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Int J Radiat Oncol Biol Phys

Prostate brachytherapy in patients with inflammatory bowel disease.

Grann A. Wallner K.
Brachytherapy Service, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: There are minimal data to support the perceived contraindication of radiation therapy in patients with inflammatory bowel disease (IBD). Because of widespread concern about the possibility of radiation-related morbidity in IBD patients, the posttreatment course for 6 patients with a history of IBD who were treated with 125I prostate implantation for early stage prostate cancer are reported here. MATERIALS AND METHODS: Six patients with a prior history of IBD and Stage T1c-T2c prostatic carcinoma underwent 125I prostate brachytherapy from 1991-1996. Three patients had Crohn's disease and three had ulcerative colitis. The treatment plans were designed to treat the preimplant prostatic margin, as defined on planning CT scan, to 150 Gy. No special effort was made to minimize the rectal surface dose. Detailed records were available for all patients, and all patients were interviewed for this report. Follow-up ranged from 1 to 6 years (median: 3.7 years). RESULTS: None of the 6 patients experienced unusual or significant gastrointestinal side effects following implantation. All 6 patients remain free of GI complications. The rectal surface area that received > 100 Gy was kept below 10 mm2 in all patients, in accordance with previously published guidelines. CONCLUSIONS: Based on the limited information available, it appears that prostate brachytherapy is safe in patients with a history of IBD.

Chemo-radiotherapy for localized pancreatic cancer: increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil.

Poen JC. Collins HL. Niederhuber JE. Oberhelman HA. Vierra MA. Bastidas AJ. Young HS. Slosberg EA. Jeffrey BR. Longacre TA. Fisher GA. Goffinet DR.
Department of Radiation Oncology, Stanford University, CA 94305, USA. poen@reyes.stanford.edu
PURPOSE: Although concomitant radiation therapy (RT) and bolus 5-Fluorouracil (5-FU) have been shown to improve survival in locally confined pancreatic cancer, most patients will eventually succumb to their disease. Since 1994, we have attempted to improve efficacy by administering 5-FU as a protracted venous infusion (PVI). This study compares treatment intensity and acute toxicity of consecutive protocols of concurrent RT and 5-FU by bolus injection or PVI. METHODS AND MATERIALS: Since 1986, 74 patients with resected or locally advanced pancreatic cancer were treated with continuous course RT and concurrent 5-FU by bolus injection (n = 44) or PVI throughout the course of RT (n = 30). Dose intensity was assessed for both 5-FU and radiotherapy. Toxicity endpoints which could be reliably and objectively quantified (e.g., neutropenia, weight loss, treatment interruption) were evaluated. RESULTS: Cumulative 5-FU dose (mean = 7.2 vs. 2.5 gm/m2, p < 0.001) and weekly 5-FU dose (mean = 1.3 vs. 0.5 gm/m2/wk, p < 0.001) were significantly higher for patients receiving PVI 5-FU. Following pancreaticoduodenectomy, 95% of PVI patients maintained a RT dose intensity of > or = 900 cGy/wk, compared with 63% of those receiving bolus 5-FU (p = 0.02). No difference was seen for patients with locally advanced disease (72% vs. 76%, p = n.s.). Grade II-III neutropenia was less common for patients treated with PVI (13% vs. 34%, p = 0.05). Grade II-III thrombocytopenia was uncommon (< or = 3%) in both treatment groups. Mean percent weight loss (3.8% vs. 4.1%, p = n.s.) and weight loss > or = 5% of pre-treatment weight (21% vs. 31%, p = n.s.) were similar for PVI and bolus treatment groups, respectively. Treatment interruptions for hematologic, gastrointestinal or other acute toxicities were less common for patients receiving PVI 5-FU (10% vs. 25%, p = 0.11). CONCLUSION: Concurrent RT and 5-FU by PVI was well tolerated and permitted greater chemotherapy and radiotherapy dose intensity with reduced hematologic toxicity and fewer treatment interruptions compared with RT and bolus 5-FU. Longer follow-up will be needed to assess late effects and the impact on overall survival.

The correlation of acute toxicity and late rectal injury in radiotherapy for cervical carcinoma: evidence suggestive of consequential late effect (CQLE).

Wang CJ. Leung SW. Chen HC. Sun LM. Fang FM. Huang EY. Hsiung CY. Changchien CC.
Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Taiwan.
PURPOSE: To correlate the acute toxicity during pelvic irradiation and the development of late rectal injury following radiation therapy for cervical carcinoma. METHODS AND MATERIALS: Two hundred and twenty patients treated with curative-intent radiation therapy between November 1987 and January 1992 were analyzed. Patients were treated initially with external beam irradiation, 40-44 Gy/20-22 fractions to whole pelvis, followed by high dose rate intracavitary brachytherapy, 7.2 Gy to point A for 3 fractions. Severity of diarrhea during radiation therapy was scored according to six criteria: fecal characteristics, frequency, onset, prescription of antidiarrheal agents, body weight loss during irradiation, and extramedical care needed. Patients were categorized as group ND (no obvious diarrhea), group MD (moderate diarrhea), and group SD (severe diarrhea) for sum score 0-1, 2-5, and > or = 6, respectively. The rate of radiation proctitis was expressed, analyzed, and compared with actuarial proctitis-free rate and prevalence. RESULTS: 1) According to the score, 76 (35%), 89 (40%), and 55 (25%) patients were categorized as group ND, group MD, and group SD, respectively. Distribution of patients and treatment characteristics among the three groups appeared similar. Patients treated with a larger field size, > or = 16.5 cm2, tended to have increased severity of diarrhea. 2) Overall, 103 patients (47%, 103 of 220) developed radiation proctitis. Twenty-one patients were in group ND (28%, 21 of 76), 43 in group MD (48%, 43 of 89), and 39 in group SD (71%, 39 of 55). 3) The five-year actuarial proctitis-free rate was 72, 52, and 29% for group ND, MD, and SD, respectively (p < 0.005). 4) Taking time evolution and recoverability into account, the effect of diarrhea on the prevalence of radiation proctitis remained statistically significant at the first through the fourth year after irradiation. 5) Severity of radiation proctitis and severity of diarrhea were not correlated (Spearman's rank correlation coefficient r(s) = 0.229, p = 0.098). 6) Cox's multivariate analysis revealed that severity of diarrhea was the only factor that significantly correlated with the development of radiation proctitis. CONCLUSION: Patients with increased acute toxicity and diarrhea during radiation therapy of cervical carcinoma significantly increased the risk of late rectal injury. This result suggested that early excessive damage of acute-responding component of rectal wall may play an important role in the initiation of late rectal injury. Radiation proctitis can be accounted, in part, as a consequential late effect.

Fraction size and dose parameters related to the incidence of pericardial effusions.

Martel MK. Sahijdak WM. Ten Haken RK. Kessler ML. Turrisi AT.
University of Michigan Medical Center, Department of Radiation Oncology, Ann Arbor 48109, USA.
PURPOSE: The influence of treatment parameters, such as (a) fraction size and (b) average and maximum dose (as derived from three-dimensional (3D) distributions), on the incidence of pericarditis was analyzed. To understand and predict the dose and volume effect on the pericardium, a normal tissue-complication probability model was tested with these complication data. METHODS AND MATERIALS: Patients (n = 57) entered in 3 consecutive University of Michigan protocols of combined modality for treatment of localized esophageal carcinoma, and having 3D treatment planning for radiation therapy were the subject of this study. Univariate and multivariate analyses were performed to determine the significance of the effect of fraction size and dose parameters on the development of any grade of pericarditis. Dose distributions were corrected for the biological effect of fraction size using the linear-quadratic method. Normal tissue complication probability (NTCP) was calculated with the Lyman model. RESULTS: Nonmalignant pericardial effusions occurred in 5 of the 57 patients; all effusions were in patients who received treatment with 3.5 Gy daily fractions. On multivariate analysis, no dose factor except fraction size predicted pericarditis, until the dose distributions were corrected for the effect of fraction size ("bio"-dose). Then, both "bio-average" and "bio-maximum" dose were significant predictive factors (p = 0.014). NTCPs for the patients with pericarditis range from 62% to 99% for the calculations with the "bio"-dose distributions vs. 0.5% to 27% for the uncorrected distributions. DISCUSSION: A normal tissue complication probability (NTCP) model predicts a trend towards a high incidence of radiation pericarditis for patients who have high complication probabilities. It is important to correct the dose distribution for the effects of fractionation, particularly when the fraction size deviates greatly from standard (2.0 Gy) fractionation.

Treatment of locally recurrent rectal carcinoma--results and prognostic factors.

Wong CS. Cummings BJ. Brierley JD. Catton CN. McLean M. Catton P. Hao Y.
Department of Radiation Oncology, Princess Margaret Hospital/University of Toronto, Ontario, Canada. shun_wong@pmh.toronto.on.ca
PURPOSE: To assess the local control and survival in patients who received pelvic irradiation for locally recurrent rectal carcinoma. METHODS AND MATERIALS: The records of 519 patients with locally recurrent rectal carcinoma treated principally with external-beam radiation therapy between 1975 to 1985 at a single institute were retrospectively reviewed. These included 326 patients who relapsed locally following previous abdominoperineal resection, 151 after previous low anterior resection, and 42 after previous local excision or electrocoagulation for the primary. No patients had received adjuvant radiation therapy or chemotherapy for the primary disease. Concurrent extrapelvic distant metastases were found in 164 (32%) patients at local recurrence and, in the remaining 355, the relapse was confined to the pelvis. There were 290 men and 229 women whose age ranged from 23 to 91 years (median = 65). Median time from initial surgery to radiation therapy for local recurrence was 18 months (3-138 months). Radiation therapy was given with varying dose-fractionation schedules, total doses ranging from 4.4 to 65.0 Gy (median = 30 Gy) over 1 to 92 days (median = 22 days). For 214 patients who received a total dose > or = 35 Gy, radiation therapy was given in 1.8 to 2.5 Gy daily fractions. RESULTS: The median survival was 14 months and the median time to local disease progression was 5 months from date of pelvic irradiation. The 5-year survival was 5%, and the pelvic disease progression-free rate was 7%. Twelve patients remained alive and free of disease at 5 years after pelvic irradiation. Upon multivariate analysis, overall survival was positively correlated with ECOG performance status (p = 0.0001), absence of extrapelvic metastases (p = 0.0001), long intervals from initial surgery to radiation therapy for local recurrence (p = 0.0001), total radiation dose (p = 0.0001), and absence of obstructive uropathy (p = 0.0013). Pelvic disease progression-free rates were positively correlated with ECOG performance status (p = 0.0001), total radiation dose (p = 0.0001), and previous conservative surgery for the primary (p = 0.02). CONCLUSIONS: Survival is poor for patients who develop local recurrence following previous surgery for rectal carcinoma. Pelvic radiation therapy provides only short-term palliation, and future efforts should be directed to the use of effective adjuvant therapy for patients with rectal carcinoma who are at high risk of local recurrence.

In search of a dose-response relationship with radiotherapy in the management of recurrent rectal carcinoma in the pelvis: a systematic review.

Wong R. Thomas G. Cummings B. Froud P. Shelley W. Withers R. Williams J.
Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, North York, Ontario, Canada.
PURPOSE: A systematic review of the literature was undertaken to address the question: "What is the most effective dose fractionation schedule for the relief of symptoms in patients with pelvic recurrence from rectal or colorectal carcinoma?" METHODS AND MATERIALS: Cancerlit/Medline-computerized databases were searched between the years 1966-1996. Studies that explored the response to radiotherapy in patients with pelvic recurrence from rectal/rectosigmoid carcinoma were included. Factors that may contribute to differences in results were postulated in advance and the variations encountered between articles were presented. Articles with data applicable to recurrent disease only were included in the primary analysis. The effect of including articles that reported outcomes of recurrences with unresectable primaries and residual disease was presented as a sensitivity analysis. RESULTS: Only retrospective series (level V evidence) were available. The many sources of potential bias inherent in retrospective analyses make the data suitable for hypothesis generation only. Comparison of response was made between "lower" vs. "higher" doses, using 45-50 Gy as the dividing dose, base on the primary analysis. There were no significant differences observable in terms of initial response and the proportion maintaining a response at 6 months, within the range of doses employed. When data from articles that reported outcomes of recurrent disease with primary untreated cancers and postoperative residual disease were included, there was a suggestion for a more favorable response with higher doses. This requires cautious interpretation within the methodological limitations of the data. CONCLUSION: The optimal dose fractionation schedule for the palliation of pelvic recurrence from rectal carcinoma remains undefined. Well-designed randomized studies, with study arms that are sufficiently diverse biologically to allow the detection of a dose-response relationship if one existed, equipped with suitable symptom control end points, are necessary to provide a clinically relevant answer.

Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer.

Sur RK. Donde B. Levin VC. Mannell A.
Department of Radiation Oncology, University of the Witwatersrand, Johannesburg, South Africa.
PURPOSE: To optimize the dose of fractionated brachytherapy for palliation of advanced esophageal cancer. METHODS AND MATERIALS: One hundred and seventy-two patients with advanced esophageal cancer were randomized to receive 12 Gy/2 fractions (group A); 16 Gy/2 fractions (group B), and 18 Gy/3 fractions (group C) by high dose rate intraluminal brachytherapy (HDRILBT). Treatment was given weekly and dose prescribed at 1 cm from the source axis. Patients were followed up monthly and assessed for dysphagia relief and development of complications. RESULTS: Twenty-two patients died before completing treatment due to advanced disease and poor general condition. The overall survival was 19.4% at the end of 12 months for the whole group (A--9.8%, B--22.46%, C--35.32%; p > 0.05). The dysphagia-free survival was 28.9% at 12 months for the whole group (A--10.8%, B--25.43%, C--38.95%; p > 0.05). Forty-three patients developed fibrotic strictures needing dilatation (A--5 of 35, B--15 of 60, C--23 of 55; p = 0.032). Twenty-seven patients had persistent luminal disease (A--11, B--6, C--10), 15 of which progressed to fistulae (A--7, B--2, C--6; p = 0.032). There was no effect of age, sex, race, histology, performance status, previous dilation, presenting dysphagia score, presenting weight, grade, tumor length, and stage on overall survival, dysphagia-free, and complication-free survival (p > 0.05). On a multivariate analysis, brachytherapy dose (p = 0.002) and tumor length (p = 0.0209) were found to have a significant effect on overall survival; brachytherapy dose was the only factor that had an impact on local tumor control (p = 0.0005), while tumor length was the only factor that had an effect on dysphagia-free survival (p = 0.0475). When compared to other forms of palliation currently available (bypass surgery, laser, chemotherapy, intubation, external radiotherapy), fractionated brachytherapy gave the best results with a median survival of 6.2 months. CONCLUSIONS: Fractionated brachytherapy is the best modality for palliation of advanced esophageal cancer. It offers the best palliation to patient when compared to all other modalities currently available. The optimal brachytherapy dose ranges between 16 Gy in two fractions and 18 Gy in three fractions given a week apart.

A phase I study of daily carboplatin and simultaneous accelerated, hyperfractionated chest irradiation in patients with regionally inoperable non-small cell lung cancer.

Kelly K. Hazuka M. Pan Z. Murphy J. Caskey J. Leonard C. Bunn PA Jr.
Division of Medical Oncology, University of Colorado Cancer Center, Denver 80262, USA.
PURPOSE: This Phase I study was designed to determine the maximally tolerated dose (MTD) of daily low dose carboplatin with concurrent accelerated hyperfractionated radiotherapy (AHFX) in patients with locally advanced non-small-cell lung cancer. Patients also received consolidation chemotherapy with carboplatin. Secondary objectives were to determine the response rate, response duration, sites of first relapse, and survival. METHODS AND MATERIALS: Thirty patients received daily carboplatin at doses of 25 or 30 mg/m2. Concurrent radiotherapy was given in 1.5 Gy fractions twice daily for a total dose of 60 Gy. Following chemoradiotherapy, patients received four cycles of carboplatin at 350 mg/m2. RESULTS: Grade 4 esophagitis developed in 2 of 6 (33%) patients receiving 30 mg/m2 of daily carboplatin and was dose limiting. The remaining 24 patients received carboplatin at 25 mg/m2, with 3 patients developing Grade 4 esophagitis (13%). One of 22 patients who received consolidation carboplatin developed Grade 4 thrombocytopenia. An objective response was observed in 70% of patients (2 complete and 17 partial). Sites of failure were local (7 patients), distant (7 patients), and both (3 patients). The median time to progression was 8.3 months, with a median survival time of 18.3 months. The 1- and 2-year survival rates were 63 and 49%, respectively. CONCLUSIONS: Esophagitis was dose limiting when 30 mg/m2 of daily carboplatin was administered with AHFX. At the MTD of 25 mg/m2 of daily carboplatin plus AHFX followed by four cycles of carboplatin, the regimen was shown to be safe and as active or more active than other regimens. Thus, further studies with this regimen are warranted.

High-dose preoperative radiation and the challenge of sphincter-preservation surgery for cancer of the distal 2 cm of the rectum.

Mohiuddin M. Regine WF. Marks GJ. Marks JW.
University of Kentucky, Department of Radiation Medicine, Lexington 40536-0084, USA.
PURPOSE: Sphincter-preserving surgery for the management of distal rectal cancer is gaining recognition as an alternative to abdominoperineal resection and loss of anal function. The use of high-dose preoperative radiation appears to enhance the options for sphincter preservation, even in the most distal segments of the rectum. MATERIALS AND METHODS: Seventy patients with tumors located in the distal 2 cm of the rectum received a minimum dose of 40 to 45 Gy over 4 1/2 weeks at 1.8 to 2.5 Gy per fraction. Patients with unfavorable tumors were given an additional boost of 10 to 15 Gy. Surgery was performed 5 to 10 weeks following completion of radiation. Radical surgical resection was performed in 48 patients and full thickness local excision in 22. Follow-up ranged from a minimum of 1 year to a maximum of 10 years, with a median of 4 years. RESULTS: There was one perioperative mortality. Two patients did not have their colostomy closed because of complications. Late diversion was required in 4 patients, primarily for recurrent disease. Sixty patients (86%) maintained long-term satisfactory sphincter function. Local recurrence was observed in 9 patients (13%) and distant metastases in 12 patients (17%). The overall five-year actuarial survival rate was 82%. The 5-year survival and local recurrence for postradiation pathological stage of disease was: T0, T1, T2, N0--95% and 8%, T3, T4, N0--91% and 4%, T(any) N+--50% and 41%, respectively. CONCLUSION: High-dose preoperative radiation, in properly selected patients with rectal cancers of the distal 2 cm, offers opportunities for sphincter-preserving surgical resection with excellent local control, survival, and enhanced quality of life.

Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.

Sandhu AP. Symonds RP. Robertson AG. Reed NS. McNee SG. Paul J.
Beatson Oncology Centre, Western Infirmary, University of Glasgow, Scotland.
PURPOSE: To report our experience in the use of interstitial iridium-192 implantation combined with external radiotherapy in anal cancer. METHODS AND MATERIALS: From 1984 to 1994, 79 patients with anal cancer were treated with radical intent using radiotherapy (plus chemotherapy) at Beatson Oncology Centre, Glasgow, Scotland. The mean and median age at presentation were 68 and 70 years, respectively (range 34-85) with a male-to-female ratio of 0.39. The histologic distribution was as follows: 48 squamous, 16 basaloid, 14 adenocarcinoma, and 1 basal cell carcinoma. The T stages were: 8 T1, 40 T2, 26 T3, and 5 T4 lesions. Twelve (15%) patients had nodal involvement at presentation. All patients underwent interstitial implantation using iridium-192 as part of the initial treatment. Seventy-six patients were treated with external radiotherapy followed by implant with a mean delay of 37 days after the end of radiotherapy. Twelve patients also received chemotherapy with 5-fluorouracil and mitomycin-C concurrently with external radiotherapy. Follow-up ranged from 6 to 123 months, with a median of 37 months. RESULTS: Seventy-nine patients were analyzed to assess local control, survival, and complications. A complete response rate of 91% (72 of 79) was achieved after planned radiation treatment. At the end of external radiotherapy, 29% (22 of 76) had achieved complete response, 58% (7 of 12) with chemotherapy and 23% (15 of 64) without it. Local control was achieved in 62 of 79 (78%) patients and 8 of 17 (47%) local failures were salvaged by abdominoperineal resection. Five patients developed inguinal node failure; four of these were salvaged. Overall, 10% of all patients developed distant metastasis as the first site of failure and 25% failed at any site after salvage therapy. Time to unsalvageable relapse was significantly different on comparing T stage (p = 0.005) and histology (p = 0.029) of tumor. Major complications requiring surgical intervention were seen in six (7.5%) patients. Anal function preservation with local control was possible in 56 of 79 (71%) patients. CONCLUSION: We report excellent results with radiotherapy in T1 and T2 lesions. The role of chemoradiotherapy as radical treatment of anal cancer should be defined in the context of locally advanced tumors.

Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres.

Lau WY. Ho S. Leung TW. Chan M. Ho R. Johnson PJ. Li AK.
Department of Surgery, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
PURPOSE: To evaluate the efficacy of intraarterial 90yttrium (90Y) microspheres in nonresectable hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Patients with nonresectable HCC, but without extrahepatic disease, who also had lung shunting < 15% and tumor-to-normal ratio > or =2, as determined by simulation using (99m)technetium macroaggregated albumin, were entered into the study. The radiation dose delivered to the lungs, tumor, and normal liver was estimated by a partition model. 90Y microspheres were infused into the hepatic artery at the time of hepatic angiography or through an implanted arterial portacatheter under fluoroscopy. Repeated treatments were given for residual or recurrent tumor. Response to treatment was monitored by serum alpha-fetoprotein or ferritin levels, together with serial computed tomography. RESULTS: Seventy-one patients, including 20 patients with postoperative recurrence, were initially treated with an activity of 0.8 to 5.0 Giga-Becquerel (GBq) (21.6-135.1 mCi) (median 3.0 GBq or 81.1 mCi) of 90Y microspheres. There was a 50% reduction in tumor volume in 19 (26.7%) patients after the first treatment. However, the overall objective response in terms of changes in alpha-fetoprotein levels was 89% [partial response (PR) 67%, complete response (CR) 22%] among the 46 patients with raised pretreatment levels. The serum ferritin level in the other 25 patients dropped by 34 to 99% after treatment. Treatment was repeated in 15 patients. The maximum number of treatments was 5 and the maximum total activity was 13.0 GBq (351.4 mCi), given in 3 treatments. The estimated radiation doses to the nontumorous liver ranged from 25 to 136 Gy (median 52 Gy) in the first treatment and the highest total radiation dose was estimated to be 324 Gy. For the tumors, the estimated radiation doses ranged from 83 to 748 Gy (median 225 Gy) in the initial treatment and the highest cumulative dose reached was 1580 Gy. The residual tumors were resected in 4 patients. Two of these had complete histological remission, but only occasional viable tumor cells were found in the necrotic centers of the tumors resected from the other 2 patients. The median survival of the 71 patients was 9.4 months (range 1.8 to 46.4 months). Treatment was well tolerated and there was no bone-marrow toxicity, or clinical evidence of radiation hepatitis or pneumonitis. CONCLUSIONS: Selective internal radiation therapy using 90Y microspheres is effective for selected cases of nonresectable HCC and is well tolerated. The objective response rate in terms of drop in tumor marker levels is higher than that based on reduction in tumor volume shown by computed tomography. The nontumorous liver appears more tolerant to internal radiation than external beam radiation. Selective internal radiation treatment may convert nonresectable tumors to resectable ones.

High dose rate brachytherapy for carcinoma of the cervix: risk factors for late rectal complications.

Uno T. Itami J. Aruga M. Kotaka K. Fujimoto H. Sato T. Minoura S. Ito H.
Department of Radiation Therapy and Oncology, International Medical Center, Tokyo, Japan.
PURPOSE: To determine the incidence of late rectal complications in patients treated with high dose rate brachytherapy for FIGO Stage IIB, IIIB carcinoma of the uterine cervix, and to evaluate the treatment factors associated with an increased probability of treatment complications. METHODS AND MATERIALS: Records of 100 patients with FIGO IIB and IIIB cervical carcinoma treated with definitive irradiation using high dose rate intracavitary brachytherapy (HDR-ICR) between 1977 and 1994 were retrospectively reviewed. For each HDR-ICR session, 6-Gy isodose volume was reconstructed retrospectively and the relationship between probability of late rectal complications and several treatment factors, including a specific point dose and parameters representing isodose volume, were examined. Statistical analyses were performed to determine the treatment factors predictive of late rectal complications. RESULTS: Of patients treated for both stages, 33% and 38% had experienced moderate to severe (Grade 2-4) complications at 3 and 5 years, respectively. Mean value of depth (D) of 6-Gy isodose volume in HDR-ICR in patients with and without complication were 51 mm and 46 mm, respectively (p = 0.0070). A significant difference was noted in complication rate between patients with D > 51 mm and D < or = 51 mm (p = 0.0023). Cumulative Point S (2 cm dorsal from the midpoint of the ovoid sources) dose (p = 0.044), and single or total point S dose by HDR-ICR (p = 0.019, each) were significantly higher in patients who developed complication, whereas these factors did not significantly affect the probability of pelvic control. Multivariate analysis revealed that D was the independent predictor for the endpoint of actuarial complication rate (p = 0.047). No significant difference was noted in the product of L, D, and W value (L x D x W) between patients with less than Grade 2 rectal complication and those with Grade 2-4. CONCLUSION: Depth of 6-Gy isodose volume determined three dimensionally (3D) has the predictive value of late rectal complications. This suggests that the shape of the high dose area in HDR-ICR influences the incidence of late rectal complications regardless of its volume.

Effect of customized small bowel displacement system in pelvic irradiation.

Huh SJ. Lim DH. Ahn YC. Kim DY. Kim MK. Wu HG. Choi DR.
Department of Radiation Oncology, Samsung Medical Center, College of Medicine, Sung Kyun Kwan University, Seoul, Korea.
PURPOSE: Authors designed a customized small bowel displacement system (SBDS) to displace the small bowel out of the pelvic radiation fields and to minimize treatment related bowel morbidity. METHODS AND MATERIALS: From August 1995 to May 1996, 55 consecutive patients who received pelvic radiation therapy with the SBDS were included in this study. The SBDS consists of a customized Styrofoam compression device that can displace the small bowel out of the radiation fields and an individualized immobilization abdominal board for easy daily setup of the patient in prone position. After opacifying the small bowel with barium, the patients were laid prone and posterior-anterior (PA) and lateral (LAT) simulation films were taken with and without the SBDS. The volume of the small bowel included in the radiation fields with and without the SBDS were compared. RESULTS: Using the SBDS, the mean small bowel volume was reduced by 59% on PA and 51% on LAT films (p = 0.0001). In six patients (6 of 55, 11%), it was possible that no small bowel was included within the treatment fields. The mean upward displacement of the most caudal small bowel was 4.8 cm using the SBDS. Patients treated with the SBDS manifested a significantly lower incidence of diarrhea requiring medication (8 of 55, 15%) vs. those without the SBDS (24 of 39, 62%) (p < 0.05). CONCLUSION: The SBDS is a novel method that can be used to displace the small bowel away from the treatment portal effectively and to reduce the radiation therapy morbidity. Compliance with setup is excellent.

The effect of radiation on the expression of intercellular adhesion molecule-1 of human adenocarcinoma cells.

Hareyama M. Imai K. Oouchi A. Takahashi H. Hinoda Y. Tsujisaki M. Adachi M. Shonai T. Sakata K. Morita K.
Department of Radiology, Sapporo Medical University, School of Medicine, Japan.
PURPOSE: To investigate the changes in antigenic expression of intercellular adhesion molecule-1 (ICAM-1) caused by ionizing radiation of cultured human adenocarcinoma cells. METHODS AND MATERIALS: Human colonic BM314 and gastric MKN45 adenocarcinoma cells were irradiated to investigate the expression of ICAM-1 on the cell membrane and in the supernatant. In addition, the ICAM-1 gene expression (mRNA) was analyzed using a ICAM-1 cDNA as a probe. RESULTS: The expression of ICAM-1 on the membrane was found to increase by irradiation. This effect was also observed in the supernatant. In addition, the irradiated cell population showed slight, but clear increases in ICAM-1 mRNA expression. CONCLUSIONS: These results show that the enhancement of expression of ICAM-1 by radiation takes place at the ICAM-1 gene expression (mRNA) level. The results suggest that the low dose radiation may be useful for accumulating LFA-1 positive cytotoxic T lymphocytes (CTL) at the local tumor tissue, by which tumor cells may be attacked.

Neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy or surgery for operable thoracic esophageal carcinoma.

Year 1998
Murakami M. Kuroda Y. Okamoto Y. Kono K. Yoden E. Kusumi F. Hajiro K. Matsusue S. Takeda H.
Department of Radiology, Tenri Hospital 200, Tenri City, Nara Prefecture, Japan.
PURPOSE: A prospective clinical trial was undertaken to investigate the feasibility of concurrent chemoradiotherapy for esophageal carcinomas. MATERIALS AND METHODS: Between June 1989 and May 1996, forty patients with operable squamous cell carcinoma of the thoracic esophagus (Stage 0 to III: UICC 1987), ages 45 to 78 years (mean: 64), were enrolled in a study of neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy (CRT group) or surgery (CRT-S group). Neoadjuvant chemoradiotherapy consisted of 44 Gy in 40 fractions for 4 weeks (2.2 Gy/2 Fr/day) through 10-MVX rays, with 2 courses of cisplatin (80-100 mg/body, mean: 60 mg/m2, Day 1, bolus injection) and 5-fluorouracil (500-1000 mg/body/day, mean: 400 mg/m2, Days 1-4, continuous infusion). After completion of neoadjuvant chemoradiotherapy, an intermediate clinical response was assessed by barium swallow, esophagoscopy with/without biopsy, EUS in most cases, thoracic and upper abdominal CT scan, and cervical US. Definitive chemoradiotherapy was performed in patients when regression of more than 75% was evident (CRT Group), and esophageal resection was indicated in those who remained at less than 75% (CRT-S Group). In CRT Group, a cumulative dose of 60-70 Gy for Tis, T1 and 65-75 Gy for T2-T4 tumor with high-dose-rate intraluminal brachytherapy and a total of 3 courses of chemotherapy were planned. In CRT-S Group, intraoperative radiotherapy for abdominal lymphatic system and postoperative supraclavicular irradiation were added. RESULTS: At the time of intermediate assessment, complete response (CR) was observed in 16 patients, a partial response (PR) in 22, and no change (NC) in 2. Thirty responding patients (CR, 16; PR, 14) entered the CRT Group, and 10 nonresponding patients (PR, 8; NC, 2) were followed by surgery (CRT-S Group). Radiotherapy was completed satisfactorily, but chemotherapy was suspended in 26 patients (65%) because of acute toxicity. Clinical CR rate at the completion of treatment showed 90% in CRT Group, and pathologic CR rate 10% in CRT-S Group. The overall median survival was 45 months, survival at 1, 2, and 3 years being 100%, 72%, and 56%, respectively. Local-regional failure was observed in 7 patients (all in CRT Group), distant failure in 6 (3 in CRT Group, 3 in CRT-S Group) and local-regional with distant failure in 1 (CRT Group). Four patients with local-regional recurrence in the CRT Group were salvaged by surgery. Overall survival at 2 and 3 years for CRT vs. CRT-S Group was 72%, 64% vs. 75%, 38%, respectively. No treatment-related mortality was observed. The rate of the 'esophagus conservation' was 65% (Stage 0: 1 of 1, 100%; Stage I: 11 of 12, 92%; Stage II: 8 of 17, 47%; Stage III: 6 of 10, 60%). CONCLUSION: Our results demonstrated that almost all early disease (Stage 0-I) and about half of advanced disease (Stage II-III) could be conserved, their esophagus treated by the multidisciplinary approach centering on high-dose radiotherapy and concurrent chemotherapy.

Accelerated hyperfractionated radiation therapy and concurrent 5-fluorouracil/cisplatin chemotherapy for locoregional squamous cell carcinoma of the thoracic esophagus: a phase II study.

Year 1998
Jeremic B. Shibamoto Y. Acimovic L. Matovic Z. Milicic B. Milisavljevic S. Nikolic N.
Department of Oncology, University Hospital, Kragujevac, Yugoslavia.
PURPOSE: To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT). MATERIAL AND METHODS: Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m2, days 1-5) and cisplatin (CDDP) (10 mg/m2, days 1-5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m2, days 1-5) and CDDP (20 mg/m2, days 1-5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6. RESULTS: The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths. CONCLUSION: The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.

Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation.

Year 1998
Valentini V. Coco C. Cellini N. Picciocchi A. Genovesi D. Mantini G. Barbaro B. Cogliandolo S. Mattana C. Ambesi-Impiombato F. Tedesco M. Cosimelli M.
Cattedra di Radioterapia, Universita Cattolica del Sacro Cuore, Rome, Italy.
PURPOSE: To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control. METHODS AND MATERIALS: Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m2, Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m2, Days 1-4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4-6 weeks after the end of chemoradiation. RESULTS: Total Grade 3-4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% (7) of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a sphincter-saving surgical procedure. In 12 (44%) of 27 patients candidate for an APR, the sphincter was preserved, as it was in 19 (95%) of 20 probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > 20 mm was observed in 21 patients (26%). Of 63 patients, 4 (6%) had moderate soilage after the sphincter-saving procedure. CONCLUSION: Preoperative combined modality therapy seems to afford some potential advantages in nonrandomized trials: patients are able to tolerate higher chemotherapy doses and they experience a lower acute toxicity. Tumor downstaging and resectability rates are high; sphincter preservation is feasible. Larger T3 tumors remained less influenced by this treatment; thus, taking into account the low toxicity rate recorded, a more aggressive schedule should be applied in these resectable tumors.

Conservative management of rectal adenocarcinoma by radiotherapy.

Year 1998
Maingon P. Guerif S. Darsouni R. Salas S. Barillot I. d'Hombres A. Bone-Lepinoy MC. Fraisse J. Horiot JC.
Radiotherapy Department, Centre Georges-Francois-Leclerc, Dijon, France. pmaingon@gfl.axiome.fr
PURPOSE: The aim of this study was to analyze the experience of Centre GF Leclerc for conservative and curative treatment by radiotherapy of low rectal cancer. PATIENTS AND METHODS: A total of 151 patients received radiotherapy alone for rectal adenocarcinoma with curative intent. They were clinically staged according to size (T1 < 3 cm, and T2 > 3 cm) and depth of infiltration (A=superficial, and B=impaired mobility and T3 fixed). Over the past 6 years, rectal ultrasound (US) has been used systematically, compared with computed tomographic scan and magnetic resonance imaging when needed. Intracavitary contact X ray was given to 129 patients (69%), and brachytherapy in 45 of 151. External radiotherapy was used in 34 cases (22.5%). RESULTS: Complete response was obtained in 93%. Local failures were observed in 50 cases (28%); two occurred in pelvic nodes after intracavitary X rays. Size (tumors > 3 cm) and alteration of mobility significantly influenced the rate of local failure (p=0.009 and 0.007). The addition of external radiotherapy in patients with poor prognostic factors improved the local control rate. A total of 39 patients with recurrence were amenable to salvage surgery. After salvage treatment, the local control rate was 82% with unlimited follow-up. The 5-year actuarial survival rate was 57%, with a specific survival of 66%. There was no difference in local control or survival according to differentiation of the tumors and distance between anal margin and the inferior level of the lesion. Severe late effect (grade 3) was 3.8%. The sphincter preservation was obtained in 104 of 124 cases (84%). The sphincter function was judged to normal in 102 of 104 patients (98%). CONCLUSION: Intracavitary contact X ray is the treatment of choice for clinical Stage T1A rectal tumors. External radiotherapy significantly improved the results of treatment of tumors > 3 cm. Clinical staging and transrectal ultrasound allows a safe selection of indications. Radiotherapy alone may be proposed for selected cases as an alternative to mutilating surgery for small rectal adenocarcinoma.

Clinical course of rectal bleeding following I-125 prostate brachytherapy.

Year 1998
Hu K. Wallner K.
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
PURPOSE: Despite the occurrence of some rectal complications in most large series of patients treated with radiation, there is surprisingly little information regarding their management. We report here the clinical course of such patients after I-125 brachytherapy, in an effort to help delineate a rational management policy. METHODS AND MATERIALS: 109 patients with stage T1 to T2 prostatic carcinoma and Gleason score 2 to 7 were treated with I-125 implantation from 1988 through 1995. No external radiation was given. The prescribed minimum radiation dose to the prostate was 140 to 160 Gy. RESULTS: Nineteen of 109 patients (actuarial incidence: 19%) developed persistent, bright red rectal bleeding, from 1 to 28 months following I-125 implantation. Most occurred in the early part of the implant experience. Bleeding resolved in 6 of the 19 patients, from 9 to 48 months from the time of onset. Nine patients were treated with steroid enemas. Laser coagulation was used in three patients, and six patients had no intervention. There was no obvious difference in the resolution rate between groups. There was no obvious difference in the rectal wall radiation for patients who did or did not experience resolution of their bleeding. CONCLUSION: Persistent, minor radiation-related bleeding after prostate brachytherapy can be a source of consternation to patients. They should be reassured that spontaneous healing is likely to occur eventually in a large portion of patients, and should be cautioned against invasive treatment, unless absolutely necessary.

Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy.

Year 1998
Katz A. Hanlon A. Lanciano R. Hoffman J. Coia L.
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
PURPOSE: CA 19-9 has been identified as a tumor marker for pancreatic carcinoma and has been shown to have some utility in predicting outcome in surgically treated patients. The purpose of this study was to evaluate its usefulness as a prognostic indicator in patients treated with radiotherapy. MATERIALS AND METHODS: A retrospective review of all patients treated with radiotherapy of definitive intent (n = 104) for carcinoma of the pancreas at Fox Chase Cancer Center from 1980-1994 was undertaken. Patients were categorized into four groups: Planned preoperative radiation with resection (n = 25); planned preoperative radiation without successful resection (n = 35); postoperative radiation (n = 21); and radiation without planned resection (n = 23). For each group, except those treated without planned resection, median dose for external beam radiotherapy was 50.4 Gy (range = 21.6-63.0 Gy). Those in the remaining fourth group were treated with a median dose of 55.8 Gy (range = 36.0-60.4 Gy). 97% of patients in the first three groups were also treated with 5-FU-based chemotherapy, as were 61% of those in the fourth group. Pretreatment and follow-up CA 19-9 levels were available for 69 patients. RESULTS: Median survival time for all groups was 10 months (range = 1-67 months). Univariate analysis showed significant differences in survival among the groups: Preop with resection 22 months; preop without resection 10 months, postop 17 months; and without planned resection 12 months (p = 0.0005). Overall, patients who underwent resection had a median survival time of 19 months, compared to 11 months in those who did not (p = 0.0006). CA 19-9 level at diagnosis was found to be a significant prognostic indicator on univariate analysis, with a median survival time of 8 months in those having a level greater than the median of 680 U/ml, compared to 20 months in those who did not (p = 0.0003). Similarly, the posttreatment nadir was significant, with a median survival time of 11 months in those with levels above the median of 162.5 U/ml, vs. 26 months in those with levels below 162.5 U/ml (p = 0.001). The median survival time for patients whose CA 19-9 levels decreased in response to treatment by more than 75% was 23 months (range = 6-34 months) vs. 8 months (range = 3-21) in those with 75% or less response (p = 0.003). On stepwise multivariate analysis, pretreatment CA 19-9 level was found to be a significant predictor of survival (p = 0.005). Other potential indicators of outcome, including age, gender, KPS, prediagnosis weight loss, location of tumor, clinical TNM staging, size of lesion, vascular involvement on angiography, and sequence of radiation with respect to resection, were evaluated and were not found to be significant. CONCLUSION: CA 19-9 was demonstrated to be a useful prognostic indicator in patients treated with radiotherapy; other, more traditional, indicators of outcome were of less utility.

Comparative treatment planning between proton and x-ray therapy in esophageal cancer.

Year 1998
Isacsson U. Lennernas B. Grusell E. Jung B. Montelius A. Glimelius B.
Department of Oncology, University of Uppsala, Akademiska sjukhuset, Sweden.
PURPOSE: Conformal treatment planning with megavoltage x-rays and protons for five patients with esophageal cancer has been studied in an attempt to determine if there are advantages of using protons instead of x-rays. METHODS AND MATERIALS: For each of the five patients, two different proton plans, one x-ray plan, and one mixed plan with x-rays and protons were made. A three-dimensional treatment planning system, TMS, was used. The evaluation of the different plans was made by applying the tumor control probability (TCP) model proposed by Nahum and Webb and the normal tissue complication (NTCP) model proposed by Lyman on the dose distributions in terms of dose-volume histograms (DVHs). RESULTS: The comparison shows advantages of using protons instead of x-rays for all five patients. The dose-limiting organs at risk are the spinal cord, the lungs, and the heart, but the proton plans also spare the kidneys better than the x-ray plan does. At 5% NTCP in any risk organ, the calculated mean TCP value for the five patients is increased by an average of 20%-units (from 2 to 23%-units) with the best proton plan compared with x-rays only. However, if we assume maximally a 1% risk in the spinal cord and a total NTCP for the two lungs of 100%, the mean TCP value for the five patients is increased from 6 to 49% with the best proton plan compared with x-rays only. The corresponding figure for the mixed plan is 27%. These gains are relatively insensitive to variations within reasonable limits in the biological parameters. CONCLUSIONS: Protons appear to have clear therapeutic advantages over conventional external radiotherapy when treating esophageal carcinoma.

Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group).

Year 1998
Arnott SJ. Duncan W. Gignoux M. Girling DJ. Hansen HS. Launois B. Nygaard K. Parmar MK. Roussel A. Spiliopoulos G. Stewart LA. Tierney JF. Mei W. Rugang Z.
St. Bartholomew's Hospital, London, UK.
PURPOSE: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. METHODS AND MATERIALS: This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. RESULTS: With a median follow-up of 9 years, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p = 0.062). No clear differences in the size of the effect by sex, age, or tumor location were apparent. CONCLUSION: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-->20%).

Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer.

Year 1998
Tannapfel A. Nusslein S. Fietkau R. Katalinic A. Kockerling F. Wittekind C.
Institute of Pathology, University of Leipzig, Germany.
PURPOSE: To investigate the relationship between apoptotic cell death, proliferative activity, and the expression of apoptosis regulating proteins in rectal cancer prior to and after radiochemotherapy. MATERIALS AND METHODS: In 32 patients dispositioned to receive preoperative radiochemotherapy for locally advanced rectal carcinoma, pretherapy biopsies and the final resected specimen after radiochemotherapy were available for analyses. Apoptotic cells were identified and quantified using in situ end labeling (ISEL) technique. The expression of the bax protein was assessed immunohistochemically. Additionally, double immunostaining was performed for apoptotic cells and bax expression. The proliferative activity was determined by immunohistochemical assessment of the Ki67 (MIB-1) and the proliferating cell nuclear antigen (PCNA). p53- and bcl-2 expression was analyzed immunohistochemically. A clinical-to-pathologic downstaging after radiochemotherapy was achieved in 25 of 32 patients (78%). During follow-up, tumor recurrence was observed in six cases. In one case, no residual tumor was detected after radiochemotherapy. RESULTS: After radiochemotherapy, the apoptotic index increased significantly in almost every case examined. In contrast, the proliferative activity was significantly decreased in resected specimens as compared to biopsies. Bax immunostaining was detected in 12/31 (39%) biopsies and in 26/31 (84%) resected specimens. In the resected specimen, significantly more apoptotic cells that were bax-positive were found than in biopsies. Bcl-2 immunostaining occurred in 15/31 biopsies and 12/31 resected specimens, respectively. Tumors that were immunohistochemically negative for p53 (20/31 [65%]) generally exhibited a higher apoptotic index and a high expression level of bax than p53-positive tumors (11/31 [35%]). However, we did not find any correlation between the (pre- and post-therapeutic) rate of apoptosis or the level of bax expression and the degree of clinical-to-pathologic downstaging or the frequency of tumor recurrence. CONCLUSION: Our results indicate that radiochemotherapy is associated with an increase in bax expression and also in apoptotic cell death. The observation of higher rates of apoptosis and bax in p53-negative tumors suggests that p53 might be a possible regulating factor of apoptosis in rectal cancer.

Acute treatment-related diarrhea during postoperative adjuvant therapy for high-risk rectal carcinoma.

Year 1998
Miller RC. Martenson JA. Sargent DJ. Kahn MJ. Krook JE.
Division of Radiation Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
PURPOSE: The combination of pelvic radiotherapy and 5-fluorouracil-based chemotherapy is associated with an increase in acute gastrointestinal toxicity during rectal adjuvant therapy, most notably an increased incidence of diarrhea. Previous randomized, prospective studies have limited their analysis to presenting rates of severe and life-threatening diarrhea (Grade 3 or greater), and few data are available detailing the extent of mild to moderate diarrhea. To provide baseline data for future studies, we conducted a detailed analysis of diarrhea from a prior clinical trial of adjuvant therapy for rectal cancer. METHODS AND MATERIALS: In a multiinstitutional clinical trial, 204 eligible patients with rectal carcinoma that either was deeply invasive (T3-T4) or involved regional lymph nodes were randomized to receive either postoperative pelvic radiotherapy alone (45 to 50.4 Gy) or pelvic radiotherapy and bolus 5-fluorouracil-based chemotherapy. Toxicity was assessed prospectively. RESULTS: For the 99 eligible patients who received pelvic radiotherapy alone, rates of Grades 0, 1, 2, 3, and 4 diarrhea during treatment were 59, 20, 17, 4, and 0%, respectively. For the 96 eligible patients who received radiotherapy and 5-fluorouracil, the overall rates of grades 0, 1, 2, 3, and 4 diarrhea were 21, 34, 23, 20, and 2%, respectively. The increased rates of diarrhea during adjuvant rectal therapy were manifested across all toxicity levels for patients receiving chemotherapy and pelvic radiotherapy. Of primary clinical importance is the substantial increase in severe or life-threatening diarrhea (Grade 3 or more) (22 vs. 4%,p = 0.001) Additionally, increased rates of any diarrhea and also severe or life-threatening diarrhea were observed in patients who had a low anterior resection compared with those who had an abdominoperineal resection (p < 0.001 and p = 0.006, respectively). CONCLUSION: These results will be of value as a baseline for investigators who want to use treatment toxicity as an end point in cancer control or cancer therapy trials utilizing similar treatment techniques. Patients receiving 5-fluorouracil and pelvic radiotherapy compared with patients receiving pelvic radiotherapy alone and patients with a prior history of a low anterior resection compared with patients who had a prior history of an abdominoperineal resection experienced increased rates of Grades 1 through 4 acute treatment-related diarrhea, and the most important increase occurred as Grade 3 toxicity.

Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma.

Year 1998
Maor MH. North LB. Cabanillas FF. Ames AL. Hess MA. Cox JD.
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
PURPOSE: To review the long-term clinical effects of unilateral kidney irradiation on overall renal function and blood pressure in patients with gastric lymphoma. METHODS AND MATERIALS: In the study were 27 patients with Stage I or II gastric lymphoma who had undergone irradiation of at least 24 Gy to > or = 1/3 of the left kidney. They include 16 women and 11 men, aged 31 to 77, with a mean age of 57.6 years (median 56). Fifteen patients had Stage I and 12 had Stage II disease. In 13 patients the whole kidney had been irradiated, and 14 had had partial kidney irradiation, at doses ranging between 24 and 40.5 Gy. All patients received combined chemotherapy with various drugs: all patients received corticosteroids, and five received cis-platinum. Their follow-up ranged between 0.7 and 7.8 years (mean 3.4 years). Data on possible effects of the treatment on blood pressure, renal function as assessed by blood urea and creatinine, and kidney shrinkage as seen by serial computed tomography scanning were collected on all patients. RESULTS: Three patients had persistent, mild elevations of urea and creatinine levels, which did not require special treatment. All three also received cis-platinum. Ipsilateral kidney shrinkage was evident in most patients. In 19 patients the craniocaudal measurement of the kidney shrank by > or = 1.6 cm. Shrinkage in other dimensions was also evident. The degree of atrophy was related to the volume of kidney irradiated. Only two patients developed hypertension, both at a low level of 150/90; one patient had had 40 Gy to the whole kidney, the other 40 Gy to half the kidney. Neither patient had elevated urea or creatinine. CONCLUSIONS: Notwithstanding the shrinkage to the irradiated part of the kidney, the treatment did not lead to clinically significant hypertension or renal dysfunction. The administration of cis-platinum to patients with gastric lymphoma that requires kidney irradiation should be further evaluated.

Treatment systems guidelines for primary rectal cancer from the 1996 Patterns of Care Study.

Year 1998
Minsky BD. Coia L. Haller D. Hoffman J. John M. Landry J. Pisansky TM. Willett C. Mahon I. Owen J. Hanks G.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: The Patterns of Care Rectal Cancer Committee was formed to develop consensus recommendations for patients with adenocarcinoma of the rectum limited to the pelvis. METHODS AND MATERIALS: The Committee was composed of a multidisciplinary group of oncologists, and clinical scenarios were chosen to address most of the major treatment controversies in the combined modality treatment of rectal cancer. A literature search was then conducted and the major articles were identified. A modified Delphi technique was used to arrive at consensus. Serial surveys were conducted by distributing questionnaires to the Committee members to consolidate expert opinion. Voting was conducted using a scoring system and opinions were unified to the highest degree possible. RESULTS: Consensus voting was performed for 4 clinical scenarios. Acceptability ratings for treatment were grouped into 3 broad categories: not acceptable, acceptable, and most acceptable. Based on the treatment options, a decision tree was developed that reflects the consensus of the committee. CONCLUSION: These options may help guide treatment decisions in rectal cancer.

The prognostic significance of p53 expression for survival and local control in rectal carcinoma treated with surgery and postoperative radiotherapy.

Year 1998
Wiggenraad R. Tamminga R. Blok P. Rouse R. Hermans J.
Department of Radiotherapy, Westeinde Hospital, Den Haag, The Netherlands.
PURPOSE: To investigate whether p53 immunoreactivity is a prognostic factor for survival and pelvic control in rectal carcinoma treated with surgery and postoperative radiotherapy. METHODS AND MATERIALS: From 1981 through 1989, 146 patients with rectal carcinoma received postoperative radiotherapy and were followed for at least 5 years or until death. The specimens of 123 of these 146 patients could be retrieved and examined immunohistochemically for p53 expression. The prognostic value for survival and pelvic control of p53 expression and other patient and treatment factors was examined by univariate and multivariate analyses. RESULTS: p53 expression has no prognostic significance for overall survival in this group of 123 patients. The only prognostic factor for survival in this material is tumor stage (p < 0.01). The actuarial pelvic recurrence rates of p53- and p53+ cases are different in favor of the p53- ones. In the univariate analysis this difference is significant (p = 0.05). However, in the multivariate analysis the influence of p53 expression, additional to stage, becomes nonsignificant (p = 0.10). This indicates that p53 expression is not a strong independent prognostic factor for pelvic recurrence. In the multivariate analysis stage turns out to be the only predictor of pelvic recurrence (p = 0.03). When only recurrences inside the radiation field are considered, there is no difference between p53+ and p53-cases. CONCLUSION: Based on this material, we have found no convincing evidence that p53 expression is an important predictor of survival or local control in rectal cancer treated with surgery and postoperative radiotherapy. We have found no evidence that possible differences in radiosensitivity between p53+ and p53- tumors have clinical significance for this group of patients.

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