all three intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow-up time of 39 months, the median survival is estimated to be 20 months. Of eight patients with nasopharyngeal or paranasal sinus cancer, none has had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring 5-FU dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not increase the CR rate over what has been reported for the combination of cisplatin and 5-FU alone. Certain subsets of patients appear to have a good prognosis when treated in this fashion. The administration of adequate adjuvant chemotherapy in patients with head and neck cancer remains difficult due to toxicity and poor patient compliance.     

晚期胃癌化疗进展

随着细胞毒药物和分子靶点药物的研发,晚期胃癌患者姑息化疗取得一定进展。患者中位生存期可接近1年。本文主要介绍新药多西紫杉醇、紫杉醇、奥沙利铂、伊立替康、卡培他滨、S1及靶向药物在晚期胃癌治疗中的作用以及局部晚期胃癌的化疗策略,尤其重点介绍Ⅲ期临床试验研究结果。提出一些新联合方案,如含多西他赛的DCF方案、含奥沙利铂的EOX和FLO方案、含卡培他滨的EOX和顺铂＋希罗达方案、含伊立替康的ILF方案、含S1的S1＋DDP方案,可以作为一线治疗晚期胃癌的新的参考方案。而靶向药物在晚期胃癌治疗中结论尚不明确,其有效性、安全性和最终收益有待进一步的研究;新辅助化疗可作为局部晚期胃癌治疗的选择。     

Chemotherapy for advanced, recurrent, and metastatic cervical cancer

When cervical cancer is beyond curative treatment with surgery or radiation therapy, the prognosis is poor and palliation is the primary objective. Early prospective studies identified cisplatin as an active drug for advanced, metastatic, or recurrent cervical cancer, and results with other platinum analogs seemed inferior to cisplatin. Several phase III trials have established the combination of cisplatin plus paclitaxel as standard therapy for comparison. Using pooled data from 3 Gynecologic Oncology Group (GOG) phase III studies, a predictive model was developed to better identify patients who are unlikely to respond to cisplatin-containing chemotherapy. The GOG is currently developing a phase III trial to investigate the impact of bevacizumab and a regimen containing topotecan instead of cisplatin in combination with paclitaxel chemotherapy and also to externally validate the predictive model. This study has the potential to radically change standard care for cervical cancer chemotherapy. Furthermore, if the predictive model is upheld, then patients with high risk factors for treatment failure may be directed to chemotherapy regimens that do not include cisplatin or to investigational trials.     

Neoadjuvant chemoradiation for rectal cancer: is more better?

Neoadjuvant chemoradiation is now considered the clear preferable adjuvant standard of care in the management of stage II/III rectal cancer. Neoadjuvant fluorouracil (5-FU) plus radiation results in a decrease in local relapse rates and a favorable toxicity profile in comparison with postoperative adjuvant 5-FU plus radiation therapy. Recent nonrandomized comparative studies have shown that capecitabine (Xeloda) plus radiation result in downstaging and pathologic complete responses equivalent to those of 5-FU plus radiation, making this combination an acceptable alternative neoadjuvant treatment. The addition of oxaliplatin (Eloxatin) or irinotecan (Camptosar) to 5-FU or capecitabine concurrently with radiation therapy appears to result in more favorable pathologic responses in phase I/II trials. These combinations should be investigated further in larger phase III studies before they are endorsed in the routine neoadjuvant treatment of rectal cancer. This article will review the progress of chemoradiation over the past 2 decades, current standards of care, and investigational treatments in the neoadjuvant treatment of rectal cancer.