Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer

The management of rectal cancer presents substantial challenges. Patients with T3 and/or node-positive rectal cancers are at high risk for local failure and distant metastases (DM). Adjuvant radiation has been shown to decrease local recurrence (LR) rates; however, this local therapy has not been demonstrated to improve survival when compared to surgery alone. In several prospective randomized trials adjuvant chemoradiation with 5-fluorouracil-(5-FU)-based chemotherapy improved LR rates, DM rates, and overall survival (OS). The optimal chemotherapeutic regimen has not been determined; however, studies comparing standard IV bolus 5-FU administration with continuous infusion (CI) 5-FU demonstrated that CI administration was superior. Preoperative therapy has potential advantages over adjuvant therapy such as less acute bowel toxicity and improved sphincter preservation. Preoperative chemoradiation has been shown in several studies to improve LR rates and OS when compared to surgery alone. Our current approach to patients with resectable T3 or N1 cancer in the distal two-thirds of the rectum on preoperative staging is preoperative chemoradiation with planned postoperative chemotherapy. This regimen offers the best chance for local control and disease-free survival while potentially downstaging the tumor and improving sphincter preservation.     

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.     

Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer

Surgery remains the primary determinant of cure in patients with localized rectal cancer, and total mesorectal excision is now widely accepted as standard of care. The widespread implementation of neoadjuvant shortcourse radiotherapy (RT) or long-course chemoradiotherapy (CRT) has reduced local recurrence rates from 25% to 40% to less than 10%; Preoperative RT in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, and down-staging effect. In this article making a comprehensive literature review searching the reliable medical data bases of PubMed and Cochrane we present all available information on the role of radiation therapy alone or in combination with chemotherapy in preoperative setting of rectal cancer. Data reported show that in locally advanced rectal cancer the addition of radiation therapy or CRT pre surgically has significantly improved sphincter prevention surgery. Moreover, the addition of chemotherapy to radiation therapy in preoperative setting has significantly improved pathologic complete response rate and loco-regional control rate without improvement in sphincter preserving surgery. Finally, the results of recently published randomized trials have shown a significant improvement of prevs postoperative CRT on local control; however, there was no effect on overall survival.     

Complete clinical response after neoadjuvant chemoradiation for distal rectal cancer

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer. The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor downsizing and downstaging, better chance of sphincter preservation, and improved functional results. A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response. Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed. The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response. Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures.     

Adjuvant radiation therapy of patients with rectal cancer

The standard in rectal cancer has been to add adjuvant radiation therapy to surgery in patients with stage II and III disease. Total mesorectal excision has led to lower local recurrence rates, and, if properly performed, may make adjuvant radiation unnecessary for certain stage II and III patients, such as T3 N0 patients with proximal lesions. There is also debate about the best method of delivering adjuvant radiotherapy. Preoperative radiotherapy at low dose per fraction with concurrent chemotherapy offers the advantages of maximizing sphincter preservation and greater tolerability. However, this will occasionally result in treating patients who are overstaged by ultrasound and may lead to greater postoperative morbidity and mortality than postoperative radiation. Preoperative radiotherapy has stronger data to support a survival advantage when added to surgery than postoperative radiation. Two randomized, phase III European studies may answer the question of which radiation technique is best for the near future. Protracted venous infusion of 5-fluorouracil (5-FU) is the standard method of radiosensitization. However, studies are ongoing using concurrent oxaliplatin, irinotecan, and oral 5-FU prodrugs. For now, we recommend that stage II and III rectal cancer patients receive protracted venous infusion 5-FU concurrent with preoperative radiation.     

Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer

Over the past 25 years, important advances have been made in the management of patients with resectable rectal cancer. Clinical studies have shown the efficacy of combined chemoradiation therapy in enhancing resectability and sphincter preservation rates, decreasing local recurrence, and improving survival of patients with rectal cancer. Although 5-fluorouracil (5-FU) remains the standard chemotherapeutic agent used concurrently with radiation therapy, newer chemotherapeutic agents including capecitabine, irinotecan, and oxaliplatin have also been studied as radiosensitizers in this setting. Novel targeted biologic agents including celecoxib and bevacizumab are being explored in combination with standard chemotherapy and radiation therapy. In this review, we will discuss the mechanism of action and the key clinical studies of each agent as a radiosensitizer.     

Management and imaging of low rectal carcinoma

Large variations in recurrence rates have been reported with the best results following total mesorectal excision (TME) surgery for low and middle rectal cancers. However, the low rectal cancers still have higher rates of local recurrence (up to 30%) whether operated by low anterior resection or abdominoperineal excision (APE) due to high rates of circumferential margin involvement. The treatment of choice for low rectal cancers that encroach upon the potential circumferential resection margin is surgery combined with preoperative neoadjuvant treatment. Preoperative chemotherapy combined with long-term radiotherapy reduces recurrence rates and preoperative loco-regional staging can help to select the patients more likely to benefit from neo-adjuvant therapy. Surface coil MRI is the most promising modality for patient selection, which can provide good views of the circumferential resection margin especially the presence or absence of tumour encroaching the intersphincteric plane.     

局部晚期直肠癌术前调强放疗同步化疗的疗效评价及预后因素分析

目的:观察并分析术前调强放疗同步化疗治疗局部晚期直肠癌的病理降期情况、临床疗效和预后因素.方法:回顾性分析2010年1月1日至2013年7月31日间接受术前同步放化疗随后行根治性手术的60例初治Ⅱ、Ⅲ期直肠癌患者的临床资料.全部患者接受调强放射治疗,总剂量为50Gy/25次,同期行氟尿嘧啶为基础的化疗,放化疗结束后间隔4~8周行手术治疗.结果:肿瘤病理退缩分级(tumor regression grading,TRG)0级为8例、1级为 12例、2级 为11例、3级为 20例、4级即病理完全缓解(complete responce rate,pCR)为9例,pCR率为15%,病理有效率为86.7%,T分期降期55%,N分期降期51.9%.手术并发症发生率为25.0%.3年总生存率(OS)为88.3%,3年无瘤生存率(DFS)为85.5%,3年局部复发率(LRR)为11.6%,3年远处转移率(DMR)为13.3%,3年无局部复发生存率(LRFS)为88.3%,3年无远处转移生存率(DRFS)为 86.7%.Kaplan-Meier分析及COX回归分析均表明TRG分级对患者总生存期的影响具有统计学意义.结论:局部晚期直肠癌术前调强放疗同期化疗能使肿瘤降期,提高手术切除率和生存率,3年局部控制好.pCR 和接近pCR 患者有更好的生存期.     

Current Options for the Management of Rectal Cancer

Opinion statement Patients diagnosed with rectal cancer should undergo locoregional staging with transrectal endoscopic ultrasound (EUS) or surface coil array MRI of the pelvis if that technique is available. Patients thought to have more than very early stage (T1 or T2) disease should undergo abdominal imaging as well by CT or MRI, and chest imaging with either CXR or preferably CT. The care of rectal cancer patients should be coordinated amongst an experienced multidisciplinary team to maximize the chance of cure and to minimize both local recurrence and complications of therapy. For patients with very early stage disease (T1N0 or T2N0), local resection with or without chemoradiation may be adequate therapy, but these patients must be selected carefully and should be without any poor prognostic factors. For the majority of patients with T3N0 or greater rectal cancer, standard therapy consists of neoadjuvant continuous 5-FU and radiation followed by surgery and further chemotherapy (either with 5-FU, capecitabine, or FOLFOX). The use of capecitabine, irinotecan, and oxaliplatin during radiotherapy shows promise, but remains investigational pending results of phase III studies. Neoadjuvant therapy is preferred because it decreases local recurrence and appears to result in improved postoperative bowel function in comparison with postoperative therapy. Select patients with high (>10 cm from the anal verge) uT3N0 tumors may be at sufficiently low risk of local recurrence to justify omission of radiotherapy. Patients who experience pathologic complete response to radiotherapy should still receive postoperative adjuvant chemotherapy to reduce systemic recurrence risk until data demonstrate that this is not necessary. Patients with stage IV rectal cancer may still require local therapy with radiation, surgery, or both; however, care should be taken in these patients that chemotherapy is not excessively delayed as this is the one modality in this case that can result in improved survival.     

The wind of change in the therapy of lung cancer

Total mesorectal excision has been established as a standard surgical procedure for rectal cancer. MRI is now routinely used for preoperative staging of rectal cancer and provides accurate assessment of the tumor relative to the circumferential margin, that is, the mesorectal fascia. This identifies patients at risk of local recurrence and those likely to benefit from neoadjuvant therapy. Compared with CT and ultrasound, MRI is more reliable for the evaluation of the extent of locoregional disease, planning radiation therapy, assessing postoperative changes and pelvic recurrence. The evaluation of nodal metastases remains a challenge with routine MRI. In this review, we describe the role of MRI in staging rectal cancer as well as highlight some limitations and recent advances to overcome these.     

Preoperative chemoradiation for locally advanced rectal adenocarcinoma-the University of Florida experience

To evaluate the efficacy of preoperative radiotherapy alone or combine with chemotherapy. Between 1975 to 1997, 318 patients with locally advanced rectal adenocarcinomas were treated with preoperative radiation therapy. Between 1991 and 1997, approximately 60% of patients received fluorouracil (5-FU)-based adjuvant chemotherapy. Patients treated since 1991 had improved downstaging compared with those treated prior to 1991. Patients treated between 1991 and 1997 were also more likely to undergo a sphincter preserving surgical procedure. Preoperative chemoradiation probably results in improved downstaging and survival compared with preoperative irradiation alone.     

Point: short-course radiation therapy is preferable in the neoadjuvant treatment of rectal cancer

There are 2 types of neoadjuvant radiation regimens accepted as standard for resectable rectal cancer: short-course (5 × 5 Gy) radiation therapy alone with immediate surgery and long-course combined chemoradiation therapy with delayed surgery. A Polish randomized study (n = 312) and an Australian randomized study (n = 326) compared these 2 schedules. Both trials showed a lower rate of early adverse effects using a short-course radiation regimen and no differences in long-term oncologic outcomes and late toxicity rates between groups. The small number of fractions makes short-course radiation less expensive and more convenient than chemoradiation therapy. These facts indicate that short-course radiation is preferable to chemoradiation for resectable cancers. Additionally, short-course preoperative radiation with a long interval to surgery is a valuable option for patients unfit for chemotherapy, with unresectable cancer or with a small tumor that is amenable to local excision. Moreover, short-course radiation enables the intensification of both radiotherapy and chemotherapy in patients with metastatic rectal cancer with potentially resectable synchronous metastatic disease.     

The Evolving Field of Neoadjuvant Therapy in Locally-advanced Rectal Cancer: Evidence and Prospects

The standard treatment of locally advanced rectal cancer comprises neoadjuvant chemoradiation followed by total mesorectal excision. This strategy provides low local recurrence rate, however distant recurrence is still an issue and may impact on survival rates. Novel approaches in the neoadjuvant setting have been tested to improve early and late outcomes, as well as to reduce treatment-related toxicity and morbidity. In this review, we discuss the current literature of neoadjuvant treatment in locally advanced rectal cancer, including total neoadjuvant methods, protocols for radiation delivery, chemotherapy regimen and efforts to add novel targeted therapies, selective withdrawal of surgery or radiotherapy, and future perspectives. Moreover, we highlight relevant issues that have emerged with these new treatment possibilities.     

Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response

PURPOSE: Preoperative chemoradiation is being utilized extensively in the treatment of rectal cancer. However, a variety of dose time factors in both delivery of chemotherapy and irradiation remain to be established. This study was undertaken to examine the impact of dose time factors on pathological complete response (pCR) rates following preoperative chemoradiation for fixed rectal cancer. METHODS AND MATERIALS: Thirty-three patients with fixed rectal cancers were treated with combined 5-fluorouracil (5-FU) chemotherapy and pelvic radiation. Twenty-one patients received bolus 5-FU during the first 3-5 days of radiation and repeated on days 28-33 of their radiation treatment. Twelve patients were treated with continuous infusion (CI) 5-FU, 225 mg/m(2) for the duration of the pelvic radiation. Fifteen patients received a planned total radiation dose of 45 to 50 Gy and 18 patients received a dose of 55 to 60 Gy. Surgical resection was then carried out 6-8 weeks after completion of treatment. RESULTS: Diarrhea was the most frequent acute toxicity. Grade 3 diarrhea was observed in 6 patients requiring treatment interruption and was not related to the chemotherapy regimen. There was no Grade 4 or 5 toxicity. pCR was observed in 2 of 21 (10%) patients treated with bolus 5-FU as compared to 8 of 12 (67%) for patients treated with CI (p = 0.002). pCR were observed in 8 of 18 (44%) patients receiving radiation dose > or = 5500 cGy as compared to 2 of 15 (13%) patients treated to a dose < or = 5000 cGy (p = 0.05). In the high-dose radiation (> or = 5500 cGy) group, a significant difference in pCR rate was observed in patients treated with CI, 8 of 12 (67%) (p = 0.017) as compared with bolus 5-FU (0 of 6). There was no significant difference in operative morbidity or in wound healing between patients treated with bolus 5-FU or CI or within the groups treated with low or high doses of radiation. Three patients have developed local recurrence at 14 and 24 months, two in the low-dose group treated with bolus 5-FU and one patient in the CVI group. The overall 5-year survival for the whole group is 71%. CONCLUSION: Dose intensity of 5-FU and dose of radiation correlate significantly with the likelihood of achieving a pCR. Continuous infusion 5-FU (CI) and a preoperative radiation dose of 5500 cGy or higher can achieve pCR rates of approximately 50%, even in fixed cancers of the rectum.     

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.     

Advances in organ preserving strategies in rectal cancer patients

Treatment of rectal cancer patients has been subjected to change over the past thirty years. Total mesorectal excision is considered the cornerstone of rectal cancer treatment, but is also associated with significant morbidity resulting in an impaired quality of life. The addition of neoadjuvant chemoradiotherapy to surgery has shown to improve survival and local control and may lead to a partial or even complete response (CR). This raises questions regarding the necessity for subsequent radical surgery. After careful patient selection local excision and wait-and-see approaches are explored, aiming to improve quality of life without compromising oncological outcome. A multimodality diagnostic approach for optimal staging is crucial in determining the appropriate neoadjuvant treatment regimen. Adequate endoscopic restaging of rectal tumours after multimodality treatment will aid in selecting patients who are eligible for an organ preserving approach. The role and accuracy of imaging in the detection of the primary tumour, residual rectal cancer or local recurrence seems vital. Alternative neoadjuvant regimens are currently explored to increase the rate of clinical CRs, which may support organ preserving approaches. This review aims to generate insight into the advances in diagnostics and treatment modalities in all stages of rectal cancer and will highlight future studies that may support further implementation of organ preservation treatment in rectal cancer.     

Chemoradiation for localized rectal cancer: Neoadjuvant versus adjuvant approaches

For many years, adjuvant postoperative chemotherapy and radiation has been the standard of care in the United States for patients with T3, T4, or node-positive rectal cancer. Preoperative chemoradiation has generally been reserved for situations in which a response to therapy would allow for sphincter-preserving surgery. Recent data support the use of chemoradiation in the preoperative setting, demonstrating improvements in tumor downstaging, treatment toxicity, rate of sphincter-preserving surgery, and pelvic recurrence.     

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.     

Novel Radiation Approaches for the Treatment of Rectal Cancer: Where Are We Now?

Over the past decade, significant strides have been made in improving local control for stage II and III rectal cancer, including the use of neoadjuvant chemoradiation and total mesorectal excision. These advancements have led to a remarkable 10-year local failure rate of just 7.1 %. This has come, however, at the cost of moderate treatment-related morbidity, emphasizing a need for further refinement of management strategies. This article will explore recent innovations and novel approaches involving radiation therapy to address these issues, including the use of intensity-modulated radiation therapy, avoidance of radical resection with the use of chemoradiation alone, total neoadjuvant chemotherapy with the selective use of chemoradiation, and the use of local excision approaches following neoadjuvant treatment. Although many of these novel strategies appear promising, data from prospective randomized trials will be necessary before implementation into standard practice.     

A current perspective on local excision of rectal cancer

Local excision of rectal cancer is appealing because of its technical ease and excellent functional results, but concern over inadequate pathologic staging and inferior treatment outcomes when compared with radical surgery remain a major hurdle for its widespread use. Local failure rates in modern series for local excision are 4%-18% for T1 rectal cancers and 22%-67% for T2 cancers, and cancer cure rates are only 70%-80%. In addition, data from the past decade suggest that preoperative staging with endorectal ultrasound, use of postoperative adjuvant chemotherapy/radiation therapy, and aggressive salvage surgery have not been reliable methods of limiting local tumor recurrence or improving long-term cure rates. At present, highly stringent criteria for patient selection are recommended, yet such stringency decreases the utility of the procedure. What are needed are new approaches to an old problem. Novel strategies under evaluation include enhanced imaging modalities for lymph node metastases, neoadjuvant chemotherapy/radiation therapy, and more liberal use of immediate salvage resection for high-risk pathologic features. Molecular profiling of tumors with genetic markers and better integration of traditional and gene-targeted systemic therapy are promising approaches for the future. This review of the literature evaluates the recent successes and failures of local excision of rectal cancer and provides a current perspective on the expanded use of local excision without compromising care.