Combined chemotherapy and radiotherapy for patients with breast cancer and extensive nodal involvement.

PURPOSE: This retrospective review examines local control, freedom from distant failure, and survival for patients with nonmetastatic breast cancer with extensive nodal disease (> 10 nodes, 45 patients; or > or = 70% involved nodes, if < 10 nodes found, 19 patients). All patients received chemotherapy and radiotherapy following mastectomy. PATIENTS AND METHODS: Sixty-four patients were treated between January 1980 and December 1988 at Westmead Hospital, Westmead, NSW Australia. The median follow-up duration for surviving patients was 91.5 months (range, 56 to 121). The median age was 51 years, and the median number of positive nodes was 11. Four successive protocols evolved, each with three phases, as follows: induction chemotherapy (doxorubicin or mitoxantrone, plus cyclophosphamide; three cycles), radiotherapy (50 Gy in 25 fractions to chest wall and regional nodes), then chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) of progressively shorter duration. Radiotherapy and chemotherapy were concurrent in the fourth regimen. RESULTS: One patient (1.5%) developed local recurrence before distant relapse, and seven patients (11%) developed local and/or regional recurrence simultaneously or after distant relapse. The 5-year actuarial freedom from distant relapse and overall survival rates were 45% and 65%, respectively. Overall survival did not vary significantly by menopausal status, nodal subgroup, or dose-intensity. There were no treatment-related deaths. CONCLUSION: Combined chemotherapy and radiotherapy in standard dosage is an acceptable approach following mastectomy for patients with extensive nodal involvement at high risk for local recurrence and distant relapse. This approach should be considered standard best therapy for any randomized trials that examine high-dose chemotherapy or bone marrow transplantation for this subgroup of patients.

Undergraduate education about cancer. A survey of clinical oncologists and clinicians responsible for cancer teaching in Australian medical schools.

Undergraduate cancer education in Australian medical schools is not integrated and there is little evidence of change in content or structure in recent years in spite of major changes in knowledge about cancer epidemiology and cancer biology, and in cancer management. A recent survey of graduating students/interns from all Australian medical schools revealed a disturbing variability in experience and lack of important knowledge. There was evidence of substantial differences in knowledge of, and rating of teaching between the different disciplines involved in cancer control and cancer management. To examine possible reasons for this, we surveyed cancer clinicians and teachers of oncology in the undergraduate curriculum at Australian medical schools. We asked them the same questions of knowledge as the students, and also to comment on the type and emphasis of teaching desirable in the medical students' cancer curriculum. The results indicate not only that the survey instrument was seen to be relevant, but also that some of the bias and misinformation detected in the student experiences may be attributed to attitude, knowledge and differences of opinion of the teachers. The results highlight the need for an integrated cancer curriculum to inform graduates about an illness which will be diagnosed in more than a quarter of the Australian population.

Undergraduate education about cancer.

The quality, quantity and balance of undergraduate cancer teaching in Australian Medical Schools were investigated by a survey, using a self-administered questionnaire, of recent graduates from all Australian medical schools. Stratified random cluster sampling was used and a response rate of 84% (389 respondents) was achieved. The results revealed substantial differences in knowledge, experience in, and rating of teaching between the medical, surgical, radiotherapeutic and palliative components of cancer management. The proportions of graduates who had never attended radiotherapy and palliative care clinics or units (42.3% and 49.9%, respectively) were more than double the proportion who had never attended medical and surgical cancer clinics or units (17.5% and 10.9%, respectively). More than twice as many graduates rated their instruction in the palliative management of cancer as poor or very poor (29.4%) compared with those rating their instruction as poor or very poor in both cancer prevention (8.4%) and treatment for cure (14.6%). The respondents displayed a considerable lack of knowledge about radiotherapy treatment options, and reported a lack of perceived competence in doing cervical smears. Their answers to questions about 5-year survival of selected cancers, about the existence of screening tests validly shown to reduce mortality, and the ages at which breast and cervical cancers are likely to develop all revealed worrying levels of incorrect knowledge. There was some important disturbing variation in levels of knowledge, experience and rating of cancer instruction between states and between universities.

ACUPS (adenocarcinoma of unknown primary site): a clinical and cost benefit analysis.

A retrospective review of 287 patients with a diagnosis of adenocarcinoma unknown primary site was performed. These patients represented 2.9% of the new referrals to the Westmead Department of Radiation Oncology between the years 1979 and 1985. Age, sex, and survival characteristics of the study population are presented. Tissue biopsy procedures are reviewed and the uniform necessity of open biopsy is questioned in the light of recent advances in FNA (fine needle aspirate) techniques. A semi-quantitative analysis of the monetary cost of the investigation of these patients has been performed. This has been correlated with the objective and symptomatic benefit accrued by the patient population. A higher incidence of speculative, low-yield investigations has been demonstrated for those patients referred from general medical and surgical units. Ante-mortem identification of the primary site remains the exception rather than the rule in this and other series. This fact, coupled with an inability of therapeutic intervention to alter the natural history of the disease means the cost and toxicity of investigation and treatment of these patients must influence approaches to their management.

The efficacy of combined chemotherapy and radiotherapy in advanced non-metastatic breast cancer.

Thirty-five patients with locally advanced (inoperable) breast cancer have been treated based on a regimen of chemotherapy-radiotherapy-chemotherapy. At the completion of all treatment a complete remission rate of 86% was achieved with acceptable toxicity. At a median follow-up of 24 months (range 4-60), relapse at the site of bulk disease occurred in 17% (10% isolated loco-regional relapse) and relapse at distant sites in 34%. The median relapse-free survival was 36 months and the median survival has not yet been reached. Following initial promising results in terms of loco-regional disease control in this group of high-risk patients, the protocol was extended to include 34 patients defined as having locally extensive disease. All patients in this subgroup had undergone a modified radical mastectomy and were categorized as (a) patients in whom the pre-operative clinical findings merited (in our opinion) inclusion in the category of locally advanced (inoperable) disease, (b) patients in whom the primary was operable but in whom extensive involvement of axillary nodes was found (greater than 10 nodes positive or greater than or equal to 70% nodes positive if less than 10 nodes found) and (c) patients without the above characteristics with a primary tumor greater than 8 cm. At a median follow-up of 23 months (range 4-48), loco-regional recurrence occurred in one patient (3%) but distant relapse occurred in 21%. Relapse-free and overall survival was not significantly different to that found in patients with locally advanced disease who did not undergo mastectomy.

Sarcomas following radiation therapy for breast cancer: a report of three cases and a review of the literature.

PURPOSE: First to describe clinical and pathologic features of sarcomas arising after radiation therapy for breast cancer and to report three cases of sarcoma arising 7, 15, and 20 years following radiation therapy for breast cancer. Second, to review the literature on this treatment complication. METHODS AND MATERIALS: Medline literature search. RESULTS: The most frequent histology is osteosarcoma and bone is affected more commonly than soft tissue at a median latency of 11 years. The scapula is the most frequently affected bone. The most frequently affected soft tissue site is now the conserved breast with a median latency of 5.5 years. The aetiologic factors relating to these sarcomas are not fully defined with factors of beam energy, radiation dose, chemotherapy and regional edema being inconsistently reported. CONCLUSION: The frequency of radiation-induced sarcoma at 10 years of follow-up is approximately 0.2%. This is an overestimate by an unknown factor because of the description of sarcomas arising metachromously in breast cancer patients, in nonirradiated areas.

Sarcoma of bone following therapeutic irradiation for breast carcinoma.

Four patients with sarcoma arising in bone following therapeutic irradiation for breast carcinoma are presented, along with a review of the 40 patients who have been previously reported in the literature. The majority of these lesions arose in the scapula and the most frequently reported histology is osteosarcoma. The incidence of these lesions has been reported as 0.05% to 0.23% in three previous series. The average latent period between irradiation and the diagnosis of the sarcoma is 10.9 years with a range of 4.5-24 years. The average survival following diagnosis in this series was 2.4 months, which is comparable to other series. However, one patient treated by forequarter amputation and another treated by chemotherapy and radiotherapy survived 4 and 3 years, respectively.

Radical radiotherapy for early nonsmall cell lung cancer.

PURPOSE: To evaluate the results of a departmental treatment policy in a consecutive series of patients with nonsmall cell carcinoma of the lung. A second purpose was to estimate the survival of patients treated with radical intent. A third purpose was to estimate the impact of comorbidity on the selection of patients for treatment and on its outcome. METHODS AND MATERIALS: The records of 720 consecutive patients referred to a single Department of Radiation Oncology between 1979 and 1985 were reviewed. One hundred fifty patients with early stage (Stage I and II disease) were studied in detail and the results are presented for the outcome of 103 patients treated by radical radiotherapy. All patients were followed for a minimum period of five years or until death. RESULTS: Patients referred for radiation therapy were elderly and usually had squamous cell carcinoma of the lung. Comorbidity was significant as was weight loss which occurred in a third of patients. The overall survival of patients treated with radical intent was 13%. In a small subgroup of patients with T1 tumors without weight loss and aged under 70 survival reached 50% at 5 years with no treatment-related mortality and with insignificant treatment-related morbidity. CONCLUSION: Highly selected subsets of patients suitable for treatment with radiotherapy can be defined equally as well as highly selected subsets of patients can be selected for surgery. Treatment outcome can be surprisingly good in these subsets indicating that the treatment of nonsmall cell lung cancer, particularly in older patients without comorbidity should not automatically be by a surgical approach.

Synchronous 5-fluorouracil, mitomycin-C and radiation therapy in the treatment of locally advanced carcinoma of the cervix.

Locally advanced carcinoma of the cervix has a poor prognosis with a high incidence of persistent or recurrent local disease contributing to distressing symptoms and poor survival. This has remained unaltered over the past 30 years in spite of the addition of other therapeutic modalities. Between 1983 and January 1986, 38 patients with locally advanced carcinoma of the cervix were treated with synchronous 5-fluorouracil, mitomycin-C, and radiotherapy. The results of this pilot study indicate both an improvement in pelvic control and in 3-year survival rate for the chemosensitized therapy compared to conventional radiotherapy alone (55% v 28%) using historical controls. Improved survival was only significant for bulky FIGO Stage IIb tumors. The toxicity of this combination was predominantly gastro-intestinal and led to modification of both radiation dose and technique with subsequent improvement in the incidence of side effects. The results suggest that the combination of synchronous chemotherapy with radiotherapy is an improved method of treatment for locally advanced carcinoma of the cervix and that a prospective randomized trial is now justified.

Persisting cyclical uterine bleeding in patients treated with radical radiation therapy and hormonal replacement for carcinoma of the cervix.

Radical radiation therapy used for carcinoma of the cervix will ablate ovarian function. Since January 1986, our policy has been to administer oral combination oestrogen-progesterone replacement hormonal therapy to all premenopausal patients undergoing radical radiation with or without synchronous chemotherapy, for invasive cervix cancer. Five out of 22 (23%) such patients unexpectedly experienced between one and four episodes of cyclical per vaginal bleeding after the completion of radiation therapy. Bleeding episodes occurred in the absence of persistent tumor or radiation reaction, and suggest persisting endometrial response to exogenous hormonal stimulation. Uterine activity was temporarily retained in these five patients despite a minimal endometrial surface dose of between 4800 and 6490 cGy. The limited number of cycles before bleeding spontaneously ceased may represent the slow death of endometrial cells subsequent to radiation or radiochemotherapy treatment, and has not previously been described. In view of the paucity of data on the radiosensitivity of normal endometrium, we have carefully examined these patients who appear to have retained endometrial sensitivity to hormonal stimuli after radical radiation-chemotherapy for uterine cervix cancer.

Breast conservation: long-term Australian data.

Long-term data on the management of early breast cancer in Australia by conservative surgery and radiation therapy is limited. To examine this issue we reviewed our experience of 131 patients with Stage I or II breast cancer treated between November 1979 and December 1985. Ninety patients had a T1 tumor and 41 a T2 tumor. The extent of surgery varied from a local excision (LE), a wide local excision, to a quadrantectomy or partial mastectomy. Sixty-two per cent of patients also had an axillary dissection. One hundred and nineteen patients were treated using 6Mev photons to the whole breast (Median dose; 50 Gy) +/- regional nodes followed by a single plane Iridium-192 boost to the primary tumor site (median dose; 30 Gy). Ten patients did not receive a boost and two elderly patients were treated with an implant only. The median follow-up of surviving patients was 83 months (range, 51-133 months). Six other patients were lost to follow-up at a median of 48 months (range, 4-62). The pattern of first relapse is: breast alone, 7.0%; breast + distant, 0.75%; breast + nodes, 0.75%; regional nodes only, 0.75%; and distant disease, 18%. The extent of surgery did not influence the probability of a recurrence in the primary tumor region. The time to a breast recurrence ranged from 12 to 127 months (median, 61 months). The 5-year actuarial rate of a breast recurrence was 4.5%. The 5-year freedom from distant relapse was 80%. The complications of treatment were acceptable. These included rib fracture (5%), symptomatic pneumonitis (4%), fat necrosis or fibrosis requiring surgery (4.5%), severe arm edema (4.5%). The treatment of the axilla by both surgery plus radiation therapy was associated with a moderate or severe arm edema rate of 29% compared to 8% for surgery alone and 6% for radiation therapy alone. Our long-term data indicate that conservative surgery plus radiation therapy is associated with low rates of breast cancer recurrence which are independent of the extent of surgical resection. Complications were acceptably low provided that the axilla was treated by surgery or radiation therapy but not by both modalities.

Multiple primary tumours in patients treated with radiotherapy for breast cancer.

Between January 1954 and March 1964, 3926 patients with primary breast cancer were referred to The Department of Clinical Oncology, Edinburgh. One hundred and eighty patients developed 195 malignancies subsequent to the treatment of their initial breast cancer. Overall, the total number of second tumours was not significantly in excess of the expected incidence in the general population. However, statistical analysis revealed a significant increase in the incidence of rectal, skin and bone tumours. The excess of bone tumours was likely due to radiation exposure. There was not an overall excess of tumours within the irradiated or scattered radiation volume.

Concurrent 5-fluorouracil, mitomycin C and irradiation in locally advanced cervix cancer.

We reviewed 177 patients treated with radical radiotherapy for locally advanced (FIGO stages IIB, IIIA, IIIB) cervix cancer between January 1979 and December 1989. The radiotherapy was given by external beam treatment to the pelvis and by an intracavitary caesium insertion. Ninety-three patients also received chemotherapy which consisted of infusional 5-fluorouracil during the first and last weeks of the external beam component of the radiotherapy, combined with bolus mitomycin C (group A, 64 patients) or without mitomycin C (group B, 29 patients). These groups were compared with patients treated by radiotherapy alone (group C, 84 patients). The median follow-up was 7.2 years. The median survival time for all patients was 47 months, but was significantly higher (87 months, p = 0.004) for group A. Rates of relapse-free survival and local control were also higher in group A. Toxicity was assessed in detail using the Franco-Italian glossary. There was a relatively high rate of complications, particularly in group A, with 36% of patients having grade 3 or 4 complications. This increase in toxicity persisted through all follow-up time intervals. Patients in group B also demonstrated a higher rate of toxicity than group C, but this increase was limited to the first 6 months of follow-up. The use of mitomycin C in addition to radiotherapy and 5-fluorouracil should be regarded with caution, as other studies have also shown that toxicity is increased, but without improvements in survival.

Fat necrosis of the breast following lumpectomy and radiation therapy for early breast cancer.

Between January 1980 and December 1985, 121 patients with early breast cancer were treated in the Department of Radiation Oncology at Westmead Hospital by external beam irradiation and an iridium wire boost following "lumpectomy". After a median follow-up of 26 months, 14 patients have developed recurrent masses in the treated breast. In four, recurrent carcinoma was strongly suspected and subsequently confirmed by fine needle aspiration biopsy, but in only two was a subsequent salvage mastectomy possible. The remaining 10 patients developed a nodule which was usually tender. With three exceptions, the nodule was at the primary tumour site and developed 4-43 months after treatment. In seven, tumour recurrence was suspected but not confirmed by biopsy and the other three were accepted as having post-treatment "radiation fibrosis". Excision biopsy was undertaken in eight of the 10 patients. Another patient underwent partial mastectomy for presumed local recurrence. The histological appearance in all cases was similar, with areas of fat necrosis and fibrosis with atypical stromal fibroblasts. Suture material was present microscopically in eight patients and was noted macroscopically (that is, by mammogram) in the one patient who did not undergo surgery. This complication is most likely caused by a combination of surgical and radiation factors. The difficulty in management is differentiation between tumour recurrence and a benign condition.

Thyroid disease following the administration of thorotrast.

Four cases of thyrotoxicosis are reported among 35 patients who had been given Thorotrast during the investigation of intracranial haemorrhage. For the group as a whole Thorotrast had been given between 11 and 31 years (mean 23.4 years) before this study. Thyrotoxicosis occurred in four patients between six and 17 years (mean 11.8 years) after the injection of Thorotrast. The fact that thyrotoxicosis did not occur in a small control group of patients who had had a subarachnoid haemorrhage and in whom Thorotrast had not been used at angiography suggests that Thorotrast may be of aetiological significance. In view of the known association between thyrotoxicosis and changes in the lymphoreticular system it is possible that the irradiation of this system by retained thorium has resulted in an abnormality of function which renders these patients more liable to the development of thyrotoxicosis.A fifth patient developed non-toxic thyroid enlargement 16 years after Thorotrast angiography.

Cell receptor studies on six anaplastic tumours of the thyroid.

Cell suspensions from six anaplastic thyroid tumours were studied for expression of lymphocyte and macrophage surface markers, and results were correlated with electron microscopy, clinical extent of disease, and response to radiotherapy. The clinical presentation of the disease was similar in all six patients. In five cases, many of the cells showed surface immunoglobulin. Electron microscopy was available on three of these and showed appearances in keeping with malignant lymphoma. The single case whose cells did not show surface immunoglobulin had an entirely different ultrastructure and was probably a carcinoma. This case was the only one that did not achieve complete remission with radiotherapy and the patient died from extensive local recurrence. It is concluded that receptor techniques are of value in distinguishing between malignant lymphoma and other anaplastic tumours of the thyroid, particularly when the results are correlated with histology.

Delay in the clinical diagnosis of breast cancer: estimating its effect on prognosis, with particular reference to medical litigation.

Medical malpractice litigation is increasing. Delay in diagnosis is the commonest basis for litigation involving the treatment of breast cancer. When delay in diagnosis has occurred, any losses for which a plaintiff seeks compensation require estimates to be made of any change in prognosis over the period of the delay relative to the extent of disease found when treatment is finally undertaken. We have examined the natural history of breast cancer and have attempted to provide evidence-based quantitative guidelines for the evaluation of the losses which may be claimed in malpractice cases.

Symptoms 2 weeks, 3 months and 12 months after treatment of early breast cancer: the patients' perspectives.

The physical symptoms and side-effects reported by patients treated for early breast cancer with surgery (S), (breast conservation or mastectomy), radiotherapy (R) and chemotherapy (C) are reported. As part of a large quality-of-life study, eligible patients were invited to complete a questionnaire at three and 12 months after treatment for early breast cancer. Symptoms 2 weeks after surgery were retrospectively collected at the 3-month questionnaire. Comparing the commonly used different therapy combinations (S, S+R, S+C and S+R+C) we found the only loco-regional symptom to show a significant difference between these groups was chest tightness (P<0.001). Both anxiety about attending for and discomfort during C were significantly higher than during R (P<0.00005 and 0.00001 respectively). We found that the addition of R and, or, C to S resulted in surprisingly little variation in physical side-effects.

Pulmonary blastoma.

Pulmonary blastoma (PB) is the least common malignant pulmonary neoplasm, with less than 100 reported cases. This tumour occurs up to three times more commonly in males. There exists an age peak in the third and fourth decades, although approximately one quarter of cases occur in children, often in association with congenital lung disease. Although the clinical features of PB are not specific, the histopathological appearance is distinctive, showing an admixture of both epithelial and mesenchymal (sarcomatous) elements. Historically, surgery has been the most commonly used modality for localized disease: however, useful data on local control rates are lacking. Extrathoracic metastases are the major cause of treatment failure in PB, with chemotherapy having little impact in this disease. The role of radiation therapy in the management of PB has not been established, however, early radioresponsiveness was demonstrated in the palliative treatment of soft tissue and bone metastases in the case presented: radiation therapy should be considered in the management of this disease.

Radiation therapy: are we getting value for money?

The aim of this study was to examine the long term cost effectiveness of radiotherapy (RT) in the treatment of cancer at the Department of Radiation Oncology, Westmead Hospital, from its inception in 1980 to December 1993. A Kaplan-Meier survival curve was constructed for all patients treated by RT during the study period. The area under this curve represented the average survival. The total number of life years was calculated by multiplying the number of patients by the average survival. Costing for one RT treatment field had previously been derived. The cost included capital costs, building costs and overheads as well as labour, goods and services, and operating costs. The cost per field was multiplied by the total number of fields given each year and the yearly total summed to give the total cost. The total cost was divided by the number of life years to give a cost per life year. An overall percentage survival gain was estimated from departmental results and the literature. Cost per life year gained (LYG) was derived by dividing the cost per life year by the percentage survival gain. Sensitivity analysis was performed with best- and worst-case survival scenarios, and high and low cost per field estimates. A total of 9868 patients were treated by radiotherapy between January 1980 and December 1993. Median follow-up was 4.2 years. Median survival was 2 years. The 5- and 10-year survival rates were 35% and 22%, respectively. The area under the survival curve (the average survival) was 4.75 years. The total number of life years of survival was thus 4.75 x 9868 = 46,873. In 1993, the cost per field was $71.52 (Australian dollars). The total number of fields treated in the study period was 758,097. Hence, the total cost in 1993 dollars was $54,219,097. The survival gain (excluding skin cancer) with RT was 16.1% and the cost/LYG was $7186. Sensitivity analysis of best and worst case scenarios gave costs/LYG of $3920 and $15,632 respectively. Efficient resource allocation can be aided by examining the relative cost-effectiveness of different prevention and treatment strategies. RT is shown to have a lower cost/LYG than other accepted treatments in current practice. Other major treatment modalities should be subjected to the same scrutiny of cost effectiveness as has been applied to RT.