Post-Mast. Radiotherapy for N(+): Arriagada (Nov. 95)

Date: Thu, 21 Nov 1996 18:56:48 -0800 (PST)
From: jbonine <jbonine@OREGON.UOREGON.EDU>
To: Breast Cancer Discussion List <BREAST-CANCER@morgan.ucs.mun.ca>
Cc: JBONINE <JBONINE@OREGON.UOREGON.EDU>
Subject: Post-Mast. Radiotherapy for N(+): Arriagada (Nov. 95)

>Couldn't you just pass along interesting articles, and let us interpret them ourselves?

Arriagada, "Adequate Locoregional Treatment for Early Breast Cancer May Prevent Secondary Dissemination," J. Clin. Oncol. 13:2869-2878 (November 1995) --

"The purpose of this report is to describe the results of the Stockholm radiotherapy trial in terms of event-free survival (EFS) . . . .

"This analysis of different events that determine EFS in a randomized trial with more than 15 years of follow-up evaluation was intended to clarify some issues in the controversy concerning the effect of adjuvant radiotherapy in early breast cancer. . . .

". . . The group of reference is the surgery-alone group. the total cumulative incidence of events was significantly decreased in groups that received adjuvant radiotherapy. Most of this effect was related to the lower percentage of local recurrences that occurred in the radiotherapy group. Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001) . . .

"Prognostic factors for metastatic dissemination. . . . [A certain analysis] implies that the size of the effect of treatment is different among N(-) and N(+) patients. In the current analysis, the relative risk of metastatic dissemination was only marginally decreased (from 1 to 0.87) among N(-) patients, but decreased from 3.31 to 1.75 for N(+) patients. . . .

"Overall survival in patients with unequivocal lymph node status. . . . In [one] model, local recurrence was introduced as a time-dependent covariate and proved to be a strong prognostic factor that increased the risk of death fourfold (p < .0001). In [this] model, the relative effect of postoperative radiotherapy, although nonsignificant, was . . . a relative risk of 1.24. . . .

"The adjusted survival curves for the control and postoperative radiotherapy groups are shown in Fig. 4. The possible benefit of radiotherapy was 2% at 10 years and 4% at 15 years among N(-) patients, and 6% and 9%, respectively, among N(+) patients.

"DISCUSSION

"It is widely recognized that radiotherapy significantly decreases the risk of local recurrence in breast cancer. [citations omitted] However, the effect on distant metastasis and overall survival remains controversial. This controversy originates from two opposing hypotheses regarding the natural history of the disease.

"The most commonly accepted interpretation today -- the systemic hypothesis -- is that almost all N(+) breast cancer patients have micrometastases already at the time of primary diagnosis. In this case, local treatment cannot prevent distant dissemination.

"The other hypothesis, often referred to as halstedian, maintains that a substantial proportion of N(+) patients do not have distant micrometastases at the time of diagnosis. In this case, prevention of local recurrences could prevent secondary dissemination, i.e., distant metastases originated from locoregional tumor-cell nests left after primary surgery.

"A supportive argument is that approximately one-third of N(+) patients who did not receive systemic treatment are alive and free of disease 20 to 25 years after diagnosis. Among these patients, about one-third will develop local recurrence if they do not receive local radiotherapy, which is able to produce a threefold reduction of this risk (from 30% to 10% at 20 years).

"According to the halstedian hypothesis, patients who benefit in terms of survival from radiotherapy will be the 20% of long-term N(+) survivors in whom local recurrence was prevented, i.e., the potential survival benefit would be in the order of 6% to 7% (0.33 x 0.20 = 0.066). Among subgroups with a lower risk of local recurrence, for example, N(-) patients, the potential survival benefit would obviously be less.

"These hypotheses should be tested in properly randomized trials. [Discussion of older studies, published in 1987 and 1990, omitted.] . . .

"[Newer] studies using megavoltage radiotherapy have not shown an increased mortality rate after 10 years in treated patients, except in N(-) patients in the Oslo trial.

"In the latter trial, the internal mammary chain was treated by a direct cobalt-60 anterior beam that delivered a relatively high dose to the anterior heart. . . . These results underscore the fact that radiation therapy in patients with a low-risk of local recurrence, i.e., node-negative patients, produces only a small benefit in terms of the absolute reduction of local recurrences. This small benefit may even be outweighed by an increase of lethal complications such as cardiovascular diseases.

"On the other hand, N(+) patients have a high risk of local recurrence, i.e., greater than 30% at 15 years of follow-up evaluation, as shown in Table 4 and in other published series.

"As shown in Tables 5 and 6, the mechanism by which postoperative radiotherapy may prevent distant dissemination may be related to the prevention of local recurrence. . . .

"The described effects of radiotherapy merit further investigation . . . . Indeed, if a beneficial effect of radiotherapy exists, it would imply a different mechanism of preventing distant dissemination as compared with xytotoxic systemic therapy. Chemotherapy is probably less effective than radiotherapy in preventing local recurrences [citations omitted] and its main mechanism of action is probably eradication of micrometastases.

"The results of a Danish trial showed that the mechanisms of radiotherapy and chemotherapy probably are different . . . . [Its] result is consistent with an addition of beneficial effects from both chemotherapy and radiotherapy. . . .

"In summary, this study showed that postmastectomy radiotherapy in breast cancer patients with positive axillary nodes may decrease the incidence of distant metastases by preventing local recurrences, which appear to serve as a source for secondary dissemination in this patient subgroup."

[Emphases added by Bonine.]

[Tomorrow, quotations from some books.]

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