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.     

Progress in the treatment of locally advanced clinically resectable rectal cancer

There have been significant developments in the adjuvant treatment of locally advanced clinically resectable (T3 and/or N+) rectal cancer. Postoperative systemic chemotherapy plus concurrent pelvic irradiation (chemoradiation) significantly improves local control and survival compared with surgery alone. The German Rectal Cancer Trial confirmed that when chemoradiation is delivered preoperatively there is a significant decrease in acute and late toxicity and a corresponding increase in local control and sphincter preservation. Despite these advances, controversies remain. Among these controversies are the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery after chemoradiation can be modified based on tumor response. Are there more accurate imaging techniques and/or molecular markers to help identify patients with positive pelvic nodes with the goal of reducing the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve outcome and modify the need for pelvic irradiation? This review examines the advances in chemoradiation as well as addresses these and other opportunities for improvement.     

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.     

Unique considerations in the patient with rectal cancer

In the past two decades, substantial progress has been made in the adjuvant management of colorectal cancer. Chemotherapy has improved overall survival in patients with node-positive (N+) disease. In contrast with colon cancer, which has a low incidence of local recurrence, patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy (chemoradiation). Patients with rectal cancer have a number of unique management considerations: for example, the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? This review will address these and other controversies specific to patients with rectal cancer.     

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.     

Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer

Simultaneous chemoradiation is used in unresectable pancreatic cancer for palliation. It is not known if the use of adjuvant surgery will benefit this group of patients. From November 1991 to September 1998, 47 patients with unresectable pancreatic cancer were treated with simultaneous preoperative radiation therapy (45 Gy) and chemotherapy. Chemotherapy followed three different protocols: cisplatin, 5-fluorouracil +/- paclitaxel; cisplatin, 5-fluorouracil (protracted infusion); and docetaxel and gemcitabine. Whipple pancreatoduodenectomy was performed 1 month after the end of radiation in patients selected for resection. Twenty-three unresectable tumors after preoperative treatment (47%) received an additional dose (10-12 Gy) of radiotherapy using intraoperative or external radiation therapy. Twelve patients (26%) were considered to have clinically resectable tumors after the preoperative treatment. Nine patients had surgery (19% of the total number of patients), and 2 of them had complete pathologic response. After chemoradiation, two patients died of pneumonia and gastrointestinal bleeding, respectively, and another two patients died in the postoperative period. Local recurrence was observed in 22% of the patients and 57% had distant metastases. Three-year survival rates for patients with unresectable and resectable tumors was 0% (median survival 10 months) and 48% (median survival 23 months), respectively (p = 0.0004). Preoperative treatment with chemotherapy and radiotherapy in patients with unresectable pancreatic cancer is feasible. In some patients, the tumor can be resected, and in addition some cases of complete pathologic response were found. Long-term survivors were observed in the group of resected tumors. More effective chemotherapy regimens are needed because the majority of the patients died of metastatic disease.     

Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

PURPOSE: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. METHODS AND MATERIALS: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-fluorouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. RESULTS: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. CONCLUSION: In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.     

Surgical treatment of pancreatic cancer: the role of adjuvant and multimodal therapies.

Surgical treatment in specialized referral centers has improved the prognosis of resectable pancreatic cancer considerably despite the generally aggressive behavior of this malignancy. At the same time, adjuvant therapy for pancreatic cancer has been shown to be effective in providing a survival benefit. However, some controversy remains over whether to use chemotherapy alone or combined chemoradiation. Few prospective randomized controlled clinical trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation have demonstrated a distinct survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. The most notable published trial is the European Study Group for Pancreatic Cancer (ESPAC)-1 trial. In addition, there are several retrospective analyses and two randomized studies on adjuvant radiation and chemoradiation. Some of these suggested increased survival rates using chemoradiation, which was subsequently widely introduced in clinical routine, especially in the United States. RCTs and a recent meta-analysis of these RCTs confirm, however, the superiority of chemotherapy over chemoradiation, except for a subgroup of patients with positive resection margins. Thus, curative surgery followed by adjuvant systemic chemotherapy should be the standard treatment for patients with resectable, locally confined pancreatic cancer. Further RCTs may clarify potential benefits of chemoradiation in the adjuvant treatment setting. Moreover, the best chemotherapy, or a combination thereof, remains to be determined in large-scale randomized trials.     

Preoperative chemoradiation followed by surgical resection for resectable pancreatic cancer: a review of current results

Background

There has been an interest in the interdisciplinary and multimodality approach that combines chemotherapy and radiation therapy as a preoperative treatment for patients with resectable pancreatic cancer.

Methods

Literature search of databases (Medline and PubMed) to identify published studies of preoperative chemoradiation for resectable pancreatic cancer (potentially resectable and borderline resectable) was undertaken. Response to treatment and survival outcomes was examined as endpoints of this review.

Results

Seventeen studies; eight phase II studies, and nine observational studies, comprising of 977 patients were reviewed. Gemcitabine-based chemotherapy with radiotherapy was the most common preoperative regimen. Following preoperative treatment, pancreatic surgical resection was performed in 35–100% (median = 61%) of patients after a range of 6–32 weeks (median = 7 weeks). Rate of pathological response was complete in 5–15% of patients, partial in 33–60% and minimal in 38–42%. The median overall survival ranged from 12 months to 40 months (median = 25 months) with a 5-year overall survival rate ranging between 8% and 36% (median = 28%). Patients who underwent chemoradiation but did not undergo surgery survived a median period of 7–11 months (median = 9 months).

Conclusion

Preoperative gemcitabine-based chemoradiation followed by restaging and surgical evaluation for pancreatic resection may identify a sub-population of patients with resectable disease who would benefit the most from surgery. Investigation of this schema of preoperative therapy in a randomized setting of resectable pancreatic cancer is warranted.     

Neoadjuvant Short-Course Radiation Therapy for Rectal Cancer: Trends and Controversies

Purpose of Review

For patients with locally advanced rectal cancer, neoadjuvant hypofractionated short-course radiation remains an underutilized regimen in the USA. We review the current clinical literature highlighting the relative merits of short-course radiation, along with modern neoadjuvant strategies that incorporate its use.

Recent Findings

As compared to long-course chemoradiation with delayed surgery, short-course radiation with early surgery offers similar oncologic efficacy for locally advanced rectal cancer patients. Delaying surgery after short-course radiation decreases post-operative complications as compared to early surgery and improves tumor downstaging. Delaying surgery also offers the opportunity to administer neoadjuvant systemic therapy, which may help increase local-regional tumor response and potentially decrease distant relapse rates, the latter a persisting problem in rectal cancer treatment.

Summary

Short-course radiation, either with immediate or with delayed surgery, represents an appealing treatment alternative to long-course chemoradiation for patients with locally advanced rectal cancer.

     

Rectal cancer: Preoperative versus postoperative irradiation as a component of adjuvant treatment

The search for improved disease control and survival for resectable but high-risk rectal cancers has led to studies that combine all 3 modalities. For surgically resected, high-risk rectal cancers, postoperative chemoradiation has been shown to improve both disease control (local and distant) and survival (disease free and overall) and was recommended as standard adjuvant treatment at the 1990 National Institute of Health Colorectal Cancer Consensus Conference. Three randomized studies showed improved overall survival (OS) and local control for patients treated with postoperative irradiation and chemotherapy when compared with surgery alone or surgery plus irradiation control arms. These include 2 US trials, Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group (NCCTG) and a Norway trial. Although most preoperative external beam radiation trials show reductions in local relapse with the addition of preoperative EBRT to resection, only the large Swedish trial of 1,100 patients showed a survival improvement when compared with a surgery alone control arm for resectable primary rectal cancers. In a recent pooled analysis of 3 postoperative adjuvant rectal cancer trials (NCCTG 794751, NCCTG 864751, and GI Intergroup 0114) survival and disease relapse were dependent on both TN and NT stage of disease (N substage within T stage and T substage within N stage). Even among N2 patients (4 or more positive nodes), T substage influenced 5-year OS (T1-2, 69%; T3, 48%; and T4, 38%; P < .001). Ongoing randomized trials are being conducted for patients with high-risk, resectable primary rectal cancers. The intent is to help define optimal combinations of postoperative chemoradiation (US GI Intergroup), to test sequencing issues of preoperative versus postoperative chemoradiation (Germany trial), and to determine if concurrent and maintenance 5-FU and leucovorin add to the benefits found with preoperative irradiation (European Organization for Research and Treatment of Cancer). For subsequent trials, it may be preferable to perform separate studies, or a planned statistical analysis, for different risk groups of patients (low, intermediate, moderately high, and high), as defined in the rectal cancer pooled analysis.     

Pathologic Response and Postoperative Complications After Short-course Radiation Therapy and Chemotherapy for Patients With Rectal Adenocarcinoma

BackgroundThe role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy.Patients and MethodsAll patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications.ResultsFifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups.ConclusionsThough not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence.     

Prediction of mesorectal nodal metastases after chemoradiation for rectal cancer: results of a randomised trial: implication for subsequent local excision.

BACKGROUND AND PURPOSE: For patients with rectal cancer treated with full thickness local excision the risk of mesorectal nodal metastases has to be very low. The aim was to assess this risk after preoperative radiotherapy in relation to pathological T-category. PATIENTS AND METHODS: Three hundred sixteen patients with resectable cT3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. The pathological reports of patients who fulfilled entry criteria and had preoperative irradiation followed by transabdominal surgery were analysed. RESULTS: Significant downstaging of primary tumour (P<0.001) and of nodal disease (P=0.007) was observed after chemoradiation in comparison with short-course irradiation. In chemoradiation group, for patients with complete pathological response and for ypT1 category, the rate of nodal metastases was low - 5% (95% confidence interval [CI] 0-14%) and 8% (95% CI 0-24%), respectively. The rate of ypN-positive disease in chemoradiation group was similar to that recorded in short-course irradiation group for ypT2 category 26% (95% CI 14-38%) vs. 28% (95% CI 16-40%), P=0.83 and for ypT3-4 category 55% (95% CI 41-69%) vs. 64% (95% CI 54-74%), respectively, P=0.37. For ypT2 category after chemoradiation, the rate of nodal disease remained high even in subgroup with low residual cancer cells density (20%, 95% CI 4-36%). CONCLUSIONS: For patients with tumours downstaged by chemoradiation to ypT0 and ypT1 full thickness local excision may be considered as an acceptable approach, because the risk of mesorectal lymph nodes metastases is low. The selection criteria for preoperative radio(chemo)therapy and local excision are discussed.     

Concurrent chemoradiation in lung cancer

Concurrent chemoradiation has become for the 15 last years the standard treatment for locally advanced non-small cell lung cancer, either as a definite therapy in non resectable tumors, or in a neoadjuvant setting in potentially resectable tumors. Associating sequential and concurrent schedules, by administering chemotherapy before or after concurrent chemoradiation, has been recently investigated, but the best sequence remains a matter of controversy. Increasing local control and survival after definite chemoradiation seems possible not only by using optimized radiation fractionation schedules and escalated total doses, but also by associating more convenient and less toxic chemotherapy agents at the right cytotoxic or radio-sensitizing dose. Moreover, recent data have suggested that surgery following induction chemoradiation is feasible and effective in selected patients without mediastinal nodes involvement, if a complete resection can be performed. In patients with localized small cell lung cancer, early concurrent chemoradiation with platinium and etoposide has been recognized as the state-of-the-art treatment. The increasing number of ongoing trials including modern radiation schedules combined with newer chemotherapy agents shows that chemoradiation is one of the most promising therapeutic strategies in thoracic oncology.     

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.     

Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation?

Background For patients with resectable rectal cancer chemoradiation (CRT) or short-course preoperative radiotherapy (SCPRT) reduces locoregional failure, without extending disease-free survival (DFS) or overall survival (OS). Compliance to postoperative adjuvant chemotherapy is poor. Neoadjuvant chemotherapy (NACT) offers an alternative strategy. Methods A systematic computerised database search identified studies exploring NACT alone or NACT preceding/succeeding radiation. The primary outcome measure was pathological complete response (pCR). Secondary outcome measures included acute toxicity, surgical morbidity, circumferential resection margin, locoregional failure, DFS and OS. Results Four case reports, 12 phase I/II studies, 4 randomised phase II and one randomised phase III study evaluated chemotherapy before CRT. Four prospective studies reviewed chemotherapy after CRT. Three phase II studies investigated chemotherapy using FOLFOX plus bevacizumab without radiotherapy. In 24 studies of 1271 patients, pCR varied from 7% to 36%, but with no impact on metastatic disease. Conclusions NACT before CRT delivers does not compromise CRT but has not increased pCR rates, R0 resection rate, improved DFS or reduced metastases. NACT following CRT is an interesting strategy, and the utility of NACT alone could be explored compared with SCPRT or CRT in selected patients with rectal cancer where the impact of radiotherapy on DFS and OS is marginal.     

直肠癌术前同步放化疗不同放疗分割方式的临床研究

目的 评价直肠癌术前改良短程放化疗与常规分割放化疗疗效和安全性。方法60例可切除直肠癌患者随机分成术前改良短程放化疗(A组,30例,30 Gy分10次)和常规分割放化疗(B组,30例,45 Gy分25次),分别在放化疗后2周和6~8周手术。结果 A组和B组病理降期率分别为30%和67%(P=0.004)、保肛率分别为53%和68%(P=0.291)、R₀切除率分别为97%和100%(P=0.236)、3年OS率分别为83%和88%(P=0.717)、3年局部复发率分别为10%和7%(P=0.639)、3年远地转移率分别为27%和30%(P=0.774)。两组中有降期及无降期患者3年OS率分别为97%及74%(P=0.016);A组1—3级放射性皮炎、2级放射性肠炎、2级白细胞减少发生率、吻合口瘘及伤口延期愈合率与B组相近(P=0.092~0.717)。结论 术前改良短程放化疗及常规分割放化疗均可作为可切除直肠癌术前新辅助放化疗选择方案,且术前改良短程放化疗有治疗周期短、住院时间短、费用低、患者易接受等优势。     

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.     

Future chemoradiation strategies in pancreatic cancer

Although not universally accepted, 5-fluorouracil (5-FU)-based chemoradiation is considered a standard treatment for patients with localized pancreatic cancer. Randomized trials have indicated that chemoradiation improves median survival of both locally advanced and resected pancreatic cancer. While the use of adjuvant chemoradiation in pancreatic cancer has been called into question since the publication of the European Study Group for Pancreatic Cancer (ESPAC)-1 trial, this study has not changed standard practice in the United States. All randomized trials investigating adjuvant chemoradiation have reported significant local as well as distant disease control limitations, making the study of novel chemoradiation and adjuvant chemotherapy important. Selected centers are investigating neoadjuvant chemoradiation in radiographically resectable patients. Advantages of neoadjuvant chemoradiation compared to postoperative therapy include increased local control, increased access to therapy, addressing the systemic disease recurrence risk without delay, and optimal patient selection for pancreaticoduodenectomy through exclusion of patients with rapidly progressive metastatic disease. In the years since it was approved for use in pancreatic cancer, gemcitabine has stood the test of time as a systemic agent but has not been widely adopted as a radiosensitzer in pancreatic cancer. Single-arm clinical trials that initially explored gemcitabine as a radiosensitzer in locally advanced pancreatic cancer demonstrated the potential for significant toxicity without dramatic improvements in efficacy. Recent strategies for improving the efficacy of chemoradiation include improved chemoradiation sensitization through the concurrent incorporation of molecular targeted agents, and the use of new radiation technology such as intensity-modulated radiotherapy (IMRT) and stereotactic radiotherapy. Herein, we discuss the relative merits of strategies that seek to improve outcome through these novel means and present recent data from novel strategies that will provide the background for future trials.     

Radiochemotherapy in the management of pancreatic cancer--part I: neoadjuvant treatment

In pancreatic cancer, complete resection offers the only hope of cure, but results of surgery alone are suboptimal. Many studies have been conducted in which the treatment regimen consists of surgery in combination with radiation and chemotherapy to improve local control and outcome. Neoadjuvant chemoradiotherapy is a fairly recent approach that appears to be feasible in resectable and locally advanced pancreatic cancer. In resectable tumors, chemoradiation therapy has been shown to be at least as effective in a neoadjuvant setting as in an adjuvant setting. Neoadjuvant therapy offers a few theoretical advantages: (1) beginning the multimodality treatment with chemoradiation therapy increases the chance that more patients will receive all of its components; (2) preoperative chemoradiation therapy provides an observation period to exclude from surgical resection those patients with rapidly progressive disease; and (3) in locally advanced tumors, it provides the opportunity for downstaging and infrequently allows patients to undergo resection. To evaluate the scope and applicability of neoadjuvant treatment, a number of areas need to be addressed. First, the definition of locally advanced disease needs to be more adequately standardized because the resectability definition sometimes varies among surgeons. In addition, because imaging examinations may underestimate the effectiveness of preoperative chemoradiation therapy, some researchers have tried to evaluate treatment response via a pathological examination of the tumor specimen; however, complete pathological response appears to be rare. Finally, more efficient novel neoadjuvant approaches are required to address the high metastatic potential of pancreatic cancer. These areas are discussed in depth.