Arne Wallgren

SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening.

We studied the effect of postoperative radiotherapy (RT) after breast sector resection for ductal carcinoma in situ (DCIS). The study protocol stipulated radical surgery but microscopically clear margins were not mandatory. We randomised 1 046 operated women to postoperative RT or control between 1987 and 1999. The primary endpoint was ipsilateral local recurrence. Secondary endpoints were contralateral breast cancer, distant metastasis and death. After a median follow-up of 5.2 years (range 0.1–13.8) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 (95% confidence interval (CI) 0.05–0.10). In the control group there were 117 recurrences giving a cumulative incidence of 0.22 (95% CI 0.18–0.26) giving an overall hazard ratio of 0.33 (95% CI 0.24–0.47, p < 0.0001). Twenty two percent of the patients had microscopically unknown or involved margins. We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence. Secondary endpoints did not differ. Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast. Seven patients needed RT-treatment to prevent one recurrence.

Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study.

The aim was to quantify the risk of post-treatment sarcoma in breast cancer patients. All 122,991 women with a breast cancer from 1958 to 1992 in the Swedish Cancer Register were followed up for soft tissue sarcomas and 116 were found, giving a standardised incidence ratio of 1.9 (95% CI 1.5-2.2). The absolute risk was 1.3 per 10(4) person-years. The sarcomas were located in the breast region or on the ipsilateral arm in 63% (67/106). There were 40 angiosarcomas and 76 sarcomas of other types. In a case-control study, angiosarcoma correlated significantly with lymphoedema of the arm, odds ratio (OR) 9.5 (95% CI 3.2-28.0), but no correlation with radiotherapy was observed. For other types of sarcoma there was a correlation with the integral dose. The dose-response relationship indicated that the risk increased linearly with the integral dose to 150-200 J and stabilised at higher energies. The OR was 2.4 (95% CI 1.4-4.2) for an energy of 50 J, approximately corresponding to the radiation of the breast after breast-conserving surgery. Thus, only oedema of the arm correlated with angiosarcoma, but for other types of sarcoma the integral dose of radiotherapy was a predictor of the risk.

Intracranial tumors after exposure to ionizing radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skin hemangioma.

The risk of intracranial tumors after exposure to ionizing radiation during infancy has been studied in a pooled analysis of two Swedish hemangioma cohorts (n = 28,008). The mean absorbed intracranial dose was low (7 cGy, range 0-11.5 Gy). The cohorts were followed up in the Swedish Cancer Register for incident intracranial tumors during the period 1958-1993. Eighty-eight tumors were found in 86 individuals compared to 60.72 expected [standardized incidence ratio (SIR) 1.42, 95% confidence interval (CI) 1.13-1.75]. The SIR increased significantly in ascending dose categories (P = 0.02). Dose-response analyses were performed with Poisson regression methods. There was a significant effect of dose, and the dose-effect relationship was negatively modified by age at first treatment. This indicates a higher risk for those exposed earlier in life. A linear dose-response model modified by age at first treatment resulted in the best fit. The excess relative risk (ERR) was 2.7/Gy (95% CI 1.0-5.6). The ERR/Gy was 4.5 if the treatment was given before 5 months of age, 1.5 if it was given at 5-7 months and 0.4 if it was given later. The study thus strongly indicates that there exists a dose-response relationship between absorbed dose in the brain and the subsequent risk of developing an intracranial tumor and that the risk is higher among infants exposed at younger ages.

Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening

The effect of postoperative radiotherapy after sector resection for stage I-II lymph node-negative breast cancer was evaluated in a patient population with access to public mammographical screening. 1187 women were randomised to no further treatment or postoperative radiotherapy following a standardised sector resection and axillary dissection. Radiation was administered to a dose of 48-54 Gy. Median age was 60 years, and median size of the detected tumours was 12 mm. Of the women 65% had their tumours detected by mammographical screening. The relative risk (RR) of ipsilateral breast recurrence was significantly higher in the non-irradiated patients compared with the irradiated patients, RR=3.33 (95% Confidence Interval (CI) 2.13-5.19, P<0.001). The corresponding cumulative incidence at 5 years was 14% versus 4%, respectively. Overall survival (OS) was similar, RR=1.16 (95% CI 0.81-1.65, P=0.41), with 5 year probabilities of 93 and 94%, respectively. Recurrence-free survival (RFS) at 5 years was significantly lower in the non-irradiated women, 77% versus 88% (P<0.001). Although women above 49 years of age, whose tumours were detected with mammographical screening, had the lowest rate of ipsilateral breast recurrence in this study, the cumulative incidence of such event amounted to 10% at 5 years if radiotherapy was not given. Such a recurrence rate has been considered as unacceptably high, but is, however, in the same range as that reported after lumpectomy and postoperative radiotherapy in published series.

Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer

PURPOSE A controversy exists regarding whether it is safe to delay radiation therapy until the completion of chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Within the context of two concurrent randomized clinical trials we had the opportunity to evaluate outcomes for patients who received breast irradiation after completing different durations of chemotherapy. METHODS AND MATERIALS From July 1986 to April 1993 the International Breast Cancer Study Group (IBCSG) Trial VI randomly assigned 1554 pre/perimenopausal node-positive breast cancer patients to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for either three consecutive courses on months 1-3, or six consecutive courses on months 1-6, both with or without reintroduction CMF. IBCSG Trial VII randomly assigned 1266 postmenopausal node-positive breast cancer patients to receive tamoxifen for 5 years, or tamoxifen for 5 years with three early cycles of CMF, both with or without three courses of delayed CMF. Both trials allowed a choice of mastectomy, or breast-conserving surgery plus radiation therapy, and both were stratified by type of surgery. Radiotherapy was delayed until the initial block of CMF was completed; 4 or 7 months after surgery for pre/perimenopausal patients, and 2 or 4 months after surgery for postmenopausal patients. Over both trials, 718 eligible patients elected to receive breast-conserving surgery plus radiation therapy: 433 on Trial VI, and 285 on Trial VII. Four-year actuarial total failure rates (failure at any site), risks of developing distant metastases (DM at any time during observation), and overall survival (OS) were estimated using the Kaplan-Meier method. To avoid potential bias due to competing causes of failure, only patients who could be followed for at least 4 years (enrolled prior to July 1, 1990) were used to evaluate the patterns of first relapse site. Crude percents of local failure with or without other sites (LF), distant metastases including regional nodal failure (DM/RNF), or other first events (second primaries/death without recurrence) were estimated for each treatment group. For this report, an intent to treat analysis was performed at a median follow-up of 48 months. RESULTS No differences were found in the 4-year actuarial total failure rates, risk of developing distant metastases, and overall survival among the two radiotherapy groups of each study. The cumulative incidence of types of first failure and the 4-year crude rates showed no treatment differences in the patterns of site of first event. Estimates for the 4-year crude percent of local failures were 8 and 9% for pre/perimenopausal patients who had radiation therapy at 4 or 7 months after surgery, and 3 and 6% for postmenopausal patients who had radiation therapy at 2 months or 4 months after surgery. CONCLUSIONS For node positive patients receiving breast-conserving surgery followed by radiation therapy, the incidence of breast recurrence in the conserved ipsilateral breast within 4 years was between 8 and 9% for pre/perimenopausal patients and between 3 and 6% for postmenopausal patients. After 48 months of median follow-up, administering radiation therapy after three or six cycles of CMF for pre/perimenopausal women, or after no cycles or three cycles of CMF for postmenopausal women does not influence overall efficacy or local control in this series.

Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma

PURPOSE To evaluate the treatment outcome after radical radiotherapy of localized prostate cancer in 50 patients (38 patients with stage T1-2 and 12 patients with stage T3) after a median follow-up time of 45 months (range 18-92 months). METHODS The treatment was given by combination of external beam radiotherapy (50 Gy) and brachytherapy (2 x 10 Gy). The brachytherapy was given using TRUS-guided percutaneously inserted temporary needles with a high dose rate remote afterloading technique with Ir-192 as the radionuclide source. Three target definitions and dose levels inside the prostate gland were used. Local control was evaluated by digital rectal examination, TRUS-guided biopsies and serum PSA evaluations. RESULTS Clinical and biopsy verified local control was achieved in 48 of the 50 (96%) patients; for stage T1-2 in 37 of 38 (97%) patients and for stage T3 in 11 of 12 (92%) patients. A posttreatment serum PSA level < or =1.0 ng/ml was seen in 42 (84%) patients, values from >1.0 to < or =2.0 ng/ml were seen in four (8%) patients and values exceeding 2.0 were seen in four (8%) patients. The late toxicity was minimal. CONCLUSION The local control results and the minimal toxicity after the combined radiotherapy treatment are promising. However, long term results are necessary before general use.

Is breast cancer a curable disease? A study of 14,731 women with breast cancer from the cancer registry of Norway

The question whether breast cancer is curable remains controversial. Late recurrences and death from the disease are not infrequent. Long term follow‐up of a large patient population is necessary to study this issue. The authors report a study of 14,731 cases of breast cancer reported to the Cancer Registry of Norway with follow‐up times ranging from 5 to 18 years. A model in which the logarithms of the survival times were assumed to be normally distributed, the lognormal model, fitted the data well for individual stages, age groups, and periods of treatment. The cured fraction, i.e., consisting of those only subject to normal mortality risks, was estimated from the model to 35 ± 1% standard error. In Stages 1, 2, 3, and 4 it was 54 ± 3%, 27 ± 1%, 19 ± 2%, and 2 ± 1%, respectively. It is concluded, however, that the estimated cure rate in Stages 3 and 4 should be regarded with caution in view of the methodological problems involved in the analysis and the small number of patients with long follow‐up. The estimated cured fraction in both the individual stages and in the entire material was significantly higher in patients younger than 55 years of age than in older patients. The median survival of noncured patients was estimated to be 3.6 years for the entire material. In Stage 1, 2, 3, and 4 it was 7.6 years, 3.4 years, 2.1 years, and 0.7 years, respectively. The lognormal model seems to be a good approximation of breast cancer survival. The model is consistent both with late excess mortality and with the presence of a cured fraction. It is noteworthy that an excess mortality was observed during the whole follow‐up period. Extrapolations from the model should therefore be cautiously judged until supported by observed data.

Cancer incidence after radiotherapy for skin haemangioma during infancy.

An infant cohort treated for skin haemangioma with 226Ra between 1930 and 1965 (n = 11,807) was studied. The median age at treatment was 5-months and 88% were treated before 12 months of age. This cohort was followed up in the Swedish Cancer Registry during the years 1958 to 1989, giving 370,517 person-years at risk. A total number of 248 malignancies have been observed and the standardized incidence ratio (SIR) was 1.21 (confidence interval (CI) 95%, 1.06-1.37). Significantly increased numbers of cancers were found in the central nervous system, 34 cases (SIR = 1.85, CI 95% 1.28-2.59), the thyroid, 15 cases (SIR = 1.88, CI 95% 1.05-3.09) and other endocrine glands, 23 cases (SIR = 2.58, CI 95% 1.64-3.87). The absorbed dose in 11 specified risk organs has been estimated using a phantom of the size of a 5-6-month-old child. The mean absorbed dose in the thyroid was 0.12 Gy and the excess relative risk (ERR) for thyroid cancer was 7.5 per Gy (CI 95% 0.4-18.1). The mean dose in the central nervous system was 0.077 Gy and the ERR for brain tumours was 10.9 per Gy (CI 95% 3.7-20.5). This cohort gives a unique opportunity to analyse long-term effects of low-dose irradiation during infancy.

Soft tissue sarcoma after treatment for breast cancer

In a register study all women in the West of Sweden Health Care Region with a breast cancer diagnosed between 1960 and 1980 (n = 13,490) were followed up in the Swedish Cancer Register to the end of 1988 for later occurrence of a soft tissue sarcoma (STS). Nineteen sarcomas were reported, whereas 8.7 were expected and the relative risk (RR) was 2.2 (CI 95% 1.3-3.4). The absolute risk was 1.7/10(4) person years (PY) in comparison with 0.8 expected. To obtain a more detailed analysis of the associations between arm lymphoedema, radiotherapy and STS development, and to control the quality of the register data, a case control study was also performed. Clinical records from the different hospitals in the region were collected for all the 19 cases as well as for three selected controls per case. The histopathology of the cases were reviewed, and one of the cases was reclassified as a malignant melanoma and excluded from further analysis. Thirteen of the cases were clustered around the treated breast area. To quantify the exposure to radiotherapy, the integral dose was estimated. The presence of lymphedema was included as a binary variable in the analysis. The exact conditional randomisation test indicated a significant correlation between the integral dose and the development of an STS (p = 0.008) and this association was still significant after stratification for arm oedema. A conditional logistic regression analysis with STS as the dependent variable and the integral dose as the explanatory variable gave an odds ratio (OR) of 5.2/100 J (CI 95% 1.3-21.2), and if this regression was restricted only to the STS developing in the radiation fields the OR was 3.2/100 J (CI 95% 0.8-12.9). Thus, the excess of STS in this breast cancer cohort was very low (0.9/10(4) PY). However the integral dose correlates well to the development of STS and can be useful in quantifying even small risks of secondary malignancies in the breast cancer population.

Long-term survival of 458 young breast cancer patients

The authors report the long‐term survival of 458 young breast cancer patients with follow‐up times ranging from 20 to 51 years. Patients with distant metastases at diagnosis were not included in the study. An excess breast cancer mortality was observed for at least 40 years after diagnosis. At 40 years, the actuarial breast cancer survival for all patients was 32% ± 3% (standard error). For patients with localized and regional disease, it was 53% ± 6% and 19% ± 3%, respectively. A persistent excess mortality after 40 years, however, could not be ruled out because too few patients remained at risk. It is concluded that a cured fraction of patients defined as a group subject only to normal mortality risks, in practice, can only be identified in young patients with a low expected mortality, since older patients give only minor contributions to long‐term survival results. In an unselected series of breast cancer patients, an excess breast cancer mortality will probably persist during a period that is longer than the life expectancy of the average patient. A parametric survival model, the log‐normal model, was found to provide a good fit to the observed survival data. The cured fraction of patients predicted by the model was similar to the actuarial breast cancer survival at 40 years. These results suggest that the model could be used as a tool for analyzing observed survival patterns in breast cancer. It might thus provide an alternative to the conventional 5‐ or 10‐year rates. The good fit of the model also suggests that late recurrences represent one end of a continuous, broad spectrum of behavior in disseminated breast cancer.