[Conservative treatment of sub-clinical noninfiltrating cancers of the breast (102 EOA in situ, TONO)]. / Le traitement conservateur des cancers du sein infra-cliniques canalaires non infiltrants (102 EOA in situ, TONO).

102 patients with sub-clinical intra ductal non invasive breast cancer (T0N0) treated by limited surgery and curative radiation therapy. Follow-up ranged from 2 to 10 years with a median follow-up of 59 months. The long term survival rate of this therapeutic approach, consisting of simple excision without any adjuvant treatment and radical mastectomy was close to 100%. The actuarial local recurrence rate was only 8.6% at 10 years (confidence interval: 4.6 to 12.6%), which strongly suggests that radiation therapy is active on multicentric foci. Salvage surgery could be performed in every case of local recurrence. The survival rate of in situ breast cancer (T0N0) treated by conservative radio-surgery is comparable to that of radical mastectomy, while cosmetic results and psychological impact appear to be better for the conservative technique (breast preservation rate = 91 to 96%).

[2d and 3d line hormonal therapy in postmenopausal metastatic breast tumor. Comparison of medroxyprogesterone acetate and aminoglutethimide in tamoxifen-resistant patients]. / Terapia ormonale di seconda e terza linea nel tumore mammario metastatico in post-menopausa. Confronto tra il medrossiprogesterone acetato e l'aminoglutetimide in pazienti divenute resistenti al tamoxifen.

In order to evaluate the effectiveness of second and third line hormone therapy for postmenopausal (spontaneous or surgical) women with metastatic tamoxifen-resistant breast cancer, 293 women aged 36 to 91 (mean 63.6) were divided into two groups submitted to a multicenter study of two treatment schedules: a) Aminoglutethimide (AG; 500 mg daily plus hydrocortisone 40 mg daily); b) Medroxyprogesterone (MPA; 1,000 mg daily per os). Of the 293 patients receiving second line hormone therapy, only 161 were available for third line treatment. In phase 1, 153 patients were treated with AG: 36% had objective responses (complete or partial); of 140 patient receiving MPA, 33% had objective responses (p = 0.045, significant). In the AG-treated group, duration of response was 11.3 +/- 8.4 months as against 8.3 +/- 5.6 months in the MPA group (p = 0.07, significant). In phase 2, 87 women previously treated with MPA received AG, and 74 previously AG-treated patients were given MPA. There were no significant differences in the results obtained. In conclusion, there were no significant differences in the results obtained by AG and MPA treatment as far as toxicity and survival was concerned but there was a statistically significant advantage for AG as second and third line management both as to objective responses and mean time until renewed progression of the disease.

[Neoadjuvant chemotherapy of stage IIb or III cancers of the uterine cervix. Long-term results of a multicenter randomized trial of 151 patients]. / Chimiothérapie néoadjuvante des cancers du col utérin aux stades IIb et III. Résultats éloignés d'un essai randomisé pluricentrique portant sur 151 patients. Groupe coopérateur de gynécologie de la Fédération nationale des centres de lutte contre le cancer (FNCLCC).

Present chemotherapy, with cisplatin combinations, currently offers the possibility of seeking adjuvant therapy in locally advanced and bulky carcinomas of the cervix, which have an unfavorable prognosis (nodal involvement). This initial adjuvant chemotherapy may improve the results of classical pelvic irradiation. From 1982 to 1987, a randomized phase III trial was performed in order to determine the long term effect of induction chemotherapy before irradiation in stage IIb-N1, III, M0 squamous cell carcinomas of the cervix. Radiotherapy (R) for all patients consisted in 50 Gy in the pelvis with a boost by external irradiation of the brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen (C + R group) was an association of methotrexate, chlorambucil, vincristine and cisplatin, given every 3 weeks, at least two courses were to be given before assessing efficacy and two more courses were given to patients who responded. After a follow up of 5-10 years, 76 patients were fully evaluable in the R arm and 75 in the C + R arm. The response rate (> 50%) to chemotherapy was 42.5% and after completion of treatment, remission rate was 93% in the R arm and 96% in the C + R arm. The disease-free survival was 40% in the C + R group and 35% in the R group, and the median survival was 42 and 45 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group when they are responding to chemotherapy, than in R group (P < 0.05). Radiotherapy was not modified whether patients had an initial chemotherapy or not; tolerance was not significantly different between the two groups. Efficacy of induction chemotherapy is an available test for long term results. This approach has the potential for improving the outlook in patients with high-risk primary cancer: earlier use and higher dose intensity of chemotherapy may be associated with a better cytoreduction, and probably a better survival. Further controlled investigations are warranted to confirm the value of adjuvant chemotherapy in cervical cancer.

Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen.

In order to evaluate the efficacy of two different sequences of second and third line hormonotherapy in advanced post-menopausal breast cancer, 257 women aged 36-91 years (mean age: 63.6 years) who had become resistant to tamoxifen (TAM), entered into a multicenter randomized trial comparing two different regimens: 1) Aminoglutethimide (Ag) 500 mg/day with hydrocortisone supplementation from 30 to 60 mg/day; and 2) oral medroxyprogesterone acetate (MPA) 500 mg twice a day. 250 patients were evaluated following second line hormone therapy and, after cross-over, 128 following third line hormonotherapy. No significant difference was observed, during either second or third line therapies, for toxicity, survival, or response rate; however, in both second and third line therapies the median time to progression was significantly longer with Ag therapy.

Inoperable recurrence after breast-conserving surgical treatment and radiotherapy.

Factors associated with inoperable local recurrence were investigated by a clinical and pathologic review of 596 patients with Stages I and II carcinoma of the breast treated by breast-conserving operations and megavoltage radiotherapy. After a median follow-up period of 71 months, 13 of 70 local recurrences observed were anatomically unsuitable for salvage surgical treatment, affecting 2.2 per cent of patients initially treated. In most, inoperable recurrences clinically resembled primary inflammatory carcinoma of the breast. All inoperable failures occurred in patients with invasive ductal carcinoma and were associated with the presence of unfavorable prognostic features (positive nodes, histologic grade 3, negative estrogen receptor, vascular invasion and lymphocytic stromal reaction). Despite doxorubicin-based chemotherapy, prognosis after inoperable recurrence was quite poor, although survival time in excess of two years was seen in receptor positive, lower grade recurrent tumors in which treatment included hormone therapy.

How important is adequate radiotherapy for the long-term results of breast-conserving treatment?

The influence of radiotherapy dose parameters on longterm local control was studied in 134 clinical stage I-II breast cancer patients treated by tumorectomy and telecesium therapy during the 1960s. Recurrence in the breast was more frequent in patients receiving 75 Gy or less to the tumor bed (31% versus 15% for higher doses, p less than 0.05), and weekly dose rates of less than 8 Gy/week were associated with increased local-regional failure (30% versus 15% for higher weekly doses, p less than 0.01). The majority of local-regional failures were observed in the 53 patients having "inadequate" total or weekly radiotherapy doses (18/53, 34% versus 9/81, 11%, p less than 0.001). The importance of adequate radiotherapy applied to both older patients, as well as those younger than 40, who appear inherently to have a higher risk of local relapse. The mean interval to recurrence was markedly longer for inadequate radiotherapy (111 months, versus 75 months for adequate treatment), so that significant differences in local control became apparent only after 5 years. These results underscore the importance of radiotherapy technique in breast-conserving treatment, and suggest that an excessive reduction in the intensity of radiotherapy may result in an inordinate number of late local failures.

[Reevaluation of indications for adjuvant hormone therapy in primary breast cancer with high metastatic risk]. / Réévaluation des indications d'une endocrino-hormonothérapie adjuvante dans les cancers primitifs du sein à haut risque métastatique.

This study concerns the correlation between ER and PR status, menopausal status and the effect of adjuvant hormonotherapy in high risk primary breast cancer patients. We have compared the results obtained in a randomized trial (Institut Paoli-Calmettes, Marseille) with those of a historic series (Centre René Huguenin, Saint-Cloud). The patients presented the same clinical and histological criteria and received identical therapeutic protocols (chemotherapy and/or hormonotherapy). Compared with patients receiving no adjuvant treatment, it appeared that: 1) in post-menopausal patients, a significant detrimental effect of tamoxifen was found in ER-negative patients, while in ER-positive patients hormonal treatment was well correlated with both the presence and level of steroid receptors; 2) in pre-menopausal patients, hormonal therapy (oophorectomy + tamoxifen) appeared to be mediated by a complex mechanism involving more than an ER-positive cell population. In the light of the published results, the present findings underline the importance of reevaluating the indications of hormonotherapy in terms of hormone receptors and menopausal status. They also indicate the importance of biological factors in the evaluation of response to therapy. They can identify, subsets of patients in whom a given therapeutic protocol is detrimental, even though it may be beneficial for the overall population. heterogeneity in response to therapy among patient subsets is one of the most important problems which confronts medical statisticians and clinical investigators.

Is breast conservation after local recurrence feasible?

The feasibility of conservative salvage surgery was addressed in a clinicopathologic study of the results of wide excision for 50 selected parenchymal intramammary recurrences after standard breast conserving treatment. After median follow-up of 51 months, 16 (32%) second local failures were observed (5-year local control 62%). Cox multivariate analysis of 18 parameters indicated that only disease-free interval and resection margins significantly influenced local control. 5-year local control was 92% for recurrences occurring after 5 years vs. 49% for shorter intervals, and 73% for negative vs. 36% for positive or indeterminate margins. Local control appeared independent of morphologic features, initial tumour stage, patient age, recurrent tumour size and location. Median survival after second local failure was 33 months; tertiary therapy obtained ultimate local-regional control in 8 of 16 cases. The authors conclude that wide excision is a particularly satisfactory alternative to salvage mastectomy for late recurrences. Negative margins are essential. Further study will be required to establish additional guidelines allowing improved patient selection.

Breast-conserving therapy for macroscopically multiple cancers.

Of 586 unilateral stage I-II breast cancers treated with conservative surgery and radiotherapy, 61 patients were found to have two or more macroscopic tumor nodules, diagnosed either clinically (n = 20), mammographically (n = 2), or on gross pathologic examination (n = 39). After a median follow-up of 71 months, 15 of 61 (25%) of the patients with multiple tumors developed recurrence in the treated breast, compared to 56 of 525 (11%) of patients with single cancers (p less than 0.005). Local failure occurred in 6 of 37 (16%) of bifocal tumors and in 9 of 24 (35%) of patients with 3 or more tumor foci. Recurrence was more frequent for multiplicity diagnosed clinically or mammographically (8 of 22 patients, 36%) than when it was apparent only to the pathologist (7 of 39 patients, 18%). Only 1 of 21 bifocal tumors diagnosed on gross examination recurred. Local failure occurred in only 1 of 22 cases with clearly negative resection margins; the remaining recurrences were associated with positive (n = 3) or indeterminate margins (n = 11). In contrast with recurrences of unifocal breast cancers, local failures in these patients tended to be located at a distance from the original foci, to be multifocal, or to be diffuse, including skin involvement. Only four recurrences presented as a single focus in the vicinity of the original primary tumors. This study indicates that macroscopically multiple breast cancers are at higher local failure risk, especially if multiplicity is clinically apparent, or if three or more gross nodules are seen on pathologic examination. Negative resection margins appear to be essential for satisfactory results.

An assessment of extensive intraductal component as a risk factor for local recurrence after breast-conserving therapy.

The influence of extensive intraductal component (EIC) on local recurrence risk was studied for 496 patients with stage I-II infiltrating ductal cancers treated by conservative surgery and irradiation. EIC was diagnosed in 65 of 231 (28%) premenopausal and 41 of 265 (15.5%) post-menopausal patients. Local recurrence risk was markedly increased in EIC+ patients (5-year actuarial risk 18% versus 8% without EIC, P less than 0.001), but this effect appeared limited to premenopausal patients. Local recurrence risk increased with increasing degree of EIC. EIC with more than 50% intraductal carcinoma was more prevalent in patients younger than 40, perhaps accounting to some degree for the higher local recurrence rates observed in younger patients. The presence of EIC had no influence on overall survival, on median time to local recurrence, or on short-term survival after local failure. The usefulness of EIC as a risk factor for local recurrence is discussed.

Why are local recurrences after breast-conserving therapy more frequent in younger patients?

The influence of patient age on risk of recurrence in the breast was retrospectively studied in 496 stage I-II invasive ductal carcinomas treated by macroscopically complete primary tumor excision followed by radiotherapy. With a median follow-up of 71 months, local recurrence occurred in 13 of 62 (21%) patients younger than 40 years, compared with 48 of 434 (11%) older patients (P less than .025). Cox multivariate analysis of 18 parameters identified four that significantly determined risk: major lymphocytic stromal reaction (MCR), unsatisfactory resection margins, increasing histologic grade, and extensive intraductal cancer (DCIS) within the primary tumor. Compared with older patients, those younger than 40 years had tumors that more often exhibited MCR (36% v 20%, P less than .01), histologic grade 3 (42% v 28%, P less than .025), and very extensive DCIS (21% v 6%, P less than .001). The status of resection margins did not differ significantly between younger and older patients. Restriction of Cox analysis to patients younger than 40 indicated that risk was adequately described by MCR and percentage of DCIS, without consideration of grade or margins. For patients younger than 40, local failure occurred in four of five (80%) tumors with both MCR and more than 50% DCIS, in eight of 25 (32%) with either, and one of 32 (3.1%) with neither of these morphologic features. This study suggests that the higher local failure risk observed in patients younger than 40 years reflects the greater prevalence of certain morphologic characteristics in breast cancers in younger patients. Age itself does not appear to be an independent determinate of risk.

Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancers treated by conservation therapy.

Risk factors for local failure were evaluated for 496 clinical Stage I-II patients with infiltrating ductal carcinomas (median follow-up, 71 months) treated by conservative surgery and radiotherapy. Monofactorial analysis identified the following factors to be correlated with increased risk: moderate/marked mononuclear cell reaction (MCR), high histologic grade (G), extensive intraductal component (EIC), tumor necrosis, macroscopic multiplicity, estrogen receptor negativity, anatomic tumor size, age younger than 40 years, and vascular invasion. Only MCR, G, and EIC proved significant in Cox multivariate analysis. These risk factors were highly age dependent, with EIC markedly more prevalent in women younger than 50, MCR and G in women younger than 40. Separate Cox analysis for premenopausal patients showed that MCR/EIC determined risk independent of resection margins: tumors with MCR had a 28%, and with EIC a 22% probability of recurring locally by 5 years. Premenopausal patients with neither risk factor had a very low failure rate (2.6% at 5 years), regardless of age. For postmenopausal patients risk of breast recurrence was determined both by adequacy of resection margins and grade, with a high local failure rate for patients having G3 tumors with positive or indeterminate margins (31% at 5 years). The authors conclude that the microscopic examination is the only useful tool for assessing the risk of local failure, which is quite low for the majority of patients treated with breast conservation. High-risk patients can be recognized morphologically. The age dependence of morphologic risk factors appears to explain the high local failure rate seen in patients younger than 40.

[Randomized trial of initial chemotherapy in 151 locally advanced carcinoma of the cervix (T2b-N1, T3b, MO)]. / Essai randomisé de chimiothérapie initiale dans 151 carcinomes du col utérin localement étendus (T2b-N1, T3b, M0).

From 1982 to 1987, a randomized phase III trial was performed in order to determine the long-term effect of induction chemotherapy before standard pelvic irradiation in stage IIb-N1, III squamous cell carcinomas of the cervix. Patients were randomized to either chemotherapy and radiotherapy (C + R group) vs radiotherapy alone (R group). Radiotherapy for all patients consisted of 50 Gy in the pelvis with a boost by external irradiation or by brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen was an association of methotrexate (10 mg/m2, D2-4), chlorambucil (4 mg/m2, D1-5), vincristine (0,7 mg/m2, D1), cisplatin (80 mg/m2, D5), given every 3 wks; at least 2 courses were to be given before assessing efficacy and 2 more courses were given to patients who responded. One hundred and fifty-one patients were fully evaluable, after a mean follow-up of 38 mths (range 2-7 years), 76 in the R arm and 75 in the C + R arm. The response rate (greater than 50%) to chemotherapy was 42.5%. After completion of treatment, the complete response rate was 86.8% in the R arm and 86.3% in the C + R arm. The 3 year disease-free survival was 58.7% in the C + R group and 54.5% in the R group, and the median survival was 39.5% and 47 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group (when chemotherapy had been active) than in the R group (p = 0.04). Although radiotherapy was not modified whether patients had initial chemotherapy or not, tolerance was not significantly different between the 2 groups. The data collected in this study indicate that: 1) efficacy of induction chemotherapy is the only available predictive test for long-term results, 2) tolerance to treatment is crucial for optimal chemotherapy delivery, 3) higher dose intensity of chemotherapy in cervical carcinoma is associated with a better tumor reduction, and probably a better survival.

The prognostic significance of late local recurrence after breast-conserving therapy.

Of 178 local recurrences occurring in 1593 patients with clinical Stages I-II breast cancer treated by conservative surgery and megavoltage radiotherapy, 71 were diagnosed after the 5th year. Compared with recurrences occurring prior to 60 months, late recurrences were less frequently inoperable (1/71, 1.4%, versus 18/107, 17%, p less than 0.001), were more often located at a distance from the initial primary tumor (23/71, 32%, versus 15/106, 14%, p less than 0.005), and had a more favorable prognosis (5-year survival 84% versus 61% for late and early operable recurrences, respectively, p = 0.05). Five-year metastasis-free survival after late failure depended mainly on the anatomic extent of the recurrence (87% for recurrences apparently confined to the breast versus 34% for relapses involving the axilla, p less than 0.002). Prognosis of late recurrence appeared to be unaffected both by location of the recurrence within the breast and by the type of salvage operation used (mastectomy versus wide excision). Local-regional control after salvage surgery was satisfactory (89% at 5 years). Whereas recurrence in the breast prior to 5 years profoundly affected survival after initial diagnosis, patients with late failure had identical 15-year survival as other 5-year survivors who never failed locally. Late recurrences were more frequent in patients younger than 40 at initial treatment, and in patients who had inadequate radiotherapy. We conclude that late local recurrences after breast conservation do not represent a serious management problem.

Local recurrence after breast-conserving surgery and radiotherapy. Frequency, time course, and prognosis.

Mammary recurrences were studied in 1593 patients with Stage I and II breast cancer treated by macroscopically complete tumor excision followed by megavoltage radiotherapy, including a boost to the tumor bed (mean dose, 78 Gy). The actuarial freedom from mammary recurrence was 93% at 5, 86% at 10, 82% at 15, and 80% at 20 years. Seventy-nine percent of the recurrences were in the vicinity of the tumor bed, but with increasing time interval, an increasing percentage of recurrences was located elsewhere in the breast. A majority of recurrences after 10 years could be considered new tumors. Only ten of 181 patients with recurrence had prior or concomitant distant metastases, and 159 of 171 isolated mammary recurrences (93%) were operable. Uncorrected overall survival after operable recurrence was 69% at 5 and 57% at 10 years. Prognosis after late recurrence (after 5 years) was favorable (84% 5-year survival). Operable early recurrences retained a favorable prognosis if smaller than 2 cm and confined to the breast (74% 5-year survival). Disease-free interval and histologic grade also appeared to be important prognostic factors after early recurrence. Survival after recurrence did not depend upon the type of salvage operation. Locoregional control was 88% at 5 years after salvage mastectomy and 64% after breast-conserving salvage procedures. The role of adjuvant systemic therapy at time of local recurrence requires additional study. This experience illustrates the important differences between mammary failure and chest wall recurrence after mastectomy, in particular the protracted time course and more favorable prognosis associated with the former.

Local recurrence after breast-conserving surgery and radiotherapy.

The time course and prognosis of local recurrence was studied for 1593 stage I-II patients treated by macroscopically complete excision of the primary tumor with or without axillary dissection, followed by megavoltage radiotherapy (mean tumor bed dose 78 Gy). The actuarial cumulative breast failure rate was 7% at 5, 14% at 10, 18% at 15 and 20% at 20 years. The proportion of recurrences occurring at a distance from the original tumor bed increased with time, most recurrences after 10 years being "new tumors". Of 178 breast recurrences observed, 159 (89%) were operable. Overall survival following operable relapse was 69% at 5 and 57% at 10 years. Prognosis after local failure depended both upon the disease-free interval and the extent of the recurrence. Late recurrences diagnosed after 5 years had an excellent outlook (5-year survival 84%). Small recurrences confined to the breast had a favorable prognosis, even if occurring before 5 years. Local control after salvage mastectomy (88% at 5 years) was better than after conservative salvage surgery. This extensive experience illustrates that recurrence in the breast after conservation therapy is characterized by a protracted course, and is not associated with the poor prognosis attributed to local relapse after mastectomy. The diagnosis and surgical treatment of mammary recurrence is an important component of the breast-conserving strategy.

[Clinically impalpable mammary carcinoma: morphologic and histogenetic analysis. Apropos of 114 cases]. / Carcinomes mammaires impalpables: analyse morphologique et histogenèse. A propos de 114 cas.

In a population of 2,372 consecutive cases of breast carcinomas, 114 cases of clinically occult non palpable breast lesions have been diagnosed (4.8%). 51% of them can be considered as minimal breast carcinomas (MBC) by Gallager's definition and 72% by that of the American College of Surgeons; whatever the definition this category has an excellent prognosis with 11% of axillary invasion for the infiltrating tumors under 5 mm and 7% for these under 10 mm and 100% 5-year survival rate in both cases. The category of infiltrating tumors of over 5 mm and 10 mm also has a good prognosis with 21% and 26% of axillary lymph node invasion respectively, with a survival rate of 83.82% and 77.92%. The comparative histological analysis shows at this stage an increase in the intraductal carcinomas (IC) (35% instead of 6% for the palpable carcinomas), the infiltrating ductal carcinomas with predominant intraductal component (IDCPIC) (19% instead of 12%) and the tubular carcinomas (11% instead of 3%). The study of the peritumoral and environmental mastopathy and the histological repartition, confirms the classical histogenetic arguments regarding breast carcinomas.