Adjuvant Treatment Of Rectal Cancer Research Articles

Impact of the new AJCC staging system and adjuvant treatment in rectal cancer.

The combination of chemoradiation and fluorouracil based chemotherapy has been the standard adjuvant treatment for colorectal cancer patients. The aim of this study was to evaluate treatment outcome of patients classified by the new AJCC staging system and to compare treatment outcome of oral doxifluridine and the standard Mayo Clinic regimen after chemoradiation in advanced rectal cancer patients. One hundred nine patients underwent curative surgical resection and chemoradiation followed by chemotherapy. 45 Gy pelvic irradiation was given to the entire pelvis and the boost radiation with 50.4 to 54 Gy, and simultaneously 5-fluorouracil (5-FU) 375 mg/m(2)/day was given on day 1 approximately 3 and 26 approximately 28. After the completion of chemoradiation, patients were given either 6 cycles of the Mayo Clinic regimen (5-FU 425 mg/m(2) plus leucovorin 20 mg/m(2) intravenous bolus infusion on day 1~5, every 4 weeks) or oral doxifluridine (600 mg/m(2)/day) for 1 year. The median follow-up duration was 30 months. Among 102 evaluable patients, 38 patients (37.3%) relapsed: the locoregional recurrence in 10 patients (9.8%) and systemic relapse in 28 patients (27.5%). The systemic relapse rate was 15.6% in the stage IIA, 25.0% in the stage IIIB , and 59.1% in the stage IIIC (p=0.048). The 5-year disease-free survival (DFS) rate was significantly higher in the IIA and IIIA patients than the IIIB and IIIC patients (72% and 100% vs 48.1% and 11.2%, respectively. p<0.001). The 5-year overall survival (OS) rate was also significantly different between in the IIA/IIIA patients and the IIIB/IIIC (67.3%/100% vs 48.4%/22.3%. p<0.001). However, the difference in DFS or OS between the oral doxifluridine group and the Mayo Clinic regimen group was not significant. Cox regression multivariate analyses showed that the new AJCC stage and tumor differentiation were significant independent prognostic factors in DFS and OS. These results support that the new AJCC staging system is superior to Dukes' staging system in the prognostic stratification. Regarding DFS and OS, oral doxifluridine is comparable to the standard Mayo Clinic regimen in rectal cancer patients when combined with postoperative chemoradiation. Stage IIIC patients should be selected for aggressive therapy as they have a dismal prognosis.

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer

Purpose 5-Fluorouracil–based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. Methods and materials Patients with Stage II–III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. Results Thirty-one patients were enrolled at the following dose levels: 1000 mg/m 2/d (3 patients), 1150 mg/m 2/d (4 patients) 1300 mg/m 2/d (6 patients), 1400 mg/m 2/d (6 patients), 1500 mg/m 2/d (3 patients), 1600 mg/m 2/d (3 patients), and 1700 mg/m 2/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m 2/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m 2/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m 2/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. Conclusion The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m 2/d in this study. This dose is recommended for additional use in Phase II-III studies.

Adjuvant therapy for rectal cancer

Abstract Surgery is the only curative treatment modality in rectal cancer. However, in patients with locally advanced T3 or T4 tumors with or without nodal involvement, the risk of local and systemic recurrence is high. Adjuvant (postoperative) therapy aims to reduce the risks of local as well as distant recurrence and decrease cancer-related mortality. Postoperative chemoradiotherapy has been the gold standard. However, the adjuvant treatment of rectal cancer is continuing to evolve due to the greater use of surgical techniques such as total mesorectal excision as well as neoadjuvant (preoperative) radiotherapy or chemoradiotherapy and new systemic agents. This review summarizes the various types of adjuvant and neoadjuvant therapies, their current status, and the morbidity of these treatment modalities. Copyright 2002, Elsevier Science (USA). All rights reserved.

320 Invited (Neo)adjuvant treatment in rectal cancer

320 Invited (Neo)adjuvant treatment in rectal cancer

The variability of the clinical target volume for rectal cancer due to internal organ motion during adjuvant treatment

Purpose: This study defined the clinical target volume (CTV) for the adjuvant treatment of rectal cancer and applied this definition to multiple CT scans obtained during the typical 5-week course of treatment to measure the modification to the CTV due to internal organ motion that would be needed to define the planning target volume (PTV).Methods and Materials: Ten patients with rectal cancer had weekly treatment planning CT scans during adjuvant radiation therapy. All patients were given oral contrast, placed prone on a rigid foam cradle with a depressed area for small bowel exclusion, and instructed to have a full bladder. The CT scans were registered according to the bones of the pelvis, and the CTV was outlined on each CT slice. Movement of the CTV in all dimensions was measured. The CT scan with the lowest and highest bladder volume for each patient was used to calculate the CTV movement due to bladder filling.Results: The largest difference in the CTV occurred 10 cm caudal to the anus, with a standard deviation of 1 cm. Bladder filling displaced the anterior border of the CTV an average of 7 mm over a cranial to caudal length of 2.5 cm. Other borders of the CTV were based on muscle, bone, or major blood vessels and were stable.Conclusion: Modification of the CTV to design a PTV can be unequal, with the largest change at the anterior border of the inferior pelvis.

Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer

Background : Tumor shrinkage by preoperative radiochemotherapy (RCT) can markedly improve surgery in locally advanced (T4) rectal cancer with clear resection margins and may enable sphincter preservation in low-lying tumors. However, tumor response varies considerably, even among tumors treated according to the same protocol. If one is able to identify patients with highly radioresponsive tumors at the time of diagnosis, a selective and individualized policy of preoperative RCT might be pursued. Methods : The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 44 patients treated uniformly according to a prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Treatment response was assessed histopathologically in the resected surgical specimen, using a five-point grading system. Expression of each marker was correlated with tumor response and relapse-free survival after curative surgery. Results : Tumors with complete ( n = 3) or good ( n = 28) response to RCT showed significantly higher pretreatment levels of apoptosis (mean AI: 2.06%) than tumors with moderate ( n = 7), minimal ( n = 5), or no regression ( n = 1) from RCT (AI: 1.44%, p = 0.003). The AI was significantly related to Ki-67 ( p = 0.05), but not to p53 and bcl-2 status. Tumor regression and AI best predicted relapse-free survival after combined modality treatment and curative surgery. Conclusion : Spontaneous apoptosis in rectal cancer may serve as an important predictor of tumor regression from RCT in rectal cancer and as a significant prognosticator of relapse-free survival. Thus, this molecular marker may finally help to tailor therapy with regard to (neo-) adjuvant treatment of rectal cancer.

Is there a role for chemotherapy in the adjuvant treatment of rectal cancer?

Is there a role for chemotherapy in the adjuvant treatment of rectal cancer?

The role of radiation therapy in the adjuvant treatment of rectal cancer

There have been several advances in the treatment of rectal cancer in the past 20 years. The recognition that surgical therapy alone leads to a local failure rate of 15 to 50% in stages II and III has led to the use of adjuvant radiation therapy. Multiple prospective, randomized trials conducted by multi-institutional cooperative groups have resulted in the use of adjuvant combined modality therapy using radiation therapy and 5-fluorouracil chemotherapy. Some of the trials fine-tuned the sequencing and dose of radiation and chemotherapy to maximize efficacy and minimize toxicity. The advent of accurate endorectal ultrasound and MRI staging has allowed the use of preoperative therapy without the unnecessary treatment of patients with early stage. This has resulted in greater sphincter preservation and fewer complications. The optimal sequencing of adjuvant therapy has yet to be found.

Preoperative Combined Radiotherapy and Chemotherapy for Middle and Lower Rectal Cancer: Preliminary Results

Adjuvant treatment for rectal cancer is still controversial. This study reports on overall survival and disease-free survival, toxicity, downstaging, and surgical morbidity in rectal cancer patients who received combined chemoradiation therapy followed by curative surgery. Between 1993 and 1998, 51 patients (31 males and 20 females; median age, 60 years; range, 33-73 years) underwent chemoradiation therapy followed by radical surgery for middle and lower rectal adenocarcinoma. Criteria for giving preoperative radiotherapy (total 45 Gy in 25 fractions of 1.8 Gy/day for 5 weeks) and chemotherapy (5-fluorouracil 350 mg/m2/day and leucovorin 10 mg/m2/day, bolus on days 1-5 and 29-33) were an age younger than 75 years; an Eastern Cooperative Oncology Group performance status score of 0 to 2; and clinical preoperative stage II-III. Forty-three low anterior and eight abdominoperineal resections were performed. Median follow-up time was 29 (range, 3-63) months. Although grade 3 to 4 toxicity occurred in 14 cases (27.4%), all patients completed the planned adjuvant therapy. At pathology, a complete response was found in eight (15.7%) cases. Of the remaining 43 cases, 22 were stage I, 12 were stage II, and 9 were stage III. Five-year actuarial disease-free survival and overall survival rates were 86.4% and 85.5%, respectively. Whereas no local recurrences were found, 4 patients had distant metastases. Three patients died (1 of cancer-related causes), 45 are alive and disease free, and 3 are alive with disease. The combined preoperative chemoradiation approach used by us seems to improve the disease-free survival and overall survival of selected patients with rectal cancer. However, a longer follow-up time is required to confirm these preliminary results.

Is there a standard adjuvant treatment for rectal cancer?: Pro:

Is there a standard adjuvant treatment for rectal cancer?: Pro:

Is there a standard adjuvant treatment for rectal cancer?: Contra:

Only half the patients who undergo surgery for rectal adenocarcinoma can be cured. Many attempts at improving the results of treatment have been made. Although for many years rectal cancers were considered resistant to radiation therapy, the biology of tumours and the effects of radiation and chemotherapy on locoregional spread and distant metastases are now better understood. Surgical resection which remains the principal curative tool for rectal cancer has benefited in recent years from different progresses leading to a better control of cancer and improved functional results. Adjuvant therapy, using radiation to improve local control and chemotherapy to prevent distant relapses, has been studied in many trials. Although most experts agree on analysis of the data, quite different conclusions have been reached: “The best current adjuvant therapy for rectal cancer involves postoperative treatment with both chemotherapy and radiotherapy” (NIH Consensus Conference, 1990)[ 1 NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990, 264, 1444–1449. Google Scholar ]; “The benefits observed with pre-operative radiation incite to test pre-operative treatment with radiotherapy and chemotherapy” (Paris Consensus Conference, 1994)[ 2 Le choix des thérapeutiques du cancer du rectum. Agence Nationale pour le Développement de l’Evaluation Médicale. Conférence de Consensus, Paris, 1994. Google Scholar ]. Are we closer to a consensus in 1998?

Is there a standard adjuvant treatment for rectal cancer?: Arbiter:

Is there a standard adjuvant treatment for rectal cancer?: Arbiter:

Mesorectal excision for rectal cancer: a view from Europe.

The local recurrence rate after rectal cancer surgery is discussed as related to conventional and total mesorectal excision (TME) techniques. Studies now show that the wide variation in results between centers and among surgeons depends, at least in part, on differences in surgical technique. We conclude that local tumor recurrence rate is lower after TME than after conventional surgery and emphasize the importance of a standardized macroscopic evaluation of the resected specimen. Population-based registration to evaluate the quality of surgery is recommended. It is also suggested that randomized studies on adjuvant treatment for rectal cancer should include a "surgery only" arm when a local tumor recurrence rate of 10% or less is being studied. Until such investigations are performed, we conclude that the role for adjuvant treatment is questionable and that TME surgery is preferred as the treatment option for Stage T1-T3 rectal cancers.

Radiochemotherapy as an adjuvant treatment for rectal cancer.

Adjuvant treatment with radiotherapy has been proposed in rectal cancer surgery, due to the high local recurrence rate. However, the rate varies substantially in the literature, an this may be one reason that adjuvant treatment is not obvious to all surgeons. The difference may be due to selection bias, different criteria for curative surgery, different follow-up routines, and/or the skill of the surgeon. The data are unequivocal from all randomized trials comparing surgery alone with surgery plus radiotherapy, given either pre- or postoperatively: the average local recurrence rate is about 29% in the surgery-alone arm. With pre- or postoperative radiotherapy the local recurrence rate is more or less halved. Moreover, preoperative irradiation is more dose efficient than postoperative irradiation, indicating that a higher dose must be used when postoperative radiotherapy is delivered, with an increased risk of damaging the normal surrounding tissues in the pelvis. This damage of normal tissue also has an impact on sphincter function and on postoperative small bowel obstruction. Since preoperative radiotherapy is more effective in killing tumor cells at a lower dose than postoperative treatment with or without chemotherapy, and since preoperative treatment is less toxic to normal tissues, preoperative radiotherapy should be used whenever radiotherapy for rectal cancer is considered.

The role of radiation therapy and 5-fluorouracil in colon and rectal cancer

Since the original report improved survival of patients with locally unresectable gastric cancer treated with irradiation and 5-fluorouacil (5-FU) in 1968, there has been extensive investigation of this treatment combination in a variety of gastrointestinal tumors, including colon and rectal cancer. There are now extensive data supporting the use of 5-FU-based chemotherapy with irradiation in the adjuvant treatment of rectal cancer and increasing experience defining its role in negotiant therapy. The value of adjuvant 5-FU-based chemotherapy and irradiation in colonies cancer is controversial, but there may be subsets of patients who benefit from this treatment. Ongoing studies in rectal and colon cancer are evaluating the role of irradiation with various modes of 5-FU adminstration (bolus v short or continuous infusion) as well as its modulation with other agents.

Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114.

The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor. We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and/or levamisole. A total of 1,696 patients were randomized and eligible for treatment with one of four treatment schemes. All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy. Chemotherapy was either 5-FU alone, 5-FU with leucovorin, 5-FU with levamisole, or 5-FU with leucovorin and levamisole. With a median follow-up duration of 48 months, there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone. There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone. Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation. There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer. Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation.

Do We Need Adjuvant Treatment for Rectal Cancer?

Recent studies have shown improved local control of rectal cancer in patients receiving preoperative radiotherapy. The reduction of local recurrence is about 50% both after 25 Gy in 5 days and 40 Gy over 4 weeks. Furthermore an improvement in survival of about 20% has been found. The long-term side-effects are still not fully evaluated. Adjuvant chemotherapy studies in Dukes' C patients have shown a significant increase in survival of between 22 and 39%. An initial study using 17–1A antibodies also in Dukes' C patients has shown a 30% increase in survival rate. However, a drawback of the trials that tested adjuvant treatment 5 to 10 years ago is that they do not reflect the modern surgical technique using perimesorectal clearance and total mesorectal excision. Centres not using adjuvant therapy are now reporting local recurrence rates of 5–10%, which is superior to surgery plus adjuvant therapy in all previously published trials. It is therefore urgent to study the effects of preoperative irradiation in patients operated on with the current surgical technique and carefully balance the side-effects against the benefits. The aim must be to obtain knowledge of how to select a subgroup of patients who definitely needs preoperative radiotherapy, e.g. those undergoing an abdominoperineal excision. Systemic adjuvant therapy is probably increasing survival rate in Dukes' C patients but more studies are necessary, particularly with the 17–1A antibody.

313 Combined radio-chemotherapy as adjuvant treatment of rectal cancer. Rational results and possible future directions

After curative surgery, the prognosis and the patterns of failure of colon and rectal cancers are quite different. The overall 5 year survivals are respectively 55% and 45% with a median time to the diagnosis of recurrence of 18 and 13 months. Liver and peritoneal metastases account for 60% of the recurrences of colon cancer whereas local failures (LF) represent about 10%. On the contrary, LF, liver and lung metastases are equally distributed and account each for 30% of rectal cancer failures. These figures explain why adjuvant treatment should be adapted to the site of the primary. The aims of adjuvant treatment in rectal cancer are both survival and local control, keeping acute and late toxicity to an acceptable level. The postoperative approach permits to select patients on the basis of the pathological findings. None of the four randomised published trials demonstrated that a 50 Gy postoperative dose is able to decrease significantly the LF rate in Dukes B and C patients. Increasing the dose seems inappropriate for multicentric trials and will certainly conduct to an increased acute and late toxicity. Combined postoperative radiotherapy and chemotherapy produced a benefit in some studies at the expense of a high rate of acute toxicity and treatment interruption in about 20–30% of the patients. Moreover, the treatments induced unacceptable high rate of late toxicity after sphincter sparing procedures. On the other hand, moderate dose, in the 25–35 Gy range, preoperative irradiation significantly reduced LF in four large randomised trials totalling more than 3000 patients. This reduction in LF had the same magnitude for all Dukes’ stages (50 to 65%). Furthermore in the latest report of the Stockholm 2 trial, a definite increase in overall survival was observed in patients treated by preoperative irradiation. The comparison of the therapeutic ratio issued from the post or preoperative adjuvant therapeutic approach, definitely favours the preoperative irradiation. The next step is to evaluate in selected patients (T3–T4 resemble stages), the optimal integration of chemotherapy with preoperative irradiation and whether post operative chemotherapy should be added. These two questions are addressed in the current EORTC 22921 protocol. Beside the main goal of this trial, increase in overall survival, the evaluation of sphincter function and quality of life have also been selected as a new end point in this trial.

Radiation therapy quality control in a clinical trial of adjuvant postoperative treatment for rectal cancer

Purpose : Deviations from protocol can detract from the reliability of results obtained in prospective clinical trials. In an effort to decrease the number of deviations in a prospective trial of adjuvant treatment for rectal cancer, we undertook pretreatment review of the irradiated fields. Methods and Materials : Before initiation of radiation therapy, patients' radiation therapy fields were simulated by their radiation oncologists and films were submitted for review. The treating physicians were then informed whether their fields were in compliance with the protocol or whether any modifications were needed. Results : Among the 625 patients participating in this study who received radiation therapy as a component of protocol treatment, 419 (67%) had no radiation therapy deviations, 127 (20%) had minor deviations, and 51 (8%) had major deviations; 28 (4%) could not be evaluated or did not receive protocol treatment because of circumstances eyond the treating radiation oncologist's control. The pretreatment quality control review identified major deviations in the radiation portals for 57 cases; these findings were communicated to the radiation oncologists prior to initiation of treatment, and, on final review, 40 had no deviation or only minor deviation. Conclusion : In the absence of pretreatment quality control review, 40 additional patients would have had major deviations from their radiation therapy protocol. On the basis of these findings, it is estimated that pretreatment quality control reduced the rate of major deviation from 15% to 8%. Pretreatment review of radiation therapy parameters is an effective method of reducing the frequency of major deviations in prospective clinical trials.

Preoperative irradiation - standard adjuvant treatment for rectal cancer

Preoperative irradiation - standard adjuvant treatment for rectal cancer