The Role of Radiation Therapy With 5-Fluorouracil in Anal Cancer

The most commonly used initial treatment of primary epidermoid cancer of the anal canal is radiation combined with concurrent 5-fluorouracil (5-FU) and mitomycin. Randomized trials have shown that these drugs, when combined with split-course or moderate-dose radiation, are superior to the same doses of radiation delivered without drugs. In another trial, the addition of mitomycin to 5-FU resulted in a better outcome thand when 5-FU alone was combined with radiation. Studies are in progress to evaluate treatment with radiation plus 5-FU and cisplatin; this combination has also produced high rates of tumor response in preliminary studies. The optimal schedules and doses of 5-FU to combine with radiation are not known-common usage favors 96- or 120-hour infustions of 5-FU at a dose of 750 to 1,000 mg/m(2)/24 hours, generally administered as one or two courses concurrently with conventional once-daily fractionated radiation. It is unclear whether 5-FU in these combinations is acting as a cytotoxic agent, a radiosensitizer, or both. Despite these uncertainties, empiric clinical studies have led to the development of effective treatment regimens that allow conservation of anorectal function in the majority of patients with anal cancer.     

Radiation Therapy and 5-Fluorouracil in Pancreatic Cancer

Combination chemotherapy has not been shown to be superior to single-agent 5-fluorouracil (5-FU) in the treatment of metastatic pancreatic cancer. Initial studies from Duke University suggest a role for radiation in the management of locally unresectable presentations of this disease. In vivo studies showed that 5-FU could act as a radiation sensitizer. This concept was subsequently tested in a randomized trial by the Gastrointestinal Tumor Study Group (GITSG). In their studies, combined modality therapy using radiation and 5-FU-based chemotherapy prolonged survival in both adjuvant and locally unresectable settings and remains as a standard therapeutic option for appropriately selected patients. Variations on this approach designed to potentiate 5-FU efficacy are under active clinical investigation. This review discussed past and current studies involving 5-FU as well as other agents currently of interest.     

The Selective Use of Radiation Therapy in Rectal Cancer Patients

Purpose of Review

Colorectal cancer has a high global incidence, and standard treatment employs a multimodality approach. In addition to cure, minimizing treatment-related toxicity and improving the therapeutic ratio is a common goal. The following article addresses the potential of omitting radiotherapy in select rectal cancer patients.

Recent Findings

Omission of radiotherapy in rectal cancer is analyzed in the context of historical findings, as well as more recent data describing risk stratification of stage II–III disease, surgical optimization, imaging limitations, improvement in systemic chemotherapeutic agents, and contemporary studies evaluating selective omission of radiotherapy.

Summary

A subset of rectal cancer patients exists that may be considered low to intermediate risk for locoregional recurrence. With appropriate staging, surgical technique, and possibly improved systemic therapy, it may be feasible to selectively omit radiotherapy in these patients. Current imaging limitations as well as evidence of increased locoregional recurrence following radiotherapy omission lend us to continue supporting the standard treatment of approach of neoadjuvant chemoradiation therapy followed by surgical resection until additional improvements and prospective evidence can support otherwise.

     

Combination of 5-Fluorouracil and Radiation in Esophageal Cancer

A review of the trends in the clinical practice of esophageal cancer treatment is presented. The preponderance of evidence indicates that concomitant chemotherapy and radiation is superior to either modality above. Chemotherapy usually, but not invariably, consists of 5-fluorouracil (5-FU) and cisplatin; radiotherapy is usually 50 Gy. Attempts to escalate to higher dose by external-beam boost or brachytherapy is still experimental. Combination treatment with surgery is also successful, but the inclusion of esophagectomy in the treatment is not universally accepted and is unlikely to be tested. A suggestion to base treatment selection on response is proposed.     

Comparative Antitumor Activity of 5-Fluorouracil and 5'-Deoxy-5-fluorouridine in Combination with Radiation Therapy in Mice Bearing Colon 26 Adcnocarcinoma

The present study compared the antitumor activities of chemotherapy with 5-fluorouracil (5-FU) and with its prodrug 5'-deoxy-5-fluorouridine (5'-DFUR) in combination with radiotherapy on a solid colon 26 adenocarcinoma in the mouse. A single administration of 5'-DFUR immediately after local irradiation on day 10 after tumor inoculation produced more than additive antitumor effects, while only an additive effect was observed in the combined treatment with 5-FU and radiation. This over-additive effect of 5'-DFUR was more obvious in a fractionated-dose treatment schedule, where the same combined modality treatment was given three times on days 6, 10 and 14 after inoculation of the tumor cells. 5'-DFUR enhanced the radiation effects on the tumor in terms of the delay in tumor growth as well as the increase in the survival time. 5-FU produced only a marginal additive antitumor effect. Furthermore, radiation damage to normal tissues (skin damage by local irradiation and bone marrow and spleen damage by whole-body irradiation) was not enhanced by 5'-DFUR, though radiation damage to the thymus was additive. On the other hand, 5-FU produced toxic effects that were additive for all normal tissues tested. Thus, at doses that were the most effective against tumors, relative therapeutic gain factors (the ratio of the effect on tumors to that on the bone marrow) of 5'-DFUR and 5-FU were 1.24 and 0.49, respectively. These results suggest that 5'-DFUR will have a greater potential than 5-FU in combined modality treatment of cancer patients.     

Combination of Irinotecan and 5-Fluorouracil with Radiation in Locally Advanced Rectal Adenocarcinoma

Objective  

To evaluate toxicity and efficacy of addition of weekly irinotecan to a regimen of chemoradiotherapy of 5-fluorouracil with concurrent pelvic radiation in patients with locally advanced rectal cancer.     

Adjuvant External Beam and Intraoperative Radiation Therapy in Rectal Cancer

The use of radical surgery has maximized local control, sphincter preservation, and overall survival in patients with rectal cancer. Despite the advances in surgical techniques, local recurrence still remains a problem. Following potentially curative surgery, the incidence of local recurrence inpatients with stages B2,C disease varies from 15% to 65%. There are four major approaches in which radiation therapy (RT) has been used in the adjuvant treatment of rectal cancer. These include postoperative RT ± chemotherapy, preoperative RT ± chemotherapy, both pre-and postoperative RT (sandwich technique), and intraoperative RT in conjunction with preoperative external beam RT. In patients with resectable rectal cancer, adjuvant RT has been shown to decrease the incidence of local recurrence and, in some series, may influence survival rates. In patients with locally advanced, unresectable, or recurrent rectal cancer, the use of preoperative radiation therapy, attempted surgical resection, and intraoperative RT further enhances local control.     

A Systematic Overview of Radiation Therapy Effects in Rectal Cancer

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for rectal cancer is based on data from 42 randomized trials and 3 meta-analyses. Moreover, data from 36 prospective studies, 7 retrospective studies and 17 other articles were used. A total of 131 scientific articles are included, involving 25 351 patients. The results were compared with those of a similar overview from 1996 including 15 042 patients. The conclusions reached can be summarized thus: The results after rectal cancer surgery have improved during the past decade. It is likely that local failure rates after 5 years of follow-up at hospitals adopting the TME-concept (TME=total mesorectal excision) have decreased from about 28% to 10-15%.Preoperative radiotherapy at biological effective doses above 30 Gy decreases the relative risk of a local failure by more than half (50-70%). Postoperative radiotherapy decreases the risk by 30-40% at doses that generally are higher than those used preoperatively.There is strong evidence that preoperative radiotherapy is more effective than postoperative.There is moderate evidence that preoperative radiotherapy significantly decreases the local failure rate (from 8% to 2% after 2 years) also with TME.There is strong evidence that preoperative radiotherapy improves survival (by about 10%).There is no evidence that postoperative radiotherapy improves survival.There is some indication that survival is prolonged when postoperative radiotherapy is combined with concomitant chemotherapy.Preoperative radiotherapy at adequate doses can be given with low acute toxicity. Higher, and unacceptable acute toxicity has been seen in some preoperative radiotherapy trials using suboptimal techniques. Postoperative radiotherapy can also be given with acceptable acute toxicity.The long-term consequences of radiotherapy appear to be limited with adequate radiation techniques, although they have been less extensively studied. Longer follow-up periods are needed before firm conclusions can be drawn.Peroperative radiotherapy, preferably preoperative since it is more effective, is routinely recommended for most patients with rectal cancer since it can substantially decrease the risk of a local failure and increases survival.In a primarily non-resectable tumour, preoperative radiotherapy can cause tumour regression allowing subsequent radical surgery. This therapy is routinely indicated. Whether radiochemotherapy is more efficient than radiotherapy alone is not clear, since the results of four small randomized trials are partly conflicting.Preoperative radiotherapy, frequently combined with chemotherapy, has been used to increase the chances of sphincter-preserving surgery in low-lying tumours. The literature is inconclusive with respect to how frequently this occurs.Radiotherapy frequently produces symptom relief in patients with rectal cancer not amendable to surgery.     

A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

BackgroundStandard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.Patients and MethodsPatients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m²/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.ResultsNine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m² dose level. There was no clear evidence of suppression of nuclear factor-κB target gene expression in biopsy samples.ConclusionThe MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.     

Response of Primary Colon Cancer Cells in Hybrid Spheroids to 5-Fluorouracil

We have measured the clonogenic survival of cells isolated directly from colon cancer surgical specimens and treated with 5-fluorouracil (5-FU). Enzymatically dissssociated cells were incorporated into hybrid spheroids, consisting predominantly of nonproliferating HeLa feeder cells. Aliquots were exposed for 1.5 hr to a range of concentrations of 5-FU. From the decrease in clonogenic survival, as deduced from the frequency of colony formers among hybrid spheroids after chemical treatment, we were able to construct survival curves in 50% of the surgical specimens tested. A striking revelation was the presence of a resistant plateau in the survival curves, reminiscent of the solid tumor response to treatment with 5-FU. This resistance was absent in monolayer cultures. Evidence is presented that this resistance is due to the absence of, or delay in, cell cycle progression of cells residing in hybrid spheroids.     

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.

     

Evaluating the Cost-Effectiveness of Hydrogel Rectal Spacer in Prostate Cancer Radiation Therapy

Purpose

A hydrogel rectal spacer (HRS) is a medical device that is approved by the U.S. Food and Drug Administration to increase the separation between the prostate and rectum. We conducted a cost-effectiveness analysis of HRS use for reduction in radiation therapy (RT) toxicities in patients with prostate cancer (PC) undergoing external beam RT (EBRT).