Alain Laugier

Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer

PURPOSE To identify predicting factors for local failure and increased risk of distant metastases by statistical analysis of the data after breast-conserving treatment for early breast cancer. METHODS AND MATERIALS Between January 1976 and December 1993, 528 patients with nonmetastatic T1 (tumors < or = 1 cm [n = 197], >1 cm [n = 220]) or T2 (tumors < or = 3 cm [n = 111]) carcinoma of the breast underwent wide excision (n = 435) or quadrantectomy (n = 93) with axillary dissection (negative nodal status [n-]: 396; 1-3 involved nodes: 100; >3 involved nodes: 32). Radiotherapy consisted of 45 Gy to the entire breast via tangential fields. Patients with positive axillary lymph nodes received 45 Gy to the axillary and supraclavicular area. Patients with positive axillary nodes and/or inner or central tumor locations received 50 Gy to the internal mammary lymph node area. A boost dose was delivered to the primary site by iridium 192 Implant in 298 patients (mean total dose: 15.2+/-0.07 Gy, range: 15-25 Gy) or by electrons in 225 patients (mean total dose: 14.8+/-0.09 Gy, range: 5-20 Gy). The mean age was 52.5+/-0.5 years (range: 26-86 years) and 267 patient were postmenopausal. Histologic types were as follows: 463 infiltrating ductal carcinomas, 39 infiltrating lobular carcinomas, and 26 other histotypes. Grade distribution according to the Scarff, Bloom, and Richardson (SBR) classification was as follows: 149 grade 1, 271 grade 2, 73 grade 3, and 35 nonclassified. The mean tumor size was 1.6+/-0.3 cm (range: 0.3-3 cm). The intraductal component of the primary tumor was extensive (EIC = IC > or = 25%) in 39 patients. Tumors were microscopically bifocal in 33 cases. Margins were assessed in the majority of cases by inking of the resection margins and were classified as positive in 13 cases, close (< or = 2 mm) in 21, negative (>2 mm tumor-free margin) in 417, and indeterminate in 77. Peritumoral vascular invasion was observed in 40 patients. Tamoxifen was administered for at least 2 years in 176 patients. At least six cycles of adjuvant systemic chemotherapy were administered in 116 patients. The mean follow-up period from the beginning of the treatment was 84.5+/-1.7 months. RESULTS First events included 44 isolated local recurrences, 8 isolated axillary node recurrences, 44 isolated distant metastases, 1 local recurrence with synchronous axillary node recurrence, 7 local recurrences with synchronous metastases, and 2 local recurrences with synchronous axillary node recurrences and distant metastases. Of 39 pathologically evaluable local recurrences, 33 were classified as true local recurrences and 6 as ipsilateral new primary carcinomas. Seventy patients died (47 of breast carcinoma, 4 of other neoplastic diseases, 10 of other diseases and 9 of unknown causes). The 5- and 10-year rates were, respectively: specific survival 93% and 86%, disease-free survival 85% and 75%, distant metastasis 8.5% and 14%, and local recurrence 7% and 14%. Mean intervals from the beginning of treatment for local recurrence or distant metastases were, respectively, 60+/-6 months (median: 47 months, range: 6-217 months) and 49.5+/-5.4 months (median: 33 months, range: 6-217 months). After local recurrence, salvage mastectomy was performed in 46 patients (85%) and systemic hormonal therapy and/or chemotherapy was administered to 43 patients. The 5-year specific survival rate after treatment for local recurrence was 78+/-8.2%. Multivariate analysis (multivariate generalization of the proportional hazards model) showed that the probability of local control was decreased by the following four independent factors: young age (< or = 40 yr vs. >40 yr; relative risk [RR]: 3.15, 95% confidence interval [CI]: 1.7-5.8, p = 0.0002), premenopausal status (pre vs. post; RR: 2.9, 95% CI: 1.4-6, p = 0.0048), bifocality (uni- vs. bifocal; RR: 2.7, 95% CI: 2.6-2.8,p = 0.018), and extensive intraductal component (IC <25% vs. IC > or = 25%; RR: 2.6, 95% CI: 13-5.2, p = 0

Epidermoid carcinoma of the anal canal treatment results and prognostic variables in a series of 242 cases

UNLABELLED From 1972 to 1985, 260 cases of anal canal epidermoid carcinoma were irradiated. Eighteen cases treated for palliation were excluded from the study; 242 (93%) were treated with curative intent. The sex ratio was 1/5.5; mean age was 66 years. HISTOLOGY 60.3% were well differentiated epidermoid carcinoma; 31.0% moderately differentiated and 8.7%, cloacogenic cases. Staging: T1: 11.5%; T2: 16.1%; T3a: 17%; T3b: 33.5%; and T4: 21.9%. Abnormal inguinal nodes were present in 15.3% of cases. Crude overall survival (Kaplan-Meier) for the 242 cases is 86.4% at 1 year, 63.9% at 3 years, 51.2% at 5 years, and 30.8% at 10 years. Radiation therapy was the sole treatment for 193 cases. No chemotherapy was given. Patients were irradiated by external beam. They received a first course of X rays (mostly 18 MV, some 6 MV) 40 to 45 Gy (box technique) over 4 to 5 weeks in the pelvis. Age and size of tumor were considered when deciding on the target volume. After a rest period of 4 to 6 weeks, a second course of 15 to 20 Gy in 2 weeks was given through a perineal field by electron-beam of suitable energy. The mean total dose was 60.56 Gy and median was 62.5 Gy; the mean overall treatment duration was 85.3 days (median 82 days) and the mean Time Dose Factor including decay factor was 98.96. In this group, 5-year determinate survival was: T1-T2, 84.5%; T3a, 74.8%; T3b, 64.9%; T4, 58.9%. In 147/193 patients (76.2%) local control was achieved. The overall anal conservation rate was 62.6%. In 106 cases (55%), the anus had maintained normal function. The 5-year survival rate by N was 73.3% in the absence of inguinal nodes (169 cases) and 36.1% if such nodes were present. There was no significant difference in survival rate according to histological type. In the second group, receiving radiation therapy plus surgery, 33/49 cases (T3b-T4) were irradiated before surgery (median dose 40.5 Gy). Post operative radiation therapy was administered in 16 cases (T3b-T4) (median dose 49.6 Gy). The 5-year determinate survival is 53.2% for T3b and 79% for T4. According to the log-rank test, there was no significant difference between survival with radiation therapy alone and radiation therapy plus surgery. Multivariate analysis of the whole group indicated that T stage is the only predictive variable.(ABSTRACT TRUNCATED AT 400 WORDS)

Interim analysis of a phase III study on preoperative radiation therapy in resectable rectal carcinoma. Trial of the gastrointestinal tract cancer cooperative group of the European organization for research on treatment of cancer (EORTC)

To improve surgical results of potentially operable rectal cancer (T2, T3, T4, Mo), the European Organization for Research on Treatment of Cancer (EORTC) conducted a two‐arm randomized clinical trial to evaluate the effect of administering radiotherapy before radical surgery. Four hundred ten patients were allocated to be treated either by surgery alone or by 34.5 Gy of radiotherapy (in 19 days overall) followed by surgery. The tolerance of the adjuvant radiation therapy was fairly good. The 5‐year survival rate was 65% overall and showed no difference between both therapeutic regimens. Similarly, the metastases‐free rate was the same in both groups. In contrast, the preoperative radiation therapy showed a marked effect on local control of the disease, the comparison of the time to local recurrence being highly significant between the two treatment groups (P = 0.001). The proportion of patients free of local recurrence at 5 years was 85% in the combined treatment versus 65% in the group of patients treated by surgery alone.

Early breast cancer: influence of type of boost (electrons vs iridium-192 implant) on local control and cosmesis after conservative surgery and radiation therapy

Between December 1981 and December 1988, 329 consecutive patients with stage I and II breast cancers who underwent wide excision (n = 261) or quadrantectomy (n = 68) with (n = 303) or without (n = 26) axillary dissection were referred to radiotherapy. Final margins of resection were microscopically free from tumor involvement in all cases. Radiotherapy consisted in 40-45 Gy over 4-4.5 weeks to the breast, with (n = 168) or without (n = 161) regional nodal irradiation of 45-50 Gy over 4.5-5 weeks. A mean booster dose of 15 Gy was delivered to the primary site by iridium-192 implant in 169 patients (group 1) or by electrons in 160 patients (group 2). Twenty-seven percent (n = 88) of patients received tamoxifen for > or = 2 years. Adjuvant chemotherapy was administered in 22% (n = 71) of patients. Groups 1 and 2 were not strictly comparable. Group 1 patients were significantly younger, had smaller tumors, were treated with cobalt at 5 x 2 Gy per week and axillary dissection was more frequently performed. Group 2 patients were more frequently bifocal and more frequently treated by quadrantectomy and tamoxifen, and irradiation used accelerator photons at 4 x 2.50 Gy per week. No difference in terms of follow-up and survival rates was observed between the two groups. For all patients the 5- and 10-year local breast relapse rates were 6.7% and 11%, respectively. No difference was observed regarding local control either by the electron or the iridium-192 implant boosts. Axillary dissection and age had an impact on the breast cosmetic outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Cataractogenesis after total body irradiation

Purpose : To evaluate the prognostic factors and the ophthalmologic follow-up on cataract formation following total body irradiation (TBI) prior to bone marrow transplantation (BMT). Methods and Materials : Between 1980 and 1992, 494 patients were referred to our department for TBI prior to BMT. The mean age was 32 ± 11 (median : 32, range : 2-63) years and the male to female ratio was 1.6 (304 :190). The majority of patients were treated for acute leukemia (lymphoblastic, n = 177, 36% ; or nonlymphoblastic, n = 139, 28%) ; 80 (16%) for chronic myeloid leukemia, 60 (12%) for non-Hodgkins lymphoma, 23 (5%) for multiple myeloma, and 15 (3%) for other malignancies. Two hundred and fifty-four (51%) patients were grafted in the first complete remission (CR), 118 (24%) in second CR. Allogeneic BMT was performed in 210 (43%) patients, and autologous BMT in 284 (57%). Methotrexate combined to steroids (n = 47, 22%) or to cyclosporine (n = 163, 78%) was administered for graft-versus-host disease (GvHD) prophylaxis. In 188 patients (38%), heparin was used in the prevention of veno-occlusive disease (VOD) of the liver. Furthermore, steroid administration was registered in 223 patients (45%). The conditioning chemotherapy consisted of cyclophosphamide (Cy) alone in 332 (67%) patients. Total-body irradiation was administered either in single dose (STBI ; 10 Gy in 1 day, n = 291) or in six fractions (FTBI ; 12 Gy over 3 consecutive days, n = 203) before BMT. The mean instantaneous dose rate was 0.0574 ± 0.0289 Gy/min (0.024-0.1783). It was < 0.048 Gy/min in 157 patients (LOW group), ≥ 0.048 Gy/min and < 0.09 Gy/min in 301 patients (MEDIUM group), and ≥ 0.09 Gy/min in 36 patients (HIGH group). Results : When considering all patients, 42 (8.5%) patients developed cataracts after 13 to 72 months (median : 42 months) with a 5-year estimated cataract incidence (ECI) of 23%. Thirty-three (113%) out of 291 patients in the STBI group, and 9 (4.4%) out of 203 patients in the FTBI group developed cataracts with 5-year estimated incidences of 34 and 11%, respectively (p = 0.0004). Seven (19.4%) out of 36 patients in the HIGH group, 33 (10.9%) out of 301 in the MEDIUM group, and 2 (1.2%) out of 157 in the LOW group developed cataracts with respective 5-year cataract incidences of 54%, 30%, and 3.5% (HIGH vs. MEDIUM, p = 0.07 ; MEDIUM vs. LOW, p = 0.0001 ; HIGH vs. LOW, p < 0.0001). On the other hand, patients who received heparin as prophylactic treatment against VOD of the liver had less cataracts than those who did not receive (5-year ECI of 16% vs. 28%, respectively ; p = 0.01). There was no statistically significant difference in terms of 5-year ECI according to age, sex, administration of steroids, GvHD prophylaxis, type of BMT, or previous cranial radiotherapy in children. Multivariate analysis revealed that the instantaneous dose rate (p = 0.001), and the administration of heparin against VOD (p = 0.05) were the two independent factors influencing the cataract incidence, while age, fractionation, and use of steroids were not Among the 42 patients who developed cataracts, 38 had bilateral extracapsular cataract extraction and intraocular lens implantation, and only 4 (10%) developed secondary cataracts in a median follow-up period of 39 months. Conclusion : Among the abovementioned TBI parameters, high instantaneous dose rate seems to be the main risk factor of cataract formation, and the administration of heparin appears to have a protective role in cataractogenesis.

Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer

PURPOSE The aims of this prospective study were to evaluate the outcome and the possibility of breast conservation therapy for patients with locally advanced noninflammatory breast cancer after primary chemotherapy followed by external preoperative irradiation. METHODS AND MATERIALS Between April 1982 and June 1990, 97 patients with locally advanced nonmetastatic and noninflammatory breast cancer were treated. The median follow-up was 93 months from the beginning of treatment. The induction treatment consisted of four courses of chemotherapy (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative irradiation (45 Gy to the breast and nodal areas). A fifth course of chemotherapy was given after irradiation therapy. Three different loco-regional approaches were proposed, depending on the tumoral response. In 37 patients (38%) with residual tumor larger than 3 cm in diameter or located behind the nipple or with bifocal tumors, mastectomy and axillary dissection were performed. Sixty other patients (62%) benefited from conservative treatment: 33 patients (34%) achieved complete remission and no surgery was done but additional radiation boost was given to the initial tumor bed; 27 patients (28%) who had a residual mass less than or equal to 3 cm in diameter were treated by wide excision and axillary dissection followed by a boost to the excision site. After completion of local therapy, all patients received a sixth course of chemotherapy. A maintenance adjuvant chemotherapy regimen without anthracycline was prescribed (12 monthly cycles). RESULTS The 5-year actuarial loco-regional relapse rate was 16% after radiotherapy alone, 16% following wide excision and radiotherapy, and 5.4% following mastectomy. The 5-year loco-regional relapse rate was significantly higher after conservative local treatment (wide excision and radiotherapy, and radiotherapy alone) than after mastectomy (p= 0.04). After conservative local treatment, the 5-year breast conserving rate of patients with loco-regional disease-free status was 84%. For all patients included in this study, the 5-year breast-conserving rate of those who were loco-regional disease-free was 52%. In multivariate analysis, the possibility of breast conservative treatment was significantly related to the initial tumor size and age (more conservative treatment for tumor size < 6cm and age < 50 years). Five- and 10-year overall survival rates and disease-free survival rates were 80, 69, 73, and 61% respectively. Five- and 10-year overall survival rates were not influenced by the local treatment (conservative vs. nonconservative local treatment, p = 0.9). On the other hand, local failure significantly decreased the 5- and 10-year overall survival rates (p , 0.0001). In multivariate analysis, three factors had a significant impact on overall survival and disease-free survival: tumor response after induction chemotherapy, initial tumor size, and clinical stage. Arm lymphedema was noted in 12.5% (8 out of 64) of the patients treated with axillary dissection and in 3% (1 out of 33) without axillary dissection. Cosmetic results were satisfactory in 79% of patients after wide excision and radiotherapy and in 71% of patients treated by radiotherapy alone. CONCLUSIONS Induction chemotherapy followed by preoperative irradiation may permit the selection of some patients with locally advanced breast cancer for conservative treatment. However, the impact of this treatment modality on long-term survival remains to be established.

Total-body irradiation and cataract incidence: A randomized comparison of two instantaneous dose rates

PURPOSE To assess the influence of instantaneous total-body irradiation dose rate in hematological malignancies, we randomized 157 patients according to different instantaneous dose rates. METHODS AND MATERIALS Between December 10, 1986 and December 31, 1989 157 patients have undergone a total-body irradiation before bone-marrow transplantation according to two different techniques: either in one fraction (1000 cGy given to the midplane at the level of L4, and 800 cGy to the lungs) or in six fractions (1200 cGy over 3 consecutive days to the midplane at the level of L4, and 900 cGy to the lungs). Patients were randomized according to two instantaneous dose rates, called LOW and HIGH, in single-dose (6 vs. 15 cGy/min) and fractionated (3 vs. 6 cGy/min) TBI groups; there were 77 cases for the LOW and 80 for the HIGH groups, with 57 patients receiving single-dose (28 LOW, 29 HIGH) and 100 patients receiving fractionated total-body irradiation (49 LOW, 51 HIGH). RESULTS As of July 1992, 16 (10%) of 157 patients developed cataracts after 17 to 46 months, with an estimated incidence of 23% at 5 years. Four (5%) of 77 patients in the LOW group, 12 (15%) of 80 patients in the HIGH group developed cataracts, with 5-year estimated incidences of 12% and 34%, respectively (p = 0.03). Ten (18%) of 57 patients in the single-dose group, and 6 (6%) of 100 patients in the fractionated group developed cataracts, with 5-year estimated incidences of 39% and 13%, respectively (p = 0.02). When the subgroups were considered, in the single-dose group, 3 (11%) of 28 LOW patients, and 7 (24%) of 29 HIGH patients developed cataracts, with 5-year estimated incidences of 24% and 53%, respectively; in the fractionated group, 1 (2%) of 49 LOW patients, and 5 (10%) of 51 HIGH patients developed cataracts, with 5-year estimated incidences of 4% and 22%, respectively (single-dose LOW vs. single-dose HIGH vs. fractionated LOW vs. fractionated HIGH, p = 0.006). There was no statistically significant difference in terms of 5-year estimated cataract incidence between the patients receiving steroids and those not (30% vs. 25%, p = 0.22). Multivariate analyses revealed that the instantaneous dose rate was the only independent factor influencing the cataractogenesis (p = 0.04). CONCLUSION We conclude that the total-body irradiation regimen (instantaneous dose rate and/or fractionation) may have an influence on the development of cataracts following bone-marrow transplantation.

Total-body irradiation before bone marrow transplantation : results of two randomized instantaneous dose rates in 157 patients

One hundred fifty‐seven patients referred to the Department of Radiation Oncology of the Hǒpital Tenon, Paris, France, between December 10, 1986 and December 31, 1989 for total‐body irradiation (TBI) were treated according to the following two techniques: (1) either in one fraction (1000 cGy administered to the midplane at L4 and 800 cGy to the lungs) or (2) in six fractions (1200 cGy on 3 consecutive days to the midplane at L4 and 900 cGy to the lungs). The patients were randomized according to two instantaneous dose rates, called LOW and HIGH, in single‐dose (6 versus 15 cGy/min) and hexafractionated (3 versus 6 cGy/min) TBI groups. There were 77 patients in the LOW group and 80 in the HIGH group, with 57 patients receiving single‐dose TBI (28 LOW and 29 HIGH) and 100 patients receiving fractionated‐dose TBI (49 LOW and 51 HIGH). In March 1991, the 4‐year relapse‐free and overall survival rates were 58.4% and 52.1%, respectively. The 4‐year relapse‐free survival and survival rates were 54.9% and 50.7% in the LOW group; 61.9% and 53.5% in the HIGH group (P = 0.69 and 0.82, respectively); 60.3% and 50.4% in the single‐dose group; and 57.9% and 53.3% in the fractionated group (P = 0.65 and 0.78, respectively). There was no difference in the incidence of graft versus host disease, interstitial pneumonitis, or venoocclusive disease either between the LOW and the HIGH groups or between the single‐dose and fractionated‐dose TBI groups. The 4‐year estimated cataract incidence was significantly higher in the single‐dose HIGH instantaneous dose rate group than in the LOW instantaneous dose rate TBI group (P = 0.049). Multivariate analyses showed that instantaneous dose rate and fractionation do not influence the relapse‐free and overall survival rates or the incidence of interstitial pneumonitis.

Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer☆

BACKGROUND AND PURPOSE To evaluate possibility of breast-conserving therapy and outcome for patients with locally advanced non-inflammatory breast cancer (LABC) and stage II >3 cm in diameter after primary chemotherapy (CT) followed by external preoperative irradiation (RT). MATERIALS AND METHODS Between 1982 and 1990, 147 patients were treated by four courses of induction CT (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative RT (45 Gy to the breast and nodal areas) and a fifth course of CT. Three different loco-regional approaches were proposed depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of CT and a maintenance adjuvant CT regimen without anthracycline. RESULTS Mastectomy and axillary dissection were performed in 52 patients, and conservative treatment in 95 patients (48 achieved complete remission and received additional radiation boost to initial tumour bed; 47 had a residual mass < or =3 cm in diameter and were treated by wide excision and axillary dissection followed by a boost to the excision site. Ten-year actuarial loco-regional failure rate was 20% after RT alone, 23% after wide excision and RT and 6% after mastectomy (P = 0.85). After multivariate analysis, possibility of breast-conserving therapy was related to initial tumour size. Ten-year overall survival rate was 66%; it was not influenced by local treatment (conservative vs. non-conservative local treatment, P = 0.89). However, local failure significantly decreased overall survival (P < 0.0001). After multivariate analysis, tumour response after induction CT and clinical stage had a significant impact on survival. CONCLUSIONS The present data indicate that induction CT followed by preoperative RT may permit the selection of some patients with LABC or stage II >3 cm for conservative treatment. The impact of this treatment modality on long term survival remains to be established.

Multidisciplinary treatment approach to locally advanced non-inflammatory breast cancer using chemotherapy and radiotherapy with or without surgery

Between April 1982 and December 1987, 82 locally advanced non-metastatic and non-inflammatory breast cancers were treated (42 stage IIIA, 40 stage IIIB). The median follow-up is 70 months from the beginning of the treatment. The initial treatment consisted of 4 courses of chemotherapy (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by irradiation (45 Gy to the breast and nodal area). A fifth course of chemotherapy was given after radiation therapy. Three different locoregional approaches were proposed depending on the tumoral response. In 32 patients (39%) with residual tumor larger than 3 cm in diameter or located behind the nipple or with multifocal tumors, mastectomy and axillary dissection were performed. Fifty other patients (61%) benefited from conservative treatment: 32 patients (39%) achieved complete remission and received a boost to the initial tumor bed; 18 patients (22%) who had a residual mass less than or equal to 3 cm in diameter were treated by tumorectomy and axillary dissection followed by a boost to the tumorectomy site. After completion of local therapy, all patients received a sixth course of chemotherapy. A maintenance adjuvant chemotherapy regimen without anthracycline was prescribed (12 monthly cycles). Three- and 5-year disease-free survival rates were 81.7% and 72% respectively. Five-year locoregional relapse rate (with or without other sites of failure) was 8.8%. In a multivariate analysis, disease-free survival was significantly influenced by the N-stage (p < 0.0001), initial tumor size (p = 0.01), and tumor response after initial chemotherapy (p = 0.02). Five-year breast conservation probability was 58.4%.(ABSTRACT TRUNCATED AT 250 WORDS)