Emmanuel Grimaud

Long term risk of sarcoma following radiation treatment for breast cancer

Between 1954 and 1983, 7620 patients were treated for breast carcinoma at Institut Gustave Roussy (France). Of these patients, 6919 were followed for at least 1 year. Out of these, 11 presented with sarcomas thought to be induced by irradiation, 2 of which were Steward-Treves Syndrome, and 9 of which were sarcomas within the irradiated fields. All histological slides were reviewed and a comparison with those of breast cancer was done. The sites of these sarcomas were: parietal wall, 1 case; second costal cartilage, 1 case; infraclavicular region, 1 case; supraclavicular region, 2 cases; internal third of the clavicle, 2 cases; axillary region 2 cases; and the internal side of the upper arm (Stewart-Treves syndrome), 2 cases. The median age of these 11 patients at the diagnosis of sarcomas was 65.8 (49-83). The mean latent period was 9.5 years (4-24). Three patients underwent radical mastectomy and nine modified radical mastectomy. Only one patient received chemotherapy. The radiation doses received at the site of the sarcoma were 45 Gy/18 fr. for 10 cases and 90-100 Gy for 1 case (due to overlapping between two fields). The histology was as follows: malignant fibrous histiocytoma, 5 cases; fibrosarcoma, 3 cases; lymphangiosarcoma, 2 cases; and osteochondrosarcoma, 1 case. The median survival following diagnosis of sarcoma was 2.4 years (4 months-9 years). Two patients are still alive: one with recurrence of her breast cancer, the other in complete remission, with 7 and 3 years follow-up, respectively. All other patients died from their sarcomas. The cumulative incidence of sarcoma following irradiation of breast cancer was 0.2% (0.09-0.47) at 10 years. The standardized incidence ratio (SIR) of sarcoma (observed n# of cases (Obs)/expected n# of cases (Exp) computed from the Danish Cancer Registry for the same period) was 1.81 (CI 0.91-3.23). This is significantly higher than one, with a p = 0.03 (One Tailed Exact Test). The mean annual excess (Obs-Exp)/100.000 person-years at risk during the same period/(100,000) was 9.92. This study suggests that patients treated by radiation for breast cancer have a risk of subsequent sarcomas that is higher than the general population. However, the benefit from adjuvant radiation therapy in the treatment of breast cancer exceeds the risk of second cancer; therefore, the potential of radiation-induced sarcomas should not be a factor in the selection of treatment for patients with breast cancer.

Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood.

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3‐year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case‐control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow‐up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34–89)). The SIR was 113 (95% CI: 62–185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2–125) after chemotherapy alone (1 STS) and 19 (95%CI: 3–60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case‐control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

SummaryThe variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood

BACKGROUND Radiotherapy and chemotherapy are associated with an increased risk of second malignant neoplasm (SMN). An association between SMN and familial aggregation has also been shown. The aim of this study was to investigate the role of familial factors in the risk of SMN and their potential interaction with the effect of treatment. METHODS We devised a case-control study of 25 children with SMN (cases) and 96 children with no SMN after a cancer treatment (controls), taken from a cohort of 649 children treated at our institution between 1953 and 1985. A complete family history was obtained for patients and controls and a familial index defined to evaluate the degree of familial aggregation. The radiation dose given at 151 sites in the body was estimated for each radiotherapy course for each child. FINDINGS Among family members of the 25 SMN cases, there were ten with early-onset (< or = 45 years) cancer, compared with eight among relatives of the 96 controls. Compared with patients who had no family history of early-onset cancer, those with one or more affected family members had an odds ratio for SMN of 4.7 (95% CI 1.3-17.1; p = 0.02). Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausens disease) did not affect this risk substantially. INTERPRETATION Both genetic factors and exposure to ionising radiation have independent effects on the risk of SMN. Follow-up of children treated for cancer should be especially vigilant when there is a family history of early-onset cancer.

Malignant breast tumors after radiotherapy for a first cancer during childhood.

PURPOSE To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors. PATIENTS AND METHODS In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean). RESULTS Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkins disease (relative risk, 7.0; 95% CI, 1.4 to 30.9). CONCLUSION The reported high risk of BC after childhood Hodgkins disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Risks of brain tumour following treatment for cancer in childhood: modification by genetic factors, radiotherapy and chemotherapy.

A cohort of 4,400 persons treated for various cancers of childhood in France and the UK was followed up over an extended period to assess risks of subsequent brain tumour in relation to the radiotherapy and chemotherapy that the children received for their first cancer. Elevated risks of subsequent brain tumours were associated with first central nervous system (CNS) tumour (two‐sided p =0.0002) and neurofibromatosis (two‐sided p =0.001). There was also elevated brain tumour risk (two‐sided p =0.003) associated with ionising radiation exposure, the risk being concentrated among benign and unspecified brain tumours. The radiation‐related risk of benign and unspecified brain tumours was significantly higher than that of malignant brain tumours (two‐sided p≤ 0.05); there was no significant change of malignant brain tumour risk with ionising radiation dose (two‐sided p > 0.2). In general, there were no strong associations between alkylating agent dose and brain tumour risk. The only significant association between brain tumour risk and alkylating agent dose was in relation to compounds used (bleomycin, chloraminophen) that are thought not to deliver substantial doses to the brain; the statistical significance of the trend with dose depended on a single case, and thus must be considered a weak result. Int. J. Cancer 78:269–275, 1998. Published 1998 Wiley‐Liss, Inc.

Estimation of the radiation dose delivered to any point outside the target volume per patient treated with external beam radiotherapy

The methodology we have developed to study dose distribution outside the target volume during external beam radiotherapy allows us to determine the dose received by the patient arising from leakage radiation and scattered radiation from both the head of the treatment machine and from the treatment room. It also allows us to evaluate the dose due to photon scattering in the patient by means of a dedicated 3-D algorithm permitting computations for the whole body of the patient and taking into account height, sex and anatomical data at the time of the treatment, dosimetric data and lung heterogeneity parameters. This methodology offers solid criteria for recommendations concerning radiation protection.

Dose distribution throughout the body from radiotherapy for Hodgkin’s disease in childhood

BACKGROUND AND PURPOSE The individual dosimetry performed for a multicentre European cohort study of second malignant neoplasm following radiotherapy for a solid cancer in childhood demonstrated a large variation in the radiation doses estimated to any site. MATERIALS AND METHODS From this study we have extracted the present work, i.e. estimation of doses for patients who underwent radiotherapy for Hodgkins disease in their childhood. These patients were treated using high energy X-rays from linear accelerators (MV group), gamma-radiation from Cobalt machines (Cobalt group), soft X-rays from orthovoltage machines (kV group) and electron beams from accelerators (MeV group) at six French and UK centres. All patients started their radiotherapy between 1955 and 1985 and about 12% of them received more than one beam quality. Most of the patients were irradiated with large mantle AP/PA or partial mantle fields. Patients with transdiaphragmatic extension were also irradiated using inverted-Y paraaortic fields. The absorbed doses at the 91 skeleton points are used to calculate the mean dose to the active bone marrow. RESULTS Estimates of the median and mean doses, standard deviations and ranges to 13 specific sites of the body and to the active bone marrow are reported. Depending upon the size and sex of patients, target volume and position and radiotherapy techniques, the estimated doses are highly spread, attaining 0.19-106.07% of the target dose. This study underscores the need for individual dosimetry in epidemiological studies. Comparison with the available measured and calculated doses to the ovary and testis shows good agreement. CONCLUSION This study underscores the need for individual dosimetry in epidemiological studies.

Epidemiological evidence for a common mechanism for neuroblastoma and differentiated thyroid tumour.

Because genetic predisposition probably plays an important role in the aetiology of most of childhood cancers, studies of second primaries occurring after these cancers may be particularly informative about possible common genetic mechanisms in both of these cancers. We have studied the incidence of thyroid tumours occurring after cancer in childhood in a cohort of 592 children treated before 1970. Among these children, six later developed a thyroid carcinoma, and 18 developed a thyroid adenoma. Radiation doses received to the thyroid by each of the irradiated children have been estimated using individual radiotherapeutic technical records. Thyroid carcinomas and thyroid adenomas were five times more frequent after irradiation for neuroblastoma than after irradiation for any other first cancer. This ratio did not depend on sex, nor on time elapsed since irradiation, nor on dose of radiation received for the thyroid gland. This result suggests that there is a common mechanism for the occurrence of neuroblastoma and of differentiated thyroid tumour.

Radiation Dose, Chemotherapy and Risk of Lung Cancer After Breast Cancer Treatment

It is of particular concern to evaluate the risk of lung cancer occurrence after breast cancer treatment as women with breast cancer quite often undergo radiation therapy as part of their initial treatment and their life expectancy remains long. From a roster of 7711 women initially treated for breast cancer between 1954 and 1984, a cohort-study was performed among 4171 1-year survivors followed during the period 1975–1995. The relationship between the radiation dose received by the lung and the risk of lung cancer was then evaluated in a nested case-control study of 11 breast-cancer patients who developed lung cancer and 22 controls matched for age at diagnosis of breast cancer, period of initial treatment and length of follow-up. Among the 4171 women, six developed lung cancer during the entire follow-up as compared to 5.4 cases expected (SIR = 1.1, 95%CI: 0.4–2.3). When considering only the women initially treated by radiotherapy with or without adjunction of chemotherapy and excluding the 10 first years of follow-up, the SIR was significantly increased (SIR = 3.2, 95%CI: 1.0–7.4). In the case-control study, nine of the 11 lung cancers occurred in the ipsilateral lung and two in the trachea. The overall odds ratio (OR) of lung cancer associated with initial radiotherapy was 1.4 (95%CI: 0.2–11.1) and an excess in the OR of 7% (90%CI: ? to 41%, p = 0.10) per gray delivered to the site of lung cancer was evidenced. Our results agree with previous studies in favor of an increased risk of lung cancer after radiation therapy for breast cancer.