Dear B-C List friends,
This Part Four deals exclusively with the June 1996 study by University of Michigan radiation oncologists Lori Pierce and Allen Lichter, who have extensively studied the question whether radiotherapy provides both local control and a survival benefit.
Comments on their study by other doctors are also included.
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Lori Pierce & Allen Lichter, "Defining the Role of Post-Mastectomy Radiotherapy: The New Evidence," Oncology, 10:991-1002 (July 1996).
These radiation oncologists from the University of Michigan analyzed studies of post-mastectomy radiotherapy in preventing recurrences and extending survival and concluded that for some women it does both.
SUMMARY
In the middle of their study, in discussing radiotherapy when there is also systemic therapy, Pierce & Lichter wrote: "Summary: . . . "The larger [recent] trials . . . show an improvement in disease-free survival and overall survival. This suggests that systemic therapy and radiotherapy individually provide benefit and that the combination of the two modalities maximizes the potential for improved disease-free and overall survival."
The prŽcis at the beginning of their article stated:
Ê"In an early meta-analysis of the post-mastectomy radiotherapy trials, the use of obsolete radiotherapy techniques resulted in increased cardiac mortality. [They are referring to Cuzick, 1987.] With maturation of these data and inclusion of more recent trials, however, a survival advantage is now emerging. [Cuzick, 1994; Arriagada, 1995.] This, in concert with the improvement in disease-free and overall survival evident in the larger studies of post-mastectomy radiotherapy with adjuvant chemotherapy [Southeastern, 1992; British Columbia, 1996; Danish, 1995] , generates a new enthusiasm in support of post-mastectomy radiotherapy. . . ." (p. 991.)
Their overview came out seven months after the November 1995 Oxford Overview was published (previously discussed). The study by Pierce & Lichter was not a "meta-analysis," in the sense of totally up patients and their results from numerous individual studies and doing statistics on the overall numbers. Rather, it was a "review" article, picking and choosing amongst different studies, based on criteria stated in the article, and trying to pull out of the best or most recent studies some trends in evidence. Their conclusions were quite different from those of
the Oxford Overview.
QUESTIONS ASKED
Pierce & Lichter directed their attention primarily to stage II breast cancer patients. They noted that the routine use of systemic therapy (chemotherapy, endocrine therapy) had caused some doctors to question the need for locoregional radiotherapy. In response, they said that one must ask three questions:
Ê(1) whether systemic therapy alone can prevent locoregional recurrences (to which they later answer, No);
Ê(2) are some subgroups of women at high risk for locoregional recurrences who would particularly benefit from radiation treatments after mastectomy (they answer, Yes); and
Ê(3) whether prevention of such recurrences extends survival (they answer, Yes).
PREDICTIONS OF LOCAL-REGIONAL RECURRENCES
Pierce & Lichter addressed the second of those questions first: who will have a local or regional recurrence? Nobody can know for sure just who will have a recurrence after a mastectomy, but studies have shown that some women are more likely to have them, particularly those with lymph nodes that are positive for cancer, those with larger tumors, and possibly those with cancer cells found in the removed breast near the edge where it was removed.
Pierce & Lichter wrote:
"The finding of positive axillary nodes has been shown consistently to be the major predictor of chest wall failure " Where there was no systemic therapy, those with 4 or more nodes positive had recurrence rates up to 42% over 10 years (Haagensen study). (p. 992.) In a study by Donegan, 1-3 nodes "was associated with a 10% to 15% recurrence rate at 5 years."] " (p. 992.) Tumors over 5 cm. had a 27% or higher recurrence rate, although without correlation with nodal status.
When chemotherapy has been given, 9% of women with 1-3 positive nodes had locoregional recurrence within 5 years, and those with 4 or more had 36% recurrence, in a 1985 study by Stefanik. Other studies found failures also. Number of nodes, size of primary tumor, and estrogen-receptor content all have been shown to correlate with local recurrences. (p. 996.)
LOCAL CONTROL AND QUALITY OF LIFE
Pierce & Lichter argued that even if survival were not benefited, prophylactic radiotherapy is important to prevent the severe compromise in quality of life from an uncontrolled local recurrence, and cited studies that delaying radiotherapy until such a recurrence takes place leads to lack of success in 50% of the cases.
LOCAL CONTROL AND INCREASED SURVIVAL
Regarding survival, they noted that some studies fail to find a correlation between local control and survival, but then discussed randomized trials in which mastectomies were followed by radiotherapy, or not (but no systemic therapy was given). They criticized most of these trials for inadequate total doses, high fraction sizes, and inappropriate targeting. They noted the 1987 Cuzick study showing an overall survival detriment from radiotherapy where treatment was begun before 1975 (20 years ago). They then noted that Cuzick's 1994 study isolated the causes of mortality and attributed them to outdated technique that are "no longer in use." (p. 993.)
With that, they focused on three studies: the Oxford Overview, the original Stockholm study, and the Arriagada re-analysis of Stockholm data. All of these involved mastectomy but not systemic therapy, and addressed the question whether radiotherapy enhanced survival. I have already noted their comments on these studies in an earlier message. Suffice it to say that they concluded that there were survival advantages shown from the more recent of the trials. (Later they reached the same conclusion from trials where chemotherapy had been included; see below.)
ÊCAN SYSTEMIC THERAPY PREVENT LOCAL-REGIONAL RECURRENCES?
If preventing locoregional recurrences is important both for quality of life and survival, the obvious next question is "whether systemic therapy can prevent locoregional recurrence following mastectomy." (p. 994.) This was the first of the questions with which they opened their article.
Pierce & Lichter wrote that although "some trials have shown some improvement in locoregional control with adjuvant chemotherapy, others have not reproduced these findings." (p. 995.) Trials in Manchester and the NSABP-B05 trial showed benefit; one in the West Midlands showed little; and one in Milan showed almost none. The Ludwig trial showed benefit from tamoxifen and a Swedish study showed that tamoxifen and CMF/LMF had benefit, but radiotherapy did a better job of preventing local recurrences. (pp. 995-996.)
PIERCE & LICHTER'S RECOMMENDATIONS FOR PREVENTING LOCAL RECURRENCES
Keeping in mind that up to this point in the article, Pierce & Lichter were still talking of preventing local-regional recurrences, "for their own sake," so to speak, and not based on any survival advantage. Seeking to prevent local-regional recurrences, they made the following recommendations:
Ê"Summary. . . . Patients with positive axillary nodes and T3 tumors remain at risk for locoregional failure despite the use of adjuvant chemoendocrine or endocrine therapy. We therefore recommend that patients with T3 tumors, four or more positive axillary nodes, and positive surgical margins undergo post-mastectomy radiotherapy. As more information becomes available on the patterns of failure in patients with one to three positive nodes, the role of post-mastectomy radiotherapy in this group of women may need to be reassessed.
WHAT ABOUT SURVIVAL? -- TRIALS OF RADIOTHERAPY AFTER MASTECTOMY AND CHEMOTHERAPY
Finally, Pierce & Lichter turned to the situation most likely to face women with positive lymph nodes, namely whether, if they are getting chemotherapy, they should also get radiotherapy. Since they had already given their recommendations based on "quality of life" alone (i.e., preventing local-regional recurrences is a goal in itself), and since chemotherapy is being widely used for survival benefits, they turned finally to the question whether radiotherapy, by reducing local recurrences, might also lengthen survival.
What do studies of survival show in these settings? Since chemotherapy is only a couple of decades old, the question is a somewhat new one. Nonetheless, there are now several studies.
Ê"Numerous randomized trials have compared radiotherapy to observation following mastectomy and adjuvant systemic therapy. [Trials summarized in table.] . . . This discussion will focus on the three studies that either enrolled the greatest number of patients or have a minimum of 9 years' median follow-up." (Some may object that this improperly excludes the smaller studies, which showed less of a benefit for radiotherapy. Pierce & Lichter respond that those studies have less "statistical power.")
Ê"Southeastern Cancer Study Group Trial. . . . [4 or more nodes] -- "WIth a median follow-up of 10 years, there was a trend toward improved disease-free survival among women receiving 6 cycles of CMF with radiotherapy compared to those receiving six cycles of CMF alone. . . . Survival did not differ between the two treatment arms [CMF with and without radiotherapy], but actuarial analyses suggested a trend in favor of radiotherapy." (pp. 997-998.)
Ê"British Columbia Trial. . . . [318 women, six cycles CMF, premenopausal, stage I or II, positive axillary nodes at surgery] -- Despite the small number of patients, which limited statistical power, a 12-year analysis demonstrated a significant improvement in disease-free survival for those randomized to the radiotherapy arm, with a 12-year disease-free survival of 57% following CMF and radiotherapy vs. 63% following CMF only (P = .02). The corresponding survival rates were 57% for CMF and 60% for CMF plus radiotherapy. (P = .09)." (p. 998.)Ê [Note from JB:Ê Final report published in New England Journal of Medicine, Oct. 2, 1997.]
Ê"Danish Trial. -- The largest trial studying the benefit of post-mastectomy radiotherapy among women receiving adjuvant chemotherapy was conducted in Denmark. [1708 women, 9 cycles CMF versus 8 CMF with radiotherapy delivered sequentially after first CMF cycle; majority of patients had positive nodes and T1 or T2 lesions] . . . With a median follow-up of 9 years, the addition of radiotherapy significantly improved locoregionalÊcontrol, disease-free survival, and overall survival: The 9-year local failure rates with and without radiotherapy were 13% vs. 40% (P < .01), respectively; disease-free survival rates for the two treatment arms were 50% and 35%, respectively (P < 0.1); and crude survival rates were 56% and 50%, respectively (P < .01). Therefore, radiotherapy improved the absolute survival rate in node-positive premenopausal women already receiving adjuvant chemotherapy by 6%." (p. 998.)Ê [Note from JB:Ê Updated report published in New England Journal of Medicine, Oct. 2, 1997.]
In short, the Southeastern, British Columbia, and Danish trials (where chemotherapy was given) provide some evidence for a survival benefit from radiotherapy after mastectomy.
ÊTRIAL OF RADIOTHERAPY AND TAMOXIFEN
Pierce & Lichter also reported on a Danish trial that attempted to determine whether, if tamoxifen were given, radiotherapy made any difference in preventing local recurrences and in survival. There was a trend, but no statistically significant numbers:
Tamoxifen. [1,375 post-menopausal women under 70 years; 30 mg/d tamoxifen with/without radiotherapy] . . . With 9-year median follow-up, there was a significant benefit in local-regional control and disease-free survival with the combined endocrine and locoregional therapy. The rate of local failure with tamoxifen alone was 45%, as compared with 12% with the addition of radiotherapy (P < .01), and disease-free survival was 31% with tamoxifen alone and 38% with combined modality therapy (P < .01). Although there was a trend toward improved survival with radiotherapy, the results were not statistically significant; crude survival rates were 45% and 50% with and without radiotherapy, respectively. [I THINK THIS IS A MISPRINT, because for there to be such a trend, he would have to mean "without and with," not "with and without".]
OVERALL CONCLUSIONS -- RADIOTHERAPY IMPROVES SURVIVAL
From all this, Pierce & Lichter concluded that a survival advantage from radiotherapy has emerged for node-positive women.
Ê"Summary. . . . [t]he larger trials . . . show an improvement in disease-free survival and overall survival. This suggests that systemic therapy and radiotherapy individually provide benefit and that the combination of the two modalities maximizes the potential for improved disease-free and overall survival."
FUTURE RESEARCH
Pierce & Lichter recommended more research:
Ê"Clearly, a great deal of controversy still surrounds the use of post-mastectomy chest wall irradiation. . . .
Ê"Resolution of questions . . . will come about only through continued clinical research. It is time to initiate a new post-mastectomy chest wall trial in north America. Such a study should incorporate high-quality systemic adjuvant chemotherapy and sophisticated radiotherapy . . . . The trial should be
Êlarge enough to detect a 6% to 7% improvement in survival, similar to that seen in the Danish study. . . ."
Of course, while professors can focus on research agendas, patients and clinicians must make "best guesses" from the research that exists. Wearing their clinical hats, Pierce & Lichter advocated radiotherapy for certain women, using the more conservative rationale of preventing local-regional recurrences, while seemingly struggling to restrain their excitement that this will produce a survival benefit as well.
Ê(F-2) RESPONSE TO PIERCE & LICHTER ARTICLE BY RECHT
Abram Recht, "The Pierce/Lichter Article Reviewed," Oncology, 10:1006 (July 1996).
The same issue of Oncology had, on pages 1006, 1007, and 1011, comments by others.
Abram Recht wrote that he had problems with an Oxford meta-analysis mentioned by Pierce and Lichter (I have quoted from his critique of the Oxford Overview earlier), and then goes on to discuss "Which Patients Should be Treated":
Ê"Although some patient groups are demonstrably at high risk of locoregional (and distant) failure following surgery, radiotherapy may also benefit patients with lower risks. . . .
Ê"In particular, it is premature to conclude that patients with one to three positive nodes should not participate in a trial of postmastectomy radiotherapy or be considered for such treatment outside of such a trial. In an update of the British Columbia trial, which was published too late to be incorporated into the Pierce-Lichter review, the use of radiotherapy resulted in an increase in the 12-year *distant* [emphasis in original] disease-free survival rate for both patients with one to three positive nodes (68%, as compared with 54% in controls [ P = 0.06] . . . and those with four or more positive nodes (41% vs 19% [P = 0.06] . . . ."
He concluded: "At present I, too, routinely recommend such treatment only for patients with large (over 5 cm) or locally advanced tumors, four or more positive axillary lymph nodes, or involved chest wall margins. However, it should be recognized that these criteria may be unduly restrictive. . . ." And as he said in the previous quote, patients with 1-3 nodes should be "considered for treatment" even outside of a randomized trial.
Ê(F-3) RESPONSE TO PIERCE & LICHTER BY HAYES & HARRIS
Daniel Hayes & Jay Harris, "The Pierce/Lichter Article Reviewed," Oncology, 10:1007-1011 (July 1996).
Daniel Hayes and Jay Harris also published a comment. Among other things, they said that Pierce and Lichter "provide an elegant review of the current data." They applaud the suggestion that another randomized trial be started, but, "It is less certain whether we should now recommend the routine delivery of post-mastectomy radiotherapy to patients at high risk of local recurrence. In other words, they are less inclined than Pierce & Lichter or Recht to recommend radiotherapy.
Ê"With currently available techniques, post-mastectomy radiation therapy appears to pose a substantially lower risk[] than were observed with the techniques used in the 1940s and '50s. Nonetheless, these risks still include pulmonary, cardiac, and neuromuscular damage and the potential for a second malignancy. none of these appears to occur in > 5% of all patients."
Ê"Of these complications, perhaps the most feared is late cardiac dysfunction." They conclude that they haven't seen this, however.
Ê"Post-mastectomy radiation therapy results in a substantial increase in the cost of care, both in terms of direct and indirect expenses. A course of chest wall radiotherapy requires approximately 4 to 6 weeks of daily treatment and, on average, costs between $10,000 and %15,000. Furthermore, it results in lost time from work, increased transportation costs, and, possibly, additional elder- and child-care costs. Thus, recommendations for routine post-mastectomy chest wall radiation therapy require a careful assessment of both local and systemic benefits and results. [NOTE FROM ME: The "Thus" sentence does NOT logically follow from the preceding part of the paragraph; they should have said something like "Thus, such recommendations are not without some societal costs."]
ÊA careful look at the Hayes and Harris critique reveals that their caution on the use of radiotherapy is largely economic, not based purely on health concerns for the patient.
The challenge is to ensure that necessary steps are taken to minimize toxicity from radiotherapy, although it appears that this is now regularly done.
Radiotherapy, in short, has the potential of achieving not only local control and a consequent improved quality of life, but improved survival as well.
John
John E. Bonine (jbonine@oregon.uoregon.edu)
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