Considerations appropriate to a clinical trial of definitive radiation therapy in adenocarcinoma of the pancreas

The Author describes criteria for selection of patients who might be eligible for entry into a clinical trial of definitive Radiation Therapy for adenocarcinoma of the pancreas. Most emphasis is placed on careful surgical staging, target volume and location, and the use of bypass procedures when appropriate.     

Combination therapy for resectable and unresectable adenocarcinoma of the pancreas

The current report summarizes our experience with 77 patients with cancer of the pancreas treated over 3.5 years. Patients were not assigned to a definite group of therapy, but through the availability of different drugs and different types of treatment several comparable groups have evolved. All patients have received radiofrequency hyperthermia and chemotherapy, but in addition, some have received selective immune stimulation with one of two low-molecular-weight compounds. The data show that radiofrequency hyperthermia permits the use of a lower dose of chemotherapy, with an apparent response to treatment. This response is enhanced significantly by the addition of selective immune stimulation. A further, more rigorously defined study will be undertaken to confirm this data.     

Adjuvant therapy of resected adenocarcinoma of the pancreas

Seventy-two patients underwent resections of pancreatic carcinomas between 1981 and 1989 at the Hospital of the University of Pennsylvania and were evaluable for follow-up. There were three treatment groups as treatment policies evolved. Initially, patients were observed after surgery without adjuvant treatment (Group 1-33 patients). Beginning in 1984, patients were offered adjuvant radiation therapy postoperatively (Group 2-19 patients) and eight of these patients also received 5-FU as an IV bolus on the first 3 days of the first and fifth weeks of treatment. Twenty patients were treated with chemosensitized radiation therapy following surgery using 96-hour 5-FU infusions during the first and fifth weeks of treatment. There were four postoperative deaths, which are excluded from the analysis, and sites of failure could not be determined for five other patients. Among evaluable patients, local recurrences occurred in 85% of the patients in group 1, 55% of the patients in group 2, and 25% of the patients in group 3. The 2-year survival was 35% in group 1, 30% in group 2, and 43% in group 3. Patients with involved surgical margins had a poor survival; only 2 of these 16 patients survived longer than 18 months. Among patients with negative margins, the 2-year survival is 41% in group 1, 33% in group 2, and 59% in group 3. Although the number of patients is smaller, the 3-year survival is 22% in group 1, 11% in group 2, and 47% in group 3. Chemosensitized irradiation is well tolerated in these patients. The major challenge in this group of patients is nutritional maintenance. There was no other significant toxicity. The trend in these observations suggests that survival following pancreatic resection is substantially improved with the addition of adjuvant chemosensitized radiation therapy.     

Definitive radiation therapy for localized prostatic adenocarcinoma

From 1974 to 1987, a total of 199 patients with prostatic carcinoma localized to the pelvis were treated with definitive external beam radiation therapy at the Istituto Medico e di Ricerca Scientifica. The median follow-up for all 126 surviving patients was 60 months. Actuarial 5-(and 10-) year overall survival rates for U.I.C.C. clinical Stage T1-2, T3 and T4 disease were 76.1% (58.5), 66% (42.5), and 27.6%, respectively. The corresponding 5- and 10-) year disease-specific survival rates were 81.7% (73), 72.5% (57.4), and 36.2%. The corresponding values of disease-free survival were 81.3% (76.8), 59.2% (57), and 17%, respectively. In 120 patients with more than 5 years of follow-up, local failure was seen alone in eight patients (6.6%) and associated with distant metastases in 19 patients (15.8%). In 28 patient (23.3%), distant metastases were observed alone. The median survival from the first evidence of metastases was 20 months, with no patient surviving beyond 5 years. The incidence of complications was acceptable. Serious complications, consisting of stenosis of both ureters and sigmoid colon requiring both urinary and intestinal diversion, occurred in two patients (1.3%). This study reveals that external radiotherapy is an efficacious and safe modality for locoregional control of prostate cancer.     

Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: the role of adjuvant pre or postoperative radiation therapy

From 1972 to 1981, 7 patients received adjuvant external beam radiation therapy before (5 patients) or after (2 patients) a curative Whipple operation for adenocarcinoma of the pancreas (5 patients) or ampulla of Vater (2 patients). Via supervoltage, 4000-4520 rad/20-25 fractions/4-5 1/2 weeks were delivered to the tumor bed and draining lymphatics. Two patients (of 4 at risk) are 5-year survivors; 3 are alive-without-disease at 1-2 years follow-up. Distant metastases have developed to date in 3 patients. A marginal miss occurred at the edge of radiation portal in 1 patient, and no true in-field failures have occurred. Complications occurred in 2 patients. Because of the high incidence of local-regional failures after curative surgery alone for adenocarcinoma of the pancreas or ampulla of Vater, the above results suggest that adjuvant radiation therapy should be considered as a modality to potentially improve treatment results.     

Adjuvant postoperative radiation therapy for rectal adenocarcinoma.

From October 1975 to August 1988, 261 patients at high risk for local recurrence after curative resection of rectal carcinoma underwent high-dose postoperative irradiation. Patients received 45 Gy by a 4-field box usually followed by a boost to 50.4 Gy or higher when small bowel could be excluded from the reduced field. Since January 1986, patients also received 5-fluorouracil (5-FU) for 3 consecutive days during the first and last week of radiotherapy. Five-year actuarial local control and disease-free survival decreased with increasing stage of disease; patients with Stage B2 and B3 disease had local control rates of 83% and 87% and disease-free survivals of 55% and 74%, respectively. In patients with Stage C1 through C3 tumors, local control rates ranged from 76% to 23%, and disease-free survivals ranged from 62% to 10%, respectively. For patients with Stage C disease, disease-free survival decreased progressively with increasing lymph node involvement, but local control was independent of the extent of lymph node involvement. For each stage of disease, local control and disease-free survival did not correlate with the dose of pelvic irradiation. Preliminary data from this study suggest a trend toward improved local control for patients with Stage B2, C1, and C2 tumors who receive 5-FU for 3 consecutive days during the first and last weeks of irradiation compared with patients who do not receive 5-FU. Current prospective randomized studies are addressing questions regarding the optimum administration of chemotherapy with pelvic irradiation for patients following resection of rectal carcinoma.     

Local excision and postoperative radiation therapy for rectal adenocarcinoma

Sixty‐seven patients with early‐stage adenocarcinoma of the rectum who had lesions thought to be unsuitable for either local excision alone or endocavitary irradiation were treated with local excision followed by postoperative radiation therapy. The purpose of this study was to evaluate the effectiveness of local excision followed by radiation therapy for treatment of rectal adenocarcinoma. The patients were treated between 1974 and 1999; follow‐up time was 6 to 273 months (median, 65 months). All living patients had follow‐up for at least 2 years. The indications for postoperative irradiation included equivocal or positive margins, invasion of the muscularis propria, endothelial‐lined space invasion, poorly differentiated histology, and perineural invasion. Cox proportional hazards regression analysis was performed using six explanatory variables including tumor size, configuration (exophytic vs. ulcerative), histologic differentiation, pathologic T stage, endothelial‐lined space invasion, and margin status. The time interval between treatment and development of recurrent disease was in the range of 11 to 48 months. The 5‐year results were as follows: local‐regional control, 86%; ultimate local‐regional control, 93%; distant metastasis‐free survival, 93%; absolute survival, 80%; and cause‐specific survival, 90%. When the Cox proportional hazards regression analysis was performed for these endpoints, margin status influenced absolute survival (P = 0.0074), cause‐specific survival (P = 0.0405), and ultimate local‐regional control (P = 0.0439). Tumor configuration marginally influenced cause‐specific survival (P = 0.0577). None of the variables had an influence on the endpoints' local‐regional control, ultimate local‐regional control with sphincter preservation, or distant metastasis. Five patients (7%) had severe complications; no complication was fatal. Local excision and postoperative radiation therapy results in a high probability of local‐regional control and survival for selected patients with relatively early‐stage rectal adenocarcinoma. Patients with ulcerative tumors may have a lower likelihood of cause‐specific survival. © 2002 Wiley‐Liss, Inc.     

Tandem-vaginal cylinder applicator for radiation therapy of uterine adenocarcinoma.

Preoperative radiotherapy for stage II adenocarcinoma of the endometrium was studied in 74 patients using the University of Kentucky tandem-vaginal cylinder applicator. The intrauterine tandem and vaginal cylinder were inserted and loaded at the same time or sequentially. Forty to 45 Gy of fractionated whole pelvis photon radiotherapy was combined with the single intracavitary insertion which gave 20 Gy to a parauterine isodose at 2 cm and to the vaginal surface. Treatment with this system gave a 5 year survival rate of 88% with a 4% complication rate for stage II corpus adenocarcinomas.     

Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas

To examine the histopathologic effect of neoadjuvant therapy and its impact on survival in patients with carcinoma of the pancreas, we retrospectively reviewed the records of 116 patients who underwent resections for pancreatic cancer from 1987 to 2000. Median follow-up of surviving patients was 19 mo (range 4–150 mo). Preoperative chemotherapy was administered in 61 patients (53%) and consisted of 5-fluorouracil/mitomycin C in 35 patients and gemcitabine in 26 patients, given concurrently with external beam radiation (5040 cGy). All resections were performed with curative intent (98 Whipples, 11 total, 6 distal, and 1 central pancreatectomy). Histopathologic examination included an estimation of the amount of fibrosis present in the tumor specimen (expressed as the percentage of fibrosis identified relative to the amount of neoplastic cells present). The mean fibrosis level for the series was 56% (range 5% to 100%). The administration of neoadjuvant therapy resulted in greater fibrosis (73%) than no preoperative treatment (38%) (p=0.0001). Higher mean fibrosis levels were observed in patients with negative lymph nodes (p=0.0006) and negative margins (p=0.05). Factors associated with improved survival (log rank test) included: negative margins (p=0.001), negative lymph nodes (p=0.03), and use of neoadjuvant therapy (p=0.03). Median survival in the neoadjuvant group was 23 mo vs 16 mo without preoperative therapy (p=0.03). In conclusion, the use of neoadjuvant therapy resulted in a greater degree of fibrosis in the specimen. Patients with negative margins and negative lymph nodes had a greater amount of fibrosis present, and these were significant predictors of improved outcome. Although retrospective, this series suggests an improvement in survival in patients treated with neoadjuvant therapy.     

Angiosarcoma of the breast after lumpectomy and radiation therapy for adenocarcinoma.

Three cases of angiosarcoma of the breast after lumpectomy and radiation therapy for adenocarcinoma are presented. Only two similar cases have been documented. The role of radiation therapy and chronic lymphedema is discussed. Although the overall survival is usually less than 22 months, two of these patients are still alive after 2 years.     

Endocavitary radiation therapy for rectal adenocarcinoma: 10-year results

Local control, survival, and toxicity in patients treated with endocavitary radiation therapy for rectal cancer were evaluated. Thirty-five patients received a total of 20 to 155 Gy in 1 to 5 fractions with 50 kV x-rays through a treatment proctoscope. Twenty-nine of the 35 patients were treated with curative intent. Median follow-up was 102 months. Local control was achieved in 23 of the 29 patients treated curatively and in 3 of the 6 treated palliatively. Local control for patients treated curatively was 76% at 10 years. No local failures occurred after 21 months. For patients treated curatively, survival was 65% at 5 years and 42% at 10 years. Toxicity within 90 days after treatment was observed in 77% of the patients. Toxicity occurring more than 90 days after treatment was observed in 80%, but only 1 patient needed a colostomy, which was for a perforation after the biopsy of a benign ulcer. In conclusion, radiation therapy resulted in a local control rate of 76% at 10 years in curatively treated patients. Although most patients experience toxicity from this treatment, loss of sphincter function is rare.     

Combination gemcitabine and docetaxel therapy in advanced adenocarcinoma of the pancreas.

OBJECTIVE: To determine the clinical and laboratory response rate of a gemcitabine and docetaxel combination in human adenocarcinoma of the pancreas in vitro and in vivo. METHODS: Fifteen patients with unresectable pancreatic cancer were treated with gemcitabine, 900 mg/m(2), and docetaxel, 90 mg/m(2), every 3 weeks. Two human pancreatic cancer lines were tested in MTT assays for their response to titrations of gemcitabine and/or docetaxel at different time points and scheduling for biochemical synergy or additional antitumor effects. RESULTS: In vitro testing showed that these two agents were minimally effective alone but when combined, they displayed additional biochemical antiproliferative effects in MTT assays. With intent-to-treat analysis of all 15 patients, 4 patients (27%) achieved an objective response by CT scan, including one complete response. Seven patients (47%) had subjective improvement and decreased serum marker levels of CA 19-9. None of the 12 patients without prior therapy developed nadir white blood cell counts below 1,000/mm(3); 2 of 3 patients with prior radiation therapy developed nadir white blood cell counts below 1,000/mm(3). CONCLUSION: This regimen is well tolerated and appears to have a significant objective response rate. Gemcitabine and docetaxel antitumor effects are additive in vitro, which may help to explain the response rate.