Advances in combined radiation therapy for the management of rectal cancer

Significant advances have been made in the use of adjuvant radiation for patients with localized rectal cancer. Recent progress in adjuvant postoperative radiation regimens relates to the integration of systemic therapy into radiation, as well as redefining the techniques and sequences for both modalities. The adjuvant radiation management approach in both North America and Europe has been shifting towards preoperative adjuvant therapy to promote sphincter-preserving surgery and to decrease acute and late toxicity. Although 5-fluorouracil-based chemotherapy in combination with radiation remains the standard adjuvant therapy for rectal cancer, the integration of novel chemotherapeutic agents and biologic modulators remains an active area of investigation.     

Advances in combined radiation therapy for the management of rectal cancer

Significant advances have been made in the use of adjuvant radiation for patients with localized rectal cancer. Recent progress in adjuvant postoperative radiation regimens relates to the integration of systemic therapy into radiation, as well as redefining the techniques and sequences for both modalities. The adjuvant radiation management approach in both North America and Europe has been shifting towards preoperative adjuvant therapy to promote sphincter-preserving surgery and to decrease acute and late toxicity. Although 5-fluorouracil-based chemotherapy in combination with radiation remains the standard adjuvant therapy for rectal cancer, the integration of novel chemotherapeutic agents and biologic modulators remains an active area of investigation.     

Combined modality treatment for rectal cancer

Significant gains have been achieved in the integration of radiation therapy (RT) and chemotherapy with surgery in the management of patients with localized rectal cancer. Treatment combinations of RT and chemotherapy with surgery have evolved to neoadjuvant approaches of these modalities to enhance sphincter preservation, tumor control, and reduction of acute and late treatment-related morbidity. Although 5-fluorouracil (5-FU)-based chemotherapy in combination with RT remains the standard adjuvant therapy for rectal cancer, the integration of novel chemotherapeutic agents and biologic modulators is being actively investigated.     

Chemoradiation with novel agents for rectal cancer

Surgery remains the mainstay of treatment for colorectal cancer. Although the role of radiation therapy in colon cancer is unclear, its role in the management of locally advanced rectal cancer has been extensively studied in clinical trials. The use of postoperative chemoradiotherapy has been shown to improve local control and disease-free survival in patients with locally advanced disease over surgery alone; however, an overall survival advantage remains unproven. Clinical trials evaluating preoperative radiotherapy have demonstrated an improved local control as well as a survival advantage. Randomized studies comparing preoperative versus postoperative combined-modality approaches have failed in the United States, mainly due to the perceived advantages of preoperative treatment: improved patient tolerance, tumor downstaging, and fewer treatment-related complications. While 5-fluorouracil-based chemotherapy remains the standard systemic agent used along with radiation, other novel agents and strategies have recently been developed and are under investigation. In this review, we discuss the use of novel anticancer agents in combination with radiation therapy for the treatment of locally advanced rectal cancer.     

Neoadjuvant therapy of rectal cancer new treatment perspectives

During the past two decades, significant advances have been made in the management of patients with rectal cancer. A number of clinical studies have demonstrated the efficacy of preoperative chemoradiation therapy with 5-fluorouracil (5-FU)-based regimens in decreasing local recurrences and improving survival and the likelihood of sphincter preservation. Although 5-FU has been the standard drug used in combination with radiation therapy for many years, new effective drugs including capecitabine, raltitrexed, irinotecan and oxaliplatin have been recently investigated in combination with radiation therapy in the preoperative setting. In addition, novel targeted biological agents including epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors have been shown to enhance the antitumor effect of both radiation and chemotherapy and are currently being explored in initial clinical trials. In the present review we summarize the results of adjuvant therapy. In addition, we will discuss the recently reported phase I-II trials with new drug plus radiation combinations in the preoperative treatment of patients with rectal cancer.     

Adjuvant therapy of resectable rectal cancer

The two conventional treatments for clinically resectable rectal cancer are surgery followed by postoperative combined modality therapy and preoperative combined modality therapy followed by surgery and postoperative chemotherapy. Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy are in progress.     

Combined-modality therapy of rectal cancer with oxaliplatin-based regimens

There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates. There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation.     

Radiation therapy in the management of rectal cancer.

Substantial advances have been made in the adjuvant management of patients with resectable rectal cancer. Increasing interest in patient quality of life has promoted the use of radiation therapy to enhance sphincter-preserving surgical approaches as an alternative to the standard abdominoperineal resection. Because of the suggestion of enhanced sphincter preservation with preoperative therapy and the potential advantage of decreased acute morbidity, randomized trials comparing preoperative and postoperative adjuvant combined modality therapy are ongoing. Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy to radiation, and redefining the techniques for both modalities. The incorporation of improved radiation planning may reduce treatment-related bowel toxicity. The integration of novel chemotherapeutic agents in the adjuvant therapy of rectal cancer remains an active area of investigation.     

Potential Novel Drugs to Combine with Radiation in Rectal Cancer

The management of rectal cancer has seen significant advances in surgery, radiation therapy, and chemotherapy in recent years. These advances have translated into improved rates of local and distant disease control, survival, and quality of life for these patients. The recent implementation of novel chemotherapeutic and targeted agents in patients with advanced colorectal cancer has led to further improvements in disease-free and overall survival. These radiosensitizing agents are now being studied in combination with radiation therapy in the neoadjuvant therapy of rectal cancer.     

Combined-modality therapy for rectal cancer: future prospects

The management of rectal cancer has undergone significant evolution with advances in surgery, radiation therapy, and chemotherapy. These advances have translated into improved rates of local control, survival, and quality of life. More recently, the integration of newer chemotherapeutic and targeted agents in patients with advanced colorectal cancer have led to further improvements in disease-free survival and overall survival. These agents are now being studied with radiation therapy in the neoadjuvant therapy of rectal cancer.     

Beyond 5-fluorouracil: the emerging role of newer chemotherapeutics and targeted agents with radiation therapy

The management of rectal cancer has undergone significant evolution with advances in surgery, radiation therapy, and chemotherapy. These advances have translated into improved rates of local control, survival, and quality of life. More recently, the integration of newer chemotherapeutic and targeted agents in patients with advanced colorectal cancer have led to further improvements in disease-free and overall survival. These agents are now being studied with radiation therapy in the neoadjuvant therapy of rectal cancer.     

Single-agent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy

Squamous cell cancer of the anal canal (anal cancer) is a rare disease but with worldwide increasing incidence. While combined therapy of 5-fluorouracil (5-FU), mitomycin, and radiation is the treatment of choice for locoregional anal cancer, the treatment of metastatic disease is less established. 5-FU and cisplatin combination has been adopted as the first-line treatment of choice for metastatic disease based on several phase II studies. However, no standard therapy has been established for stage IV anal cancer after the failure of this combination. Paclitaxel, a microtubule-stabilizing chemotherapeutic agent, has established clinical activity in squamous cell cancer of the head and neck. One prior report described the activity of paclitaxel in five patients with anal cancer. In this report, we describe our experience using this agent in seven patients suffering from metastatic anal cancer with prior progression on cisplatin and 5-FU. Four patients had an objective response and one patient experienced stable disease. Our results confirm activity of weekly-paclitaxel in patients with 5-FU and cisplatin-resistant metastatic anal cancer.     

Future directions in neoadjuvant therapy of rectal cancer: Maximizing pathological complete response rates

Neoadjuvant therapy is widely accepted as the current standard of care for localized rectal cancer. Downstaging of disease has been significantly improved and pathological complete response rates (pCR) which were historically below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemo-radiation. While the availability of new chemotherapeutic drugs (Irinotecan, Oxaliplatin, etc.) and molecular targeted agents (Bevacizamab, Cetuximab, etc.) hold a great deal of promise, results of recent studies indicate that the pCR rate with neoadjuvant therapy appears to have plateaued at 20–30%. The use of more intensive multidrug combinations has, however, significantly increased the toxicity of treatment. New paradigms in neoadjuvant therapy are therefore needed to further improve results of treatment. This review presents strategies for neoadjuvant therapy, with the potential to improve pCR rates and also survival of patients.     

Role of Combined-Modality Therapy in the Management of Locally Advanced Rectal Cancer

The majority of patients with nonmetastatic rectal cancer are candidates for an aggressive multimodality approach with curative intent. Preoperative staging is critical in determining which patients should be offered neoadjuvant therapy. Available staging tools include digital rectal examination, transrectal ultrasound, computed tomography, positron-emission tomography, and magnetic resonance imaging scans. Magnetic resonance imaging has emerged as the most accurate staging modality in experienced centers. Multidisciplinary preoperative patient evaluation, better staging techniques, neoadjuvant chemoradiation, acceptance of shorter distal rectal margins, and transanal excision of T1 N0 rectal tumors in close proximity to the anal sphincter have resulted in decreased rates of abdominoperineal resections. Total mesorectal excision has been adopted as the standard surgical approach because of a reduction in rates of pelvic relapse. Preoperative and postoperative radiation therapy was shown to decrease the local recurrence rate, but not overall survival, in patients with resectable rectal cancer. The addition of chemotherapy to radiation was consistently shown to improve local control, and in some trials, improved overall survival. Neoadjuvant combined chemotherapy and radiation therapy are superior to adjuvant combined-modality therapy because of higher rates of sphincter preservation, less toxicity, and lower local recurrence rates. For patients with stage II or III disease, neoadjuvant continuous-infusion 5-fluorouracil (5-FU), concurrently with pelvic radiation, followed by postoperative 5-FU–based chemotherapy, remains the standard multimodality approach. Ongoing trials are testing the integration of newer cytotoxic agents such as capecitabine, oxaliplatin, irinotecan, and biologic agents such as cetuximab and bevacizumab to chemoradiation.     

Adjuvant therapy for rectal cancer: results and controversies

During the past decade, advances have been made in the adjuvant treatment of resectable rectal cancer. Postoperative combined-modality therapy significantly improves local control and survival. Recent Inter-group postoperative trials have focused on the identification of optimal chemotherapeutic agents and their method of administration. Preoperative therapy has the potential advantages of producing less acute toxicity and increasing the likelihood of sphincter preservation. New chemotherapeutic agents and radiation techniques are active areas of investigation.     

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.     

Recent Advances in the Systemic Therapy of Metastatic Colorectal Cancer

Worldwide, colorectal cancer ranks third in terms of both incidence and mortality and is the second most prevalent cancer after breast cancer. There is an estimated 2.4 million people alive with the disease diagnosed in the previous 5 years. Chemotherapy has been shown to improve time to disease progression and overall survival and to improve quality-of-life compared with supportive care alone. The most widely used chemotherapeutic agent in this setting is fluorouracil, which is included in most chemotherapy regimens for colorectal cancer. Over the last few years a number of new drugs have been studied and several of these have become standard therapies. This paper also discusses emerging chemotherapy combinations and novel biological agents and concludes with some practical considerations regarding systemic therapy of metastatic colorectal cancer including the treatment of elderly patients and the optimal duration of therapy.     

Adjuvant therapy for pancreatic cancer: back to the future

Purpose: The role of adjuvant therapy in the management of pancreatic cancer, resected with curative intent, remains controversial. This editorial review updates the status of adjuvant therapy in this context and introduces the first North American co-operative group study in this arena in roughly 20 years.Results: To the extent that there has been a “standard” of care in this context, it has been defined in large part by the early work of the Gastrointestinal Study Group (GITSG). Their trial was activated in the mid 1970’s using split course radiation therapy and bolus 5-FU. In the intervening 20+ years the morbidity/mortality of pancreaticoduodenectomy (PDD) has been dramatically reduced; concurrently, understanding of prognostic factors impacting on outcomes for resected patients has been significantly enhanced. In major centers the mortality of PDD is roughly 1% and survival has been shown to correlate with a number of factors including tumor size, nodal involvement, and margin status. With currently available techniques doses of continuous course radiation therapy in the range of 50–55 Gy to sites of pancreatic tumor resection and adjacent lymph node regions have been given in a number of trials with acceptable morbidity. 5-FU sequencing and administration have been advanced and gemcitabine, an agent with clear radiosensitizing properties, has been approved for use against pancreatic cancer.Conclusions: Following PDD increasing numbers of physiologically intact patients are confronting the survival statistics associated with resected pancreatic cancer. Their interest in improved therapeutic outcomes, combined with the noted improvements in radiation and chemotherapeutic management, has set the stage for renewed and intensified study. Accordingly, the intergroup mechanism of the Cancer Therapy and Evaluation Program (CTEP) of the NCI has designed, approved, and activated a modern Phase III, adjuvant protocol incorporating recently gained knowledge in this management context. Prospective randomization will be utilized to compare gemcitabine and 5-FU as single agents before and after chemoradiotherapy with 5-FU. Successful and timely completion of this newly activated intergroup study, RTOG 97-04, will establish a current, cooperative group experience, data base, and standard in the context of adjuvant therapy for pancreatic cancer and serve to provide momentum for further studies.     

New trends in prostatic cancer research. Three-dimensional conformal radiation therapy (3-D CRT), brachytherapy, and new therapeutic modalities

In prostatic cancer research three-dimensional conformal radiation therapy (3-D CRT), brachytherapy and new therapeutic modalities have been applied. Treatment planning and delivery of radiation therapy have substantially evolved in the past 20 years. The treatment of localized carcinoma of the prostate with 3-D CRT is described, preliminary clinical results are presented and compared with those with standard radiation therapy (SRT). The benefit of 3-D CRT hypothetically could be linked to improved local tumor control because of a better coverage of the target volume with a specific dose of irradiation, less acute and late toxicity, possibility of carrying out dose-escalation studies. Intensity modulated radiation therapy (IMRT) may be particularly useful in some cases. Further efforts are necessary with collaboration of urologists and radiation oncologists to continue to explore approaches to optimally select and manage patients with localized prostate cancer. A reliable assessment of the impact of 3-D CRT and IMRT on outcome should come from prospective randomized long-term studies. As for brachytherapy, standardized protocols should be developed to objectively evaluate brachytherapy in localized prostatic cancer. Recently a great deal of interest has been focused on new therapeutic modalities with chemotherapeutic agents, a new agent named prostate specific enhancer, a regulatory element of the PSA gene is being tested. Laboratory and animal studies of the viral construct have been reported. A phase I human clinical trial is being initiated in the U.S.A. in patients with postirradiation hormone refractory prostate cancer.     

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.