Radiotherapy 3: Stockholm Study, Others

Date: Wed, 11 Dec 1996 06:29:40 -0800
From: John Bonine <jbonine@OREGON.UOREGON.EDU>
To: Multiple recipients of list BREAST-CANCER <BREAST-CANCER@morgan.ucs.mun.ca>
Subject: Radiotherapy 3: Stockholm Study, Others

╩Dear B-C List friends,

╩This is my continuing attempt to sort through recent information on whether radiotherapy is useful for some after mastectomy. I welcome any corrections or comments, as I try to draw all the information together.

╩E.THE RECENT STOCKHOLM META-ANALYSIS

╩In this Part Three, I now want to go through excerpts from a recent study by Arriagada, et al., concerning radiation therapy in Stockholm, Sweden, where modern techniques minimized heart exposure, and a survival benefit emerged. I will also discuss an editorial published in the same issue by Dr. Abram Recht of Harvard.

╩The study, published just a year ago, concluded that in women who did not receive chemotherapy (the study started in 1971) but did receive modified radical mastectomies, post-mastectomy radiotherapy produced a 6 percent overall survival benefit 10 years after surgery and a 9.2 percent overall survival benefit 15 years after surgery, for node-positive patients (and lesser benefits of 2 and 3.7% for node-negative patients). (A Danish study, in which patients did in addition receive chemotherapy, namely CMF, also produced a 7% survival benefit in those who also had radiotherapy; this is discussed at the end of this study.)

╩I previously spent time studying and summarizing the November 1995 "Oxford Overview" that found a benefit in terms of disease-free survival, but very little overall benefit, when mixing together about 35 studies including some very old ones. I also provided the criticisms of that Oxford Overview that other researchers have published. Then I summarized the 1994 Cuzick study, which showed that where radiotherapy has caused harm and produced little benefit, it was due to the unqualified mixing together of older and newer studies (similar to what the Oxford Overview did).

╩In a subsequent Part Four, I will address a 1996 study by Pierce & Lichter that shows a survival benefit from modern radiotherapy used post-mastectomy for some patients, and a 1996 British Columbia study that confirms that.

╩In this Part Three, in addition to providing excerpts from the Arriagada Stockholm study, I will provide excerpts from an editorial by Dr. Abram Recht about the study.

╩==========================================

╩(E-1) ARRIAGADA'S STOCKHOLM II STUDY

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

╩In December 1995, one year ago, an international team of researchers headed by the Italian-French doctor Rodrigo Arriagada (but mostly consisting of doctors from Sweden) published a new statistical analysis of data from the "Stockholm trial" of the early 1970s.

╩(This happened to take place at the same time that the Early Breast Cancer Trialists' Collaborative Group were publishing the Oxford Overview on November 30, 1995.)

╩They wrote:

╩"The purpose of this report is to describe the results of the Stockholm radiotherapy trial in terms of event-free survival (EFS)." At the end, they wrote: "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."

╩The Stockholm radiotherapy trial, in which patients entered the trial from 1971 to 1976, involved 960 patients with a unilateral, operable breast cancer, who received modified radical mastectomy and either radiotherapy or not (but no chemotherapy).

╩SOME IMPORTANT RESULTS: FEWER RECURRENCES, MORE SURVIVAL

╩I have decided to list here, in sequence, what seem to me to be some of the most important results in Arriagada's analysis:

╩1. "The total cumulative incidence of events was significantly decreased in groups that received adjuvant radiotherapy." (p. 2871.)

╩2. "Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001 [or 99.99% confidence level]." (p. 2871.)

╩3. "Using the total event rate method, radiation also significantly decreased (P = 0.04 [96% confidence]) the rate of distant metastases." (p. 2871.)

╩4. "[D]istant metastases [appeared] after local recurrences in many patients." (p. 2871.)

╩5. "[O]nly histologic lymph node status and postoperative radiotherapy were independent prognostic factors" for local recurrence. "The relative risk of local recurrence was 3.25 (95% confidence interval [C.I.] . . . ) for N(+) patients compared with N(-) patients and 0.22 (95 % C.I.) for patients in the radiotherapy group compared with those in the control group." (p. 2871-72.)

╩6. "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." (p. 2872-73.)

╩7. "[In another] analysis . . . local recurrence . . . proved to be a highly significant prognostic factor (P < 0.0001) that increased the risk of metastases by a factor of six." (p. 2873.)

╩8. "In N(-) patients . . . [t]he only significant prognostic variable [predictive of distant metastases] was the appearance of local recurrence . . . which increased the risk of dissemination by a factor of 5.19 (95% C.I. . . .)." (p. 2873.)

╩9. "[In the first of two statistical models concerning N(+) patients,] age and postoperative radiotherapy were significant prognostic factors that decreased the risk of dissemination [i.e., distant metastasis] to 0.56 and 0.63, respectively." (p. 2873.)

╩10. "In the second model, the appearance of local recurrence as a time-dependent covariate proved to be a strong prognostic factor (P < 0.0001) [for the subsequent appearance of distant metastasis] that nullified the effect of postoperative radiotherapy." (p. 2873.) I **believe** that this means that in those instances when local recurrence **did** take place even among those who were irradiated, radiotherapy also made no difference in whether distant metastases would appear. My supposition is based on the next quoted sentence:

╩11. "This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence because of the strong correlation between postoperative radiotherapy and the appearance of local recurrence." (p. 2873.) I **believe** that this says that because postoperative radiotherapy lessens the chance of local recurrence, it also probably decreases the chance of distant metastases.

╩12. For patients who had positive nodes, who were or were not irradiated, and who developed local recurrences anyway, "[a]pproximately 20% of patients did not develop distant metastases up to 8 years after local recurrence." (p. 2873.) The obverse of this is, of course, that 80% of patients who developed local recurrences subsequently developed distant metastases in that time.

╩13. Finally, the study produced the 6 to 9 % survival benefit for 10 years and 15 years for node-positive patients, quoted above.

╩DISCUSSION -- THEORETICAL REASONING, PLUS OTHER STUDIES

╩Under "DISCUSSION." Arriagada and the others wrote:

╩"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.

╩TWO HYPOTHESES

╩"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.] . . .

╩NODE-NEGATIVE PATIENTS MIGHT NOT BENEFIT FROM RADIOTHERAPY

╩"[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. . . ."

╩NODE-POSITIVE PATIENTS, RADIOTHERAPY, AND CHEMOTHERAPY

╩"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 Cytotoxic 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 In this randomized trial, . . . [t]he adjuvant radiotherapy significantly increased the overal survival rate by 7% at 7 years. This result is consistent with an addition of beneficial effects from both chemotherapy and radiotherapy. . . ."

╩SUMMARY

╩"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."

╩(E-2) RECHT'S COMMENTS ON ARRIAGADA STUDY, PLUS MORE INFORMATION

╩Abram Recht, "The Return (?) of Postmastectomy Radiotherapy," J. Clin. Oncol. 13:2861-2864 (December 1995) (editorial).

╩As I described above, Arriagada, et al., published their new statistical analysis of the Stockholm trials at the same time that the Oxford Group was publishing its meta-analysis of radiotherapy.

╩In conjunction with publication of that December 1995 study, Dr. Abram Recht published an editorial comment.

╩STOCKHOLM TECHNIQUES ARE CLOSER TO MODERN TECHNIQUES

╩Dr. Recht called the Stockholm trials "one of the best-conducted of the randomized trials" concerning the effects of radiotherapy after mastectomy. He also wrote:

╩"It is also one of the few trials to use radiotherapy practices similar (but not identical) to those currently in widespread use."

╩RADIOTHERAPY TO PREVENT LATER METASTASIS

╩Dr. Recht wrote that the "elegant statistical techniques of Arriagada et al indicate that tumor cells remaining in the skin, chest wall, or regional lymph nodes after mastectomy may subsequently metastasize."

╩Dr. Recht stated that the data from the Arriagada study "support the breast cancer paradigm recently summarized by [Dr. Samuel] Hellman [of the University of Chicago]." According to this, some women have hidden local-regional disease and combatting that possibility with radiotherapy whle combatting the possibility of distant metastases with chemotherapy is an important combination.

╩One aspect of the Stockholm data that may be of significance for some is that, since the patients accrued to that study in the early 1970s, before screening mammography became widespread, most of those patients had larger tumors.

╩VALUE OF COMBINING CHEMOTHERAPY WITH RADIOTHERAPY

╩Dr. Recht wrote that available data do not prove that adjuvant systemic therapy (chemotherapy and tamoxifen) necessarily prevent local-regional recurrences, and concluded: "Clearly, chemotherapy and tamoxifen do not work as well as radiotherapy in the preventon of local-regional recurrence."

╩Dr. Recht wrote that a number of randomized studies, not only this Stockholm study, have compared systemic therapy alone to systemic therapy plus radiotherapy, and the larger studies show statistically significant survival benefits when radiotherapy is also used.

╩IMPROVED SURVIVAL SHOWN IN DANISH STUDIES

╩In the two Danish Breast Cancer Group trials 82b and 82c, the 7-year relapse-free survival rates are 13% better for premenopausal patients and 10% better for postmenopausal patients. In the 82b study, furthermore, "a significant improvement of 7% in the 7-year overall survival rate was found in the . . . (CMF)-radiotherapy arm, compared with the CMF-only arm." Dr. Recht noted that this was consistent with the 9% survival rate improvement in the node-positive group in the Stockholm trial.

╩Dr. Recht said that these survival improvements occurred despite radiotherapy techniques that caused cardiovascular damage in some patients (these are the techniques that he said are no longer in use here).

╩RECHT'S OWN PRACTICE

╩Dr. Recht wrote that his own practice is to recommend radiotherapy after mastectomy for patients who have EITHER large tumors, 4+ positive lymph nodes, or other factors, and also to recommend it sometimes ("clinical judgment") for others.

╩Next, the 1996 Pierce & Lichter Overview.

╩John

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