Sector resection with or without postoperative radiotherapy for stage I breast cancer: five-year results of a randomized trial. Uppsala-Orebro Breast Cancer Study Group.

BACKGROUND: The effectiveness of routine postoperative irradiation following breast-conserving treatment of breast cancer has not previously been assessed in randomized clinical trials that have taken place in settings where mammography has been a major pathway to diagnosis or that have followed patients treated surgically by sector resection. PURPOSE: The aim of this study was to determine if treatment of stage I breast cancer by strictly standardized surgical technique with meticulous confirmation of a complete excision can reduce the local recurrence rate to an acceptable level without routine adjuvant radiotherapy. METHODS: In this trial conducted in Sweden, 381 women with stage I breast cancer were surgically treated by sector resection plus axillary dissection; then 184 women were randomly selected to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group). Patient accrual started in October 1981 and ended in September 1988. Criteria for eligibility were a unifocal cancer 20 mm or less in diameter (visible on mammogram) and radical excision and no histopathologic signs of axillary metastases. RESULTS: After median follow-up times of 65 and 63 months, the 5-year local recurrence rate was 2.3% (95% confidence interval [CI] = 0.1%-4.3%) in the XRT group and 18.4% (95% CI = 12.5%-24.2%) in the non-XRT group, respectively. The life-table curves were significantly different (P = .0001). The two treatment groups did not differ in overall survival: For the XRT group, the value was 91.0% (95% CI = 86.4%-95.4%); for the non-XRT group, it was 90.3% (95% CI = 85.8%-94.8%). The same was true for survival free from regional and distant recurrence: XRT group, 90.0% (95% CI = 85.3%-94.5%); non-XRT group, 87.1% (95% CI = 82.3%-92.0%). The rate of local recurrences was significantly higher in patients treated more recently (P. = 003). CONCLUSIONS: Sector resection plus radiotherapy to the breast very effectively achieves local tumor control. Surgery alone results in similar survival prospects, but the probability of local recurrence approaches 20% at 5 years. IMPLICATIONS: The increase in recurrence rate observed over time suggests that surgical technique and patient selection should be improved. The benefits of reduced cost and patient inconvenience that would result from the elimination of postoperative radiotherapy must be carefully weighed against the disadvantages of local recurrence. Longer term follow-up must be done to estimate the risk of cancer recurrence in these women 10 and 15 years later, and methods must be developed to identify those women who have a higher risk of recurrence. Finally, economic analyses of this and similar trials are needed to give empirical underpinnings for optimal use of radiotherapy.

Factors that influence the incidence of brachial oedema after treatment of breast cancer.

Six factors that may increase the likelihood of swelling of the arm after treatment of breast cancer were investigated in 136 patients who had undergone treatment. The highest incidence of oedema was among patients who had received radiotherapy in high doses with few fractions to the axilla (60%), and in patients with a history of one or more infections in the arm on the operated side (89%). Overweight, oblique surgical incision, infection in the arm, and radiotherapy correlated with arm swelling. The age of the patient and whether the operation had been done on the dominant or non-dominant side correlated less with the incidence of oedema.

The narrow proton beam therapy unit at the the Svedberg Laboratory in Uppsala.

The synchrocyclotron at the The Svedberg Laboratory (TSL) in Uppsala is now reconstructed and can presently operate with fixed frequency and proton energies up to 100 MeV. A first treatment room with a narrow proton beam unit for therapy of eye tumours is now in operation. Therapy of eye melanomas started in April, 1989 and during 1989 and 1990, 19 patients were treated with 72 MeV protons. The narrow beam unit provides a fixed horizontal beam and the patient is treated in a seated position. The present paper describes mainly the technical aspects of the unit which so far has been used only for eye melanomas. In the future, modifications of the unit will allow therapy of intracranial targets when higher proton energies are available. In its final form, the proton therapy facility at TSL will harbour a second treatment unit. Here a rotating gantry for 200 MeV protons will provide a broad beam, which will enable treatment of tumours located anywhere in the body.

Computed tomography in early diagnosis of local recurrence of rectal carcinoma.

Local recurrence is a common problem among patients treated surgically for adenocarcinoma of the rectum and rectosigmoid. When a local recurrence has become clinically manifest, curative therapy is virtually impossible. Asymptomatic local recurrences are difficult to find clinically, especially in patients treated with an abdominoperineal resection. In 177 patients who had undergone locally curative surgery and had had an uneventful recovery, a postoperative follow-up program, including computed tomography (CT), was carried out. In 77 per cent (137/177) a mass was observed in the pelvis at the first postoperative CT. This mass partly represents fibrosis due to radiation therapy. The risk of developing local recurrence cannot be foreseen from a CT image. CT should not be performed by routine but only in patients with symptoms in whom local recurrence cannot be verified by clinical examination, and always with CT-guided needle biopsy of the detected mass.

Local anaesthetics modifying the dermal response of irradiation. An experimental study.

In a series of experiments in rabbits the dermal reaction, provoked by a single dose or intermittent doses of irradiation, was prevented or modified by topical or parenteral administration of local anaesthetics, compared to irradiated control animals. The topical application of a eutectic lidocaine/prilocaine cream, EMLA 5%, was found to be more effective than intravenously injected lidocaine (Xylocain 1%).

Sequential methotrexate--5-FU--leucovorin (MFL) in advanced colorectal cancer.

Methotrexate (MTX) (250 mg/m2) was given as an i.v. infusion over 2 hr. At hour three and 23, 5-FU (500 mg/m2, maximally 1000 mg) was given as a bolus i.v. injection. The Leucovorin rescue was initiated hour 24. The chemotherapy course was repeated every 14 days for eight courses, then every third to fourth week. At least four courses of the regime were given to 50 patients with measurable advanced colorectal carcinoma. Toxicity was usually very mild but in seven patients an increase of serum creatinine was registered. Two of these patients had a severe period of uremia. With a more careful observation of kidney function, these episodes should have been foreseen. An objective response rate of 50% with six complete remissions (CR) and 19 partial remissions (PR) was found. Eighty-eight per cent (21/24) of the patients with tumour-related symptoms experienced symptomatic relief. The median response duration amounts to 5 months. It is concluded that the MFL regime is effective in inducing anti-tumour response in patients with advanced colorectal cancer.

Pre- versus postoperative radiotherapy in rectal carcinoma: an interim report from a randomized multicentre trial.

Since October 1980 a randomized multicentre trial has been in progress among patients with rectal carcinoma, in whom high-dose fractionated pre-operative irradiation (total dose 25.5 Gy in 5-7 days) is being tested against postoperative irradiation to a high dose level using a conventional fractionation scheme (totally 60 Gy in 8 weeks) delivered only to a high-risk group of patients (Dukes' stages B and C). The primary aim of the trial is to investigate whether local recurrence rate differs between the two groups, and a secondary aim is to see whether 5-year survival will differ between the two groups of patients. Up to October 1984, 360 patients have been randomly allocated to these two groups. Locally curative surgery has been performed in 161 patients in the pre-operative irradiation group and in 152 patients in the postoperative irradiation group. Pre-operative irradiation was extremely well tolerated and there were no irradiation-related complications; 95 per cent of these patients received their treatment according to the intended schedule. However, 48 of the 161 patients had a tumour in Dukes' stage A. Pre-operative radiotherapy had no impact on postoperative mortality or the occurrence of anastomosis dehiscence, but significantly more patients with perineal wound sepsis after an abdominoperineal resection were found in the group of patients receiving pre-operative radiotherapy. This prolonged the stay in hospital after surgery. Postoperative radiotherapy was not so well tolerated as pre-operative treatment, and in a substantial number of patients the treatment could not be commenced until a relatively long time after surgery. To date, the local recurrence rate is acceptably low (approximately 10 per cent) in both treatment groups.

Proton radiotherapy with the Uppsala cyclotron. Experience and plans.

From 1957 to 1968, the 230-cm synchrocyclotron at the Gustaf Werner Institute was used for clinical tests with a 185 MeV proton beam. The radiotherapeutic research was part of an extensive research programme in physics, chemistry, biology and medicine. Only a small series of patients were treated. A brief review of the early development and clinical experience of the cyclotron activities at Uppsala from 1957 to 1968 is given. The former accelerator is now being converted. Beams are expected to be available in the new radiotherapy treatment rooms in 1986. Plans for the new facilities with special reference to alternative methods of proton acceleration and beam transport, i.e. fixed beams or an gantry system are presented. The corresponding activities at the Institute of Theoretical and Experimental Physics (ITEP) in Moscow are also referred to thanks to a bilateral research programme which has existed in the past and from which the Uppsala group has benefited greatly.

Preoperative irradiation of primarily non-resectable adenocarcinoma of the rectum and rectosigmoid.

In a series of 328 patients with adenocarcinoma of the rectum and rectosigmoid, 39 had a tumour which was considered locally non-resectable (19 patients) or borderline resectable (20 patients). Twenty-eight of these patients received radiation therapy with a daily target dose of 2 Gy up to a total of 46 Gy. If the tumour was still considered non-resectable 3 weeks later, radiation therapy was usually continued up to a total dose of 64 Gy together with 5-fluorouracil. Fifteen patients with a non-resectable tumour received radiation therapy up to a total dose of either 46 Gy (7 patients) or 64 Gy (8 patients). Only two patients underwent resection. Of the 20 patients with a tumour that was considered borderline resectable, 13 received 46 Gy. Nine patients in this group were radically resected. Totally 11 tumours were resected, constituting 39 per cent of the patients who were treated up to 46 Gy or more. Truly locally inoperable tumours in this series were thus rarely converted to extirpative tumours by means of radiation therapy. Most patients with a tumour considered borderline resectable seemed to benefit from the treatment. In addition, the palliative effect of radiation therapy was excellent.

Computed tomography in staging of rectal carcinoma.

Computed tomography (CT) was performed on 204 patients with rectal carcinoma in an attempt to determine the tumour stage preoperatively. In 154 patients CT and histopathology could be compared. Correct staging was achieved in 60 to 70 per cent of the patients, but considerable over- and understaging limit the use of CT in preoperative staging of rectal carcinoma.

Radioprotection of the kidney with degradable microspheres. A pilot study in the dog with repeated irradiation.

The left kidney of 9 dogs was irradiated daily for three days with 300 kVp X-rays. Radioprotection was attempted in 5 of the kidneys by administration of degradable microspheres in the renal artery, immediately before irradiation. Protected kidneys received 3 X 8 or 3 X 12 Gy in midplane dose, unprotected kidneys 3 X 5.2 or 3 X 8 Gy. A protective effect due to induced hypoxia could be demonstrated in creatinine clearance, which was significantly higher in protected than in unprotected kidneys at 7 - 13 weeks after irradiation.

Prognostic implication of estrogen receptor content in breast cancer.

The cytosolic estrogen receptor (ER) content of the primary tumor was determined by isoelectric focusing in 170 consecutive women with unilateral breast cancer diagnosed in 1977 through 1980. No adjuvant treatment over and above surgery and radiotherapy was given. The overall corrected survival was not significantly (p greater than 0.05) higher in ER-rich (less than 0.1 nmol/g DNA) than in ER-poor tumors, but the median period from recurrence to death was longer in the former (16 months) than in the latter (10 months) group. The difference in disease-free survival (DFS) in favour of the ER-rich tumors achieved its maximum-about 15%-after two years (p less than 0.01). At prolonged follow-up, however, the curves converged and there was no significant difference when the whole six year period of observation was taken into account. In patients without axillary metastases the same pattern emerged, with earlier recurrences in ER-poor tumors and a difference in DFS between the two ER groups at two years (p less than 0.01) which was diminished after five years (p less than 0.05). The ER content provided no significant prognostic information in patients with axillary node metastases or locally advanced disease. We conclude from the present and other available data that the ER content in breast cancer would seem to be an indicator of growth rate rather than of metastatic potential and accordingly a predictor of the pattern of recurrence and length of disease-free survival rather than of long-term survival.

Radiation therapy of anal carcinoma.

Between 1978 and 1982, 30 consecutive patients with anal carcinoma were given radiation therapy. Irradiation alone was given to cloacogenic carcinoma and in combination with bleomycin to squamous cell carcinoma. Patients with an early tumour (T1, T2) were treated to 65 Gy (60 Gy + bleomycin) directly, whereas patients with a moderately advanced tumour (T3) were treated to the same radiation dose only if no evidence of residual disease existed after approximately 50 Gy (45 Gy + bleomycin); if a palpable tumour still remained 3 to 4 weeks after the end of the irradiation, surgery was performed. Seven of 7 patients with an early lesion (T1, T2) and 5 of 9 with a tumour in stage T3 treated according to this regime are alive with no evidence of disease and with preserved anal anatomy and function. Only one of 9 patients in stage T3 and T4, also treated with an abdominoperineal resection had viable tumour at surgery and 6 of them are alive without disease; 2 died postoperatively and one developed a recurrence in the urinary bladder. The results indicate that anal carcinomas are sensitive to radiation and often curable by irradiation.

Preoperative irradiation with high-dose fractionation in adenocarcinoma of the rectum and rectosigmoid.

The incidence of local pelvic recurrence after 'curative' resection for rectal carcinoma is high. Adjuvant irradiation given pre- or postoperatively has led to a decreased incidence of pelvic recurrences. In a series of 58 consecutive patients between 1979 and 1980, those with primarily operable rectal tumours received preoperative irradiation in a total dose of 25.5 Gy in fractions of 5.1 Gy daily for 5 days. A locally 'curative' resection was performed in 41 patients 2 to 5 days later. The radiation therapy was well tolerated without early or late complications. All patients were followed up every 6 months with computed tomography over the pelvic region; aspiration biopsies were taken whenever any possible pathology was made. A local recurrence occurred in only 2 patients during the follow-up period (24-42 months). In a retrospective material from 1976 to 1979, totally 107 patients were admitted for surgery. Of 81 patients operated upon for 'local cure', 38 (47%) have had local recurrence to date, 32 (40%) of them within 2 years. These results indicate that a high-dose fractionated preoperative irradiation reduces the incidence of local recurrences, is well tolerated and does not influence the period of hospitalization.

Computed tomography of recurrent rectal carcinoma.

Computed tomography was performed in 28 patients and gave a correct diagnosis in 21 of 22 cases with abdomino-perineal excision of the rectum and in 5 of 6 with anterior resection. CT is of considerable value in the diagnosis of local recurrence of rectal carcinoma, particularly after rectal excision.

Kidney radioprotection by temporary hypoxia. Experiments with degradable microspheres.

Deep hypoxia protects biological tissue against ionizing radiation. By intra-arterial injection of degradable starch microspheres the renal circulation was temporarily blocked in unilaterally nephrectomized rats. The induced hypoxia was utilized for protection of the kidney against single doses of high-voltage X-rays. Renal function and survival date were compared between animals protected by hypoxia and non-protected animals. The survival rate of the former animals exceeded that of the latter by a factor of 1.6. All irradiated animals showed a lower glomerular filtration rate, Hippuran clearance and urine osmolarity than non-irradiated controls. Surviving, protected animals irradiated with 42 Gy and 52 Gy showed a glomerular filtration rate of about 0.5 ml/min and a Hippuran clearance of about 2 ml/min, whereas all non-protected animals irradiated with 42 Gy died.

Bronchial carcinoma. I. A prospective five year study on an unselected carcinoma population in a Swedish county.

No prospective clinical investigations of unselected total materials of bronchial carcinoma have been reported. The clinical profile of 273 patients with histologically verified bronchial carcinoma from a Swedish county during 1971-1976 is presented. The difficulties in making valid comparisons with other literature reports makes it necessary to describe in detail the total material. Such a description is given in the present paper. In order to avoid different selection mechanisms an attempt was made to collect an almost total material. No patients were lost in the follow-up. Autopsy was performed in 95% of the deceased patients. The distribution of the histological WHO groups in the total material was: 44% group I, 18% group II, 29% group III and 9% group IV. The material was used for randomized investigations of radiotherapy, chemotherapy and placebo treatment in inoperable patients with the purpose of studying the quality of survival in addition to survival time. For the measurement of the quality of survival the Carlens vitagram index was used (Carlens et al. 1970). The influence of a general health survey with mass miniature chest X-ray was also studied, since such a survey was performed in the region of the study. The expected 5-year survival is estimated to be 7%. Only 20 patients with resectional therapy without known signs of metastases are expected to survive. Nine (45%) of these patients were discovered by mass miniature chest X-ray and thus for a limited number of patients the detection by the general health survey gives a better prognosis.