A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer.

We randomized 122 premenopausal women to receive tamoxifen or to undergo a surgical oophorectomy. Of 54 evaluable women treated with tamoxifen, 24% had an objective response, as compared with 21% of 53 women having an oophorectomy. The median duration of response for tamoxifen (20 months) was longer than that for surgical oophorectomy (7 months), but this did not achieve statistical significance (P = .056). Overall median survival was 15 months for 58 patients receiving tamoxifen and 25 months for 53 patients undergoing oophorectomy (P = .18). Toxicity was greater in those undergoing oophorectomy, though both treatments were well tolerated. In those premenopausal women for whom hormonal therapy is indicated, tamoxifen is a suitable alternative to surgical oophorectomy.

Extensive stage small cell carcinoma of the bronchus. A randomised study of etoposide given orally by one-day or five-day schedule together with intravenous adriamycin and cyclophosphamide.

Fifty-four patients whose disease had been staged as extensive small cell carcinoma of the bronchus were randomised to receive either CAV1 (cyclophosphamide 600 mg m-2 i.v., adriamycin 50 mg m-2 i.v., given on day 1, and etoposide 500 mg m-2 p.o. given on day 3) or CAV5 (cyclophosphamide and adriamycin given as for CAV1, etoposide 500 mg m-2 given in divided dose over days 3-7) on a 21-day schedule. The two regimens proved comparable (CR + PR 55% vs 56%), and the survival curves were virtually superimposable (median survival: CAV1, 8 months; CAV5, 9 months). Only five patients are still alive. The toxicity of the two treatments was similar. The scheduling of etoposide over 1 or 5 days seemed clinically unimportant in this study, perhaps because of concurrent use of other effective chemotherapy drugs.

Photodynamic therapy in the treatment of malignant tumours of the skin and head and neck.

Photodynamic therapy utilizes a tumour-localizing photosensitive substance which, when activated by light of an appropriate wavelength, releases cytotoxic substances causing destruction of the malignant tumour with preservation of surrounding normal tissues. In this technique the only drug/light combination which has been regularly used to date is that of haematoporphyrin derivative and red light at a wavelength of 630 nm usually produced by a dye or gold vapour laser. A pilot/feasibility study was set up in Southampton in 1983, with ethical permission, to treat tumours of the skin and head and neck which had failed all other treatment modalities or for which there was no practical alternative therapy. Thirty-eight patients were treated in this study and all tumours showed a response; significant palliation was achieved in a number of patients. Basal cell carcinomas and the multiple lesions of Bowen's disease were found to be particularly suitable for this form of therapy and prolonged local control was achieved in a number of patients.

Adjuvant chemotherapy in the treatment of breast cancer: results of a multicentre study.

248 patients with locally radically treated early breast cancer (196 node-positive) were randomized post-operatively between 6 courses of a 'CMF like' chemotherapy and no further treatment. Results (with a minimum of 5 years follow-up on every patient) favour chemotherapy with a significant increase in the median time to recurrence from 31 to 50 months for all patients (P = 0.04) and from 26 to 49 months for node-positive patients (P = 0.023). No significant effect on survival is seen although there is a trend towards longer survival in the treated group. The regimen used was relatively non-toxic when compared to the traditional CMF with 34% of patients experiencing mild nausea and vomiting immediately post-injection and only 11% complaining of more severe nausea and vomiting. Because of this lower toxicity the treatment was found to be amenable to administration in both regional hospitals and specialized centres.

Strontium-89 chloride for pain palliation in prostatic skeletal malignancy.

In a multi-centre study strontium-89 was shown to be effective in relieving bone pain from prostatic carcinoma in patients who had failed conventional therapies. Of 83 patients assessed at 3 months, following the administration of a dose of at least 1.5 MBq/kg, 75% derived benefit and 22% became pain free. Symptomatic improvement usually occurred within 6 weeks and continued for between 4 and 15 months (mean 6 months). Based on the dose estimation part of this study the recommended dose of strontium-89 is 150 MBq. Toxicity was low, provided platelet levels were above 100 x 10(9) l-1 at the time of treatment. Repeat treatments with strontium-89 may be given at intervals of not less than 3 months. Strontium-89 is administered intravenously on an out-patient basis with no special radiological protection precautions.

An audit and evaluation of bladder movements during radical radiotherapy.

With the introduction of the conformal approach for radical radiotherapy for prostate cancer, there has been renewed interest in the movement of the prostate and other pelvic organs during the course of radical pelvic radiotherapy. Many patients reviewed during a course of radical radiotherapy for bladder carcinoma have urinary flow symptoms, which may suggest impaired bladder emptying. There is concern, therefore, that the bladder volume may increase during such treatment, leading to inadequate coverage of the bladder by the planning target volume. We used serial CT scans to assess bladder size in 20 patients during the course of radical bladder radiotherapy. Our results showed that there was little variation in the left to right direction and, in 12 of the 20 patients studied, the anteriorposterior (AP) movement was < 1 cm. The bladder dome rose out of the treatment field in two patients during the course of therapy. However, in 16 patients, the target volume was encompassed as planned throughout.

Irradiation of the scrotum: what some men need MOST: the Manual Orchid Shielding Technique.

Although the need for radiotherapy to the scrotum is now unusual, shielding for the contralateral testis is used to maintain fertility and to preserve the endocrine function of the testis. We report a simple radiotherapy technique to achieve this by manually removing the contralateral testis proximally from the scrotum, to the level of the inguinal ring, where it is held by the patient during radiotherapy. A lead shield placed over the hand, testis and penis reduces the dose to the testis to an acceptable < 1.5% of the tumour dose. This can be confirmed by thermoluminescent dosimetry.

A randomized trial to assess the efficacy of 5-aminosalicylic acid for the prevention of radiation enteritis.

Sulphasalazine is an effective treatment for diarrhoea occurring during pelvic radiotherapy. We report the results of a trial to assess the value of its active moiety, 5-aminosalicylic acid, (5-ASA) in a prophylactic setting. Seventy-three patients planned for external beam radiotherapy to the pelvis were randomized on a double-blind basis to receive prophylactic 5-ASA or placebo. The severity of the acute radiation bowel reaction was documented by a weekly questionnaire. Surprisingly, diarrhoea occurred in a higher proportion of patients in the 5-ASA arm than the placebo arm (91.2% versus 73.7%, P = 0.070). The maximum change in both the severity of diarrhoea and the number of days per week on which diarrhoea occurred (from pre-radiotherapy level to the worst level at any time during treatment) were both significantly greater in patients taking 5-ASA than those taking placebo (P = 0.014 and P = 0.026, respectively). The average change (the sum of the weekly scores divided by the number of weeks of treatment, minus the pre-radiotherapy score) for both severity and days per week of diarrhoea were again greater in the 5-ASA than the placebo arm, but failed to reach statistical significance (P = 0.095 and P = 0.079, respectively). The use of anti-diarrhoeal medicines was significantly greater in the 5-ASA arm (P = 0.011). Constipation was more common in the placebo arm but this did not reach significance (P = 0.20). 5-ASA thus has no protective effect against acute radiation enteritis and appears to worsen it. Possible reasons for this surprising finding are discussed.

After surgery for breast cancer: which mode of surveillance?

Five hundred and ten women attending a specialized breast clinic for follow-up after surgery of early breast cancer (Stage I and II) have been studied. Recurrence was found most often (58%) in symptomatic women who returned to the clinic earlier than planned. Only 3% of asymptomatic patients had recurrent disease. It is concluded that counselling in symptoms of recurrent breast cancer would allow more efficient follow-up.

Clinical observations on the effects of elemental diet supplementation during irradiation.

A study has been conducted to assess the effects of adding an elemental diet as a supplement to a standard low-roughage diet recommended to a group of patients receiving a fractionated course of abdominal irradiation. The supplement was not found to modify patient experience of radiotherapy-induced complications.

Failure of scalp hypothermia to prevent hair loss when cyclophosphamide is added to doxorubicin and vincristine.

Scalp hypothermia can prevent alopecia caused by low doses of doxorubicin alone or in simple combinations. The technique was used in 60 patients with breast cancer (24 receiving adjuvant therapy; 36 with advanced recurrent disease) receiving chemotherapy with iv doxorubicin (40 mg/m2) and vincristine (1.4 mg/m2) on Day 1 together with oral cyclophosphamide (200 mg/m2) on Days 2-5. The patients' desire to continue scalp hypothermia, reflecting their perception of benefit, and an objective assessment of hair retention were the study end points. The mean number of cycles of chemotherapy given (6.1 in patients receiving adjuvant therapy; 3.8 in those with advanced disease) exceeded the number of cycles with hypothermia (2.1 in patients receiving adjuvant therapy; 1.6 in those with advanced disease); no patients retained enough hair to encourage them to continue scalp hypothermia throughout chemotherapy. All patients were rated as having poor hair retention. Scalp hypothermia is ineffective when used with combinations of drugs, each causing alopecia, or with high doses of doxorubicin.

Mediastinal germ cell tumour associated with malignant histiocytosis and high rubella titres.

Two further cases of a haematological malignancy are reported in patients with mediastinal germ cell tumours. Two young men developed bone marrow infiltration with histiocytes showing erythrophagocytosis shortly after subtotal excision of a malignant teratoma of the anterior mediastinum. Serial viral titres showed a rise in rubella antibody titres by haemoagglutination inhibition in both cases, antirubella IgG (ELISA) in one case and rubella RH zone in the other, in the absence of detectable IgM rubella antibodies. In case 1 a diagnosis of virus associated haemophagocytic syndrome was made and he was treated with interferon and steroids. In case 2 the diagnosis was initially idiopathic thrombocytopenia purpura but he deteriorated on steroids, and was subsequently unsuccessfully treated with chemotherapy and gamma globulin infusions. The disease ran a rapid downhill course with progressive marrow failure and they both died 5 months after diagnosis. Review of the presenting histology, the progressive course of the disease and post mortem histology, suggests that they had malignant histiocytosis. The association between mediastinal teratoma and haematological malignancy is of biological importance. Serial viral titres should be measured in patients with malignant histiocytosis to see if there is a raised rubella titre. Such viral studies are also warranted where there is an association between a mediastinal germ cell tumour and haematological malignancy.

Treatment of early breast cancer.

The early follow-up of patients treated by simple mastectomy alone or simple mastectomy combined with radical radiotherapy is presented. Both groups were well matched for age, menopausal status, duration of symptoms, size of tumour, and lymph-node involvement. There was no significant difference in survival of patients in the two groups at three years, but local recurrence was significantly more frequent (28%) in the mastectomy-alone patients. Early survival was not adversely affected by radiotherapy.

An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer.

We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% +/- 12% and for mortality 6% +/- 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.

Combination chemotherapy using high or low dose methotrexate for small cell carcinoma of the lung--a randomised trial.

Eighty-three patients with histologically proven small cell carcinoma of the lung were entered into a prospective randomised clinical trial to evaluate two induction regimes. A 'low' dose methotrexate regime which employed three cycles of etoposide, adriamycin and methotrexate given at conventional dosage was compared with a regime which employed three cycles of etoposide and adriamycin together with five courses of high dose methotrexate and folinic acid rescue. All patients achieving a complete response (CR) received prophylactic cranial irradiation. Patients with limited disease who achieved a CR received additional radiotherapy to the primary site. An alternative four drug regime (procarbazine, vincristine, cyclophosphamide and CCNU) was evaluated in patients failing to achieve or subsequently relapsing from a complete response. Response rates for the low dose and high dose methotrexate arms were 54 and 55% respectively with median survivals of 8.6 and 9.7 months. Median survival for complete and partial responders was 20.2 and 11 months respectively. The alternative four drug regime showed limited activity in patients failing to achieve a complete response after primary therapy. We conclude that high dose methotrexate as used in this study has no role in small cell lung cancer. The 'low' dose regime was well tolerated by outpatients, is effective and is suitable for generalised use in the palliation of small cell lung cancer.

The metabolic effects of abdominal irradiation in man with and without dietary therapy with an elemental diet.

The metabolic effects of abdominal radiotherapy were assessed in patients with pelvic neoplasms, and the effects of supplementation of the diet with an 'elemental' diet assessed. Therapeutic irradiation led to significant mean weight losses of 1.4 kg in control patients and 1.0 kg in patients receiving 'elemental' diet supplements. Irradiation was associated with small falls in plasma potassium and calcium concentrations in both groups. In the 'elemental' group there was a small increase in circulating alanine and insulin concentrations and a fall in glycerol and ketone body concentrations, but all variables remained within or close to normal basal reference ranges. Plasma albumin fell slightly but significantly in the 'elemental' diet group from 44 +/- 1 to 42 +/- 1 g/litre during treatment. Is is concluded that modern radiotherapy is no more than a modest catabolic stimulus. Long-term dietary supplementation with 'elemental' diets in ill subjects did not produce adverse effects.