Covered self-expandable metal stents in pancreatic malignancy regardless of resectability: a new concept validated by a decision analysis.

BACKGROUND AND STUDY AIMS: The current treatment model for the management of malignant biliary obstruction is to place a plastic stent for unstaged pancreatic cancer. In patients with unresectable disease but a life expectancy of more than 6 months, self-expandable metal stents (SEMS) are favored because of their more prolonged patency. We analyzed the efficacy and cost-effectiveness of covered SEMS (CSEMS) in patients with pancreatic cancer and distal biliary obstruction without regard to surgical resectability. PATIENTS AND METHODS: Between March 2001 and March 2005, 101 consecutive patients with obstructive jaundice secondary to pancreatic cancer underwent placement of a CSEMS. Patients with resectable tumor were offered pancreaticoduodenectomy. A model was developed to compare the costs of CSEMS and polyethylene and DoubleLayer stents. RESULTS: A total of 21 patients underwent staging laparoscopy, of whom 16 had a resection (76%). The 85 patients who did not have a resection had a mean survival of 5.9 months (range 1-25 months) and a mean CSEMS patency duration of 5.5 months (range 1-16 months). Life-table analysis demonstrated CSEMS patency rates of 97% at 3 months, 85% at 6 months, and 68% at 12 months. In a cost model that accounted for polyethylene and DoubleLayer stent malfunction and surgical resections, initial CSEMS placement (3177 euros per patient) was a less costly intervention than either DoubleLayer stent placement (3224 euros per patient) or polyethylene stent placement with revision (3570 euros per patient). CONCLUSIONS: Covered SEMS are an effective treatment for distal biliary obstructions caused by pancreatic carcinoma. Their prolonged patency and removability makes them an attractive option for biliary decompression, regardless of resectability. The strategy of initial covered SEMS placement might be the most cost-effective strategy in these patients.

Potentiation of murine MCa-4 carcinoma radioresponse by 9-amino-20(S)-camptothecin.

9-Amino-20(S)-camptothecin (9-AC) has demonstrated efficacy against several human cancer xenografts, including cancers of the colon, breast, lung, ovary, and stomach and malignant melanoma, and is currently undergoing Phase I clinical trials. In vitro data indicate that the addition of topoisomerase I inhibitors shortly after irradiation causes conversion of single-strand breaks to double-strand breaks, resulting in synergistic lethality to cultured log-phase or quiescent malignant cells. In our study, the efficacy of 9-AC as a potential radiosensitizing agent in vivo was assessed in C3Hf/Kam female mice bearing 7.6-8-mm MCa-4 mammary tumors implanted i.m. into the right posterior thigh. In one series of experiments to determine the dose dependence of 9-AC, mice were injected twice a week with either 0.5, 1.0, or 2.0 mg/kg 9-AC (total doses of 2, 4, and 8 mg/kg, respectively) either alone or 1 h before irradiation. In a second series of experiments, the schedule dependence of 9-AC was determined by giving a constant total dose of 4 mg/kg 9-AC once (2 mg/kg), twice (1 mg/kg every third day), or four (0.5 mg/kg every other day) times per week for 2 weeks, either alone or combined with radiation. The same radiation regimen was used in all experiments: 2-Gy fractions daily for 14 consecutive days, giving a total dose of 28 Gy to the tumor-bearing leg only. Tumor response was assessed by regrowth delay and dose modification factors (DMFs) obtained by comparing regrowth delay in the groups given 9-AC alone with those given the same dose of 9-AC and radiation. 9-AC significantly delayed tumor growth when combined with radiation, and this effect was dependent on drug dose; DMFs of 2.4 [95% confidence interval (CI), 2.0-3.1], 3.7 (95% CI, 3.1-4.6), and 3.3 (95% CI, 2.7-4.1) were obtained for groups treated with total drug doses of 2.0, 4.0, and 8.0 mg/kg 9-AC, respectively. In addition, the same total dose of 4 mg/kg 9-AC was more effective when given either twice or four times a week compared with once a week, giving DMFs of 2.8 (95% CI, 2.2-3.9), 2.6 (95% CI, 2.0-3.6), and 1.7 (95% CI, 1.3-2.4), respectively. The effect of 9-AC and radiation on normal tissue toxicity was assessed in two normal tissues, jejunum and skin, in separate groups of mice. Jejunal crypt cell survival was decreased in those mice given single doses of 9-AC ranging from 0.5-4.0 mg/kg and 12.5 Gy of total body radiation compared with those given 12.5 Gy of total body irradiation alone. The same regimen of drug and radiation did not modify acute skin reactions. These results suggest that 9-AC is an effective in vivo radiosensitizing agent when given in divided doses with fractionated irradiation. In addition, the gastrointestinal tract but not skin could be a critical target tissue for the use of 9-AC combined with radiation.

A pilot study of protracted venous infusion of 5-fluorouracil and concomitant radiation therapy.

A method to potentially increase the effectiveness of combination 5-fluorouracil (5-FU) and radiation therapy (XRT) using protracted (more than 30 days) venous infusion (PVI) of 5-FU with conventionally fractionated XRT (180 to 200 cGy per day) (100 cGy = 100 rad) is described. Forty-one patients were treated with this combination with acceptable acute toxicity. In 95% of patients, the toxicity was mild or moderate and symptom control was achieved with medications or a short treatment interruption. In two patients (5%), severe gastrointestinal side effects resulted in cessation of all therapy. This method of administration of 5-FU is feasible, and we have demonstrated that it can be safely used with a course of conventionally fractionated, high-dose (approximately to 6,500 cGy) radiation therapy.

Potentially curative surgery of colon cancer: patterns of failure and survival.

In an effort to determine the patterns of failure and survival of colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. For the entire group, the 5-year crude survival rate was 68% and the actuarial rate was 80%. Survival decreased with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Although survival varied with the tumor site, none of the differences was statistically significant. Other variables, including the grade of adenocarcinoma, size, and the type of surgery had a significant impact on survival. Patterns of failure, expressed as the actuarial incidence of first diagnosed failure at 5 years, were examined by stage and site. There was a trend toward increased failure with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Abdominal failure, either as the only site or as a component of failure, was the most common type of failure. When compared by site, patients with cecal carcinoma had a significantly lower incidence of local and distant failure than patients with disease in other selected sites. No differences in patterns of failure were seen in patients with carcinomas in the mobile sections of the colon compared with those who had disease arising in the nonmobile sections of the colon. These data may be useful in identifying those patients who might benefit most from adjuvant therapy.

Potentially curative surgery of colon cancer: the influence of blood vessel invasion.

A number of series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, there are little data available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. Patients whose tumors had BVI experienced a significant decrease in the 5-year actuarial survival rate. BVI had little impact on the patterns of failure in stage B2 disease, but a significant increase in total failure and local failure (as a component of failure) occurred in stage C2. However, when examined by proportional hazards analysis, BVI was found not to be an independent prognostic variable. For patients with stage C2 tumors, which are also BVI+, radiation therapy to the tumor bed might play a contributory role in overall management.

Evaluation of pre- and postoperative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

Thirty-five consecutive patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative and three or four postoperative chemotherapy courses consisting of etoposide, fluorouracil, and cisplatin (EFP) to evaluate the rate of curative resection, clinical and pathologic response, toxic effects, and survival. One hundred thirty-seven courses with a median number of five courses (range, one to six) were administered. Preoperative EFP resulted in 17 (49%) major responses, including six patients who did not have carcinoma cells in the repeat endoscopic biopsy specimens and cytologic brushings. Among 32 patients who had surgery, 25 (78%) had curative resection, one patient had a complete pathologic response, and one had microscopic carcinoma in the resected specimen. Six patients had microscopic carcinoma at the resection margins and received postoperative radiotherapy. At a median follow-up of 20 months, the projected survival of 35 patients is 23 months (range, 6 to 33+). Fifteen patients died of their carcinomas, and 15 patients were alive (median follow-up, 20+ months; range, 15+ to 33+ months) with no evidence of relapse. There were no deaths related to chemotherapy, surgery, or radiotherapy. EFP-induced toxic reactions were moderate. Our data suggest that multiple courses of EFP are feasible. Future strategies for this disease should consider prolonged chemotherapy with regimens that result frequently in pathologic complete responses.

Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.

PURPOSE: The effects of preoperative versus postoperative fluorouracil (5-FU)-based chemotherapy and irradiation on treatment toxicity, duration of treatment, tumor recurrence, and survival were compared in patients who underwent potentially curative therapy for adenocarcinoma of the pancreatic head during a 5-year period. METHODS: From July 1990 to July 1995, 142 patients with localized adenocarcinoma of the pancreatic head deemed resectable on the basis of radiographic images were treated with curative intent using a multimodality approach involving either preoperative or postoperative chemoradiation. Patients with biopsy confirmation of adenocarcinoma and a low-density mass in the pancreatic head identified by computed tomography (CT) received preoperative chemoradiation. Patients without a mass on CT or in whom the preoperative biopsy was negative underwent pancreaticoduodenectomy with planned postoperative chemoradiation. Protocol-based preoperative chemoradiation consisted of external-beam irradiation at a dose of 50.4 Gy (standard fractionation; 1.8 Gy/d, 5 d/wk) or 30 Gy (rapid fractionation; 3 Gy/d, 5 d/wk) combined with continuous infusion 5-FU (300 mg/m2/d, 5 d/wk). Postoperative chemoradiation combined 50.4 Gy of external-beam irradiation (standard fractionation) with continuous-infusion 5-FU. RESULTS: No patient who received preoperative chemoradiation experienced a delay in surgery because of chemoradiation toxicity, but six of 25 eligible patients (24%) did not receive postoperative chemoradiation because of delayed recovery after pancreaticoduodenectomy. No significant differences in toxicities from chemoradiation were observed between groups. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly (P < .01) shorter duration of treatment (median, 62.5 days) compared with patients who received postoperative chemoradiation (median, 98.5 days) or standard-fractionation preoperative chemoradiation (median, 91.0 days). At a median followup of 19 months, no significant differences in survival were observed between treatment groups. No patient who received preoperative chemoradiation and pancreaticoduodenectomy experienced a local recurrence; peritoneal (regional) recurrence occurred in 10% of these patients. Local or regional recurrence occurred in 21% of patients who received pancreaticoduodenectomy and postoperative chemoradiation. CONCLUSION: Delivery of preoperative and postoperative chemoradiation in patients who underwent potentially curative pancreaticoduodenectomy for adenocarcinoma of the pancreatic head resulted in similar treatment toxicity, patterns of tumor recurrence, and survival. Rapid-fractionation preoperative chemoradiation ensured the delivery of all components of therapy to all eligible patients with a significantly shorter duration of treatment than with standard-fractionation chemoradiation given either before or after pancreaticoduodenectomy. Prolonged recovery after pancreaticoduodenectomy prevents the delivery of postoperative adjuvant chemoradiation in up to one fourth of eligible patients.

Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer.

This study was conducted to investigate the value of p53 immunohistochemical staining of pretreatment biopsy specimens in predicting the response of rectal cancer to chemoradiation. The study group comprised 42 patients with high-risk rectal cancer treated between July 1990 and July 1995 with a preoperative chemoradiation regimen of 45 Gy of external-beam irradiation and continuous-infusion 5-fluorouracil followed by surgical resection. p53 immunohistochemical staining was performed on pretreatment biopsy specimens. p53 immunohistochemical staining pattern and standard clinical and pathological parameters were correlated with extent of residual cancer in the surgical specimen. Twenty tumors were positive for p53 on immunohistochemical staining, 19 were negative, and 3 were focally positive. Thirteen patients experienced a complete response to chemoradiation. Aberrant p53 protein accumulation, as measured by immunohistochemical staining, correlated inversely with a complete pathological response to chemoradiation (P = 0.005; correlation coefficient = -0.43) and directly with an increased likelihood of residual cancer in the lymph nodes of surgical specimens (P = 0.02; correlation coefficient = 0.39). p53 immunohistochemical staining of pretreatment biopsy specimens correlates with the extent of residual disease after chemoradiation in patients with high-risk rectal cancer.

Prolonged chemotherapy for localised squamous carcinoma of the oesophagus.

We evaluated the feasibility of six courses of chemotherapy in 34 consecutive patients with localised squamous cell carcinoma of the oesophagus. All 32 evaluable patients first received at least two courses of chemotherapy. There were 18 patients with resectable carcinomas who underwent surgery and 14 patients with unresectable carcinomas who received definitive chemoradiotherapy. After two courses of 5-fluorouracil and cisplatin 21 (66%) of 32 patients had either a complete or major response. A median of five courses (range, 1-6 courses) was administered. 17 out of 18 (94%) patients with resectable carcinoma had a 'curative' resection (negative proximal, distal, and radial margins by histopathology in an en-block resection specimen) and 2 patients had a complete pathological response. The median survival duration of all patients was 28 months (range, 2-46+ months). The median survival duration of 14 patients with unresectable carcinoma was 23 months (range, 8-36+ months), and the median survival duration of 18 patients with resectable carcinoma has not been reached at a median follow-up of 24+ months (range, 10+ to 46+ months). No deaths occurred because of chemotherapy or chemoradiation therapy. Our data suggest that prolonged chemotherapy is feasible in patients with locoregional squamous carcinoma of the oesophagus. An ongoing controlled trial will determine the contribution of chemotherapy to patients' survival.

Radiation therapy for pancreatic cancer: eleven year experience at the JCRT.

Radiation therapy (XRT) for 41 patients with unresectable pancreatic cancer resulted in a median survival of 7.0 months. There was no difference in median survival for patients receiving external beam alone (3500 to 5600 cGy) (n = 28), intraoperative (IORT) boost plus external beam (5040 to 6750 cGy) (n = 9), or a gold-198 implant +/- external beam radiation (n = 4). A pilot study using orthovoltage IORT boost indicates no acute toxicity with doses of 1250 to 1750 cGy. Serious late damage has not been observed in any patients followed to 2 years. Local recurrence in patients treated post-operatively after "radical" surgery occurred in one of 10 (10%). This adjuvant treatment is safe and appears to improve local control rates compared to historical data, but survival is still poor. The median survival for the post-operative group is 10 months; three patients are alive without disease 8 months to 8.3 years after treatment.

Radiation enhancement by 9-aminocamptothecin: the effect of fractionation and timing of administration.

PURPOSE: The camptothecins (CPTs) are potent radiation sensitizers in vivo but the optimal schedule of administration is unknown. In this article, the effects of irradiation combined with 9-aminocamptothecin (9AC) on a mouse mammary cancer and the gastrointestinal tract were compared for single and fractionated treatment. We also examined the circadian dependency for cytotoxicity, radiation sensitization, and acute toxicity after single doses of 9AC given at six different times over 24 h. MATERIALS AND METHODS: 9AC was administered intramuscularly to C3Hf/Kam mice with and without an 8 mm mouse mammary carcinoma (MCa-4). Acute toxicity was assessed by examination of body weight loss, peripheral blood counts, clinical assessment of diarrhea, and survival. Radiation sensitization was assessed using the tumor regrowth delay model. RESULTS: Regrowth delay of MCa-4 tumor after a single treatment of 15 Gy is comparable to 28 Gy given in 14 fractions (absolute regrowth delays of 7.1 days and 6.6 days, respectively). With 9AC alone, comparable tumor regrowth was obtained with a total dose of 4 mg/kg given intramuscularly repeated twice weekly (1 mg/kg doses X 4), or as a single injection of 4 mg/kg (2.9 days and 3.8 days, respectively). 9-AC and irradiation together in single doses of 15 Gy and 4 mg/kg resulted in little radiation sensitization compared to the repeated 9AC schedule combined with fractionated irradiation [Dose Modifying Factors (DMF) of 1.12 vs. 2.8, respectively]. Acute normal tissue toxicity after single or fractionated 9AC treatment was assessed at six times over a 24-h period (6 A.M., 10 A.M., 2 P.M., 6 P.M., 10 P.M., and 2 A.M.) and was highest at 2 A.M. after either single or multiple doses. A single dose of 9AC administered with single fraction irradiation could be escalated by 33% when given at the best-tolerated time. CONCLUSION: The frequency and timing of CPT administration with irradiation are important factors to be considered in the design of clinical protocols. CPTs are S-phase inhibitors that are better tolerated by the mouse when given during the rest phase when intestinal mucosal proliferation is relatively low. A modest increase in CPT dosage was possible by choosing the best tolerated time to administer the radiation sensitizer. This concept could potentially be evaluated in clinical trials with this class of agents.

Radiosensitization of cultured human colon adenocarcinoma cells by 5-fluorouracil: effects on cell survival, DNA repair, and cell recovery.

Although 5-fluorouracil (5-FU) is commonly used in conjunction with radiotherapy to treat gastrointestinal malignancies, the molecular mechanisms underlying the clinically observed therapeutic advantage of this combination of agents have not been clearly established. The present in vitro studies addressed the possibility that the radiosensitization of log-phase cultured human colon adenocarcinoma cells by postirradiation administration of 5-FU was accompanied by an interference either with the rejoining of radiation-induced DNA double-strand breaks (DSB's) or with recovery from potentially lethal damage (PLD). Significantly more killing was observed in cells exposed to gamma-rays (1-6 Gy) and then treated with 5-FU (100 micrograms/mL; 0.77 mM) for 1 hr at 37 degrees C than in cells given gamma-rays but not 5-FU; essentially, the survival curve shoulder was removed. DSB rejoining measured using the neutral filter elution method after exposure to 25 Gy was identical regardless of whether 5-FU (100 micrograms/mL) was present during the repair period; thus, radiosensitization by this high-concentration postirradiation 5-FU protocol does not appear to be a result of interference with the overall rate of ligation of gamma-ray-induced DSB's. The effect of 5-FU on the ability of log-phase cells to recover from that sector of PLD that can be expressed by postirradiation incubation with hypertonic (0.5 M) salt solution (HSS) was also examined. When irradiated cells were treated with 5-FU during their recovery period and then incubated with HSS, no clonogenic cells survived. Therefore, although it was not possible to assess the actual kinetics of recovery from gamma-ray-induced PLD in 5-FU-treated cells, the drug clearly altered the metabolism or structure of the cells such that their susceptibility to HSS was markedly enhanced.

Lymphatic vessel invasion is an independent prognostic factor for survival in colorectal cancer.

To assess whether lymphatic vessel invasion (LVI) is an independent prognostic factor in colorectal cancer, we retrospectively reviewed the records of 462 patients who underwent potentially curative surgery for carcinoma of the colon and rectosigmoid/rectum (rs/rectum) at the New England Deaconess Hospital from 1965-1978. Sixty-one patients were identified as having tumors with lymphatic vessel invasion (LVI+), and they were compared with the remaining group of 401 patients who had tumors without lymphatic vessel invasion (LVI-). The incidence of lymphatic vessel invasion was significantly increased in tumors with blood vessel invasion (24% vs. 5%, p = 0.000001). Patients with LVI+ tumors also had a significantly increased incidence of positive nodes (59% vs. 25%, p = 0.0004), the average number of positive nodes (4.8 vs. 2.2, p = 0.0003), and a lower 5-year survival rate (colon: 57% vs. 84%, p = 0.0001; rs/rectum: 38% vs. 71%, p = 0.004). There was a significant (p less than or equal to 0.05) increase in local (16% vs. 7%), abdominal (33% vs. 9%), and distant (13% vs. 4%) failure as a component of component of failure in patients with LVI+ colon cancer and a significant increase in abdominal (33% vs. 11%) and distant (13% vs. 8%) failure as a component of failure in patients with LVI+ rectosigmoid/rectal cancer. Proportional hazards analysis demonstrated that lymphatic vessel invasion was an independent prognostic factor for survival.

Professional liability in radiotherapy: experience of the Fletcher Society.

We have conducted a study to ascertain the pattern and background of lawsuits related to the practice of radiotherapy among physician-members of the Gilbert H. Fletcher Society. Eighty-four percent of the members of the society replied to the questionnaire; one-third have sustained a lawsuit with an actuarial probability of 30% at 10 years, 50% at 20 years, and 65% at 30 years. Lawsuits occurred across the spectrum of practice type, location, experience, disease site, and technique. Two-thirds of the suits were dropped or successfully defended. Regardless of the outcome, the experience of being sued was found to have influenced 33% of those sued to practice more conservatively. Recommendations of the membership directed towards minimizing the risk of being sued, while maintaining an aggressive treatment philosophy, are presented. Based on this study, we believe that formal medicolegal education should be included in the curriculum of radiotherapy residents' training program.

5-Fluorouracil-radiation interactions in human colon adenocarcinoma cells.

PURPOSE: To determine the effect of cellular proliferation and cell cycle stage on the ability of postirradiation 5-fluorouracil (5-FU) to radiosensitize cultured human colon adenocarcinoma Clone A cells. METHODS AND MATERIALS: Cell survival curves were generated for irradiated: (a) log- and plateau-phase Clone A cells; and (b) Clone A cells separated by centrifugal elutriation into the various phases of the cell cycle; with and without postirradiation treatment with 100 micrograms/ml 5-FU. RESULTS: Postirradiation treatment with 5-FU sensitized proliferating cells to a greater degree than it sensitized cells growing in plateau phase. The beta component of cell kill in log-phase cells was increased by a factor of 1.5 with a sensitizer enhancement ratio of 1.21 at the 0.01 survival level. Plateau-phase cells showed less radiosensitization (sensitizer enhancement ratio of 1.13 at the 0.01 survival level); however, there was a mild increase in both alpha and beta kill in plateau-phase cells. Elutriated G1 cells were the most radiosensitive, independent of treatment with 5-FU. The phase of the cell cycle had little effect on the ability of fluorouracil to radiosensitize Clone A cells. CONCLUSION: Proliferating cells are more susceptible to radiosensitization with 5-FU than plateau-phase cells are, but this effect appears to be independent of the phase of the cell cycle.

Postoperative adjuvant radiotherapy for adenocarcinoma of the rectum and rectosigmoid.

One hundred five patients treated with potentially curative surgery and adjuvant postoperative radiotherapy for adenocarcinoma of the rectum and rectosigmoid from 1973 through 1981 were reviewed. Radiation therapy was given with 18-25 MeV X rays in doses of 40-50 Gy in 5 weeks (midline dose) using AP-PA fields in 97 patients. A boost of 6 to 10 Gy was directed to the area of maximum risk by anterior-posterior or perineal fields in 71 patients. Local failure occurred in 15 patients and was documented pathologically in 8 patients, or clinically or radiologically in 7 patients. The local recurrences according to the Modified Astler-Coller staging criteria were: B1: 0% (0/3); B2: 4% (1/24); B3: 31% (4/13); C1: 8% (1/12); C2: 18% (8/45); C3: 20% (1/5). Local failure after adjuvant radiotherapy versus surgery alone was compared. The comparison of local failure of combined treatment versus surgery alone, from our institution, is as follows: B2-4% vs 13%, B3-31% vs 26%, C2-18% vs 30%, and C3-20% vs 49%. Sixty-one patients (58.1%) have been followed for 5 years, with a median of 73 months and a minimum of 24 months. The actuarial 5-year survival (disease-free) for the entire group is 55% and is not statistically different for the groups with negative or positive nodes. Fourteen patients (13%) required surgery for small bowel complications; four others (4%) had symptomatic small bowel obstruction treated with conservative therapy only. Small bowel obstruction occurred in 4 of 16 (25%) treated with radiation fields above L5, whereas those treated below L5 had an 11% incidence. Postoperative adjuvant radiotherapy can increase local tumor control compared to surgery alone. The small bowel complication rate in this series most likely reflects AP-PA treatment technique and can be decreased by the use of multiple fields with maximum shielding of the small intestine.

Extramammary Paget's disease of the perineal skin: role of radiotherapy.

We have reviewed our treatment results in 65 patients with extramammary Paget's disease arising in the vulva, perianal area, or scrotum. In 30 patients with primary disease, positive surgical margins were found in 53%, and there was an actuarial local recurrence rate of 40% within 5 years. The median follow-up period for primary extramammary Paget's disease patients treated with surgery alone was 198 months, and none died of this disease. Three patients treated with definitive radiotherapy were without recurrence at 12, 21, and 60 months after 56 Gy of supervoltage x-rays. In 22 patients with extramammary Paget's disease and associated adnexal or rectal adenocarcinoma, nine treated with surgery alone had a 75% local control rate. Three patients treated with surgery and adjuvant radiotherapy all had local control; of two patients treated with radiotherapy alone, one had persistent adenocarcinoma. The median survival for all patients with extramammary Paget's disease and adenocarcinoma was 22 months. We conclude that patients with extramammary Paget's disease have excellent survival but that local recurrence and morbidity from surgery, especially in the elderly, can be high. Radiotherapy greater than 50 Gy as primary treatment for extramammary Paget's disease in those medically unfit for surgery, or as an alternative to further surgery for recurrence after surgery and for anyone wishing to avoid mutilating surgery, is indicated. For those with adenocarcinoma and extramammary Paget's disease, the use of adjuvant postoperative radiotherapy in doses greater than 55 Gy is indicated because of the high risk of local recurrence after surgery alone.

Radiotherapy for anal cancer: experience from 1979-1987.

Seventy patients with squamous cell carcinoma or cloacogenic carcinoma of the anus treated from 1979-1987 were reviewed. Five groups were analyzed: (a) local excision (LE) with postoperative radiotherapy (n = 9); (b) abdominoperineal resection (APR) with either pre- or postoperative radiotherapy (n = 22); (c) definitive radiotherapy alone (n = 8); (d) radiotherapy with continuous 5-Fluorouracil (5-FU) infusion (chemoradiation) (n = 25); and (e) patients treated for recurrent disease (n = 6). Abdomino-perineal resection and radiotherapy resulted in an actuarial local control (LC) rate of 90% and an overall 5-year survival rate of 77% (median follow-up, 48 months). All patients in Group 1 and 5/8 patients in Group 3 had locally controlled disease and were disease-free. The chemoradiation protocol resulted in a complete clinical response rate of 75% (18/24, one patient died during treatment) assessed 4-6 weeks after treatment. The colostomy-free local control rate with chemoradiation is 67% (16/24). Local control was 50% for all stages receiving 45-49 Gy and 90% for those patients receiving greater than or equal to 55 Gy but was not correlated with total 5-FU dose. Abdomino-perineal resection was performed to salvage six patients with persistent disease and two with recurrent disease, resulting in an overall local control rate of 92% (22/24). The actuarial survival was 96% (median follow-up, 14 months; range, 1-30). The acute complications of radiotherapy included diarrhea and perineal skin reactions that were increased by 5-FU infusion. However, diarrhea can be ameliorated by a modified treatment technique that reduces irradiation to the small intestine. For the entire patient group, minor late complications occurred in 23%, and major complications occurred in 9%.