Prevention of implantation metastases after resection of proximal bile duct tumours with pre-operative low dose radiation therapy.

AIMS: Pre-operative endoscopic retrograde cholangiopancreatography (ERCP) with biliary drainage is associated with a greater risk of implantation metastases after resection of proximal bile duct tumours. In a previous study among patients who had undergone biliary drainage before resection, eight patients (20%) developed implantation metastases, within 1 year following resection. The aim of this analysis was to evaluate the results of pre-operative irradiation with regard to a possible reduction of implantation metastases. METHODS: Twenty-one patients with proximal bile duct tumours who had undergone resection following pre-operative irradiation were retrospectively analysed. Pre-operative radiation therapy consisted of three fractions of 3.5 Gy external beam irradiation of the hilar area. RESULTS: Pre-operative biliary drainage was performed in 19 patients (90%). All patients received pre-operative radiotherapy during which no complications were noted. None of the patients developed implantation metastases within a follow-up time of 2 to 79 months. CONCLUSION: The results of this study suggest that pre-operative radiotherapy in patients with a resectable proximal bile duct tumour who have undergone pre-operative drainage, decreases the risk of implantation metastases. To be certain about the role of pre-operative radiotherapy, a randomized study is required. Until then, we advocate standard low dose radiotherapy preceding resection in all patients with lesions suggestive of a proximal bile duct tumour who have undergone biliary drainage.

A limited role for adjuvant radiotherapy after the Wertheim/Okabayashi radical hysterectomy for cervical cancer confined to the cervix.

BACKGROUND: The indications for radiotherapy after radical hysterectomy for early stage cervical cancer are changing. In the past only tumor outside the cervix was considered an indication for radiotherapy. Today adjuvant radiotherapy is also considered for an "intermediate-risk" group with tumor confined to the cervix but poor prognostic primary tumor parameters such as large tumor diameter, vascular space invasion, and deep stromal penetration. OBJECTIVE: The aims of this study were to determine the risk of isolated pelvic recurrences in an intermediate-risk group (GOG Study No. 92) and to analyze whether this group will theoretically benefit from adjuvant pelvic radiotherapy. PATIENTS AND METHODS: A retrospective analysis was performed on 271 patients with early cervical cancer treated by a radical hysterectomy in a uniform fashion in one institute. Radiotherapy was administered only when tumor was found outside the cervix. Tumor diameter, capillary lymphatic space invasion, and depth of stromal penetration were assessed in all patients. Recurrence pattern, disease-specific survival, and recurrence-free interval were determined in the intermediate-risk group and compared with the remaining patients of the group with tumor confined to the cervix. RESULTS: A significant difference in disease-specific survival (89% versus 97%, P < 0.03) and 5-year recurrence-free interval (86% versus 95%, P < 0.02) was noted in the intermediate-risk group (n = 56) compared with the total group with tumor confined to the cervix. Three patients in the intermediate-risk group died of disease with a pelvic recurrence. Two of these patients had a combined pelvic and distant recurrence. CONCLUSION: Our retrospective results fail to support a survival benefit of extending indications for adjuvant radiotherapy other than postive nodes, parametrial extension, and positive margins.

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

OBJECTIVE: The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA: A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS: Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS: Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS: Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.

Pulse frequency in pulsed brachytherapy based on tissue repair kinetics.

PURPOSE: Investigation of normal tissue sparing in pulsed brachytherapy (PB) relative to continuous low-dose rate irradiation (CLDR) by adjusting pulse frequency based on tissue repair characteristics. METHOD: Using the linear quadratic model, the relative effectiveness (RE) of a 20 Gy boost was calculated for tissue with an alpha/beta ratio ranging from 2 to 10 Gy and a half-time of sublethal damage repair between 0.1 and 3 h. The boost dose was considered to be delivered either in a number of pulses varying from 2 to 25, or continuously at a dose rate of 0.50, 0.80, or 1.20 Gy/h. RESULTS: The RE of 20 Gy was found to be identical for PB in 25 pulses of 0.80 Gy each h and CLDR delivered at 0.80 Gy/h for any alpha/beta value and for a repair half-time > 0.75 h. When normal tissue repair half-times are assumed to be longer than tumor repair half-times, normal tissue sparing can be obtained, within the restriction of a fixed overall treatment time, with higher dose per pulse and longer period time (time elapsed between start of pulse n and start of pulse n + 1). An optimum relative normal tissue sparing larger than 10% was found with 4 pulses of 5 Gy every 8 h. Hence, a therapeutic gain might be obtained when changing from CLDR to PB by adjusting the physical dose in such a way that the biological dose on the tumor is maintained. The normal tissue-sparing phenomenon can be explained by an increase in RE with longer period time for tissue with high alpha/beta ratio and fast or intermediate repair half-time, and the RE for tissue with low alpha/beta ratio and long repair half-time remains almost constant. CONCLUSION: Within the benchmark of the LQ model, advantage in normal tissue-sparing is expected when matching the pulse frequency to the repair kinetics of the normal tissue exposed. A period time longer than 1 h may lead to a reduction of late normal tissue complications. This theoretical advantage emphasizes the need for better knowledge of human tissue-repair kinetics.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: data from a phase III trial.

PURPOSE: The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS: Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS: Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS: An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.

PURPOSE: To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. MATERIALS AND METHODS: From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. RESULTS: The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. CONCLUSION: The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.

Quality assurance of the EORTC Trial 22881/10882: boost versus no boost in breast conserving therapy. An overview.

BACKGROUND: The initial quality assurance programme of the EORTC Radiotherapy Cooperative Group in trial 22881/10882 is described. The implications of its results for quality assurance in future trials are discussed. METHODS: In the EORTC trial 22881/10882 patients with stage I or II breast cancer are treated with tumor excision, axillary dissection, 50 Gy whole breast irradiation and then randomized to receive a boost dose of 15 Gy or no boost following complete tumor excision or between 10 Gy or 25 Gy in case of incomplete excision. To avoid or diminish protocol deviations and to quantify inevitable variations an extensive initial quality assurance programme was conducted. The programme consisted of a dummy run procedure an individual case review procedure, in vivo dosimetry studies and phantom dosimetry studies. RESULTS: This combination of quality assurance procedures allows a good estimation of patient to patient and inter-institutional variations, and early detection of (potential) systematic protocol deviations of 3 types: 1. Deviations due to ambiguities in the protocol prescriptions. 2. Deviations not known to the institution, such as mistakes in implementation of treatment planning algorithms resulting in a systematic overdosage or underdosage. 3. Inability of an institution to cope with (precise) protocol prescriptions for technical or logistic reasons. DISCUSSION: The first 2 types of deviations may be corrected or avoided by direct discussions and recommendations. With respect to the third type it is up to the trial coordinator to accept participation or not, depending upon the relative importance of the particular deviation(s) for the trial end points. To be effective, such a quality assurance programme must be implemented as early as possible in the course of a clinical trial.

Accelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study.

The EORTC Radiotherapy Cooperative Group performed a prospective phase II study in glioblastoma multiforme using accelerated radiotherapy in escalating doses. The aims of the study were to investigate acute and late toxicity as well as tumor response and survival. Only the CT-enhanced tumor zone plus a margin of 2-3 cm were treated (mean volume, 1034 +/- 477 cm3). Radiotherapy was administered with 5-18 MV photons. The radiation schedule consisted of 3 fractions of 2 Gy/day, separated with at least 4 h. The first group of patients was scheduled to receive a total dose of 42 Gy, 21 fractions in 9 days. The total dose was then escalated up to 48 Gy (24 fractions in 10 days), 54 Gy (27 fractions in 11 days) and 60 Gy (30 fractions in 12 days). The numbers of patients entered in each dose-level group were 15, 17, 18 and 16, respectively. Acute toxicity was mild, nausea/vomiting was absent in 91% of the patients. In 80% of the patients the neurological condition improved or remained stable compared with the start of radiotherapy but in 58% of the patients steroids were necessary, either increased in dose or initiated. Acute toxicity did not increase with increasing radiation doses although patients treated with 60 Gy more often required steroids than the other groups. Late toxicity was strongly suspected in 2 patients receiving 52 Gy and 56 Gy, respectively. Within the whole group of 66 patients only one recurrence outside the primary site was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Metastatic tumors to the orbit--management and prognosis.

In a retrospective study the records of 34 consecutive cases with tumors metastatic to the orbit were reviewed with special attention to the management and prognosis of these patients. The primary tumor site was the breast in 20 patients, prostate in 5, kidney in 2 and skin in 2. The remaining 5 patients had other primary tumour sites. The symptoms of orbital metastasis preceded the detection of the primary tumor in 8 cases (24%). Twenty patients died after a mean interval of 25 months following the diagnosis of the orbital metastasis. This study gives a summary of the clinical features of these patients. With improved methods of treatment it was possible to obtain a relief of orbital symptoms in 24 patients (71%). Although the life expectancy of these patients remains poor, treatment can result in symptomatic relief and in an improvement in the quality of life, which is the main goal in the management of these patients.

Palliative radiation therapy for AIDS-associated Kaposi's sarcoma by using a single fraction of 800 cGy.

A single radiation fraction of 800 cGy was used in the treatment of acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). A total of 74 radiation treatments was given to a total of 31 patients. Of all 74 evaluable treatments, there were 25 objective major responses (6 complete, 19 partial) according to the WHO criteria, while 67 treatments resulted in subjective palliation of the main reason to treat (cosmetic discomfort, pain, or oedema). However, it appeared that the duration of these responses was rather short; in 23 of 36 radiation treatments with a follow-up of more than 4 months, progression of the tumour was seen within that time, while the palliative effect outlasted the survival of the patients in only four cases. It is concluded that a single dose of 800 cGy is an effective treatment for patients with a predicted survival of only a few months, and it should be determined whether a higher fractionated dose improves duration of responses, especially for patients with a good performance.

Nicardipine and propranolol in the treatment of hypertension: similar antihypertensive but dissimilar hemodynamic actions.

Although the precise cause of essential hypertension is not known, empiric treatment is indicated to reduce cardiovascular risks. Several pharmacologic classes of a antihypertensive drugs are available to reduce blood pressure, but they do so by different hemodynamic mechanisms. The physiologic therapeutic goal in patients with hypertension is to normalize the systemic vascular resistance without inducing major alterations in the cardiac output. In this study we compared the antihypertensive and hemodynamic actions of nicardipine, a calcium antagonist, with propranolol, a beta-blocking drug. Both drugs were effective in the treatment of hypertension. However, while propranolol therapy decreased the resting and exercise left ventricular ejection fraction and cardiac output, cardiac function was well preserved during nicardipine therapy. It is concluded that both nicardipine and propranolol exert similar antihypertensive actions but that they cause dissimilar hemodynamic consequences in patients with uncomplicated hypertension.

Geriatric hypertension: antihypertensive therapy in coronary artery disease.

Systemic hypertension is a common clinical problem in the elderly. There is emerging evidence to suggest that with careful utilization of antihypertensive drugs, blood pressure can be lowered in the elderly population. Whether isolated systolic hypertension should be treated aggressively remains an unanswered question despite the evidence that systolic hypertension can cause certain cardiovascular complications. An elderly patient with hypertension and concomitant coronary artery disease merits proper blood pressure control with appropriate drugs to prevent progression of coronary disease. The therapeutic objective is not only to lower the blood pressure but to accomplish this goal with drugs which are likely to have a favorable effect on coronary artery disease. Changing trends in the drug therapy of hypertension indicate that calcium antagonists and beta-blocking drugs offer a therapeutic advantage in elderly hypertensive patients with coronary artery diseases.

Therapeutic survey: hypertensive emergencies.

The most crucial aspect is to ascertain whether the patient's condition truly warrants emergency management. The choice of oral versus parenteral drug(s) depends on the urgency of the situation as well as the patient's general condition. The level to which the blood pressure should be lowered varies with the type of hypertensive crisis and should be strictly individualized. There is no predestined level for the goal of therapy. Complications of therapy--namely, hypotension and ischemic brain damage, can occur in patients receiving multiple potent antihypertensive drugs in large doses without adequate monitoring. Such complications can be minimized by gentle lowering of blood pressure. An asymptomatic patient who presents with severe hypertension, i.e., a diastolic blood pressure 130-140 mmHg, need not be treated with parenteral drugs. After the resolution of a hypertensive crisis, one should determine the possible factors that might have contributed to the development of the hypertensive crisis such as non-adherence to prescribed therapy or the presence and/or progression of a secondary form of hypertension such as renal artery stenosis.

Renal hemodynamic effects of ketanserin therapy in essential hypertension.

Ketanserin is a novel agent that has been shown to be a specific 5-HT2-serotonergic antagonist. It has useful antihypertensive properties. Owing to its unique mechanism of action, it has been suggested that ketanserin may have a favorable effect on tissue blood flow during chronic therapy for hypertension. This double-blind study was designed to evaluate the acute (1 week) and chronic (8 weeks) effects of ketanserin on renal hemodynamic parameters and renin-aldosterone axis in patients with uncomplicated hypertension. Compared to placebo, ketanserin caused a significant blood pressure reduction at the end of the 8-week study period. Despite the reduction in systematic arterial pressure, glomerular filtration rate and renal plasma flow were preserved. Ketanserin therapy induced a slight reduction in plasma renin activity and a marginal increase in the sodium excretion. Although the results of this study are limited by the small number of patients, it appears that ketanserin may have favorable renal hemodynamic effects in uncomplicated essential hypertension.

Quality assurance control in the EORTC cooperative group of radiotherapy. 1. Assessment of radiotherapy staff and equipment. European Organization for Research and Treatment of Cancer.

A quality control study was carried out by the EORTC Cooperative Group of Radiotherapy. From January 1982 to December 1984, 17 institutions were visited by a group of "experts" in radiotherapy and radiation physics. The evaluation included three steps: a comparison of megavoltage units, technical and staff environment, and data present in clinical and radiotherapy charts for each center; radiation physics calibration of photon and electron beams; and radiation physics measurements on a stimulated clinical case using an Alderson Rando anatomical phantom. This paper presents the results of Part 1. The results of Parts 2 and 3 will be analyzed in separate papers. Large variations were observed in the number of patients treated per year, per radiotherapist, per radiation physicist and per technician. On average, 400 patients were treated per year per megavoltage unit, but 8/17 centers treated more than 500 patients per unit per year. The number of simulators was suboptimal in 12/17 centers. These observations were summarized by a workload and staff index, and this index shows that in 5/17 centers major problems are present which make it difficult to comply with all the requirements of EORTC protocols. The quality of work-up regarding tumor extension was considered to be satisfactory in all centers. Dental care in patients irradiated to the head and neck was not well organized in 5/17 centers. Interaction between CT scan and dosimetry treatment planning could be improved in most centers and this should be one of the primary objectives of future quality control.