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Biomedical subjects

T A Rich

Publications and source records attributed to T A Rich.

At least 19 recordsLinked to original sources
PubMed2001

Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer.

PURPOSE: To assess pelvic chemoradiotherapy (CXRT) without colostomy as a component of the multidisciplinary management of patients presenting with metastatic rectal cancer. METHODS AND MATERIALS: Eighty patients with synchronous distant metastases from rectal cancer were treated with initial CXRT. Hypofractionated radiotherapy was administered usually with concurrent 5-FU (92%, 300 mg/m(2)/day, M-F). Three-field belly-board technique was used in 89%. Group 1 had CXRT alone (n = 55). Group 2 (n = 25) patients were selected for primary disease resection, and sometimes HAI chemotherapy (n = 10) or hepatic resection (n = 5). Subsequently, 78% received systemic chemotherapy. RESULTS: Symptoms from primary tumor resolved in 94%. Endoscopic complete clinical response rate was 36%. Two-year survival (11% vs. 46%, p < 0.0001) and symptomatic pelvic control (PC, 81% vs. 91%, p = 0.111) were higher in Group 2, but colostomy-free rate (CFR) was lower (79% vs. 51% p = 0.02). CFR was 87% in Group 1 patients managed initially without fecal diversion (n = 50). Examining all patients using multivariate analysis, pelvic pain at presentation (p < 0.00001), BED (biologic equivalent dose at 2 Gy/fraction) < 35 Gy (p = 0.077), and poor differentiation (0.079) predicted worse PC. Poor differentiation (p = 0.017) and selection for CXRT alone (p < 0.0001) predicted worse survival. There were 4 RTOG of Grade 3 or greater acute complications, 5 severe perioperative complications, and no significant late treatment-related complications. CONCLUSION: Durable PC can be safely achieved without colostomy in most patients presenting with primary rectal cancer and synchronous systemic metastases using hypofractionated pelvic chemoradiation. A BED greater than 35 Gy is recommended. Selected patients appear to benefit from resection of primary disease. Higher doses should be investigated in patients with pelvic pain.

Adult↗
PubMed2001

A pilot study of preoperative chemoradiotherapy for resectable gastric cancer.

BACKGROUND: The goals of this study were to assess the feasibility and toxicity of a regimen of preoperative chemoradiotherapy, surgery, and intraoperative radiotherapy in the treatment of patients with potentially resectable gastric cancer. A secondary objective was to assess pathologic response to chemoradiotherapy in the treated tumors. METHODS: Twenty-four patients were entered in the protocol. Treatment regimen consisted of 45 Gy of external beam radiotherapy with concurrent 5-FU given as a continuous infusion at a dose of 300 mg/m2. Patients were restaged 4-6 weeks after chemoradiotherapy and then underwent surgical resection and intraoperative radiotherapy to a dose of 10 Gy. RESULTS: Twenty-three patients (96%) completed chemoradiotherapy in accordance with the study protocol. Nineteen (83%) of 23 patients who completed chemoradiotherapy underwent surgical resection with D2 lymphadenectomy. Four patients (17%) had progressive disease and were not resected. The morbidity and mortality rates were 32% and 5%, respectively. Of the resected patients, two (11%) had complete pathologic responses while 12 (63%) had pathologic evidence of significant treatment effect. CONCLUSIONS: Preoperative chemoradiotherapy for gastric cancer can be delivered safely and is well tolerated. The rate of surgical complications is consistent with that of other recently reported prospective trials of gastrectomy alone. Preoperative chemoradiotherapy resulted in significant pathologic responses in the majority of treated tumors, and complete pathologic responses were achieved in some patients.

Adenocarcinoma↗
PubMed2001

A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer.

BACKGROUND: Dose limiting acute toxicity from chemoradiation for pancreatic cancer occurs in 15% -20% of patients treated with post-operative adjuvant therapy. Reported here is a pilot study using chronomodulated infusional 5-fluorouracil (5-FU) chemoradiation (CIC) for pancreatic cancer, a treatment designed to reduce normal tissue toxicity and maintain efficacy, with specific evaluation of acute and late morbidity, patterns of disease progression, and survival. PATIENTS AND METHODS: Twenty-three patients with adenocarcinoma of the pancreas were treated with 5-FU CIC between January 1997 and September 1999. The median age was 64, and there were 9 males and 14 females. Six patients were considered unresectable and seventeen others were treated post-operatively. The median external beam irradiation dose was 50.4 Gy. 5-FU infusion was given five days per week (300 mg/m2/d) and the median total dose was 8.4 g/m2. The chronomodulated 5-FU infusion consists of a low basal infusion rate for 16 hours followed by an eight-hour escalating-deescalating infusion peaking at 10 p.m. All patients were followed from the time of initial diagnosis until last follow-up or death; the median follow-up was 16 months. RESULTS: No RTOG grade 3 or 4 hematologic toxicity occurred. Twelve of seventeen patients treated postoperatively have been controlled locally, and seven patients have no evidence of disease. The median survival is 28 months and one-year actuarial survival is 88% in the group of resected patients. The 6 patients treated for unresectable disease have a median survival of 13 months. CONCLUSIONS: Acute toxicity of 5-FU CIC appears to be less frequent and less severe than that reported with flat infusional or bolus 5-FU based chemoradiation used for adjuvant post-operative therapy for pancreatic cancer. This method may warrant further examination, as it may be attractive for the elderly or those who cannot tolerate the toxicity associated with standard post-operative treatment protocols.

Adenocarcinoma↗
PubMed2001

Camptothecin schedule and timing of administration with irradiation.

The camptothecins are a new class of chemotherapeutic radiation sensitizers. Clinical trials with camptothecins alone show higher toxicity than predicted by preclinical models, which has created the challenge of finding new ways to widen the therapeutic window. Camptothecin dose, schedule, and timing with irradiation are important factors that need to be considered in the design of new studies with these S-phase agents. Data are reviewed from early phase I and II chemoradiation trials, including a multicenter, phase II study planned by the Radiation Therapy Oncology Group (RTOG) in operable rectal cancer using irinotecan (CPT-11, Camptosar). One novel approach (based on preclinical observations) with the potential to widen the therapeutic window may be the use of a chronomodulated camptothecin delivery schedule with irradiation.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Modulation of dose intensity in aerodigestive tract cancers: strategies to reduce toxicity.

Advances in diagnostic and therapeutic radiology and a better understanding of cell biology are being applied in practical ways to modulate treatment morbidity. Conformal radiotherapy targets the cancer precisely and can be combined with new systemically administered radiosensitizers. The successes of conventional chemoradiation programs support continued study of newer ways to deliver systemic radiosensitizing chemotherapy. However, chemoradiation creates a narrower therapeutic window compared to irradiation alone and increased treatment intensity, even with conformal chemoradiation techniques, can potentially result in frequent complications, detrimental treatment delays, and decreased quality of life. Treatment schedules employing a "best tolerated time" modelfor systemic administration of radiosensitizing chemotherapy, based on the concept of chronotolerance, offer attractive ways to address the challenging problem of normal tissue toxicity associated with conformal chemoradiation. This approach may be beneficial in the elderly and those medically unfit to tolerate traditional dose-intense combined-modality schedules. Further evaluation of this concept is warranted, based on existing data.

Antineoplastic Agents↗
PubMed2000

Nuclear scintigraphic assessment of intestinal dysfunction after combined treatment with 9-amino-20(S)-camptothecin (9-AC) and irradiation.

PURPOSE: The camptothecins (CPTs) are potent radiosensitizers of malignant tumors in vivo. The extent of normal tissue damage after combined CPT and radiation treatment is unknown. In this article, a jejunal absorption assay with (99m)Tc- pertechnetate (Na[(99m)TcO(4)]) was used to assess C3H/Kam mice given total body irradiation (TBI) of 4 Gy, 6 Gy, and 8 Gy, 2 mg/kg single intramuscular injection of 9-AC or a combination of 2 mg/kg 9-AC + 4 Gy TBI. We also correlated the absorption data with morphologic changes in the jejunal mucosa. MATERIALS AND METHODS: ((99m)TcO(4))(-) absorption from the intestinal lumen into the circulation was studied with dynamic gamma-scintigraphy combined with a multichannel analyzer to record the radiometry data in a time-dependent fashion. Jejunal cross sections were scored for the number of cells per villus and the percentage of apoptotic and mitotic cells in the crypt compartment. The jejunal microcolony assay was used to quantify jejunal crypt survival. RESULTS: A dose-dependent decrease in the absorption function was observed 3.5 days following TBI. The mean absorption rate was reduced to 89 +/- 16% of control in response to a sublethal 4 Gy TBI and dropped to 47. 5 (9.8% in response to 8 Gy TBI. The mean rate of intestinal absorption was delayed by single sublethal 2 mg/kg 9-AC injection to 62 (11% in comparison with control values. The combination of a single 4 Gy TBI with a 9-AC treatment decreased the ((99m)TcO(4))(-) jejunal absorption in an additive fashion producing absorption lifetime values more than twofold longer than controls. The decrease in ((99m)TcO(4))(-) absorption at 3.5 days after irradiation, 9-AC treatment or the combination of the two agents correlates with the number of cells per villus and the percentage of apoptotic cells in the crypt compartment. CONCLUSION: Dynamic enteroscintigraphy with (99m)Tc-pertechnetate is a sensitive functional assay for rapid evaluation of radiation and chemotherapy induced intestinal damage. Reduced intestinal absorptive function has a cellular basis and correlates directly with the numbers of cells lost per villus in a treatment-dependent manner.

Animals↗
PubMed2000

Avoidance of colostomy placement in advanced colorectal cancer with twice weekly hypofractionated radiation plus continuous infusion 5-fluorouracil.

The purpose of this study was to determine the efficacy of twice weekly hypo-fractionated radiation therapy (RT) plus continuous infusion 5-fluorouracil for unresectable or locally advanced colorectal cancer with synchronous metastases. Palliative radiation consisting of 30 Gy/6 fractions/3 weeks was administered to 87 patients from 1982-1995 with 3 field belly board technique. Diverting colostomy was required for obstruction in 14 (16%) prior to radiation; 47 patients (54%) had recurrent disease following prior resection and 58 (66%) had distant metastases on presentation. Median follow-up was 12 months (1-104 months). Stabilization/regression of pelvic disease was accomplished in 65 patients (75%). Complete resection of the pelvic disease was accomplished in 5 patients (6%), all of whom had synchronous metastases. Diverting colostomy was required in only 11 patients after chemoradiation because of progressive pelvic tumor; 2 of these 11 patients (18%) had isolated progression of pelvic disease. Overall, colostomy was not required in 48 of the 72 patients (67%) who did not present with a stoma. Median survival was 11 months if metastatic disease was present and only 6 months when disease was limited to the pelvis. Grade 3 acute radiation toxicities occurred in <10% and no grade 4 acute toxicities were observed. No significant late radiation effects were noted. Twice weekly hypofractionated RT is well tolerated and provides durable palliation of symptoms related to locally advanced primary or recurrent colorectal cancer with metastatic disease.

Colorectal Neoplasms↗
PubMed2000

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.

Adenocarcinoma↗
PubMed2000

Nuclear scintigraphic assessment of radiation-induced intestinal dysfunction.

Radiation-induced damage to the intestine can be measured by abnormalities in the absorption of various nutrients. Changes in intestinal absorption occur after irradiation because of loss of the intestinal absorptive surface and a consequent decrease in active transport. In our study, the jejunal absorption of (99m)Tc-pertechnetate, an actively transported gamma-ray emitter, was assessed in C3H/Kam mice given total-body irradiation with doses of 4, 6, 8 and 12.5 Gy and correlated with morphological changes in the intestinal epithelium. The absorption of (99m)Tc-pertechnetate from the intestinal lumen into the circulation was studied with a dynamic gamma-ray-scintigraphy assay combined with a multichannel analyzer to record the radiometry data automatically in a time-dependent regimen. The resulting radioactivity-time curves obtained for irradiated animals were compared to those for control animals. A dose-dependent decrease in absorptive function was observed 3.5 days after irradiation. The mean absorption rate was reduced to 78.8 +/- 9.3% of control levels in response to 4 Gy total-body irradiation (mean +/- SEM tracer absorption lifetime was 237 +/- 23 s compared to 187 +/- 12 s in nonirradiated controls) and to 28.3 +/- 3.7% in response to 12.5 Gy (660 +/- 76 s). The decrease in absorption of (99m)Tc-pertechnetate at 3.5 days after irradiation correlated strongly (P < 0.001) with TBI dose, with the number of cells per villus, and with the percentage of cells in the crypt compartment that were apoptotic or mitotic. A jejunal microcolony assay showed no loss of crypts and hence no measured dose-response effects after 4, 6 or 8 Gy TBI. These results show that dynamic enteroscintigraphy with sodium (99m)Tc-pertechnetate is a sensitive functional assay for rapid evaluation of radiation-induced intestinal damage in the clinically relevant dose range and has a cellular basis.

Animals↗
PubMed1999

Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience.

PURPOSE: To evaluate the rates of tumor downstaging after preoperative chemoradiation for locally advanced rectal cancer. MATERIALS AND METHODS: Preoperative chemoradiotherapy (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. RESULTS: The pathological tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4NI in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor downstaging occurred in 72 (62%) cases. Only 3% of cases had pathologic evidence of progressive disease. Pretreatment tumor size (< 5 cm vs. > or = 5 cm) was the only factor predictive of tumor downstaging (p < 0.04). A decrease of > 1 T-stage level was accomplished in 45% of those downstaged. Overall, a sphincter-saving (SP) procedure was possible in 59% of patients and an abdominoperineal resection (APR) was required in 41 % of cases. Factors predictive of SP included downstaging (p < 0.03), age > 40 years (p < 0.007), pretreatment tumor distance, 3 to 6 cm from the anal verge (p < 0.00001), tumor size <6 cm (p < 0.02), mobility (p < 0.004), tumor stage 6 cm from the anal verge, SP was performed in 14 of the 15 (93%) patients with a CR and 32 of 33 (97%) of patients with residual disease (p < 0.00004). CONCLUSIONS: Significant tumor downstaging results from preoperative chemoradiation allowing sphincter sparing surgery in over 40% of patients whose tumors were located < 6 cm from the anal verge and who otherwise would have required colostomy.

Adult↗
PubMed1999

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.

Animals↗
PubMed1999

Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: To evaluate the influence of response to preoperative infusional chemoradiation on outcome parameters among patients with locally advanced rectal cancer. MATERIALS AND METHODS: Preoperative chemoradiotherapy, 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2 per day), was given to 117 patients. As determined by pretreatment endorectal ultrasound (EUS), 96% of cases were Stage T3, and 51% had EUS evidence of perirectal adenopathy. Surgery was performed approximately 6 weeks after chemoradiation therapy. Postoperatively adjuvant systemic therapy, consisting of 400-425 mg/m2 of 5-fluorouracil plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for six cycles. Outcome parameters of local control (LC), freedom from distant metastases (DMC), disease-free survival (DFS) and cancer specific survival (CSS) were evaluated relative to primary tumor characteristics. RESULTS: The final post-treatment pathological tumor stages were complete response in 27%, Tis-2 N0 in 26%, T2 N1 in 5%, T3 N0 in 21%, T3 N1 in 15%, T4 N0 in 5% and T4 N1 in 1%. Down-staging occurred in 61% of cases. The pretreatment primary tumor size only influenced rates of local control (P < 0.03) and had no other influence on outcome parameters. Pretreatment evidence of perirectal lymph node involvement had no impact on outcome parameters. Pathologic evidence of nodal involvement did affect DMC (P < 0.002) and DFS (P < 0.003). Pathologic evidence of response did influence freedom from the development of distant metastases (P < 0.004). On pairwise analysis this relationship held only when responders were compared to non-responders. No difference was observed based on the level of downstaging at the primary tumor. Correspondingly, DFS was improved when non-responders were compared to downstaged patients (P < 0.01). Response to preoperative chemoradiation failed to affect rates of LC or CSS. For the group as a whole, adjuvant chemotherapy improved only CSS (P < 0.03). Adjuvant chemotherapy was given to 74 patients, 36 of whom had responded to preoperative chemoradiation. Improvements were only seen in DFS (P < 0.03) when down-staged patients were compared to the non-responders who received adjuvant chemotherapy. In addition, the DFS rates were lower in the non-responder group who received adjuvant chemotherapy even when they were compared to down-staged patients who did not receive adjuvant chemotherapy (P < 0.04). CONCLUSION: Consistent with other reports, disease free survival and subsequent development of distant metastases is reduced in the more than 60% of patients who respond to preoperative infusional chemoradiation. Evidence of response appears more significant than the degree of response. At present, no impact is seen on cancer specific survival rates. Consideration should be given for strategies that base selection of subsequent adjuvant chemotherapy on response to preoperative chemoradiation.

Adult↗
PubMed1999

Non-metastatic Ewing's sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy.

Eighty-five patients (37 female, 48 male; median age 14 years) with non-metastatic Ewing's sarcoma received definitive treatment at the University of Texas M.D. Anderson Cancer Center between 1969 and 1988. Multidisciplinary therapy was administered as follows: combination chemotherapy (CC) and local radiotherapy (XRT): 65 patients; CC, XRT and surgery, 19 patients; and XRT and surgery, 1 patient. This permitted a 10-20 year follow-up for 75% of our patients. The overall survival at 5 and 10-20 years was 46.1%, and 37.2%, respectively. At 5 years, 80.5% of live patients had control of local disease. The influence of sex, age, ethnicity, primary site, size, lactic dehydrogenase (LDH) level, presence or absence of systemic symptoms, and XRT dose (<60 Gy and </=60 Gy) was analyzed and was not found to be of prognostic significance in survival. The presence of a soft tissue mass at diagnosis was found to be a significant unfavorable prognostic variable. Nine of 11 patient who underwent resection after CC and/or XRT had residual tumor in the surgical specimen. Patients who received surgery as part of the planned treatment of their primary tumor had significantly better local control and disease-free survival than those who did not undergo resection. Complications in long-term survivors are described.

Adolescent↗