In!. J. Radralron Oncology Bwl Phw Vol. Printed in the U.S.A. All rights reserved.
20. pp.
523-527
0360-3016/91 53.Otl + .XJ Copyright 0 199 Pergamon Press plc
I
l Editorial
TRIALS AND TRIBULATIONS: DO CLINICAL TRIALS PROVE THAT IRRADIATION INCREASES CARDIAC AND SECONDARY CANCER MORTALITY IN THE BREAST CANCER PATIENT? SEYMOUR
H.
LEVITT,
M.D.’
AND GILBERT
H.
FLETCHER,
M.D.2
‘Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Hospital, Box 436, Minneapolis, MN 55455; and ‘Division of Radiotherapy, M.D. Anderson Hospital, 15 15 Holcombe Blvd., Houston, TX 77030
INTRODUCTION
predictive of all approaches to adjuvant irradiation of breast cancer or is caused by the radiation techniques used and/or possibly biased selection of patients. With these factors in mind, analysis of the recent update of the two trials included in the latest meta-analysis will help us to evaluate the applicability and validity of their findings to present-day statistical and radiotherapeutic techniques.
In this issue, the reader will find a number of articles which demonstrate the beneficial effect of radiation in the treatment of breast cancer. This benefit is reported for practically all stages of the disease. However, recent reports of the harmful and lethal effect of radiation in the treatment of breast cancer contradict the beneficial reports and confuse the entire gamut on oncologists. Is there in fact a harmful effect of radiation therapy for the breast cancer patient? A 1987 report in the medical literature based on metaanalysis of “randomized” clinical trials of adjuvant irradiation in the treatment of breast cancer claimed an increased mortality for patients treated with radiation (7, 8). This increased mortality was noted only after a period of 10 to 15 years. More recent reports of two of the individual trials included in the meta-analysis which contributed the majority of patients to the meta-analysis have also noted an increased mortality after 10 years ( 10, 12). All oncologists agree that adjuvant irradiation significantly decreases the incidence of local recurrences; however, because of these reports, many medical oncologists and radiation oncologists have ceased recommending adjuvant radiation therapy post-mastectomy even when indicated. Conceivably, these reports could also negatively affect the role of irradiation in the conservation treatment of breast cancer. There can be no question that irradiation can be carcinogenic and can produce serious acute and chronic damage in normal tissue, possibly leading to death. However, before discarding the use of radiation in the adjuvant treatment of breast cancer, it is important to determine whether the increased mortality noted in these studies is
METHODS
AND
MATERIALS
Manchester trial The first report was a 34-year follow-up of the Manchester Trial (12). In this paper the authors reported a significant increase in cardiovascular mortality after 15 years in patients treated with radiation as compared with those who were not. Statistical analysis. There was published evidence of inappropriate randomization techniques with accompanying patient selection exclusion and bias ( 13). Radiation therapy analysis. The Manchester Trial of postoperative irradiation from 1949 to 1955 involved two trials of different orthovoltage irradiation techniquesthe peripheral and the quadrate. In the quadrate technique, the chest wall and the axilla were irradiated through tangential fields. In the peripheral technique, the supraclavicular area and the internal mammary chain were irradiated. Neither technique adequately covered the appropriate target areas. The dose was 3500 to 4000 roentgen in 3 weeks. Although it is not stated, it is very unlikely that all fields were treated every day so that the fraction size per treatment was high (17, 18). Comment. The authors of the current follow-up of the Manchester trial admit these problems, but assert that
Rutqvist of the Radiumhemmet, Karolinska Hospital for his advice and suggestions. Accepted for publication 9 November 1990.
Reprint requests to: Seymour H. Levitt, M.D., Box 436 UMHC, University of Minnesota Hospital and Clinic, Harvard St. at East River Rd., Minneapolis, MN 55455. Acknowledgment-The authors would like to thank Dr. L. E. 523
524
I. J. Radiation Oncology 0 Biology 0 Physics
“Any inadequacies in the treatment, any bias in the allocation, or any imbalance regarding the giving of ovarian irradiation would be most likely to have an effect during the first few years of follow-up. They would not be expected to have an effect on the prognosis of survivors beyond 15 years. Consequently, it would not seem justified to dismiss the treatment effect seen after 15 years because of possible imperfections in the design of the trial.” We have reviewed the statistical literature and have found no source in that literature to justify their statement that after a set number of years bias would not affect the results (14). Finally, it is known that premenopausal patients who have been castrated have a higher incidence of cardiac complication than non-castrated patients (6, 9, 19). The claim of the report is that patients treated with adjuvant irradiation for breast cancer will have an increased cardiovascular mortality after 15 years. Because of the faulty irradiation technique and doses, and with all the imbalances and bias in patient selection and treatment that exist in this trial, one cannot assume that the findings are valid ( 14). British Cancer Campaign randomized trial The second recent review of another of the trials has also found an increased hazard for the irradiated patients ( IO). This article evaluates the data from the British Cancer Research Campaign Randomized Trial for early breast cancer. The authors report a significant increased incidence of other malignancies and cardiac disease in breast cancer patients treated with postoperative irradiation after simple mastectomy as compared with those who did not receive postoperative irradiation after the mastectomy. The increase in cardiac mortality and other tumors is slight, but significantly increased in patients who had tumors of the left breast and who received orthovoltage radiation treatment. There was no significantly increased risk of mortality found due to either malignancy or cardiac death in patients who received supervoltage irradiation. Statistical analysis. The recent CRC report evaluated 1,376 patients who received irradiation, in comparison with 1,424 who did not. In a previous article the same authors noted that of the 1,376 patients allocated to deep X ray therapy, 273 were non-evaluable (an approximately 20% inevaluability rate). Of the 1,103 who were evaluable, 36 patients did not receive irradiation in spite of being allocated to the deep X ray therapy group and 48 patients were not irradiated in all areas (3). Radiation therapy technique analysis. A review of the CRC radiation therapy techniques reveals a great variation in the recommended and received radiation doses for both the orthovoltage and supervoltage treated patients. The recommended treatments were varied with regard to fractionation daily dose and total dose, and patients could be treated with either supervoltage or orthovoltage. In the CRC trials, most of the treatments were given in lo-24 fractions in 15-29 days, and many of the treatments were given two or three times a week with high fraction sizes.
July 1991, Volume 21, Number 2
Despite the diverse recommendations for radiation dose, 33% of the patients fell outside the recommended ranges and 10% had a higher dose than prescribed (3). The doses were prescribed in rets using the NSD concept and were assumed to be equivalent. Unfortunately, for this approach, the NSD formula does not give a correct estimate of late complications-this has been demonstrated repeatedly ( 1, 2, 11, 15, 16). Comment. The authors do not report whether or not these approximately 300 inevaluable patients are included in their present analysis. Indeed, the validity of the entire trial would be in question if the standards of Simon and Wittes of excluding trials from publication if greater than 15% inevaluability had been used by the editors (22). DISCUSSION The basic premise of any randomized trial is that with randomization, bias can be eliminated (4,5,2 1). The various mechanisms used in each study to assure blinding and the elimination of bias are essential for the reliability of the study. A basic assumption in performing and analyzing a randomized trial is that the findings based on the sample of population tested can be generalized to that population as a whole. If there is bias in the selection of the sample populations, that is, an imbalance in one of the arms of the trial, then the assumptions based on the trials are not valid for the entire sample population, and are applicable only to a similar sample or group of patients, if at all. The reason for this is that unless randomization is properly done, there is no assurance that the totality of uncontrollable sources of variability and noncomparability will have a symmetric distribution among the treatment groups. Thus, the trial results have a very strong possibility of being incorrect (2 1). Another essential in conducting a randomized clinical trial is that the treatments be standardized. “If the therapies are not standardized, then conclusions apply if at all only to a mixture of patients receiving the same types of local therapy only as those studied” (2 1). There are, in addition to these basic premises, guidelines in the literature for reporting clinical trials, which neither of these trials fulfills, and which are essential for the reader to know but are not included here because of a lack of space (22). The authors of the two articles updating these two trials have noted increased mortality due to adjuvant irradiation based on “randomized” studies. These studies are unacceptable in that they have not satisfied the basic premises of randomized trials of avoidance of bias and standardization of treatment. Because of that failure, the trials are of questionable validity for any aspect measured. The bias in the Manchester Trial is demonstrated by the fact that there was no significant difference in cardiovascular mortality between those patients with left- or right-sided tumors, that is, there was no dose-response relationship. This observation contradicts the hypothesis that irradiation caused the difference between the radiotherapy and control-allocated patients. Since there was
Trials and tribulations 0 S. Table I. Postoperative radiotherapy after radical mastectomy in patients with oositive axillarv 1vmDh nodes Patients with tumors inner quadrants Number of patients Institute Gustave Roussy Surgery Surgery + RT Radiumhemmett Surgery Surgery + RT Norwegian Radium Hospital (T, tumors) Surgery Surgery + RT Adapted
from: Tubiana,
in
Survival at 10 years %
36 35
39 ,2
35 45
60 72
34 38
42 58
p < 0.05
M. IZIal. (6).
no dose-response relationship, it would appear more likely that the difference was caused by other factors, for example, the biased treatment allocation. In the CRC Trial, note that the increased mortality caused by other cancers was not the result of tumors close to the irradiated area, but by an increased number of cancers at distant sites, for example, colon and ovarian cancer. If irradiation were the cause of the increase of second cancers, one would expect a dose relationship, that is, an increase in sites close to the irradiated area, for example, breast and/or lung cancer. This inconsistency may be caused by incorrect diagnoses of metastases due to breast cancer as a second primary. This circumstance places additional doubt on the validity of the study. We have noted in our comment section the unorthodox fractions and field arrangements used in both trials cited, and have pointed out the evidence of serious damage associated with such approaches. The best clinical illustration of this phenomenon is found in a series of patients treated in Denmark, by Overgaard et al., twice a week using the NSD formula to determine the dose. Skin atrophy, fibrosis of the tissues of the shoulder, and limitation of motion were found to be much more severe in patients treated with a 2- versus 5fraction schedule ( 15). Another illustration is the Oslo trial using 6oCo, in which 50 Gy were given in 4 weeks with fractions of 2.5 Gy. producing significant cardiac damage ( 11). This is, incidentally, the only trial using megavoltage irradiation which demonstrated cardiac damage caused by irradiation. However, the daily fraction sizes were large and most likely produced the damage reported. Others have also demonstrated the lack of validity of using the NSD to compare fractionation schemes and doses included in radiation protocols and the problems resulting from such use (1, 2, 11, 15, 16). It is FZOW well known from numerous clinical reports and Thames’ survey of experiments in animal tumor systems that fraction sizes above 2 Gy are conducive to severe
H. LEVITT AND
G.
H. FLETCHER
525
sequelae (23). Currently, one should never use fractions sizes in excess of 2 Gy. Because of the reported morbidity and mortality related to adjuvant breast irradiation, there is much debate as to whether radiation should be used at all or whether it is worthwhile to irradiate the internal mammary chain nodes. Three clinical randomized trials from Stockholm (20) Oslo (1 1), and Institut Gustave Roussy (24) in Paris have shown improved survival rates by irradiating the chain in the patients having histologically positive axillary nodes and when the tumor is located in the inner quadrants (See Table 1). Because the involvement of the internal mammary chain nodes is almost always limited to the first three interspaces, the treatment fields need not be extended to the botton of the xyphoid, this diminishing the volume of heart muscle irradiated (See Figs. 1, 2). Electron beam should also be used, which will practically eliminate any significant dose to the heart muscle. There is a prevailing concept nowadays that preventing recurrences in the locoregional area is unimportant. However, if one does not eradicate disease in the localregional area, the disease will unquestionably progress. In clinical trials from Stockholm, Oslo, and Denmark (16) the incidence of locoregional failures correlates with distant metastases and disease-free survival rates. Note that adjuvant chemotherapy alone will not prevent local recurrence in patients with four or more positive nodes, and the consequences of these recurrences are severe.
Fig. 1. From: Fletcher, G.H.; Montague, E.D. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int. J. Radiat. Oncol. Biol. Phys. 4:481; 1978.
526
1. J. Radiation Oncology 0 Biology 0 Physics
Fig. 2. From: Fletcher, G.H.; Montague, E.D. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int. J. Radiat. Oncol. Biol. Phys. 48:481; 1978.
Something if the data
is to be learned are controversial.
from One
these must
past trials, be careful
even not to
amount of radiation to the heart muscle. To avoid this, the use of electron beam irradiation alone or combined with photons is necessary. The treatment of the chest wall is also best done with electron beams, as compared to tangential portals, providing a minimum of radiation to the lung and the cardiac muscle (See Fig. 3). Modern irradiation should not be dismissed, if indicated, because of questionable potential complications from antiquated and harmful techniques, no more than one should condemn surgical procedures because they were associated with complications in the days prior to modern anesthesia, blood transfusions, and antibiotics. Furthermore, oncologists must be aware of the basic essentials of the randomized clinical trial and must eval-
give any significant
July 1991, Volume 21, Number 2
Fig. 3. A 60-year-old woman with a T4 (skin fixation) upper outer quadrant breast cancer. A radical mastectomy was performed on June 25, 1970; 14 axillary nodes were positive out of 28 recovered. Postoperative irradiation to the chest wall (5,000 cGy with 7 MeV electron beam). internal mammary chain (5,000 cGy with 15 MeV electron beam), and supraclavicular area (5.000 cGy with 11 MeV electron beam) was completed in September 1970. The patient has remained disease-free until March 1990. From: Tapley, N duV.; Spanos, W.J.: Fletcher, G.H.; Montague, E.D.; Oswald, M.J. Results in patients with breast cancer treated by radical mastectomy and postoperative irradiation with no adjuvant chemotherapy. Cancer 49: 13 16- I3 19; 1982.
uate such studies critically. Our colleagues, our patients, and the general public must be informed when studies are faulty and lead to erroneous conclusions. No less important is informing them of the necessity of providing quality irradiation, the benefits derived there from, and the hazards of inappropriate techniques and fractionation schemes. lfthis is not done, the beneficial major advances made in the treatment of breast cancer using modern techniques of radiotherapy will most certainly be unjustly jeopardized.
REFERENCES 1. Baltas, D.; Fehrentz,
D.; Turesson, I. Analysis of late effects data using dose-response models: application to human skin telangiectasia data. Radiother. Oncol. 16:41-53; 1989. 2. Bentzen, S. M.; Overgaard, M.; Thames, H. D. Fractionation sensitivity of a functional endpoint: impaired shoulder movement after post-mastectomy radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 17:531-537; 1989.
3. Brinkley, D.; Haybittle, J. L.; Houghton, J. The cancer research campaign (King’s/Cambridge) trial for early breast cancer: an analysis of the radiotherapy data. Br. J. Radiat. 57:309-316; 1984. 4. Chalmers, T. C. The control of bias in clinical trials. In: Shapiro, ed. Issues and approaches. NY: Marcel Dekker; 1983:115-127.
Trials and tribulations 0 S. H. LEVITTAND G. H. 5. Chalmers, T. C.; Celano, P.; Sacks, H. S.; Smith H. Bias in treatment assignment in controlled clinical trials. N. Engl. J. Med. 309(22):1358-1361; 1983. 6. Colditz, G. A.; Willett, W. C.; Stampfer, M. J.; Rosner, B.: Speizer, F. E.; Hennekens. C. H. Menopause and the risk of coronary heart disease in women. N. Engl. J. Med. 3 16: 1106-l 1IO; 1987. 7. Cuzick, J.; Stewart, H.; Peto, R.: Baum, M.; Fisher. B.; Host. H.: Lythgoe, J. P.; Ribeiro, G.; Scheurlen, H.; Wallgren, A. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat. Rep. 7 I ( 1):I 529: 1987. 8. Cuzick, J.; Stewart, H.; Peto, R.; Fisher, B.; Kaae, S.; Johansen, H.: Lythgoe. J. P.; Prescott. R. J. Overview of randomized trials comparing radical mastectomy with radiotherapy against simple mastectomy with radiotherapy in breast cancer. Cancer Treat. Rep. 7 I( 1):7- 14; 1987. 9. Gordon. T.; Kannel, W. B.: Hjortland, M. C.: McNamara. P. M. Menopause and coronary heart disease. Ann. Intern. Med. 89(20):157-161; 1978. IO. Haybittle, J. L.; Brinkley, D.: Houghton, J.; A’Hern. R. P.: Baum, M. Postoperative radiotherapy and late mortality: evidence from the cancer research campaign trial for earl! breast cancer. Br. Med. J. 298:1611-1614: 1989. I I. Host. H.: Brennhovd, I. 0.: Loeb. M. Postoperative radiotherapy in breast cancer-long-term results from the Oslo study. Int. J. Radiat. Oncol. Biol. Phys. 12:727-732; 1986. 12. Jones, J. M.; Ribeiro, G. G. Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin. Radio]. 40:204-208: 1989. 13. Levitt, S. H. Is there a role for post-operative adjuvant radiation in breast cancer? Beautiful hypothesis versus ugly facts: 1987 Gilbert H. Fletcher lecture. Int. J. Radiat. Oncol. Biol. Phys. 14:787-796; 1988. 14. Levitt, S. H. Mortality patterns of breast cancer patients. Clin. Radiol. 41:145: 1990. 15. Overgaard. M.: Bentzen, S. M.: Christensen, J. J.: Madsen, E. H. The value of the NSD formula in equation of acute and late radiation complications in normal tissue following
16.
17. 18. 19.
20.
21.
22. 23.
24.
FLETCHER
527
2 and 5 fractions per week in breast cancer patients treated with postmastectomy irradiation. Radiother. Oncol. 9: I 12; 1987. Overgaard, M.; Christensen, J. J.; Johansen, H.; Nybo-Rasmussen. N.: Brincker, H.: van der Koou, P.; Frederiksen. P. L.; Laursen, F.; Panduro, J.; Sorensen, N. E.; Gadebera, C. C.: Hjelm-Hansen, M.; Overgaard, J.; West Andersen, K.; Zedeler, K. Postmastectomy irradiation in high-risk breast cancer patients. Acta Oncol. 27(6a):707-7 14; 1988. Paterson, R. Breast cancer: a report of two clinical trials. J. Royal College Surgeons Edinburgh 7(4):243-254: 1962. Paterson. R.; Russell, M. H. Clinical trials in malignant disease. J. Faculty Radio]. 10(4): 175- 180; 1959. Rosenberg, L.; Hennekens, C. H.; Rosner, B.: Belanger, C.; Rothman, K. J.; Speizer, F. E. Early menopause and the risk of myocardial infarction. Am. J. Obstet. Gynecol. 139: 47: 1981. Rutqvist, L. E.; Cedemark, B.: Glas, U.: Johansson. H.; Rotstein, S.; Skoog, L.; Some]], A.: Theve. T.: Askergren, J.: Friberg, S.; Bergstrom, J.; Blomstedt, B.: Raf, L.; Silfversward, C.: Einhorn, J. Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials. lnt. J. Radiat. Oncol. Biol. Phys. 16:629-639: 1989. Simon, R. Heterogeneity and standardization in clinical trials. In: Controversies in cancer-design of trials and treatment. Proceedings from EORTC Symposium, April. 1978. New York: Masson: 1979:37-49. Simon, R.: Wittes, R. E. Methodologic guidelines for reports of clinical trials. Cancer Treat. Rep. 69(l): 1-3; 1985. Thames. H. D.; Withers, H. R.; Peters, L. J.; Fletcher, G. H. Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships. lnt. J. Radiat. Oncol. Biol. Phys. 8:2 19-226; 1982. Tubiana, M.; Arriagada, R.; Sarrazin, D. Human cancer natural history, radiation induced immunodepression and post-operative radiation therapy. lnt. J. Radiat. Oncol. Biol. Phys. 12:477-485: 1986.
20. pp.
523-527
0360-3016/91 53.Otl + .XJ Copyright 0 199 Pergamon Press plc
I
l Editorial
TRIALS AND TRIBULATIONS: DO CLINICAL TRIALS PROVE THAT IRRADIATION INCREASES CARDIAC AND SECONDARY CANCER MORTALITY IN THE BREAST CANCER PATIENT? SEYMOUR
H.
LEVITT,
M.D.’
AND GILBERT
H.
FLETCHER,
M.D.2
‘Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Hospital, Box 436, Minneapolis, MN 55455; and ‘Division of Radiotherapy, M.D. Anderson Hospital, 15 15 Holcombe Blvd., Houston, TX 77030
INTRODUCTION
predictive of all approaches to adjuvant irradiation of breast cancer or is caused by the radiation techniques used and/or possibly biased selection of patients. With these factors in mind, analysis of the recent update of the two trials included in the latest meta-analysis will help us to evaluate the applicability and validity of their findings to present-day statistical and radiotherapeutic techniques.
In this issue, the reader will find a number of articles which demonstrate the beneficial effect of radiation in the treatment of breast cancer. This benefit is reported for practically all stages of the disease. However, recent reports of the harmful and lethal effect of radiation in the treatment of breast cancer contradict the beneficial reports and confuse the entire gamut on oncologists. Is there in fact a harmful effect of radiation therapy for the breast cancer patient? A 1987 report in the medical literature based on metaanalysis of “randomized” clinical trials of adjuvant irradiation in the treatment of breast cancer claimed an increased mortality for patients treated with radiation (7, 8). This increased mortality was noted only after a period of 10 to 15 years. More recent reports of two of the individual trials included in the meta-analysis which contributed the majority of patients to the meta-analysis have also noted an increased mortality after 10 years ( 10, 12). All oncologists agree that adjuvant irradiation significantly decreases the incidence of local recurrences; however, because of these reports, many medical oncologists and radiation oncologists have ceased recommending adjuvant radiation therapy post-mastectomy even when indicated. Conceivably, these reports could also negatively affect the role of irradiation in the conservation treatment of breast cancer. There can be no question that irradiation can be carcinogenic and can produce serious acute and chronic damage in normal tissue, possibly leading to death. However, before discarding the use of radiation in the adjuvant treatment of breast cancer, it is important to determine whether the increased mortality noted in these studies is
METHODS
AND
MATERIALS
Manchester trial The first report was a 34-year follow-up of the Manchester Trial (12). In this paper the authors reported a significant increase in cardiovascular mortality after 15 years in patients treated with radiation as compared with those who were not. Statistical analysis. There was published evidence of inappropriate randomization techniques with accompanying patient selection exclusion and bias ( 13). Radiation therapy analysis. The Manchester Trial of postoperative irradiation from 1949 to 1955 involved two trials of different orthovoltage irradiation techniquesthe peripheral and the quadrate. In the quadrate technique, the chest wall and the axilla were irradiated through tangential fields. In the peripheral technique, the supraclavicular area and the internal mammary chain were irradiated. Neither technique adequately covered the appropriate target areas. The dose was 3500 to 4000 roentgen in 3 weeks. Although it is not stated, it is very unlikely that all fields were treated every day so that the fraction size per treatment was high (17, 18). Comment. The authors of the current follow-up of the Manchester trial admit these problems, but assert that
Rutqvist of the Radiumhemmet, Karolinska Hospital for his advice and suggestions. Accepted for publication 9 November 1990.
Reprint requests to: Seymour H. Levitt, M.D., Box 436 UMHC, University of Minnesota Hospital and Clinic, Harvard St. at East River Rd., Minneapolis, MN 55455. Acknowledgment-The authors would like to thank Dr. L. E. 523
524
I. J. Radiation Oncology 0 Biology 0 Physics
“Any inadequacies in the treatment, any bias in the allocation, or any imbalance regarding the giving of ovarian irradiation would be most likely to have an effect during the first few years of follow-up. They would not be expected to have an effect on the prognosis of survivors beyond 15 years. Consequently, it would not seem justified to dismiss the treatment effect seen after 15 years because of possible imperfections in the design of the trial.” We have reviewed the statistical literature and have found no source in that literature to justify their statement that after a set number of years bias would not affect the results (14). Finally, it is known that premenopausal patients who have been castrated have a higher incidence of cardiac complication than non-castrated patients (6, 9, 19). The claim of the report is that patients treated with adjuvant irradiation for breast cancer will have an increased cardiovascular mortality after 15 years. Because of the faulty irradiation technique and doses, and with all the imbalances and bias in patient selection and treatment that exist in this trial, one cannot assume that the findings are valid ( 14). British Cancer Campaign randomized trial The second recent review of another of the trials has also found an increased hazard for the irradiated patients ( IO). This article evaluates the data from the British Cancer Research Campaign Randomized Trial for early breast cancer. The authors report a significant increased incidence of other malignancies and cardiac disease in breast cancer patients treated with postoperative irradiation after simple mastectomy as compared with those who did not receive postoperative irradiation after the mastectomy. The increase in cardiac mortality and other tumors is slight, but significantly increased in patients who had tumors of the left breast and who received orthovoltage radiation treatment. There was no significantly increased risk of mortality found due to either malignancy or cardiac death in patients who received supervoltage irradiation. Statistical analysis. The recent CRC report evaluated 1,376 patients who received irradiation, in comparison with 1,424 who did not. In a previous article the same authors noted that of the 1,376 patients allocated to deep X ray therapy, 273 were non-evaluable (an approximately 20% inevaluability rate). Of the 1,103 who were evaluable, 36 patients did not receive irradiation in spite of being allocated to the deep X ray therapy group and 48 patients were not irradiated in all areas (3). Radiation therapy technique analysis. A review of the CRC radiation therapy techniques reveals a great variation in the recommended and received radiation doses for both the orthovoltage and supervoltage treated patients. The recommended treatments were varied with regard to fractionation daily dose and total dose, and patients could be treated with either supervoltage or orthovoltage. In the CRC trials, most of the treatments were given in lo-24 fractions in 15-29 days, and many of the treatments were given two or three times a week with high fraction sizes.
July 1991, Volume 21, Number 2
Despite the diverse recommendations for radiation dose, 33% of the patients fell outside the recommended ranges and 10% had a higher dose than prescribed (3). The doses were prescribed in rets using the NSD concept and were assumed to be equivalent. Unfortunately, for this approach, the NSD formula does not give a correct estimate of late complications-this has been demonstrated repeatedly ( 1, 2, 11, 15, 16). Comment. The authors do not report whether or not these approximately 300 inevaluable patients are included in their present analysis. Indeed, the validity of the entire trial would be in question if the standards of Simon and Wittes of excluding trials from publication if greater than 15% inevaluability had been used by the editors (22). DISCUSSION The basic premise of any randomized trial is that with randomization, bias can be eliminated (4,5,2 1). The various mechanisms used in each study to assure blinding and the elimination of bias are essential for the reliability of the study. A basic assumption in performing and analyzing a randomized trial is that the findings based on the sample of population tested can be generalized to that population as a whole. If there is bias in the selection of the sample populations, that is, an imbalance in one of the arms of the trial, then the assumptions based on the trials are not valid for the entire sample population, and are applicable only to a similar sample or group of patients, if at all. The reason for this is that unless randomization is properly done, there is no assurance that the totality of uncontrollable sources of variability and noncomparability will have a symmetric distribution among the treatment groups. Thus, the trial results have a very strong possibility of being incorrect (2 1). Another essential in conducting a randomized clinical trial is that the treatments be standardized. “If the therapies are not standardized, then conclusions apply if at all only to a mixture of patients receiving the same types of local therapy only as those studied” (2 1). There are, in addition to these basic premises, guidelines in the literature for reporting clinical trials, which neither of these trials fulfills, and which are essential for the reader to know but are not included here because of a lack of space (22). The authors of the two articles updating these two trials have noted increased mortality due to adjuvant irradiation based on “randomized” studies. These studies are unacceptable in that they have not satisfied the basic premises of randomized trials of avoidance of bias and standardization of treatment. Because of that failure, the trials are of questionable validity for any aspect measured. The bias in the Manchester Trial is demonstrated by the fact that there was no significant difference in cardiovascular mortality between those patients with left- or right-sided tumors, that is, there was no dose-response relationship. This observation contradicts the hypothesis that irradiation caused the difference between the radiotherapy and control-allocated patients. Since there was
Trials and tribulations 0 S. Table I. Postoperative radiotherapy after radical mastectomy in patients with oositive axillarv 1vmDh nodes Patients with tumors inner quadrants Number of patients Institute Gustave Roussy Surgery Surgery + RT Radiumhemmett Surgery Surgery + RT Norwegian Radium Hospital (T, tumors) Surgery Surgery + RT Adapted
from: Tubiana,
in
Survival at 10 years %
36 35
39 ,2
35 45
60 72
34 38
42 58
p < 0.05
M. IZIal. (6).
no dose-response relationship, it would appear more likely that the difference was caused by other factors, for example, the biased treatment allocation. In the CRC Trial, note that the increased mortality caused by other cancers was not the result of tumors close to the irradiated area, but by an increased number of cancers at distant sites, for example, colon and ovarian cancer. If irradiation were the cause of the increase of second cancers, one would expect a dose relationship, that is, an increase in sites close to the irradiated area, for example, breast and/or lung cancer. This inconsistency may be caused by incorrect diagnoses of metastases due to breast cancer as a second primary. This circumstance places additional doubt on the validity of the study. We have noted in our comment section the unorthodox fractions and field arrangements used in both trials cited, and have pointed out the evidence of serious damage associated with such approaches. The best clinical illustration of this phenomenon is found in a series of patients treated in Denmark, by Overgaard et al., twice a week using the NSD formula to determine the dose. Skin atrophy, fibrosis of the tissues of the shoulder, and limitation of motion were found to be much more severe in patients treated with a 2- versus 5fraction schedule ( 15). Another illustration is the Oslo trial using 6oCo, in which 50 Gy were given in 4 weeks with fractions of 2.5 Gy. producing significant cardiac damage ( 11). This is, incidentally, the only trial using megavoltage irradiation which demonstrated cardiac damage caused by irradiation. However, the daily fraction sizes were large and most likely produced the damage reported. Others have also demonstrated the lack of validity of using the NSD to compare fractionation schemes and doses included in radiation protocols and the problems resulting from such use (1, 2, 11, 15, 16). It is FZOW well known from numerous clinical reports and Thames’ survey of experiments in animal tumor systems that fraction sizes above 2 Gy are conducive to severe
H. LEVITT AND
G.
H. FLETCHER
525
sequelae (23). Currently, one should never use fractions sizes in excess of 2 Gy. Because of the reported morbidity and mortality related to adjuvant breast irradiation, there is much debate as to whether radiation should be used at all or whether it is worthwhile to irradiate the internal mammary chain nodes. Three clinical randomized trials from Stockholm (20) Oslo (1 1), and Institut Gustave Roussy (24) in Paris have shown improved survival rates by irradiating the chain in the patients having histologically positive axillary nodes and when the tumor is located in the inner quadrants (See Table 1). Because the involvement of the internal mammary chain nodes is almost always limited to the first three interspaces, the treatment fields need not be extended to the botton of the xyphoid, this diminishing the volume of heart muscle irradiated (See Figs. 1, 2). Electron beam should also be used, which will practically eliminate any significant dose to the heart muscle. There is a prevailing concept nowadays that preventing recurrences in the locoregional area is unimportant. However, if one does not eradicate disease in the localregional area, the disease will unquestionably progress. In clinical trials from Stockholm, Oslo, and Denmark (16) the incidence of locoregional failures correlates with distant metastases and disease-free survival rates. Note that adjuvant chemotherapy alone will not prevent local recurrence in patients with four or more positive nodes, and the consequences of these recurrences are severe.
Fig. 1. From: Fletcher, G.H.; Montague, E.D. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int. J. Radiat. Oncol. Biol. Phys. 4:481; 1978.
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Fig. 2. From: Fletcher, G.H.; Montague, E.D. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int. J. Radiat. Oncol. Biol. Phys. 48:481; 1978.
Something if the data
is to be learned are controversial.
from One
these must
past trials, be careful
even not to
amount of radiation to the heart muscle. To avoid this, the use of electron beam irradiation alone or combined with photons is necessary. The treatment of the chest wall is also best done with electron beams, as compared to tangential portals, providing a minimum of radiation to the lung and the cardiac muscle (See Fig. 3). Modern irradiation should not be dismissed, if indicated, because of questionable potential complications from antiquated and harmful techniques, no more than one should condemn surgical procedures because they were associated with complications in the days prior to modern anesthesia, blood transfusions, and antibiotics. Furthermore, oncologists must be aware of the basic essentials of the randomized clinical trial and must eval-
give any significant
July 1991, Volume 21, Number 2
Fig. 3. A 60-year-old woman with a T4 (skin fixation) upper outer quadrant breast cancer. A radical mastectomy was performed on June 25, 1970; 14 axillary nodes were positive out of 28 recovered. Postoperative irradiation to the chest wall (5,000 cGy with 7 MeV electron beam). internal mammary chain (5,000 cGy with 15 MeV electron beam), and supraclavicular area (5.000 cGy with 11 MeV electron beam) was completed in September 1970. The patient has remained disease-free until March 1990. From: Tapley, N duV.; Spanos, W.J.: Fletcher, G.H.; Montague, E.D.; Oswald, M.J. Results in patients with breast cancer treated by radical mastectomy and postoperative irradiation with no adjuvant chemotherapy. Cancer 49: 13 16- I3 19; 1982.
uate such studies critically. Our colleagues, our patients, and the general public must be informed when studies are faulty and lead to erroneous conclusions. No less important is informing them of the necessity of providing quality irradiation, the benefits derived there from, and the hazards of inappropriate techniques and fractionation schemes. lfthis is not done, the beneficial major advances made in the treatment of breast cancer using modern techniques of radiotherapy will most certainly be unjustly jeopardized.
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