Modality Therapy For Rectal Cancer Research Articles

Combined Modality Therapy for Rectal Cancer.

The primary therapy for any potentially curative rectal cancer is surgery. For locally advanced tumors (i.e., T3-4 and/or node positive), the very high rate of local and distant recurrences has necessitated a standard adjuvant regimen of preoperative chemoradiation and postoperative chemotherapy. Several controversies regarding this approach remain, including the technique and fractionation scheme of radiation therapy prior to surgery, the choice of concomitant chemotherapy, and whether all patients require postoperative systemic therapy. Furthermore, in an era of improving staging imaging and surgical techniques, an opportunity for de-escalation of therapy to improve patient morbidity and quality of life may arise. At the same time, advances in radiation and systemic therapy may help facilitate less invasive, sphincter-preserving surgery. This review addresses these questions and others that remain areas of active clinical investigation.

Future directions in combined modality therapy for rectal cancer: reevaluating the role of total mesorectal excision after chemoradiotherapy

Most patients who develop rectal cancer present with locoregionally advanced (T3 or node-positive) disease. The standard management of locoregionally advanced rectal cancer is neoadjuvant concurrent chemoradiotherapy (nCRT), followed by radical resection (low-anterior resection or abdominoperineal resection with total mesorectal excision). Approximately 15% of patients can have a pathologic complete response (pCR) at the time of surgery, indicating that some patients can have no detectable residual disease after nCRT. The actual benefit of surgery in this group of patients is unclear. It is possible that omission of surgery in these patients, termed selective nonoperative management, can limit the toxicities associated with standard, multimodal combined modality therapy without compromising disease control. In this review, we discuss the clinical experiences to date using selective nonoperative management and various attempts at escalation of nCRT to improve the number of patients who have a pCR. We also explore several clinical, laboratory, imaging, histopathologic, and genetic biomarkers that have been tested as tools to predict which patients are most likely to have a pCR after nCRT.

Combined Modality Therapy for Rectal Cancer: Too Much Too Often?

The refinement and implementation of multimodal therapy for rectal cancer, including surgery, radiotherapy, and chemotherapy, is certainly one of the most meaningful achievements in the history of clinical cancer research to date. It is thus important to set any harsh critique of current treatment methods and outcomes within this context. Just 30 years ago, the risk of local recurrence after rectal resection ranged from 20 to 40 %. It was often lethal and was associated with significant morbidity, pain, and suffering. This began to change with the report from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Cooperative Group R01 trial in 1985, which demonstrated a reduction in local recurrence from 25 to 16 % with the addition of postoperative long-course chemoradiotherapy. The NSABP trial was followed by serial studies designed to improve results through addition and resequencing. The Gastrointestinal Tumor Study Group (GITSG) reported a 55–33 % reduction in all recurrence with the addition of adjuvant chemotherapy and radiotherapy, leading the National Institutes of Health to generate a consensus statement asserting that chemoradiotherapy should be delivered postoperatively for all stage II and III tumors. The German Rectal Cancer Study later demonstrated improved outcome when long-course chemoradiotherapy was delivered preoperatively rather than postoperatively to clinical stage II and III rectal cancers. Local recurrence at 46 months was reduced from 13 to 6 % without change in distant recurrence. At 10 years, the difference in local recurrence was of a lower magnitude but remained significant (7 vs. 10 %). Disease-free and overall survival did not differ between the groups. This changed the standard of practice to preoperative rather than postoperative long-course chemoradiotherapy for stage II and III rectal cancers. While North America and Central Europe employed a regimen of long-course postoperative chemoradiotherapy administered over 5–6 weeks, Northern Europe was utilizing short-course radiotherapy delivered over 5 days before surgery, and demonstrating similar improvements in outcome. The Swedish Rectal Cancer Trial showed that preoperative short-course radiotherapy reduced local recurrence from 27 to 11 % and increased survival from 65 to 74 % compared with surgery alone. This brings us to 2013, when patients are much less likely to experience local recurrence and more likely to retain sphincter function than decades ago. However, two reports in this issue of Annals of Surgical Oncology remind us that more is not necessarily better, and that one size does not fit all. Lange et al. report on a series of rectal cancer patients treated traditionally under the supervision of Warren Enker, an international leader and pioneer who has spent his career spreading the word about the methodical techniques of anatomic rectal resection and the benefits of total mesorectal excision. In total, 368 patients underwent rectal resection, with a median follow-up of 8 years. Seventy percent underwent sphincter-preserving surgery, with an average anastomotic height of 5.4 cm. Only 5 % of patients undergoing low anterior resection experienced anastomotic leak. The oncologic results are equally impressive. Five-year overall survival was 76 %: 92 % for stage I disease, 78 % for stage II disease, and 69 % for stage III disease. The 5-year local recurrence rate was 5.2 %: 0.8 % for stage I disease, 4.7 % for stage II disease, and 5.4 % for stage III disease. The 5-year rate of distant metastasis was 22 %: 3.9 % for stage I disease, 21 % for stage II disease, and 27 % for stage III disease. Analysis of functional outcome was measured in 50 patients. Irradiated patients had, on average, 3.2 bowel movements per day, compared to 1.2 in nonirradiated Society of Surgical Oncology 2013

Disparity in the use of combined modality therapy for rectal cancer in the older adult

The standard treatment strategy for patients with rectal adenocarcinoma having T3 or T4 tumors or positive lymph nodes includes concurrent chemoradiation, surgery and chemotherapy. Population based studies show relatively low rates of usage of standard therapy for rectal cancer in the older adult. Two decades of cases of stage II and stage III rectal cancer from two academic teaching hospitals were reviewed. Comparisons were made of subjects ≤70 or ≥71years with regard to initiation and completion of radiation, chemotherapy and surgery. Subjects ≥71years of age had significantly lower proportions of surgical resection (84 vs. 94%) and of initiation of all three component of standard therapy (49 vs. 66%) compared to those ≤70years of age. Subjects ≥71years had significantly more co-morbidities; however, the difference in initiation of therapy remained after adjusting for stage, treating hospital, co-morbid status, race or sex in multivariable analysis. The odds for initiation of therapy were reduced by ≈22% in older adults in the adjusted analysis. Among all patients who started therapy only 56% completed it without dose reduction or delay. There were trends to increased completion among those receiving neo-adjuvant vs. post-operative chemoradiation and among those with stage III as opposed to stage II cancer. Our study indicates that a major disparity in the use of standard therapy for rectal cancer in the older adult exists in academic hospital settings. It will be important for oncologists to reconsider increasing the usage of curative therapy in these patients.

Pulmonary Recurrence Predominates After Combined Modality Therapy for Rectal Cancer

To characterize patterns of recurrence in locally advanced rectal cancer treated with combined modality therapy (CMT): neoadjuvant chemoradiation + total mesorectal excision + adjuvant chemotherapy. A total of 593 consecutive rectal cancer patients (1998 to 2007) with locally advanced (stage II/III) disease (noted on endorectal ultrasound or magnetic resonance imaging) who received CMT were analyzed for patterns of recurrence. After median 44-month follow-up (interquartile range, 25 to 64 months), 119 patients (20%) recurred: 105 distant, 7 local, 7 local and distant, and 112 distant-only recurrence. Ninety-three (78%) had single-organ recurrence, and 26 (22%) had multiple-organ recurrence. The most common site of distant recurrence was lung (69% of all patients with distant relapse); 20% had liver recurrence. Fourteen patients (2.4%) recurred locally. Pulmonary metastases were most commonly identified by computed tomographic scan versus abnormal positron emission tomographic (PET) scan or carcinoembryonic antigen (CEA). Risk factors associated with pulmonary recurrence were the following: pathologic stage, tumor distance from anal verge, lymphovascular or perineural invasion. Five-year freedom from pulmonary recurrence for patients with 0, 1, 2, or 3 risk factors was 99%, 90%, 61%, and 42%, respectively. Thirty of 59 patents with pulmonary recurrence underwent lung metastasectomy; 3-year freedom from recurrence was 37%. Unlike colon cancer, which most frequently recurs in the liver, locally advanced rectal cancer treated with CMT relapses most frequently in the lung. Pulmonary metastasis was associated with advanced pathologic stage, low-lying tumor, lymphovascular invasion, or perineural invasion. Confirmation of pulmonary metastasis usually requires serial imaging because metastases are often small when initially detected, well below the resolution of PET, and not necessarily associated with elevated CEA. Individualized risk-based surveillance strategies are recommended in this patient population.

Is there any significant difference between tumor regression grade systems of rectal cancer?

3583 Background: Tumor regression grade (TRG) is a measure of histopathologic response of rectal cancer to preoperative chemoradiation (CRT) and correlates with outcomes. Several TRG systems have been reported including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan Kettering Cancer Center (MSKCC), and American Joint Committee of Cancer (AJCC). The purpose of this study is to compare the different TRG systems and determine which one(s) best predict recurrence and survival. Methods: Review of prospective maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/4 and/or N1) and treated with long-course CRT followed by total mesorectal excision. TRG was determined by measuring proportion of tumor mass replaced by fibrosis. Patients were then classified into the various TRG schemes which were compared by analyzing association with recurrence and survival using concordance index (CI) and reclassification index. CI is a measure that summarizes the predictive strength of a marker. Computing and contrasting CI across several markers is a way of selecting the best prognostic marker. Results: 75% of patients were noted to have clinical stage III disease by endorectal ultrasound or rectal MRI. Following resection with median follow-up of 39.3 months, 2% developed local recurrence and 17% developed distant metastasis. The median interval time between completion of CRT and surgery is 48 days. 20% demonstarted complete pathological response. CI of the 3 tier Mandard, 3 tier Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694, respectively (higher number indicates better prediction). The AJCC was significantly more accurate in predicting recurrence than the 3- tier Mandard (p=0.002), and Dowrak/Rodel (p=0.006). AJCC had a higher CI than MSKCC although it did not reach significance (p=0.068). Comparing the 3 tier systems, MSKCC was most accurate and correctly reclassified 17 % and 23 % of the patients Mandard and Dowrak/Rodel systems, respectively. Conclusions: TRG predicts recurrence and survival following combined modality therapy for rectal cancer. The TRG system that recently was proposed in the 7thAJCC staging is currently the most accurate predictor.

Combined Modality Therapy for Rectal Cancer: The Relative Value of Posttreatment Versus Pretreatment CEA as a Prognostic Marker for Disease Recurrence

To evaluate the prognostic significance of the first postsurgery carcinoembryonic antigen (CEA) level in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation (nCRT) and total mesorectal excision. A total of 100 patients underwent nCRT and had baseline and posttreatment CEA levels recorded within 6 months of surgery. The median radiotherapy dose was 50.4 Gy. Eighty-six patients received adjuvant 5-fluorouracil-based chemotherapy. Prognostic factors were analyzed for possible associations with freedom from failure (FFF) by univariate and multivariate analyses. Median follow-up was 30 months. The median CEA (ng/ml) levels at baseline before nCRT, after nCRT, and after total mesorectal excision were 3.6, 1.7, and 1.3, respectively. Pathologic complete response was observed in 22%. FFF at 36 months was 78%. Local failure and distant failure occurred in 4 and 20% of the patients, respectively. On univariate analysis, pathologic complete response, margin status, and both pretreatment and postsurgery CEA levels were associated with recurrence (all P < 0.05). On multivariate analysis, pathologic complete response (P < 0.007), margin status (P < 0.001), and postsurgery CEA level (P = 0.003), but not baseline CEA level (P = 0.2), were found to be associated with recurrence. After nCRT for rectal cancer, postsurgery CEA level may have more prognostic value than pretreatment level. Patients with a postsurgery CEA level of >2.5 ng/ml have higher rates of recurrence and may warrant closer surveillance.

Tolerability of Combined Modality Therapy for Rectal Cancer in Elderly Patients Aged 75 Years and Older

To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham & Women's Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fisher's exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed≥4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p=0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p=1.0). The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of combined modality therapy for rectal cancer should be performed with caution in elderly patients, who require aggressive supportive care to complete treatment.

Combined Modality Therapy for Rectal Cancer: Analysis of Potential Differences in Disease Presentation, Treatment Adherence, and Treatment Outcome According to Race

Population-based studies suggest that African Americans (AAs) with rectal cancer have a worse overall outcome compared to whites. This relationship was explored in a cohort of locally advanced rectal cancer patients treated with preoperative chemoradiation (CRT) and surgery at two urban academic cancer centers. A total of 146 patients underwent curative-intent combined modality therapy for adenocarcinoma of the rectum. The median age was 57 years. Median dose was 50.4 Gy, given with 5-flourouracil based concurrent chemotherapy. Analysis was performed to test for differences in disease presentation, adherence to recommended therapy, and treatment outcome (freedom from failure, FFF) by race. Median follow-up was 34 months from completion of chemoRT. Twenty-six patients (18%) were AA, and 120 (82%) patients were White, Asian, or Hispanic. AA patients had longer times from diagnosis to start of therapy (median 45 days vs. 35 days, p < 0.01) and from CRT completion to surgery (median 42 days vs. 46 days, p = 0.03). CRT treatment time was no different between the two groups (median 38 days for both groups, p = 0.53). In the subset of patients with preoperative staging by endoscopic ultrasound (EUS, n = 119), AA patients presented with more favorable disease (20% stage I, 47% stage II, 33% stage II) compared with non-AA patients (0% stage I, 50% stage II, 48% stage III, 2% stage IV, p < 0.01). Among patients with stage II-IV disease (n = 116), the rate of any T or N downstaging was lower for AA patients (58% vs. 79%, p = 0.13). Pathologic complete response rates were also lower (17% vs. 26% for non-AA patients, p = 0.47), although not statistically different. AA patients were less likely to receive adjuvant chemotherapy (58% vs. 89%, p = 0.01). Log-rank analysis showed that time from diagnosis to therapy, and time from CRT to surgery were not associated with any difference in FFF when stratified by the median value. Similarly, completion of adjuvant chemotherapy was not associated with FFF. Overall, AA patients were not more likely to recur after therapy (FFF-3y, 100% for AA patients vs. 81% for non-AA patients, p = 0.09). This analysis reflects differences in time from preoperative therapy to surgery and a lower rate of adjuvant therapy in AA patients with rectal cancer treated in at two urban academic cancer centers. These differences did not appear to result in inferior disease outcome for this cohort. Further study is necessary to explore the reasons underlying the delays in therapy and lower rates of adjuvant chemotherapy for AA patients.

Post-treatment CEA Values, and CEA Trends at the Time of Uncertain Post-treatment Imaging, Have Prognostic Value after Combined Modality Therapy for Rectal Cancer

Post-treatment CEA Values, and CEA Trends at the Time of Uncertain Post-treatment Imaging, Have Prognostic Value after Combined Modality Therapy for Rectal Cancer

Combined Modality Therapy for Rectal Cancer

The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after 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? These questions and others remain active areas of clinical investigation.

Positron emission tomography during preoperative combined modality therapy for rectal cancer may predict ultimate pathologic response: A prospective analysis

3612 Introduction: Early knowledge of rectal cancer response to preoperative combined modality therapy (CMT) may provide an opportunity to identify patients with minimal response and who may benefit from alternative treatment regimens. We prospectively evaluated the novel concept of assessing rectal cancer response with fluorodeoxyglucose positron emission tomography (PET) early after the commencement of preoperative CMT. Methods: 21 prospectively accrued patients with locally advanced rectal cancer (ERUS T3–4/N1) received preoperative CMT (5040 cGy with 5-FU-based chemotherapy). Patients were imaged with a PET scan prior to and 10–12 days after (early PET) commencement of CMT. PET scans were interpreted by two Nuclear Medicine physicians using four specific parameters [(SUVmax, SUVaverage, total lesion glycolysis (TLG), and visual response score (VRS)]. Percent pathologic response was quantified using whole mount sections. Pathologic complete response (pCR) was defined as no viable tumor cells on patholo...

Combined modality therapy for rectal cancer

Combined modality therapy for rectal cancer

Markers of Cell Cycle-Mediated Drug Resistance And Prognosis Of Patients Receiving Preoperative Combined Modality Therapy For Rectal Cancer

Markers of Cell Cycle-Mediated Drug Resistance And Prognosis Of Patients Receiving Preoperative Combined Modality Therapy For Rectal Cancer

Combined modality therapy for rectal cancer.

Combined modality therapy for rectal cancer.

Adjuvant combined modality therapy for rectal cancer.

Combined modality therapy is an integral component in the management of rectal cancer. There are two components of adjuvant therapy: pelvic radiation and 5-FU based chemotherapy. In patients with clinically resectable disease, the role of radiation therapy is to decrease local recurrence and increase the chance of sphincter preservation. In patients with locally advanced/ unresectable disease, radiation therapy has the added role of increasing the resectablility rate. The role of chemotherapy, regardless of the resectability status, is to enhance the benefits of radiation (radiosensitization) as well as improve survival by decreasing the incidence of distant metastasis. This chapter will examine the rationale and results of preoperative and postoperative therapy in patients with clinically resectable rectal cancer treated in the adjuvant setting. The results of radiation therapy will be presented followed by a discussion of combined modality therapy.

Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer.

To determine the relationship between acute gastrointestinal (GI) toxicity during the combined modality segment and the volume of small bowel in the pelvic radiation field in patients who receive either preoperative or postoperative therapy for rectal cancer. The patient population was derived from four consecutive phase I dose-escalation trials. Combined modality therapy included fluorouracil (5-FU), leucovorin ([LV] bolus daily x 5, days 1 and 29), and pelvic radiation. Twenty patients who received postoperative therapy had a larger volume of small bowel in the pelvic radiation field as compared with 60 who received preoperative therapy (462 +/- 129 v 212 +/- 44 cm3, P = .002). The most significant relationship between acute GI toxicity and volume of small bowel was seen in 12 patients who were treated on the preoperative sequential low-dose LV trial, all of whom received the maximum-tolerated dose (MTD) of 5-FU. The volume of small bowel in patients who experienced grade 3+ toxicity was 731 +/- 274 cm3, as compared with 145 +/- 58 in those who experienced grade 0 to 2 toxicity (P = .005). Likewise, logistic regression analysis showed that 26 patients who received the MTD of 5-FU had the most significant association between GI toxicity and volume of small bowel (P = .036). Our data suggest that the volume of small bowel in the pelvic radiation field may be dose-limiting in the delivery of high-dose 5-FU when combined with LV and radiation therapy.