[Long-term results of exclusive radiotherapy and brachytherapy of breast cancer]. / Cancer du sein traité exclusivement par l'association d'une irradiation externe et d'une curiethérapie exclusive: résultats à long terme.

PURPOSE: To report retrospective long-term results of historical experience of breast radiotherapy (RT) including external beam radiotherapy (EBRT) followed by low dose rate (LDR) brachytherapy. PATIENTS AND METHODS: Between 1971 and 1983, at our service 474 breast cancer patients underwent exclusive conserving radiotherapy treatment. The RT included an initial external irradiation followed by interstitial LDR brachytherapy (37Gy) to the residual tumour. The local regional nodes received 47.5Gy followed by a 15Gy boost delivered to the mammary nodes internal (IMN) and 25Gy axilla. RESULTS: Median follow-up was 139months (8-342). There were 40 T1, 356 T2, and 78 T3. Local recurrences (LR) were observed in 20% of cases. The rate of recurrences free at 5, 10, 15 and 20years were 86%, 77%, 73% and 67% respectively. At 5, 10, 15 and 20-year, the disease-free survival rates were 63%, 42%, 32% and 24%. Overall survival rates at 5, 10, 15 and 20-years were 75%, 53%, 34% and 25% respectively. CONCLUSION: Although the historical retrospective character of these series, it is interesting to have this experience and to analyse it according to our new knowledge and advances. The described technique was a standard for many years and could be still used in some cases.

Curie medal lecture 2000. The optimization of delivered dose in radiotherapy: is it related to low dose rate?

From the beginning of the 20th century with Pierre and Marie Curie, it was found that the preparation of radium into needles and tubes results in a continuous low dose rate radiation in which the total time to give an optimal dose of 60 Gy is reduced to 5 or 6 days. Clinical results quickly followed, showing that tumour sterilization was better ensured by low dose rate radiation over several days than by fractionated high dose rate radiation over several weeks. In the light of my experience of very good results with modern 192 Ir endocurietherapy at an optimal dose rate of 0.6 Gy per h for very bulky tumours, I finally became convinced of the need to study low dose rate in teletherapy using telecobalt with low activity sources (1 Gy per h to achieve long duration sessions of 7-8 h per day over a short total duration of 5 or 7 days).I started in January 1970, at the Institut Gustave Roussy and, after my appointment, at the Henri Mondor Hospital in Creteil, a variety of cancer sites were treated but mostly advanced head and neck cancers. Finally I decided to do a trial of classical fractionated high dose rate radiation vs. subcontinuous low dose rate radiation of advanced breast cancers (T3). The results at 3 months were conclusive: 20% of the cancers treated by 45 Gy fractionated irradiation at high dose rate were sterilized while the proportion sterilized at low dose rate was 70% whether the patients received 45 or 35 Gy. This work opened the way to further study but my retirement loomed and I was not able to pursue it.

The hazy dawn of brachytherapy.

The discovery of radium by Pierre and Marie Curie in December 1898 opened a new era in science and within a few years provided medicine with a new means of tumor treatment. Their personal contribution to the start and early development of clinical applications should not be overlooked. The Curies did not limit their support to providing radium sources to medical pioneers but took a deep interest in the horizons of radium therapy. Pierre was one of the first to search for and demonstrate a biological effect of radium radiation. He investigated the radioactivity of the waters of hydrotherapeutic resorts. Marie took care of the measurement of the medical sources personally, convinced that the result of the treatment depends on the precise knowledge of the amount of radium applied. Her perseverance resulted in the establishment of the Institut du Radium (1909) in which, besides the physico-chemical laboratory, a biological department was set up. The latter became the Fondation Curie (1920), a leading medical center of treatment and training, with an integrated team of physicists, radiobiologists and clinicians led by Regaud. One hundred years after the discovery of radium, patients benefit today from the extensive clinical experience that has been collected over the years and from sophisticated developments in application techniques, dosimetry and quality assurance; the professional risk has been precisely assessed and the improvements in material and procedure have enabled the medical personnel to work in hazard-free conditions. This outcome results from the continuous progress that the pioneers gave impulse to. This paper intends to recall their efforts and achievements, as well as the difficulties and the problems they encountered during the first 2 decades when the sturdy foundations of brachytherapy were built.

[Place of iridium 192 implantation in irradiation of T1-T2 squamous cell carcinoma of the velopharyngeal arch]. / Place de l'endocuriethérapie par iridium 192 dans l'irradiation exclusive des carcinomes épidermoïdes T1-T2 de l'arche véloamygdalienne.

We have reviewed the results of 165 T1 and T2 squamous cell carcinomas of the faucial arch treated by definitive irradiation including or not iridium 192 brachytherapy to ascertain whether a significant relationship exists between iridium implantation, local control, complications and survival. From March 1971 to November 1990, 58 T1 and 107 T2 (NO: 107/165; N1: 30/165; N2: 9/165; N3: 19/165) biopsy proven squamous cell carcinomas of the tonsillar region (104/165) and the soft palate and uvula (61/165) were treated in the Henri Mondor Hospital by definitive irradiation with curative intent. From 1971 to 1981 (period 1), only guide gutter technique was available, so that implants were reserved for small tumors: patients were either managed by definitive telecobaltherapy to tumor site and neck node areas (group I; n = 48; mean dose: 70 Gy; confidence interval: +/- 5.5, 5 fractions of 1.8 Gy per week) or by exclusive iridium implant (group 2; n = 11; all T1NO; 64 Gy +/- 4.8) or by a combination of external beam radiation therapy to tumor site and neck nodes areas and iridium implant (group 3; n = 40). In 1981 (period 2), a new plastic tube technique, which enables implantation of larger areas, was introduced and all patients (group 4; n = 66) were then managed by external radiation therapy (group 3 + 4: 47 Gy +/- 4.3) followed by an iridium implant (31 Gy +/- 10.5). Clinically positive neck nodes either received additional external dose with electrons or were excised. Overall 5-year survival (Kaplan Meier) was 23%, 50.5%, and 60% in groups 1, 2 and 3 + 4, respectively (p < 0.001, log rank). Five-year local control was 58%, 100%, and 91%, respectively (p < 0.001). Five-year necrosis rate was 10%, 25% and 30%, respectively (NS). Comparison of results between the two periods of the study (group 1 + 2 + 3 vs group 4) shows that these two groups are statistically comparable according to site and size of tumor and N status and that both local control (77% vs 94% at 5 years; p < 0.01) and disease free survival (56% vs 71%; p = 0.03) were improved after 1980, while there was a trend to an increase in overall survival (42% vs 53% at 5 years; p = 0.08); nodal control (86% vs 95% at 5 years) and necrosis rate (11% vs 20% at 5 years) were not modified. Multivariate analysis showed that both local control (p < 0.0001) and overall survival (p < 0.0001) were improved when tumor was implanted. We recommend then to treat T1 and T2 squamous cell carcinomas of the faucial arch by external radiation therapy to tumor site and neck areas (45 Gy/25 fractions/5 weeks) followed by a 30 Gy iridium implant and, for patients with clinically positive nodes, either a further 25-30 Gy electron beam irradiation to the nodes or neck node dissection.

Effects of FGA and PMSG on follicular growth and LH secretion in Suffolk ewes.

The effects of fluorogestone acetate (FGA) and/or pregnant mare serum gonadotrophin (PMSG) on follicular growth and LH secretion in cyclic ewes were determined. Suffolk ewes (n=40), previously synchronized with cloprostenol were divided into 4 experimental groups (n=10 ewes per group). Group I served as the control, while groups II, III and IV received FGA, PMSG, FGA and PMSG respectively. Four ewes of each group underwent daily laparascopy for 17 d. All the ovarian follicles>or=2 mm were measured, and their relative locations were recorded on an ovarian map in order to follow the sequential development of each individual follicle. Comparisons were made of the mean day of emergence and the mean number of small, medium and large follicles, the atresia rate and the ovulation rate. For each group, 3 waves of follicular growth and atresia were observed during the cycle. During luteal phase, FGA treatment accelerated the mechanisms of follicular growth but reduced the number of large follicles and increased the atresia rate. In the follicular phase, FGA treatment was detrimental to both the number of large follicles and the ovulation rate. By contrast, PMSG enhanced recruitment of small follicles and the ovulation rate. Serial blood samples were collected during the luteal and follicular phases to study LH secretion. None of the treatments had any effect on LH secretion patterns.

Management of epistaxis in Rendu-Osler disease: is brachytherapy effective?

PURPOSE: This paper reviews the results of intranasal brachytherapy for epistaxis in 43 patients with Rendu-Osler disease treated between 1971-1991 at Henri Mondor Hospital. METHODS AND MATERIALS: 2-3 intranasal catheters were afterloaded with 192Ir sources. Computer dosimetry was performed and then the dose was prescribed to an isodose thought to cover the nasal mucosa. The dose rate ranged from 0.16 Gy/h-0.63 Gy/h with a median of 0.34 Gy/h. Dose at one application ranged from 15-35 Gy with a median of 30 Gy. The severity of epistaxis was graded 1 to 5. RESULTS: The time to recurrence of significant epistaxis ranged from 6-178 months with a median of 24 months. The dose prescribed did not correlate with control rate. The only brachytherapy complication was septal perforation in 4 patients; in one this was a result of repeated nasal coagulation. CONCLUSION: We suggest that intranasal brachytherapy is a useful modality in the management of epistaxis in Rendu-Osler disease.

Effect of intersource spacing on local control and complications in brachytherapy of mobile tongue and floor of mouth.

From 1971 to 1988, 133 T1 and 141 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by Iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 274 implants have been analysed to look for a possible influence of intersource spacing on local control and necrosis. Follow up for patients free of local recurrence is 1-180 months with median of 35 months. The 274 tumors were divided into two groups according to intersource spacing: 9-14 mm (n = 204), and 15-20 mm (n = 70). At 5 years, the estimated local control (Kaplan Meier) was 86% and 76%; respectively (p = 0.13); the necrosis rate was 33% and 46%, respectively (p = 0.04). Multivariate analysis shows that dose and activity of wires were significantly related to local control, while only tumor site was predictive of necrosis; there was a non-statistically significant relationship between intersource spacing of wires and local control (p = 0.055). When considering only patients with oral tongue cancers, necrosis was significantly related to activity of wires (p = 0.013), and there was a non-significant trend to a relationship between necrosis and intersource spacing (p = 0.066) and tumor diameter (p = 0.065). For patients with floor of mouth cancer, none of these factors was significantly related to necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Time factors in breast carcinoma: influence of delay between external irradiation and brachytherapy.

From 1971 to 1983, 398 (33 T1, 309 T2, 56 T3) biopsy-proven breast adenocarcinomas were treated conservatively at Hôpital Henri Mondor by an initial course of external irradiation (45 Gy, 25 fractions, 5 weeks) followed by interstitial iridium-192 implant for a further 37 Gy to the tumor. The mean interval between external irradiation and brachytherapy was 5.9 weeks (S.D. 1.7, range 1-18). Seventy-seven local failures were observed at 10-148 months (median 34.5). The actuarial probabilities (S.E.) of local control at 5 and 10 years were 0.86 (0.02) and 0.74 (0.03), respectively. The follow-up for patients free of local recurrence was 4-205 months (median 95). Multivariate analysis showed an increasing probability of local failure with longer interval between external irradiation and brachytherapy (Relative Risk [R.R.] 1.23 [95% confidence limits: 1.07, 1.41] per week, p = 0.005), and a lower risk of failure in case of complete tumor regression after external irradiation (R.R. 0.47 [0.25, 0.90], p = 0.022), and higher brachytherapy dose rate (R.R. 0.13 [0.02, 1.02] per Gy/h, p = 0.053). No influence of tumor size and total dose (possibly because only limited variations in total dose were observed), or histological grading (not performed in 140 [35%] patients) was found. Because of the lack of dose-control relationship, quantification of the effects of delay between external irradiation and brachytherapy (in terms of compensatory dose) and of dose rate (Incomplete Repair Model) was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Dosimetry of intraluminal brachytherapy.

Dose specification in intraluminal brachytherapy varies considerably in the literature. A terminology is proposed, inspired from the Paris System of interstitial brachytherapy, to define some dosimetric guidelines. The dose is specified in the central plane which is a plane perpendicular to the source and passing through its centre. The reference dose rate is calculated in this plane. The treated volume is the volume encompassed by the reference isodose. The hyperdose sleeve is the volume receiving a dose equal to or greater than twice the reference dose. A study of the dose distribution along a linear source of iridium-192 was undertaken. Results obtained, also valid for caesium-137 and cobalt-60, show that the radius of the hyperdose sleeve is relatively independent of the length of the source. It is approximately 0.6 times the distance between the source axis and the point of dose specification when the active length varies from 3 to 20 cm. Reporting not only the dose, but also the thickness of tissue covered by the reference isodose and the thickness of tissue included in the hyperdose sleeve, is recommended to assist in evaluation of the results of treatment and to facilitate the exchange of clinical information in intraluminal brachytherapy. Practical examples are given.

Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx.

The risk of second cancer in the head and neck region following definitive radiation therapy was evaluated among 600 patients who were treated for T1 and T2 cancers of the oral cavity and oropharynx at the Henri Mondor hospital between January 1970 and March 1987. Seventy-five patients (12.5%) were managed with external irradiation only, 243 (40.5%) with RT and Iridium 192, and 282 (47%) with Iridium 192 alone. One hundred fifteen patients (19%) developed a second cancer from 3 to 183 months after initial therapy (median: 32 months), including 69 patients (11.5%) in whom the second malignancy was diagnosed in the head and neck region. An increased and constant actuarial risk of development of second head and neck cancer was found (2.7%/year of observation). Univariate analysis showed that age, sex, stage, and modality of the initial treatment did not influence the risk of second head and neck cancer; there was a greater risk of second head and neck malignancy for those patients with soft palate carcinoma (p less than 0.05). Multivariate analysis revealed that the only group of patients who developed a second head and neck cancer more frequently were those who were irradiated with Iridium 192 only (p = 0.0076). There was a trend toward a greater risk of second head and neck malignancy for those with soft palate carcinoma (p = 0.059). Radical treatment of the second head and neck malignancy by surgery and/or re-irradiation was performed for 67% of patients. Patients initially treated by Iridium 192 only could undergo salvage treatment more often than those who previously received external beam radiotherapy (79% vs 53%, p = 0.02). The overall 2-year and 5-year survivals after the diagnosis of the second head and neck cancer were 32% and 10%, respectively.

Influence of dose rate on local control of breast carcinoma treated by external beam irradiation plus iridium 192 implant.

From 1971 to 1983, 20 T1, 267 T2, and 53 T3 biopsy-proven adenocarcinomas of breast were definitively managed by radiotherapy. The breast and regional nodes received 45 Gy of 60Co irradiation in 25 fractions over 5 weeks (45 Gy/25/5 wks). Electrons were used to deliver a further 15 Gy/7/1.5 weeks to the internal mammary chain and 25 Gy/11/2.5 weeks to the lower axilla. The primary tumor was boosted by Iridium 192 implant for a further 37 Gy prescribed at 85% of the basal dose rate (Paris system). Rigid needles were secured by templates in single plane (58/398) or double plane (340/398) geometry. Results of the 340 two-plane implants have been analyzed to look for a possible influence of dose rate on local control. Follow-up for patients free of local recurrence is 4-204 months (median: 92 months). The 340 tumors were divided into three groups according to dose rate: 0.32-0.49 Gy/hr (n = 95), 0.50-0.59 Gy/hr (n = 120), and 0.60-0.90 Gy/hr (n = 125). The three groups are statistically comparable according to age, tumor size, mean 60Co dose, mean Iridium dose, overall treatment time, and follow-up. The local failure rate in the three groups is 27% (26/95), 20% (24/120), and 13% (16/125) (p less than 0.03, Chi square). At 15 years the estimated local control (Kaplan Meier) is 60%, 72%, and 84% (p less than 0.02, Logrank), respectively. This analysis indicates that there is a significant effect of dose rate on local control for carcinoma of the breast treated by combined external beam (45 Gy) plus Iridium 192 implantation (37 Gy). To maximize local control the authors recommend an implant dose rate of greater than or equal to 0.6 Gy/hr.

External irradiation prior to conservative surgery for breast cancer treatment.

From 1981 to 1987, 138 patients with breast cancer unsuitable for primary tumorectomy received initial external radiotherapy (45 Gy/25f/35d) in order to reduce the tumor volume so that secondary limited surgery could be performed. There were 81 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. After completion of the radiotherapy, 22 patients (16%) showed no more evidence of a tumor either clinically or radiologically and received a boost of 25 Gy. In 52 cases (38%) the tumor regression allowed for secondary tumorectomy followed by a boost of 20 Gy. Sixty-four patients (46%) showed either little or no tumor regression: radical surgery was performed in 14 cases (10%) and high dose boost curietherapy (37 Gy) in the 50 (36%) remaining patients who refused mastectomy. Breast conservation in good condition was thus obtained in 74 patients (54%). Sufficient tumor regression to allow secondary tumorectomy was more often observed in T2 than in T3, in poorly differentiated tumors or mucinous type, and in tumor with well defined mammographic aspects. Actuarial 5-year local control and disease-free survival rates after limited surgery were, respectively, 90% and 73%. No particular complications were observed after secondary tumorectomy. This therapeutic approach is encouraging in patients with large T2 and T3 breast tumors, but a longer follow-up is required to assess definitive conclusions.

Stage I-II squamous cell carcinoma of the oral cavity treated by iridium-192: is elective neck dissection indicated?

This is a retrospective analysis of 233 evaluable patients with stage I-II squamous cell carcinoma of the oral cavity treated by definitive branchytherapy. Minimum follow-up is 3 years. Treatment of neck was chosen by a multidisciplinary team, according to age, medical status and availability for regular follow-up. One hundred and ten patients (47%) underwent elective neck dissection (END); 28 (25%) had positive nodes and received neck irradiation post-operatively. One hundred and twenty three patients (53%) were regularly followed up only, with therapeutic neck dissection (TND) reserved for cases of node relapses. In the END group, there were 19 neck relapses (17%): 12/60 (20%) in patients with mobile tongue carcinoma and 7/50 (14%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 9/19 (47%) cases. In the TND group, there were 21 neck relapses (17%): 16/82 (20%) in patients with mobile tongue carcinoma and 5/41 (10%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 13/21 (62%) cases. Ten-year survival is 37% for the END group and 31% for the TND group. Tumour stage and infiltration into underlying tissues increased the probability of neck relapse and death. Furthermore, a multivariate analysis showed that patients treated in the TND group had a higher probability of death than patients treated in the END group (p less than 0.04).

Effect of dose rate on local control and complications in definitive irradiation of T1-2 squamous cell carcinomas of mobile tongue and floor of mouth with interstitial iridium-192.

From 1971 to 1988, 134 T1 and 145 T2 biopsy-proven squamous cell carcinomas of mobile tongue and floor of mouth were definitively managed by iridium-192. Implantations were performed using either guide gutters or afterloading plastic catheters. The prescribed dose at the reference isodose (85% of the basal dose rate, Paris system) was 60-70 Gy. Total dose was not adjusted to dose rate or tumor volume. Results of the 279 implants have been analysed to look for a possible influence of dose rate on local control and necrosis. Follow-up patients free of local recurrence is 1-180 months with average of 51 months. The 279 tumors were divided in four groups according to dose and dose rate: greater than or equal to 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 130), greater than or equal to 62.5 Gy and less than 0.5 Gy/h (n = 36), less than 62.5 Gy and greater than or equal to 0.5 Gy/h (n = 81), less than 62.5 Gy and less than 0.5 Gy/h (n = 32). The four groups were comparable according to age, sex, tumor diameter and macroscopic aspect. At 5 years, the estimated local control (Kaplan Meier) was 93, 87, 79 and 52%, respectively (dose adjusted to dose rate: p less than 0.001, dose rate adjusted to dose: p less than 0.01, Log-rank); the necrosis rate was 44, 24, 37 and 5%, respectively (dose adjusted to dose rate: p = 0.08, dose rate adjusted to dose: p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Conservative treatment for breast cancer: long-term results (15 years).

From 1961 to 1974, 245 patients with unilateral "operable" breast cancer (25% T1, 56% T2, 19% T3) were treated with breast conservation and irradiation at the Gustave Roussy Institute (1961-1969) or at the Henri Mondor Hospital (1970-1974). The minimum follow-up is 15 years. Most patients with T greater than 3 cm underwent radiation therapy with the tumor in place, while the greater part of patients with T less than 3 cm received radiation therapy after tumorectomy. The breast and draining lymph node areas received widefield telecobalt irradiation to 45 Gy. The dose to the tumor site was boosted using iridium-192 implantation. Additional irradiation was given to the internal mammary and lower axillary nodes using an electron beam. The 15 years NED survival rate was 63%, 51% and 26% for T1, T2 and T3 tumors, respectively. The NED survival for T less than or equal to 1 cm was 86%. The local recurrence rate was 8, 12 and 19% for T1, T2 and T3 tumors, respectively. Of the patients with local recurrence, 85% underwent surgical salvage. Complications were rare. Cosmetic results were satisfactory in most patients including the T3 group. The proportion of breasts conserved among patients living NED at 15 years, was 97, 88 and 93% for T1, T2 and T3 tumors, respectively. In 1980, after almost 20 years experience using breast conserving techniques, we modified our treatment policies in close collaboration with our surgical team, hel cbye extending the indications for tumorectomy and associating routine surgical exploration of the lower axilla.