Relation between breast tumour growth rate and metastatic potential.
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Biomedical subjects
Publications and source records attributed to J R Yarnold.
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The requirement for palliative chest radiotherapy in patients with non-small cell lung cancer (NSCLC) was assessed in a study of 134 inoperable patients not suitable for radical radiotherapy. Immediate chest radiotherapy was judged necessary in 86 (64%) because of significant symptoms from intrathoracic tumour or involvement of proximal airways. Forty-eight patients were monitored regularly without initial radiotherapy and of these, 26 (54%) required later chest irradiation because of progressive and significant symptoms due to intrathoracic disease. Median symptom-free survival in this group was 10 months. The requirement for immediate or delayed chest irradiation could not be predicted from either patient or tumour characteristics. The proportion of patients with NSCLC requiring palliative chest irradiation may have been overestimated from this study population; even so 22 of 134 patients (16%) did not at any stage in their illness require radiotherapy for chest symptoms.
CNS relapse after PCI may reflect either suboptimal radiation dose schedules or reseeding from other sites of active disease. A retrospective study has been undertaken to investigate these alternative mechanisms of treatment failure. Between August 1981 and December 1983, 30 patients with SCLC treated by induction chemotherapy, followed by high-dose cyclophosphamide (7 Gm/m2), were selected for PCI on the basis of clinical, radiological, and bronchoscopic CR. Pretreatment CT brain scans were normal in all patients, and 20 Gy mid-plane dose in 5 daily fractions were delivered by lateral fields to whole brain using megavoltage X rays and localizing check films. Progressive focal neurological signs of cranial metastases developed in 7/30 (23%) patients 3-11 months after PCI, confirmed on CT scanning in 4 patients. Relapse at other sites, predominantly the thorax, occurred in all seven patients at intervals of 1-6 months prior to CNS relapse. Published clinical data of tumor volume doubling times in SCLC predict longer CNS relapse-free intervals after PCI than those observed in our patients if reseeding was responsible for relapse. This suggests that incomplete eradication of intracranial disease is the main cause of CNS relapse after PCI. Higher equivalent radiation doses may improve the results of PCI.
Tumour growth delay has been investigated as an endpoint of radiation effect in selected patients with superficial metastases measured by calipers and ultrasound. Of 42 patients referred for study with two or more nodules, 17 were suitable for entry into protocols evaluating single or multifraction treatment. The reproducibility of tumour growth delay to the same dose schedule was evaluable in four patients and the sensitivity to 10-20% differences in total dose was evaluable in three patients. No significant size dependency was detected in the response of nodules to radiotherapy and the findings suggest that the growth delay endpoint is sensitive to 20% differences in radiation dose. Evaluable patients with multiple measurable nodules are uncommon but constitute a valuable resource for the testing of biological response modifiers, including radiosensitizers.
A prospective randomised trial comparing a single fraction of 8 Gy with 30 Gy in 10 daily fractions for the relief of metastatic bone pain was performed. In 28 months, 288 patients were randomised. Pain was assessed using a questionnaire completed by the patient at home on a daily basis. No difference was found in the speed of onset or duration of pain relief between the two treatment regimes, and pain relief was independent of the histology of the primary tumour.
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Thirty-nine of 225 patients with small cell lung cancer developed brain metastases after the initiation of chemotherapy. Treatment with high-dose dexamethasone in all 39 patients and cranial irradiation in 32 patients resulted in a complete neurological recovery in only eight of 39 patients (20%). Twenty-one of 39 patients (53%) failed to derive lasting benefit from their palliative treatment. Thirteen of 24 patients with limited disease with cranial relapse had no clinical evidence of other distant metastases prior to death and in these patients the CNS disease was an important cause of morbidity. On the basis of this study, it appears that palliative treatment of overt cranial metastases is relatively unsuccessful and that patients with limited disease represent a group with much to gain from effective prophylactic cranial irradiation.
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Within an original consecutive series of 94 patients, 36 eligible patients with small cell lung carcinoma were treated with high-dose cyclophosphamide 7 g/m2 after conventional chemotherapy with VP16, adriamycin, and vincristine. The first 17 also underwent autologous bone marrow rescue. Treatment was well tolerated apart from one treatment-related death. Measurable tumour was still present in 15 patients before high-dose cyclophosphamide, and although 12 (80%) of these achieved further tumour response, these responses were all short-lived, with a median duration of 9 weeks. In 14 limited-disease patients already in complete remission before high-dose therapy the initial result was better, but 11 (79%) have now relapsed following overall median response duration of 10 months. High-dose cyclophosphamide after conventional chemotherapy is feasible and achieves a high response rate, but it does not appear to be associated with significant survival benefit either overall or in patient subgroup.
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High-dose lymphatic irradiation is a contributory factor to the morbidity of treatment after local excision and high-dose radiotherapy for early stage breast cancer and may detract significantly from the cosmetic result. The apparent inability of lymphatic irradiation to influence the survival of patients with early stage breast cancer supports an argument for the selective avoidance of regional radiotherapy in a proportion of patients. Based on a review of the effects of lymphatic radiotherapy on lymphatic control, complications, cosmesis, survival and the effects of withholding lymphatic irradiation, recommendations are made for the selective treatment of patients at high risk of regional recurrence. In patients submitted to full axillary dissection, node negative patients require no lymphatic irradiation. After full axillary dissection radiotherapy is confined to the supraclavicular fossa in patients with heavy axillary involvement. A policy for patients having limited axillary dissection is discussed which identifies approximately 50% of patients as eligible for careful watch policy following local excision and high-dose radiotherapy to the primary disease.
Acute and delayed normal tissue damage has been investigated in 63 advanced stage testicular non-seminoma patients receiving elective involved-field irradiation after chemotherapy and in 53 patients who had chemotherapy given for relapse after prior irradiation. The risk of death from complications due to chemotherapy was 0% and 9.4% (p less than 0.025) in the two groups respectively. Gastro-intestinal damage and/or subcutaneous fibrosis was present in 12.6% and 24.5% of patients respectively, although only three patients have serious persisting disability. In patients receiving 35-45 Gy to the retroperitoneum the incidence of normal tissue damage was 0% and 25% (p less than 0.001), respectively. In addition to the sequence in which chemotherapy and radiotherapy was delivered, the time interval between completion of radiotherapy and start of chemotherapy was important with 6/6 patients receiving drugs within 2 months of irradiation developing fibrosis. Abdominal surgery appeared not to influence the risk of damage. Of nine patients receiving drugs after infradiaphragmatic and supra-diaphragmatic irradiation two died of neutropenic sepsis.
A study of the relationship between bulk disease and sites of relapse has been undertaken in 95 patients treated by radiotherapy for early stage Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. In a group of 80 pathologically staged patients the pattern of relapse in 39 patients confirms an association between recurrence and sites of bulk involvement in the mediastinum, neck and axilla. Bulk disease predisposes to recurrence by virtue of local failure inside the treatment volume as well as marginal recurrence. A small number of patients relapsed initially in sites that were irradiated prophylactically.
A study of the factors affecting relapse following combination chemotherapy has been undertaken in 64 previously untreated patients with Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. Bulk disease was significantly more common in the treatment failure group, being present in 23 out of 37 patients who failed compared to eight out of 27 patients who remain relapse-free (P less than 0.025). Reduced drug dosage was associated with treatment failure in 19 out of 37 patients receiving suboptimal chemotherapy compared to only four of 27 patients in the relapse-free group (P less than 0.01). Patients over the age of 50 years were more likely to receive suboptimal drug dosages (P less than 0.05).
The outcome of serious radiation injuries to the pelvic viscera in 400 patients treated by radiotherapy for carcinoma of the uterus between January 1974 and December 1978 has been reviewed. Twenty-eight instances of serious radiation damage have been found, 13 of predominantly small bowel damage, 11 of predominantly large bowel damage and 4 of bladder damage. Many patients had involvement at multiple sites. Fourteen patients have died, and 9 survivors have artificial abdominal stomas. Leaking anastomoses and progressive sepsis were major problems in the postoperative period and could be related either to inadequate resection of irradiated bowel or to damage to other organs at operation. The possibilities of earlier diagnosis and better surgical procedures are discussed.
One hundred and six patients dying of malignant melanoma have been studied to test alternative explanations of long disease-free intervals following primary excision. The time intervals from excision to relapse with local, lymphatic-borne or blood-borne recurrences do not correlate with the subsequent survival of the patient. If the experimental technique is valid, it supports the hypothesis that a long latent interval following primary excision represents a variable period of growth restraint followed by reactivation of disease rather than a period of continuous tumour growth throughout the disease-free interval.
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