Hypofractionated radiotherapy with concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced colorectal cancer. A phase II study

In a pilot study we treated 19 patients suffering from recurrent or locally advanced inoperable colorectal cancer, with concurrent hypofractionated radiotherapy (4-5 Gy/fraction, 2 fractions per week) and 5-fluorouracil bolus, 1 hour before RT at doses of 300 mg/m2. For 16 patients treated with radical intent the Normalised Total Dose for alpha/beta = 10 Gy ranged between 56-74 Gy (median 62 Gy). The schedule used was very well tolerated. Moderate grade II haematological toxicity was observed in 11% of cases and diarrhoea grade II/III resulting in 2-4 weeks treatment delay was observed in 26% of cases. One case with bowel perforation and one with painful subcutaneous fibrosis was observed during 12-27 months of follow-up. Out of 16 patients treated with radical intent 4 (25%) showed complete response and the overall response rate was 56% (9/16). The one-year symptom-free survival was obtained in 11/16 (69%) radically treated patients. It is concluded that hypofractionated radiochemotherapy with 5-fluorouracil for recurrent or locally advanced colorectal cancer is an effective regimen and has acceptable acute and late toxicity. Further investigation is required.     

Asymptomatic carotid endarterectomy. Patient and surgeon selection

PURPOSE: The detection of an infraclinical primary by tonsillectomy in case of cervical lymph node of an epidermoid carcinoma with unknown primary after a radical neck dissection, allows avoiding irradiation of the normal larynx. The aim of this study is to quantify the rate of tonsil primary to justify this procedure. METHODS AND MATERIALS: From 1969 to 1992, 87 patients had a tonsillectomy as part of the workup for cervical nodal metastasis of an epidermoid carcinoma with unknown primary. The mean age was 57 years (range: 39-75 years) and the sex ratio was 8.6. Sixty-seven patients had a single cervical adenopathy (17 N1, 30 N2a, 5 N3, 15 Nx), and 20 patients multiple cervical adenopathies (17 N2b, 3 N2c). The treatments included always an irradiation to the node areas (50 Gy), and to the pharyngolarynx in case of normal tonsil (50 Gy), or to the tonsil if it was the primary (50 Gy with a brachytherapy boost of 20-25 Gy). In this last case, the larynx could be protected. RESULTS: Tonsillectomy never induced specific complication. Out of 87 patients, 26% had a tonsil primary. There was not specific histological differentiation in this group. In the 67 patients with a single cervical adenopathy, 31% had a tonsil primary (6 N1, 7 N2, 1 N3, 7 Nx). It was a subdigastric adenopathy in 38%, a submandibular in 28% and a midjugulocarotidian in 23%. Among the 17 patients N2b, none had a tonsil primary. In the three patients N2c, two presented a tonsil carcinoma (two subdigastric nodes). CONCLUSION: Tonsillectomy allows avoiding irradiation of normal larynx in 26% of patients who have a cervical lymph node with unknown primary. It should be performed in case of a single node of the subdigastric, midjugulocarotidian or submandibular area or bilateral subdigastric adenopathies.     

The value of conventionally fractionated radiotherapy in the local treatment of HIV-related Kaposi's sarcoma

BACKGROUND: During the course of AIDS, 25 to 44% of homosexual patients infected with the human immunodeficiency virus develop Kaposi's sarcoma. Main manifestation is the skin. Response rates of 80 to 100% can be achieved with total dosage up to 50 Gy. Nevertheless, remissions can also be attained with 20 Gy of fractionated radiotherapy. As clinical data on low dose conventional fractionated radiotherapy are insufficient we analysed the response rates of an overall dose of 20 Gy in conventional fractionation. PATIENTS AND METHODS: From June 1991 to June 1993, 43 patients with 111 HIV-associated Kaposi's sarcoma of the skin or oral cavity were treated. Lesions were irradiated with 5 to 12 MeV electrons or 60Co gamma-rays. The fractionation scheme was 5 times 2 Gy/week for skin and endoral lesions with a total reference dosage of up to 20 Gy. Side effects were assessed during therapy and the therapeutic result 6 weeks after end of treatment. RESULTS: Thirty-eight out of 111 lesions were judged as complete response (CR) (34%), 61/111 as partial response (PR) (55%) and 12/111 were judged as no change (NC) (11%). Overall response (CR + PR) was 89%. Two patients with lesions of oral cavity suffered from RTOG grade-IV mucositis after 10 and 14 Gy. In 71/106 skin lesions (67%), radiation induced RTOG grade-1 reactions were observed. CONCLUSION: In patients with HIV associated Kaposi's sarcoma effective palliation can be achieved by means of radiotherapy with an overall dose of 20 Gy in conventional fractionation. Yet, the fraction of patients with complete responses is with 34 to 47% lower compared with doses above 20 Gy (66 to 100%). With reference to the reported data our results point to a dose-response relationship for Kaposi's sarcoma. Therefore higher total reference doses, e.g. 30 Gy with weekly 5 times 2 Gy or 24 Gy with 5 times 1.6 Gy for mucous lesions, respectively, are suggested as by this mean the complete response rate can be doubled.     

Molecular analysis of Plasmodium vivax relapses using the MSP1 molecule as a genetic marker

PURPOSE: To evaluate radiation therapy regimens for improvement in local control in patients with limited-stage small cell lung cancer. MATERIALS AND METHODS: Radical radiation therapy results in 117 patients with limited-stage small cell lung cancer were retrospectively reviewed. The protocols in 90 patients were 40 Gy in 20 fractions (n = 28), 50 Gy in 25 fractions (n = 32), and 45 Gy in 30 fractions (accelerated hyperfractionation, n = 30). The other 27 patients received thoracic irradiation (dose range, 20-60 Gy; median dose, 54 Gy). All patients underwent systemic chemotherapy. RESULTS: The 5-year Kaplan-Meier survival rates in the patients with N0, N1, N2, and N3 disease were 26%, 34%, 18%, and 0%, respectively; the rates of in-field relapse were 25%, 36%, 26%, and 25%, respectively; and the rates of marginal relapse were 0%, 9%, 15%, and 29%, respectively. In 56% of patients with marginal relapse, the relapse site was at the upper margin. The 4-year in-field control rates for the patients who underwent 40, 50, and 45 Gy were 51%, 70%, and 56%, respectively. CONCLUSION: Patients with N3 limited-stage small cell lung cancer should undergo a separate protocol, and the upper margin should be extended in patients with N2 or N3 disease.     

Combination chemotherapy (cisplatin, vinblastin) and low-dose irradiation in the treatment of pineal parenchymal cell tumors

Pineal parenchymal cell tumors (PPCTs) with or without metastasis into the lumbar region by way of the cerebrospinal fluid were treated successfully with combination chemotherapy using cisplatin, vinblastin, and bleomycin (PVB) or cisplatin and vinblastin (PV) and low-dose irradiation (25 approximately 30 Gy). Our series included a case of pineoblastoma, two cases of mixed pinocytoma/pineoblastoma, and a case of pineocytoma, compared to which the data held by the All Japan Brain Tumor Registry (AJBTR) included information on 47 cases pineocytoma and 20 of pineoblastoma. All our patients have survived, with scores of 90% or over on Karnofsky's performance scale, for 2-12 years of follow-up so far; however, the 5-year survival rates of the patients recorded by AJBTR were 83% for pineocytoma treated with radiation and 43% without radiation; and 42% for pineoblastoma treated with radiation and 50% without radiation. Incomplete or varied chemotherapeutic regimens used in different medical centers to treat PPCTs precluded an evaluation such as was made by AJBTR. Our results suggested that combination chemotherapy with low-dose back-up radiotherapy may be the treatment of choice for primary or recurrent disease with or without dissemination in PPCTs.     

Determination of factors affecting the therapeutic outcome of radioiodine therapy in patients with Graves' disease

AIM: Of this study was to determine whether success of radioiodine therapy (RIT) in Graves' disease depends on thyroid volume, function, thyroideal receptor antibodies (TRAK), thyreostasis, therapeutic dosage, 131I uptake, or effective half-life. METHOD: 78 patients received an average of 626 +/- 251 MBq of iodine-131 orally for thyroid ablation. 60 were assessed for successful therapy 3 months after RIT. RESULTS: In patients showing hyperthyreosis or a TRAK value > 11 U/l at the beginning of RIT, a significantly lower therapeutic dosage and effective iodine half-life were found than in non-hyperthyreotic patients or patients with TRAK < or = 11 U/l. Patients with a thyroid volume < or = 25 ml showed a significantly lower 131I uptake, but a significantly higher relative uptake (131I uptake/ volume) than patients with a thyroid volume > 25 ml. All failures were treated thyreostatically during RIT and showed a significantly lower therapeutic iodine dosage and relative uptake, as well as a significantly higher thyroid volume than patients with a successful therapy. RIT caused a thyroid volume reduction of 44%, with therapy failures showing a significantly lower volume reduction. Patients who received a therapeutic dosage of < or = 250 Gy showed significantly worse results than did those who had received > 250 Gy. Only one case of therapy failure received a dosage > 250 Gy, while 50% of failures received dosages > 200 Gy but < 250 Gy. Multivariate analyses (MANOVA, factor analyses) showed thyreostasis as the decisive negative factor for a successful course of therapy. CONCLUSIONS: Since most treatment failures occurred in patients under thyreostatic medication we recommend raising the target dosage to 250 Gy for these cases.     

Combined radiation therapy and cisplatin for locally advanced carcinoma of the urinary bladder

BACKGROUND: This study evaluates feasibility and results of combined treatment of cisplatin and radiation therapy for patients with inoperable invasive bladder carcinoma. METHODS: From January 1988 to October 1991, 69 patients received radiation therapy and concomitant cisplatin. Median age was 71 years. Most tumors were locally advanced and high grade. A macroscopically complete transurethral resection was performed initially in 18 patients. Dose of pelvic radiation ranged from 40 Gy to 45 Gy, and total dose to the bladder ranged from 55 Gy to 60 Gy. Concomitant continuous cisplatin infusion at a dose of 20-25 mg/m2/day for 5 days was delivered during the 2nd and 5th weeks of radiation. RESULTS: As of April 1993, the median follow-up time was 36.4 months (range, 18-70 months). Ninety-one percent of the patients completed radiation therapy as planned, and 78.3% completed two courses of chemotherapy. Despite one treatment-related death due to renal failure, toxicity was generally mild and acceptable. Sixty-three patients were evaluable for response. Forty-eight patients (76.2%) achieved a complete response. Actuarial overall 3-year survival rate was 37.1% for all patients. Among the patients who experienced complete response, the 3-year actuarial local control and disease-free survival rates were 65.4% and 56.3%, respectively. Twenty-six patients (37.7%) are alive and disease-free with bladder preservation. One patient is alive and disease-free after salvage cystectomy. CONCLUSIONS: Concomitant cisplatin and radiation therapy offers high probability of complete response and local control in patients with invasive bladder cancer unsuitable for surgery. These results provide a basis for randomized studies comparing this approach with conventional therapy for patients with operable carcinoma.     

A case of left main bronchus obstruction due to recurrent esophageal cancer successfully treated by Nd-YAG laser followed by radiotherapy, low-dose CDDP and continuous infusion of 5-FU

A 63-year-old female patient with obstruction of left main bronchus due to recurrent esophageal cancer was treated by emergency Nd-YAG laser therapy under bronchoscopy. Severe dyspnea subsided dramatically and she was the given radiotherapy with a total dose of 50 Gy (2 Gy/f and 25 f/5 wks). Concurrent chemotherapy was performed at the 3rd week of radiation therapy. In this chemotherapy of CDDP plus 5-FU, CDDP (10 mg/day) was given for 5 days by intravenous and 5-FU (500 mg/day) for 5 days by continuous infusion the same week. By this treatment, a partial response (PR) was obtained, and the patient returned to normal life. But after 4 months, she had a recurrent lesion at the same place, and underwent only palliative laser therapy. Nd-YAG laser therapy for obstructive lesion of trachea due to recurrent cancer is the most useful one, but some subsequent treatment is required.     

Fecundity changes induced by low-doses of gamma radiation on Biomphalaria straminea (Dunker, 1848)

A population of 420 snails Biomphalaria straminea, an intermediate host of Schistosoma mansoni, received gamma-rays obtained from a 60Co source in low-doses (0/2,5/5/7,5/10/15/20 and 25 Gy); half population was kept in colonies (allowing cross fertilization) and the other half was maintained in sexual isolation (allowing self fertilization). Results showed that 15 Gy stimulates the fertility of both groups but the colonies were more sensitive and at this dose its fertility overpasses the control group dose. The possible hormonal role played in the observed phenomena is under investigation.     

Radiation therapy in the management of desmoid tumors

PURPOSE: To evaluate the outcome of patients with extra-mesenteric desmoid tumors treated with radiation therapy, with or without surgery. METHODS AND MATERIALS: The outcome for 75 patients receiving radiation for desmoid tumor with or without complete gross resection between 1965 and 1994 was retrospectively reviewed utilizing univariate and multivariate statistical methods. RESULTS: With a median follow-up of 7.5 years, the overall freedom from relapse was 78% and 75% at 5 and 10 years, respectively. Of the total, 23 patients received radiation for gross disease because it was not resectable. Of these 23 patients, 7 sustained local recurrence, yielding a 31% actuarial relapse rate at 5 years. Radiation dose was the only significant determinant of disease control in this group. A dose of 50 Gy was associated with a 60% relapse rate, whereas higher doses yielded a 23% relapse rate (p < 0.05). The other 52 patients received radiation in conjunction with gross total resection of tumor. The 5- and 10-year relapse rates were 18% and 23%, respectively. No factor correlated significantly with disease outcome. There was no evidence that radiation doses exceeding 50 Gy improved outcome. Positive resection margins were not significantly deleterious in this group of irradiated patients. For all 75 patients, there was no evidence that radiation margins exceeding 5 cm beyond the tumor or surgical field improved local-regional control. Ultimately, 72 of the 75 patients were rendered disease-free, but 3 required extensive surgery (amputation, hemipelvectomy) to achieve this status. Significant radiation complications were seen in 13 patients. Radiation dose correlated with the incidence of complications. Doses of 56 Gy or less produced a 5% 15-year complication rate, compared to a 30% incidence with higher doses (p < 0.05). CONCLUSIONS: Radiation is an effective modality for desmoid tumors, either alone or as an adjuvant to resection. For patients with negative resection margins, postoperative radiation is not recommended. Patients with positive margins should almost always receive 50 Gy of postoperative radiation. Unresectable tumors should be irradiated to a dose of approximately 56 Gy, with a 75% expectation of local control.     

Hereditary deficiency of vitamin K-dependent coagulation factors with skeletal abnormalities

Thirteen patients with localized unresectable pancreas carcinoma were treated with a combination of accelerated radiotherapy and 5-fluorouracil. Radiotherapy consisted in 3 fractions of 1.1 Gy per day during 3 weeks up to a total dose of 45-50 Gy. 5-Fluorouracil was administered as continuous infusion in a dosis of 25 mg/kg/24 h the first and the third week concomitantly to radiotherapy. Grade 3 mucositis, diarrhoea and nausea/vomiting were observed in 15% of the patients. Eleven patients completed the treatment without modifications and in two patients the dose of 5-fluorouracil was reduced to 75% during the third week of treatment. Radiotherapy was always administered as planned. Median survival was 36 weeks.     

Specificity of the BAX polymerase chain reaction system for detection of the foodborne pathogen Listeria monocytogenes

PURPOSE: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. METHODS AND MATERIALS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m2, days 1 and 22) and 5-FU (1000 mg/m2/24 h x 4 days; days 1 and 22) were given for two or three cycles. RESULTS: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.     

Surgeons'' opinions about the NHMRC clinical practice guidelines for the management of early breast cancer

BACKGROUND: In-vitro and in-vivo studies demonstrated the radiosensitizing effect of interferon beta on malignant tumor tissue as well as simultaneously a radioprotective effect on normal lung tissue. In this phase II study the outcome of combining radiotherapy with interferon beta in patients with advanced non-small cell lung cancer was evaluated. PATIENTS AND METHOD: From February 1994 until November 1996 14 patients with non-small cell lung cancer, stage IIIB were treated with locoregional radiation up to 59.4 Gy, with daily doses of 1.8 Gy and 5 fractions per week. Five million units of interferon beta (Fiblaferon) were given intravenously immediately preceding radiotherapy on the first 3 days of week 1, 3 and 5. RESULTS: Four of 14 patients (28.6%) showed complete response and 7 patients (50%) partial response, resulting in an overall response rate of 78.6%. After a mean follow-up time of 23.3 months the 1-, 2- and 3-year survival rates were 56.3%, 37.5% and 37.5%, respectively. The median survival time was 13 months. Three of 14 patients (21.4%) suffered from 7 Grade-3 acute side effects and 2 patients (14.3%) from 1 Grade-3 late toxicity in each case. One further patient, whose right lung was resected 3 months after completion of radiotherapy, developed as a consequence of this operation 2 Grade-4 complications. CONCLUSION: Considering the toxicity and the preliminary results of combining irradiation and interferon beta in the treatment of locally advanced non-small cell lung cancer it seems, that this procedure is worth to be tested in a phase III study.     

Perceptions of tonal changes in normal laryngeal, esophageal, and artificial laryngeal male Cantonese speakers

PURPOSE: Present radiobiological studies for different cell lines in vitro demonstrate the equivalence and efficacy of continuous low-dose-rate brachytherapy (LDR-BT) and pulsed dose rate brachytherapy (PDR-BT) when using small and frequent dose pulses. The aim of this study was to examine monolayer fibroblast cultures in vitro to examine the biological effects of different pulse doses and dose rates under clinically conditions. MATERIAL AND METHODS: B14 cells, Hy B14 FAF 28, peritoneal fibroblasts, were cultured in multi-well plates and exposed to a PDR radiation source at a distance of 9 mm. The following PDR-schemes were compared: dose per pulse: 1 Gy, 2.5 Gy and 5 Gy to a total dose of 5 Gy/5 h (overall time), 10 Gy/10 h, 20 Gy/20 h and 30 Gy/30 h. The pulse duration for the examination of dose rate effects was 20 min, 30 min or 52 min corresponding by dye pulse dose rate of 300 cGy/h, 200 cGy/h or 115 cGy/h. Treatment endpoints were cell measured by dye exclusion test and clonogenic cell survival. RESULTS: Cell survival decreased for pulse doses of 5 Gy compared to 2.5 Gy or 1 Gy per pulse (mean dose rate 200 to 300 cGy/h). No differences were observed with dose rates during irradiation of 300 cGy/h, 200 cGy/h or 115 cGy/h (20 Gy/1 Gy). CONCLUSION: Radiobiological effects of PDR-RT are dependent on the dose per pulse, with differences in biological effects only with a dose per pulse of more than 2.5 Gy, considering the described in-vitro conditions. More examinations with a more pronounced difference in dose rate will be continued for evaluation of dose rate effects.     

Radiotherapy and local control in rectal cancer

Recurrence is a stage in the natural history of rectal cancer. Preoperative radiotherapy or postoperative radiochemotherapy lower the rate of recurrence, improving local control. From 1980 to 1997, at the "Divisione di Radioterapia" of the "Università Cattolica del S. Cuore" of Rome 380 patients with rectal cancer of early clinical stage T2-3, candidates for surgery for cure, underwent radiation therapy. 119 patients underwent postoperative radiotherapy (45-50 Gy); 45 patients underwent "sandwich" radiotherapy (45 Gy:27 Gy before and 28 Gy after surgery), of whom 7 were treated with preoperative radiotherapy alone; 145 patients underwent preoperative concomitant radiochemotherapy according to 3 different protocols, radiotherapy (38 Gy) combined with mitomycin C and 5-FU; radiotherapy (50.4 Gy) combined with cisplatin and 5-FU; radiotherapy (45 Gy) combined with 5-FU and folinic acid. 71 patients were treated with preoperative radiotherapy (38 Gy) combined with IORT (10 Gy). Median follow-up was 6 years. Overall local control was 85% at 3 years, 83% at 5 years, 81% at 10 years. The rate of local control at 5 years was: 76% for postoperative radiotherapy, 83% for "sandwich" radiotherapy, 84% for preoperative radiochemotherapy and 93% for preoperative radiotherapy combined with IORT. Local control was shown to be significantly better with preoperative treatment as compared to postoperative treatment (p = 0.02). The incidence of metastases was 35% in the patients with local recurrence and 16% in those with local control. The difference in survival was highly significant in patients with local control as compared to those with local recurrence: at 5 years 87% and 32% respectively. Patients with local control showed a lower incidence of metastasis and a better survival.     

Zamifenacin (UK-76, 654) a potent gut M3 selective muscarinic antagonist, reduces colonic motor activity in patients with irritable bowel syndrome

PURPOSE: Retrospective studies suggest that prolonged treatment time adversely affects control rates of squamous carcinomas managed by radiotherapy. From 1989 to 1994 a prospective clinical trial was conducted to assess the feasibility and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for advanced uterine cervical carcinoma. METHODS AND MATERIALS: Twenty newly diagnosed patients with FIGO stage III squamous cell carcinoma of the cervix were irradiated using a CBASF regimen. Patients received 45 Gy administered to the whole pelvis in 25 fractions in 5 weeks. On Monday, Wednesday, and Friday of the last 3 weeks, an additional 1.6 Gy boost was given 6 hours after the whole pelvis treatment. The 9 boost treatments, totaling 14.4 Gy, were given via lateral fields encompassing the parametria and primary tumor for a cumulative tumor dose of 59.4 Gy. A single low-dose rate brachytherapy procedure was performed within 1 week after the external beam radiotherapy to raise the point A dose to 85-90 Gy in 42 days. Primary endpoints of analysis were local control, complications, and patterns of failure. Results are compared with the outcomes of 21 patients treated with conventionally fractionated (CF) radiotherapy during the same years. RESULTS: Median total treatment time was 46 days in the CBASF group (range 37-62). Median follow-up interval among surviving CBASF patients is 3.8 years. The four-year actuarial local control rates are 78% and 70% in the CBASF and CF groups, respectively (p = ns). Only 2 CBASF patients required a treatment break because of acute toxicity, but severe late complications occurred in 8/20 CBASF patients for a crude rate of 40%. Distant failure was more common than local failure in the CBASF group, and para-aortic node failure occurred in six of the eight CBASF patients with distant failure. CONCLUSIONS: In the management of stage III cervix cancer, the CBASF regimen produced a trend toward improved local control when compared with the CF regimen, shifting the patterns of failure toward a higher rate of isolated distant failures. The high frequency of para-aortic node failure warrants consideration of elective treatment to this region in stage III patients treated with curative intent. Although the high local control rate of the CBASF regimen supports further investigation of accelerated treatment regimens for locally advanced cervix cancer, the unacceptable risk of late complications necessitates refinement in technique and scheduling to improve the therapeutic ratio.     

Direction of predator approach and the decision to flee to a refuge

PURPOSE: We report the local control and survival of two Phase I dose escalation trials of combined preoperative 5-fluorouracil (5-FU), low-dose leucovorin (LV), and radiation therapy followed by postoperative LV/5-FU for the treatment of patients with locally advanced and unresectable rectal cancer. METHODS AND MATERIALS: A total of 36 patients (30 primary and 6 recurrent) received two monthly cycles of LV/5-FU (bolus daily x 5). Radiation therapy (50.40 Gy) began on day 1 in the 25 patients who received concurrent treatment and on day 8 in the 11 patients who received sequential treatment. Postoperatively, patients received a median of four monthly cycles of LV/5-FU. RESULTS: The resectability rate with negative margins was 97%. The complete response rate was 11% pathologic and 14% clinical for a total of 25%. The 4-year actuarial disease-free survival was 67% and the overall survival was 76%. The crude local failure rate was 14% and the 4-year actuarial local failure rate was 30%. Crude local failure was lower in the four patients who had a pathologic complete response (0%) compared with those who either did not have a pathologic complete response (16%) or who had a clinical complete response (20%). CONCLUSION: Our preliminary data with the low-dose LV regimen reveal encouraging downstaging, local control, and survival rates. Additional follow-up is needed to determine the 5-year results. The benefit of downstaging on local control is greatest in patients who achieve a pathologic complete response.     

HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits

HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine.     

Transfusion associated hepatitis: the Indian scenario

The purpose of this study was to evaluate the effect of partial renal shielding used in conjunction with total body irradiation (TBI) on the incidence of bone marrow transplantation nephropathy (BMT Np) seen as a late sequelae after transplantation. Of 402 patients who have undergone bone marrow transplantation (BMT) at the Medical College of Wisconsin (MCW) 157 were greater than 18 years of age, received 14 Gy TBI and survived at least 100 days post-transplant. The incidence of BMT nephropathy was evaluated in these patients by dose to the kidneys. In the 72 patients who received 14 Gy TBI with no renal shielding, the actuarial risk of developing BMT Np at 2 1/2 years (30 months) post-BMT was 29 +/- 7%. Sixty-eight patients received 14 Gy TBI with partial renal shielding of 15% (renal dose = 11.9 Gy), the actuarial risk of developing BMT Np was 14 +/- 5% at 2 1/2 years. Seventeen patients received 14 Gy TBI with renal shielding of 30% (renal dose = 9.8 Gy); none of this group have developed BMT Np despite a median follow-up of over 2 1/2 years (985 days). The trend of decreasing BMT Np with increasing shielding is statistically significant (P = 0.012). Prognostic factors such as age, type of transplant and good-risk vs poor-risk disease status were evaluated and were similar in each cohort of patients described above. We conclude that given the statistically significant benefit seen here in the reduced incidence of BMT Np by the use of selective renal shielding, this should be seriously considered for all patients who receive TBI, but especially for patients whose renal doses exceed 10 Gy.     

Clerodane diterpenoids, long chain esters of coumaric acid and other compounds from Baccharis myrsinites

PURPOSE: To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS: The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION: Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.