Preoperative Chemoradiation For Rectal Cancer Research Articles

Effect of Suboptimal Chemotherapy on Preoperative Chemoradiation in Rectal Cancer

Effect of Suboptimal Chemotherapy on Preoperative Chemoradiation in Rectal Cancer

Cyclooxygenase-2 Expression in Pretreatment Biopsy as a Predictor of Tumor Responses After Preoperative Chemoradiation in Rectal Cancer—Invited Critique

Cyclooxygenase-2 Expression in Pretreatment Biopsy as a Predictor of Tumor Responses After Preoperative Chemoradiation in Rectal Cancer—Invited Critique

Cyclooxygenase-2 Expression in Pretreatment Biopsy as a Predictor of Tumor Responses After Preoperative Chemoradiation in Rectal Cancer

To determine whether cyclooxygenase-2 (COX-2) expression in pretreatment biopsy specimens is a useful predictive marker of tumor response to preoperative chemoradiation (CRT) in rectal cancer. Case series. Colorectal cancer clinic. Thirty patients with locally advanced rectal cancer were given preoperative CRT of 5040 cGy for 6 weeks with concurrent administration of 5-fluorouracil and leucovorin. Immunohistochemical staining for COX-2 and angiogenesis markers (vascular endothelial growth factor, thymidine phosphorylase, and CD34) were performed on biopsy specimens obtained before preoperative CRT. The responses to preoperative CRT were assessed by radiologic downsizing (measured using magnetic resonance imaging volumetry), histopathologic downstaging, and a 3-point tumor regression grade (TRG) evaluation, based on the ratio of residual cancer to fibrosis. Tumor downstaging was seen in 15 patients (50.0%) and nodal downstaging was noted in 14 patients (46.7%). Tumor regression grade 1 (good response) was shown by 7 patients (23.3%); TRG2 (moderate response) in 15 patients (50.0%); and TRG3 (poor response) in 8 patients (26.7%). Patients with COX-2 overexpression were more likely to show a poor TRG (P = .003) and were less likely to achieve histopathologic nodal downstaging (P = .03) than those with normal COX-2 expression. Vascular endothelial growth factor overexpression was found to be associated with COX-2 overexpression (P = .02). Overexpression of COX-2 in pretreatment biopsies might be predictive of poor tumor regression after preoperative CRT. Administration of COX-2 inhibitors to patients with COX-2 overexpression, in an attempt to improve response rate to preoperative CRT, warrants assessment in clinical trials.

Phase I Study of Preoperative Radiation Therapy With Concurrent Infusional 5-Fluorouracil and Oxaliplatin Followed by Surgery and Postoperative 5-Fluorouracil Plus Leucovorin for T3/T4 Rectal Adenocarcinoma: ECOG E1297

Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.

Comparison of Chemotherapy Regimen in Preoperative Chemoradiation for Rectal Cancer

Comparison of Chemotherapy Regimen in Preoperative Chemoradiation for Rectal Cancer

Prognostic factors for tumor histological response to preoperative chemoradiation in rectal cancer

4094 Background: Tumor histological response following preoperative chemoradiation for locally advanced rectal cancer (LARC) is a surrogate for patient outcome. However, predictive factors for this surrogate have not been fully defined as of yet. The aim of this study was to identify pretreatment patient and tumor factors that may predict tumor histological response. Methods: Between 1997 and 2007, 292 patients (pts) with LARC, defined as T3–4 Nx, TxN+ or distal (<6 cm from the anus) T2N0, underwent preoperative chemoradiation followed by surgery at the participating centers. The radiotherapy protocol was standard (50.4–54 Gy in 1.8 Gy fractions) while chemotherapy consisted of several common fluoropyrimidine-based regimens. Patients’ medical files were retrived and various epidemiological, clinical, pathological and treatment parameters were collected. The study cohort was divided into two: responders - pts achieving pathological complete response (pCR) or having only microscopic residual disease (mRD), and non-responders - those who did not achieve pCR or mRD. Results: The median age of the whole group was 67 years (range: 28–86) and 50% were males. Pretreatment TNM stage, available in 271 pts, was: T2N0–13%, T3–4N0–53%, T1-T2N1- 2%, and T3-T4N1–32%. Data on histological response was available for all pts: pCR was documented in 16% and mRD in 12%. With a relatively short follow-up (median: 40 months, range: 5–118), disease free (p=0.049) and overall survival (p=0.004) were significantly different for responders and non-responders. Survival rates of pts with pCR and mRD were equal (95% and 94% 5-year survival, respectively). On univariate analysis, lower pretreatment clinical stage (p=0.024), chemotherapy consisting of oral fluoropyrimidines (p=0.049), age >60 (p=0.017) and pretreatment hemoglobin (Hb) level >12 gr/dl (p=0.027) were associated with significantly higher rates of histological response. On multivariate analysis, all these factors retained statistical significance. Conclusions: Pretreatment clinical stage and Hb level, age, and the chemotherapy regimen can predict tumor histological response following preoperative chemoradiation in pts with LARC. The prognostic impact of histological response was again noted. No significant financial relationships to disclose.

Pathologic Complete Remission after Preoperative Chemoradiation for Rectal Cancer: Analysis of Clinicopathologic Characteristics and Oncologic Outcome

Purpose: To assess the clinico-pathologic characteristics associated with pathologic complete remission (pCR) after preoperative chemoradiotherapy (PCRT) for rectal cancer and evaluate predictive factors for pCR and prognostic impact of pCR. Methods: We analyzed 325 patients who underwent PCRT and surgical resection between September 1999 and September 2006. We have treated 319 patients with PCRT for locally advanced rectal cancer and 6 patients for sphincter-saving procedure. Chemotherapy consisted of either of bolus 5-FU (325 mg/m2/d) or capecitabine (1,650 mg/m2/d) for the duration of radiation and after surgery. Radiation therapy was delivered and surgery was performed 4∼6 weeks following the completion of PCRT. We compared pCR patients with non-pCR patients according to the clinico-pathologic characteristics and followed up with a median of 32 (range, 12∼91) months. Results: The pCR (n=41, 12.6%) and non-pCR (n=284) groups were comparable in age, sex, location of the tumor, chemotherapy regimen, pre-CRT CEA level except pre-CRT clinical stage (12.2% vs. 0.4% in stage I, P= 0.047). There was no significant difference in genetic characteristics between groups. There was no specific predictive factors for pCR except pre-CRT T category (pCR in T2 (5/8, 62.5%) vs. T3 (33/283, 11.7%) or T4 (3/33, 9.1%), P=0.001). The 3-year disease free survival (DFS) was 100% and 83.6% in the pCR and non-pCR group respectively (P=0.012). There were 5 local and 34 systemic recurrences only in non-pCR group. Conclusions: Rectal cancer patients with pCR after PCRT have an excellent prognosis and are unlikely to fail locally or systemically because of the effect of stage. However there was no specific predictive factor for pCR except preoperative T category.

Complete Clinical Response After Preoperative Chemoradiation in Rectal Cancer: Is a “Wait and See” Policy Justified?

A proportion of patients, who receive preoperative chemoradiation for locally advanced (T3, T4, NX) rectal cancer achieve a complete clinical response and a pathologic complete response in the region of 15 to 30 percent. Support is growing in the United Kingdom for the concept of "waiting to see" and not proceeding to radical surgery when a complete clinical response is observed. The purpose of this review was to use a literature search to assess how often complete clinical response is achieved after neoadjuvant chemoradiation, the concordance of this finding with pathologic complete response, and to determine whether it is feasible to observe patients who achieve complete clinical response rather than proceed to surgery. In total, 218 Phase I/II or retrospective studies and 28 Phase III trials of preoperative radiotherapy or chemoradiation were identified: 96 percent of trials documented the pathologic complete response, but only 38 trials presented data on the achievement of a complete clinical response/partial clinical response. Only five studies were found in which patients with clinically staged T2/T3 tumors were treated with radiotherapy/chemoradiation and did not routinely proceed to surgery and also reported on the long-term outcome of a "wait and see" policy. It remains uncertain whether the degree of response to chemoradiation in terms of complete clinical response or pathologic complete response is a useful clinical end point. Studies that include T3 rectal cancer are associated with high local recurrence rates after nonsurgical treatment. Few studies report long-term outcome after achievement of a complete clinical response. The end point of complete clinical response is inconsistently defined and seems insufficiently robust with only partial concordance with pathologic complete response. The rationale of a "wait and see" policy when complete clinical response status is achieved relies on retrospective observations, which are currently insufficient to support this policy except in patients who are recognized to be unfit for or refuse radical surgery.

Surgical treatment of rectal cancer after neoadjuvant chemoradiation. Where are we going?

Anterior resection of the rectum and abdominoperineal resection with total mesorectal excision represent the standard surgical approach after preoperative chemoradiation in rectal cancer. Many clinical trials seem to validate laparoscopic approach, even if long-term outcome has not been still reported. Some authors recently focused their research on organ-saving surgery, either local excision or non-operative treatment. In this paper we present a brief revision of what rectal cancer treatment is reaching.

Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer

The objective of this study was to identify predictive factors for pathologic complete response and tumor downstaging after preoperative chemoradiation for rectal cancer. Between 1989 and 2004, 562 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation and underwent mesorectal excision. The median radiation dose was 45 Gray (Gy) (range, 19.8-58.6 Gy), 77% of patients received concurrent infusional 5-fluorouracil, 20% of patients received concurrent capecitabine, and 3% of patients received other regimens. Nineteen percent of patients achieved a pathologic complete response (CR), whereas 20% of patients had only microscopic residual disease at surgery, and 61% of patients had macroscopic residual disease at surgery. Downstaging of the tumor stage occurred in 57% of patients. The results from a univariate analysis indicated that tumor circumferential extent>60% (P=.033) and pretreatment carcinoembryonic antigen (CEA) level>2.5 ng/mL (P=.015) were associated significantly with lower pathologic CR rates. The univariate analysis also indicated that tumor circumferential extent>60% (P=.001), pretreatment CEA level>2.5 ng/mL (P=.006), and distance from the anal verge>5 cm (P=.035) were associated significantly with lower downstaging rates. The results from a multivariate logistic regression analysis indicated that greater circumferential extent of tumor (odds ratio [OR], 0.43; P=.033) independently predicted a lower pathologic CR rate. The multivariate logistic regression analysis also indicated that greater circumferential extent of tumor (OR, 0.49; P=.020) and greater distance from the anal verge (OR, 0.46; P=.010) independently predicted a lower downstaging rate. Circumferential extent of tumor, CEA level, and distance from the anal verge predicted for the pathologic response to preoperative chemoradiation for patients with rectal cancer. Therefore, these factors may be used to predict outcomes for patients, to develop risk-adapted treatment strategies, and to target patients who participate in trials of newer therapies.

Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors

Background Our goals were to examine the impact of neoadjuvant chemoradiation for rectal cancer on surgical outcomes and to determine prognostic factors predicting improved survival. Methods Retrospective cohort of 56 male and 44 female patients. Results After preoperative chemoradiation, 73% of patients had sphincter-preserving surgery. The 5-year disease-free (DFS) and overall survival rates were 77% and 81%, respectively. Twenty-five percent of patients showed a complete pathologic response. T-level downstaging and pathologic T stage did not correlate with recurrence or survival rates. Pathologic nodal stage was associated with a significant difference in recurrence rates (N 0 19%, N 1 20%, and N 2 75%, P = .038) and DFS (N 0/N 1 vs. N 2, 79% vs. 25%, P = .002). Conclusion Neoadjuvant chemoradiation resulted in a high rate of sphincter preservation. Complete pathologic responses after surgery were frequent and although pathologic T stage after surgery did not affect recurrence rates, pathologic nodal response was associated with improved recurrence and survival rates.

Disadvantages of Preoperative Chemoradiation in Rectal Cancer

Disadvantages of Preoperative Chemoradiation in Rectal Cancer

1067: Predictors of Tumor Response and Downstaging in Patients Treated with Preoperative Chemoradiation for Rectal Cancer

1067: Predictors of Tumor Response and Downstaging in Patients Treated with Preoperative Chemoradiation for Rectal Cancer

Alternative clinical end points in rectal cancer—are we getting closer?

Background: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%–40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6–8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible.Methods: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points.Results: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials.Conclusions: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.

Preoperative chemoradiation in rectal cancer: Retrospective comparison between capecitabine and continuous infusion of 5‐fluorouracil

We compared the efficacy and toxicity of oral capecitabine and continuous infusion of 5-fluorouracil (5-FU) in the preoperative chemoradiation treatment of patients with rectal cancer. The files of 89 patients with rectal cancer, 43 treated preoperatively with oral capecitabine and 46 with intravenous 5-FU, were reviewed, and the outcome of the groups was compared. There was no statistically significant difference in the complete pathological response rate between the capecitabine and the 5-FU groups (30% vs. 17%, P = 0.15). The downstaging rate was higher in the capecitabine group (77% vs. 50%, P = 0.009). Toxicity was mild in both groups. The rate of Grade 3 gastrointestinal toxicity was similar in the two groups (diarrhea 2% vs. 4%, proctitis 5% vs. 7%), except for one patient in the 5-FU group (2%) who developed a rectovaginal fistula. In the capecitabine group, one patient (2%) had Grade 3 hand-foot syndrome, and another had an acute myocardial infarction. In the 5-FU group, two patients (4%) had Grade 3 hematological toxicity, and three (6%) had complications from Port-a-Cath insertion. Preoperative chemoradiation with oral capecitabine appears to be safe and well tolerated, and at least as good as continuous 5-FU.

Serum CEA as a predictor for the response to preoperative chemoradiation in rectal cancer

Recent data suggest that good responders to preoperative chemoradiation (CRT) have a favorable prognosis in rectal cancer patients. The aim of this study was to investigate the predictive value of serum carcinoembryonic antigen (CEA) levels for the tumor response to preoperative CRT in rectal cancer patients. The study comprised 141 rectal adenocarcinoma patients who underwent preoperative radiotherapy with 5-fluorouracil (FU) based chemotherapy, followed by radical surgery. The staging workup was consisted of endorectal ultrasound, abdominopelvic computed tomography scan, or magnetic resonance imaging. The outcome parameters were cancer-specific survival and disease-free survival. Pre-CRT clinicopathologic features, including age, gender, location of the tumor, clinical tumor (cT) classification, clinical nodal (cN) classification, and serum CEA levels were investigated as possible predictors for the response to preoperative CRT. Pathologic complete or near complete responses (good responders, GR) occurred in 26 (19%) patients, while partial or no response (poor responders, PR) occurred in the remaining 115 (81%) patients. GR showed better cancer-specific survival (P = 0.028) and disease-free survival rates (P = 0.011) than PR. Univariate analysis revealed that positive cN and elevated (>5 ng/ml) pre-CRT serum CEA levels are associated with poor tumor response to preoperative CRT. Using logistic regression analysis, elevated pre-CRT serum CEA levels were the only significant predictor for the poor response to CRT (Odd ratio = 2.876, 95% confidence interval = 1.04-7.46, P = 0.041). Our data suggest that elevated pre-CRT serum CEA levels are associated with poor tumor response to CRT. Therefore, pre-CRT serum CEA levels provide useful information about tumor response to preoperative CRT in rectal cancer patients.

Clinical Examination Following Preoperative Chemoradiation for Rectal Cancer Is Not a Reliable Surrogate End Point

Clinical Examination Following Preoperative Chemoradiation for Rectal Cancer Is Not a Reliable Surrogate End Point

Preoperative Chemoradiation for Rectal Cancer Causes Prolonged Pudendal Nerve Terminal Motor Latency

A worsened anorectal function after chemoradiation for high-risk rectal cancer is often attributed to radiation damage of the anorectum and pelvic floor. Its impact on pudendal nerve function is unclear. This prospective study evaluated the short-term effect of preoperative combined chemoradiation on anorectal physiologic and pudendal nerve function. Sixty-six patients (39 men, 27 women) with localized resectable (T3, T4, or N1) rectal cancer were included in the study. All patients received 45 Gy (1.8 Gy/day in 25 fractions) over five weeks, plus 5-fluorouracil (350 mg/m2/day) and leucovorin (20 mg/m2/day) concurrently on days 1 to 5 and 29 to 33. Patients who had rectal cancer with a distal margin within 6 cm of the anal verge had the anus included in the field of radiotherapy (Group A, n = 26). Patients who had rectal cancer with a distal margin 6 to 12 cm from the anal verge had shielding of the anus during radiotherapy (Group B, n = 40). The Wexner continence score, anorectal manometry and pudendal nerve terminal motor latency were assessed at baseline and four weeks after completion of chemoradiation. The median Wexner score deteriorated significantly (P < 0.0001) from 0 to 2.5 for both Groups A (range, 0-8) and B (range, 0-14). The maximum resting anal pressures were unchanged after chemoradiation. The maximum squeeze anal pressures were reduced (mean = 166.5-157.5 mmHg) after chemoradiation. This change was similar in both Groups A and B. Eighteen patients (Group A = 7, Group B = 11) developed prolonged pudendal nerve terminal motor latency after chemoradiation. These 18 patients similarly had a worsened median Wexner continence score (range, 0-3) and maximum squeeze anal pressures (mean = 165.5-144 mmHg). The results obtained were independent of tumor response to chemoradiation. Preoperative chemoradiation for rectal cancer carries a significant risk of pudendal neuropathy, which might contribute to the incidence of fecal incontinence after restorative proctectomy for rectal cancer.

628 POSTER Pathological complete response following preoperative chemoradiation in rectal cancer: An updated analysis of phase II/III trials

Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)–based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU–based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also a highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.

692 PUBLICATION Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil

692 PUBLICATION Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil