Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?

BACKGROUND: in the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity. MATERIAL AND METHODS: this review article focuses on phase II-III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. RESULTS: after preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal, or investigator's discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease. CONCLUSION: whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.

Differences between clinical trial participants and patients in a population-based registry: the German Rectal Cancer Study vs. the Rostock Cancer Registry.

PURPOSE: There are few data on whether the samples of randomized phase III studies are representative for cancer patients in general populations. METHODS: We compared patient and disease characteristics of patients with stage II or III rectal cancer from the German Rectal Cancer Study (657 patients, 1995-2002) or the Rostock Cancer Registry (371 patients, 1997-2003). Differences between the Study and the Registry were analyzed for subgroups who received neoadjuvant chemoradiotherapy before resection or primary resection with or without postoperative chemoradiotherapy. RESULTS: Study and Registry patients differed in age (median, 61.7 vs. 65.0 years, P < 0.001) and proportion of women (31.3 percent vs. 38.4 percent, P < 0.004). Significant age and gender differences were seen in primary resection but not in neoadjuvant subgroups. In neoadjuvant and in primary resection subgroups, Study participants were more likely than Registry patients to have tumor location in the lower third of the rectum, a higher rate of R0 resection, a greater number of lymph nodes assessed, and fewer T4 tumors. In the primary resection subgroups, Study participants were more likely to have received postoperative chemoradiotherapy. Multivariate analyses showed no effect of population type (Study vs. Registry) on disease-free or overall survival in neoadjuvant subgroups, but increased risk for Registry patients in primary resection subgroups. CONCLUSIONS: Participants in clinical trials such as the German Rectal Cancer Study are not representative of all cancer patients of a general population. To enable wider extrapolation of results, future studies should include elderly and high-risk patients.

Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: results of study CAO/ARO/AIO-94.

PURPOSE: The impact of the delivery of radiotherapy (RT) on treatment results in rectal cancer patients is unknown. METHODS AND MATERIALS: The data from 788 patients with rectal cancer treated within the German CAO/AIO/ARO-94 phase III trial were analyzed concerning the impact of the delivery of RT (adequate RT: minimal radiation RT dose delivered, 4300 cGy for neoadjuvant RT or 4700 cGy for adjuvant RT; completion of RT in <44 days for neoadjuvant RT or <49 days for adjuvant RT) in different centers on the locoregional recurrence rate (LRR) and disease-free survival (DFS) at 5 years. The LRR, DFS, and delivery of RT were analyzed as endpoints in multivariate analysis. RESULTS: A significant difference was found between the centers and the delivery of RT. The overall delivery of RT was a prognostic factor for the LRR (no RT, 29.6% +/- 7.8%; inadequate RT, 21.2% +/- 5.6%; adequate RT, 6.8% +/- 1.4%; p = 0.0001) and DFS (no RT, 55.1% +/- 9.1%; inadequate RT, 57.4% +/- 6.3%; adequate RT, 69.1% +/- 2.3%; p = 0.02). Postoperatively, delivery of RT was a prognostic factor for LRR on multivariate analysis (together with pathologic stage) but not for DFS (independent parameters, pathologic stage and age). Preoperatively, on multivariate analysis, pathologic stage, but not delivery of RT, was an independent prognostic parameter for LRR and DFS (together with adequate chemotherapy). On multivariate analysis, the treatment center, treatment schedule (neoadjuvant vs. adjuvant RT), and gender were prognostic parameters for adequate RT. CONCLUSION: Delivery of RT should be regarded as a prognostic factor for LRR in rectal cancer and is influenced by the treatment center, treatment schedule, and patient gender.

Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer.

PURPOSE: We assessed the impact of tumor regression grading (TRG) and its value in correlation to established prognostic factors in a cohort of rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: TRG was evaluated on surgical specimens of 385 patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial: 50.4 Gy was delivered, fluorouracil was given in the first and fifth week, and surgery was performed 6 weeks thereafter. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 0 when fibrosis was completely absent. TRG 3 was defined as regression more than 50% with fibrosis outgrowing the tumor mass, TRG 2 was defined as regression less than 50%, and TRG 1 was defined basically as a morphologically unaltered tumor mass. We performed an initially unplanned, hypothesis-generating analysis with respect to the prognostic value of this TRG system. RESULTS: TRG 4, 3, 2, 1, 0 was found in 10.4%, 52.2%, 13.8%, 15.3%, and 8.3% of the resected specimens, respectively. Five-year disease-free survival (DFS) after CRT and curative resection was 86% for TRG 4, 75% for grouped TRG 2 + 3, and 63% for grouped TRG 0 + 1 (P = .006). On multivariate analysis, the pathologic T category and the nodal status after CRT were the most important independent prognostic factors for DFS. CONCLUSION: In this exploratory analysis, complete (TRG 4) and intermediate pathologic response (TRG 2 + 3) suggested improved DFS after preoperative CRT. TRG assessment should be implemented in pathologic evaluation and prospectively validated in further studies.

Preoperative versus postoperative chemoradiotherapy for rectal cancer.

BACKGROUND: Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. METHODS: We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. RESULTS: Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). CONCLUSIONS: Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.

Total mesorectal excision for middle and lower rectal cancer: a single institution experience with 337 consecutive patients.

BACKGROUND AND OBJECTIVES: There have been reports on improved prognosis after TME for middle and lower rectal cancer. No prospective randomized studies have yet been performed. This is a large single institution series evaluating its own results of TME. METHODS: This retrospective study analyses data of 337 patients with middle and lower rectal cancer, treated with either curative or palliative intention between 1990 and 1998. RESULTS: Of all patients, 212 had lower rectal and 125 middle rectal carcinomas. The rate of rectal resections with TME was 96%. A total of 223 patients were treated by anterior rectal resection; 92 patients had to undergo abdomino-perineal resection. Ten patients were operated by a Hartmann resection. Postoperative morbidity was 35% with a leakage rate of 9%. Postoperative mortality was 4%. The rate of local recurrence was 8.6%. The 5-year survival rate after curative resection was 69.3%. The multivariate analysis outlined the tumor stage as independent prognostic factor. CONCLUSIONS: In our experience, TME is feasible with acceptable postoperative morbidity and low mortality. The local recurrence rate can be decreased to lower than 10%. The almost 70% 5-year survival rate indicates a clear benefit for the patients. These findings recommend TME as standard procedure for middle and lower rectal cancer.

Cultured human intestinal mast cells express functional IL-3 receptors and respond to IL-3 by enhancing growth and IgE receptor-dependent mediator release.

Mast cells are immunoregulatory effector cells capable of releasing different mediators and cytokines implicated in inflammatory tissue processes. Previous studies suggested that IL-3 regulates growth and function of murine mast cells and human mast cell precursors, but does not affect mature human mast cells. In the present study, we found expression of IL-3 receptors (IL-3R) in freshly isolated human intestinal mast cells by reverse transcriptase (RT)-PCR and in mast cells cultured with stem cell factor (SCF) using RT-PCR and flow cytometry. IL-3R expression was enhanced when the culture medium was supplemented with IL-4 in addition to SCF. In the presence of SCF, IL-3 significantly enhanced mast cell growth in a dose-dependent fashion (179+/-51% of control, p

Late embolization of an unfractured port catheter into the heart: report of a case.

This case report describes the embolization of an unfractured venous port catheter, 18 months after its implantation into the heart. To our knowledge, this complication has never been documented before. A 33-year-old woman underwent placement of a totally implantable venous access port for chemotherapy to treat advanced gastric cancer. The catheter tip was repositioned by a transfemoral sling after dislocation into the right jugular vein 2 months before embolization. After embolization into the heart, the catheter was successfully removed by a percutaneous femoral vein approach using a dormia basket. As totally implantable venous access ports become used more frequently, problems associated with their extended use will be encountered.

Long-term follow-up after surgery for advanced colorectal carcinoma involving the urogenital tract.

OBJECTIVES: Advanced colorectal carcinomas frequently involve the urogenital tract. In the following we evaluate the long-term survival after radical surgical extirpation and the prognostic significance of involvement of specific urological organs. METHODS: Between January 1985 and April 1996, 101 patients underwent interdisciplinary tumour extirpation of an advanced colorectal carcinoma involving the urogenital tract. RESULTS: Of 68 men and 33 women, 40 presented with primary and 61 with recurrent carcinoma. As far as urological organs are concerned, the ureter was removed in 82 patients, followed by bladder (n=52), seminal vesicles (n=25), prostate (n=22), kidney, testicle and penis. Histology revealed cancerous infiltration in 52% of the organs resected. A negative surgical margin was obtained in 54% of the patients, 43% showed positive lymph nodes. There was a 41% peri-operative complication with a mortality rate of 5%. Five year overall survival was 24.4% (median 23 months) with prognostic factors being type of tumour (primary versus recurrent), surgical margin and lymph node status. Stratification according to these factors showed removal of bladder and prostate to be a favourable and ureteral removal to be an omnious factor. CONCLUSION: We conclude that multivisceral extirpation of advanced colorectal carcinomas involving the urogenital tract should be recommended in selected patients. Our data showed it to be a safe surgical procedure, which is associated with favourable long-term outcome in non-metastatic patients in whom complete surgical resection could be achieved.