hr.
_I. Radiation
Oncology
Bid.
Phys..
1976, Vol.
1, pp. 769279.
Pcrgamon
Press.
Printed
in the U.S.A.
REFLECTIONS ON BREAST CANCER? GILBERT
H.
FLETCHER,
M.D.4
Department of Radiotherapy, The University of Texas System Cancer Center, hf. D. Anderson Hospital and Tumor Institute at Houston, Houston, TX 77030, U.S.A. Breast~isavery~~ediseaaerurdlOyePrwvvivalrstesPreessentiPlfor~ evahmtfon of any method of treamt. Treatme!nt of the supradavkular and internal ~mammaryychafnnodes,eftherbysnrgkafdiaeectionorirrsdktim,haddftfontotheradfcal mrrstectoray,cenonlycprethose~whoheve~~norbothaftheseprepsbut IneWtBs.Thereaore,ufs~tbattbcreisno wbodonotlmveoa!ultd&Btant evidence of improved overall mrvfval rates by treatment of the perfpheral lymphatks sfnce onlyamaUsubeetdtbepatkntpopmWoncanbemefitframthe--t. Close to MO55lomqfoaal control of d&ease is secured by combining 45fML!50@0 rad (1000 rad per week) to the chest wall and peripheral lymphatfcs wftb radical m&e&my or simple IMStWtoElIy. Spamlathfutsbeenmadethatfrradia~fsdbeaweofadecrease &UtheT lymphocgte&Thaepre~o~on1oyeuwrviorrl~~,to~this~. Whetbuekche ~py~be~~tobecarptiveurdifso,inwhptpemntpge ofthepatfmts,remafnstobedeWmfned by1Oyearsuwivalrates.
Breast cancer, Irrad&&n, Immanoeuppression, Cbemotberapy.
INTRODUCTION A curative attack against breast cancer started with the radical mastectomy some 80 years ago. As of today, there is no convincing evidence that this radical procedure yields higher survival rates than any one of the more conservative procedures. This is perhaps the most outstanding example of how elusive the management of breast cancer remains. In around 1950, epidemiologistsmade an impressive argument that no evidence existed that any treatment actually cured patients with breast cancer. All treatments to that time had been essentially locoregional, although ovarian ablation, either by oophorectomy or by irradiation, had been used either electively or to manage disseminated disease. However, elective castration had not been undertaken systematically. The inability to improve survival rates is ascribed to the fact that the fate of patients with occult distant metastases is not influenced by any form of locoregional treatment. Presently, there is great enthusiasm for
elective chemotherapy or immunotherapy after the initial mastectomy, leading breast oncologists to overlook the benefits of locoregional therapy. In addition, in evahmting elective chemotherapy, there is a trend to abandon the M-year follow-up in favor of short periods of observation, some series utilizing less than l-year median follow-up. It is timely, therefore, to review the present status of the art with various treatment modalities-surgery, irradiation, chemotherapy and immunotherapy.
tThis investigation was supported in part by Public Health Service Research Grants CA06294
and CA05654 from the National Cancer Institute. $Professor and Head.
NATURAL HISTORY OF BREAST CANCER The evaluation of the management of breast cancer is made elusive by the natural history of the disease. This is the only malignant disease in which there are well-documented data on long survivals in untreated patients (Fig. 1). Any physician who has had many year’s association with a large oncology practice has seen patients with tumor replacing the whole breast, the disease unquestiona-
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1976. Vol. 1, Number 7 and Number 8
survival rates in patients with breast cancer are meaningless because a significant percentage of the patients are alive with disease and an additional significant percentage will experience clinical activation of disease between 5 and 10 years after the initial treatment. After 10 years, disease will develop only in 5% of the patients.
Duration, in Years. of Life from Onset of Symptoms
Fig.
1. Survival of untreated breast cancer. (Curves: Bloom et al.;f Greenwood;‘9 Nathanson and Welchn) Courtesy of British Medical Journal.
bly having been present for 15-20 years. Often these patients will have neither palpable axillary nor supraclavicular nodes nor evidence of distant metastases. Breast cancer is also the only malignant disease where a local recurrence (skin nodules on the chest wall) may appear 20 or more years after the initial surgical excision. In the squamous cell carcinomas, at least 95% of locoregional recurrences are clinically manifest by 2 years, whereas in breast cancer after radical mastectomy, only 75% of locoregional failures have appeared by 3 years.“*‘2 From the standpoint of cure, j-year
Locoregional failures Patients who are at a high risk of locoregional failures have been well defined by several studies. Positive axillary nodes and the location of the tumor in the breast correlate with infestation of the supraclavicular and internal mammary chain nodes.zo3s Advanced disease in the breast and/or heavy infestation of the axilla are associated with a high incidence of chest wall recurrences after radical mastectomy (Table 1).20V33 The infestation of the lymphatics of the dermis is so diffuse that it cannot be resected even with wide excision of the breast requiring skin grafting. Distant metastases The size of the primary tumor in the breast and the grave signs of Haagensen” can be correlated to some degree with survival rates, although there is no universal agreement in all the series reported. The survival rates in all
Table 1. Patients exposed to a high risk of locoregional failure in breast cancer Supraclavicular
Axilla positive in surgical specimen 20-26% (Paterson and Russell,M Robbins et ak3’)
Parastemal
Axilla positive in surgical specimen 9% W/264) central or inner quadrant (Urba#
Chest wall
Radical mastectomy only Extensive axillary involvement only 45% (Sprattt)-” 35-40% (Haagensen#’ Locally advanced breast lesion 33% (Spmtt)” 47% (Haagensen and Stout)”
tNumber
of nodes involved not specified. Sin 17 Stage A and 33 Stage B with 8 or more positive axillary nodes. From: Fletcher,16 courtesy of Masson & Cie, Paris.
Reflections on breast cancer 0 G. H. FLETCHER
series correlate closely with the percentage of patients with positive axillary nodes. The prognosis also is related to the percentage of nodes involved. One must keep in mind that finding disease in the axilla depends on the intensity and meticulousness of the search for it. For instance, with the clearing technique used at Columbia-Presbyterian Center more patients with positive axillary nodes and a higher percentage of nodes involved will be found than with an ordinary study of the axillary contents. EVALUATION OF TEE EFFECTIVENESS OF IRRADIATION WITH MASTECTOMY For approximately 50 years, irradiation has been used in combination with radical mastectomy. Techniques have varied considerably both in the anatomical areas covered and in
the doses given. It was not until around 1950 that the internal mammary nodes specifically were identified in the tissues to be irradiated after radical mastectomy. Both improved and nonimproved survival rates have been reported in innumerable articles on the results of postoperative irradiation. Perhaps the most publicized data comes from the Manchester randomized trial which showed that survival rates were not improved despite some diminution in locoregional failures.W There are a few series in which postoperative irradiation has increased survival rates in a subset of patients.‘.” Elective irradiation of the supraclavicdar area and of the internal mammary chain secures almost 100% freedom from disease in these areas (Table 2). In a randomized trial of preoperative irradiation versus primary
Table 2. Results of combined surgery and irradiation in patients exposed to a high risk of locoregional recurrences Site of recurrence
Supraclavicular
Parastemal
Extent of disease and method of treatment Axilla positive in the surgical specimen Radical mastectomy and postop. irrad. Recurrence rate to the peripheral lymphatics 1.5% 4500-5000 rad/5 weeks (Fletchert)” Axilla positive in the surgical specimen and central tumor or in the inner quadrant Recurrence Radical mastectomy and postop. in-ad. rate to the peripheral lymphatics 0% 4SOO-SOOOrad/5weeks (MDAHjM. D. Anderson Hospital (O/204)
> 20% Positive axillary nodes and/or grave signs Recurrence Radical mastectomy plus 5OOOrad/5weeks rate to the peripheral lymphatics and Chest wall
771
chest wall (MDAH)-M. D. Anderson Hospital 10% Locally advanced and/or extensive axillary involvements+ Simple mastectomy plus SOOOrad/Sweeks Recurrence to peripheral lymphatics and chest 3.5%0 wall (MDAHj-M. D. Anderson Hospital
tFletcher, G. H.15 SThe lesions were technically suitable for radical mastectomy. At least one of the following clinical features were present: Primary: >5 cm-less than 0.5 breast Edema or peau d’orunge or wheals CO.5 breast Central satellite nodules Erythema CO..5 breast Axillary nodes: Multiple or chain 23 cm. $In 89 patients, 1 axillary recurrence and 1 parasternal nodule. From: Fletcher,16 courtesy of Masson & Cie, Paris.
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Radiation Oncology 0 Biology 0 Physics
45OOrad (875 rad per week)
to the
axilla cuts in half the incidence of patients with positive axillary nodes and almost by two-thirds the incidence of patients with extranodal disease (Table 3). The effectiveness of irradiation to eradicate subclinical disease in the breast is well established in a study in which one recurrence only appeared in 18 patients who had had a tumorectomy with the margins of surgical resection involved by tumor on microscopic examination.” In the patients who are exposed to a high risk of chest wall recurrence, elective irradiation of the chest wall drastically diminishes the appearance of recurrences (Table 2). Simple mastectomy followed by 5000 rad in 5 weeks produces excellent control on the chest wall in patients with advanced
1976. Vol. 1. Number 7 and Number 8
disease, of the same order as in the series of Haagensen and StouP and Spratt3’ EFFECT OF EXTRNDRD RADICAL MASTECTOMY ON SURVIVAL RATES That patients are cured by the dissection of the internal mammary chain is shown in Table 4.sA)6 From 1953 to 1968 an International group collected 1580 cases of breast cancer randomized into two therapeutic groupsradical mastectomy and extended radical mastectomy.” The results (Table 5) show that there is no dilIerence in the overall survival rates and that only those patients with T1 and T2 lesions located in the inner or medial quadrants and with positive axillary nodes benefit by the extended procedure. This subset being only 13% of the overall group of
Table 3. Eifect of preoperative irradiation on the incidence of metastatic disease in the axillarynodes as shown at the histopathological examinationof the surgicalspecimen Incidence of
Preoperative hadiation primnry surgery
positive axihrynodes No. %
Incidence of extranodal disease No. %
21t 39t
19* (4121) 52.S (40176)
(21/99) (76/l%)
tx’ = 9.266 p c 0.005. S$ = 7.499 p < 0.010. From: de Schryver,’ courtesy of Masson & Cie, Paris.
Table 4. Survival rates by nodal involvement Intemal malmnary cllain only
National Cancer Institute Milan, Italy’ 610 patients 5 years National Institute of Neoplastic Diseases Lima, Peru6 548 patients 5Years Memorial Hospital (NYC)= 315 patients 10 years
Internal mammary chain + axilla
%
No. patients
%
No. patients
78.6
(28)
27.8
(126)
53.3
(15)
29.2
(89)
52.0
(23)
21.0
(75)
Reflectionson breast cancer 0 G. H. FLETCHER
773
Table 5. Five year survival rates by type of operation
All patients 1%366
Patients with T, + T2 lesions of inner and medial quadrants and N + 1963-68
Cw
Halsted Halsted and internal mammary dissection
543t 5061
70 70
52% \_ ,p
- 0.01
71%
tThe incidence of patients with positive axillary nodes (N +) is 58% in the Halsted group and 55% in the Halsted and internal mammary dissection group. In the years 1%7 and 1968 the incidence of patients with positive axillary nodes is 60% in 205 patients in the Hal&d group and 50% in 195 patients in the Halsted and internal mammary dissection group (p = 0.02) and, therefore, these two groups are not comparable. From: Lacour et al.,” courtesy of Cancer. patients, it is expected that the overall survival rates would not be affected. HORMONAL THEEAPY All experienced breast oncologists have seen patients with considerable tumor burden treated with hormonal therapy who are free from disease 10 years or more after the treatment. Presumably these patients are cured. Irradiation of the ovaries with 450rad improved survival rates in a Manchester clinical trial.2g In a recent trial, bilateral adrenalectomy has been carried out in postmenopausal women with 4 or more positive axillary nodes.’ Of 17 patients who were followed from 10 to 69 months, 3 patients have experienced a recurrence. Using historical controls according to the life table plots of probability of recurrence, between 5.2 and 15.07 nonadrenalectomixed patients should have experienced a recurrence,8 a difference significant at the 1% level.’ IMMUNE RESPONSE It is not in the scope of this paper to review the experimental and laboratory data on the immune response. Following irradiation, because of a depression in lymphocyte count, predominantly the 7’ lymphocytes, there has
been speculation that irradiation is deleterious. Before concluding that diminution of the lymphocyte count promotes the growth of cancer in patients with cancer of the breast, one must have evidence that more patients having had inadiation combined with a surgical procedure have recurrent disease at 5 and 10 years than those who had the same surgical procedure alone. There is as yet no single series which shows statistically significant difFerences in survival rates in patients who had surgery alone versus surgery and irradiation. In a recent publieation, using the Mantel-Haenxel statistical technique, it was concluded by combining several randomized trials of surgery alone versus surgery and irradiation, that irradiation increases the overall mortality rates.y Since the publication is quoted widely, the series utilized must be reviewed critically. (1) The Edinburgh and Copenhagen randomized trials which are included, cpmpare radical mastectomy with simple mastectomy plus irradiation (Table 6). An evaluation of postoperative irradiation can be made only if the same surgical procedure has been utilized in both series. Furthermore, the survival rates are identical in the Copenhagen trial and a difference of 76 and 66% in survival rates used for the statistical technique came from a
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1976, Vol. 1, Number 7 and Number 8
Table 6. Comparison of results in patients treated with surgery alone or surgery and irradiation Survival ratest
Frequent y of disease by
5 years+. Survival
rate (o/o) Study Mancheste? “Quadrate” Technique Radical mastectomy with or without postop irrad. “Peripheral” Technique Radical mastectomy with or without postop irrad. Copenhagenz) Extended radical mastectomy versus simple mastectomy and lrracl.
Years Surg. + postop. irrad.
Surg. only
Increased mortality in irradiated groups (%)6
Postop in-ad.
Placebo
5 10
55.0 42.7
56.5 44.0
1.5 1.3
N/A N/A
N/A N/A
5 10
56.5 44.2
61.0 47.5
4.5 3.3
N/A N/A
N/A N/A
5
66.0
67.0
1.0
N/A
N/A
10.0 (3%li)
N/A N/A
N/A N/A
6.0
49.4
50.4
EdinburghV Badical mastectomy versus simple mastectomy and irrad.
5
N.S.A.B.P.’ 1970” Badical mastectomy with postop Grad. or placebo
5
56.0
62.0
tStjemsward, J.w *Fisher, B.‘* QComparing surg. only against surg. +irrad. by the Mantel-HaenzeI procedure gives x2 = 4.22 (p = 0.04). llIn a recent evaluation the j-year survival rate is 72% for simple mastectomy + irradiation and 74% for radical mastectomy alone. Hamilton, et aLP ‘National Surgical Adjuvant Breast Project. preliminary analysis of the Edinburgh trial. This difference has narrowed to 74 and 72% in a recent publication.a (2) If, in the NSABP trial of radical mastectomy alone versus radical mastectomy and irradiation, instead of comparing survival rates at 5 years, one compares failure rates, one sees (Table 6) that 49.4% of patients receiving postoperative irradiation had recurrent disease by 5 years, whereas there is a 50.4% failure receiving the placebo, i.e. an increase of 1% in the placebo-treated group.‘* (3) Concerning the subset of patients with positive azillary nodes, if, instead of comparing mortality rates at 3 years in the patients with positive axillary nodes (Table 7) one compares the frequency of disease by 5 years
one sees that the frequency of disease in the placebo-treated patients is increased in relation to either nodal involvement or menopausal status.‘* Only the Manchester data remain for utilization of the Mantel-Haenzel combination procedure. It becomes apparent that the alleged statistically valid proof of the deleteriousness of postoperative irradiation was created artilkally and that one cannot conclude that postoperative irradiation has promoted the growth of cancer. Table 8 shows IO-year survival rates at the M. D. Anderson Hospital in a group of patients (9% histologically positive axiBary nodes) who were treated with radical mastectomy alone and a group (2% histologically
775
Reflections on breast cancer 0 G. H. FLETCHER
Table7. Comparisonof resultsinpatientstreatedwithsurgery Increasedmortality7
after postop. irrad. in breast caocer patients as compared with operation only in relation to age or menstrual status Mauchesta4 (5 yr) age s45 Age=-65 N.S.A.B.P.5 (3 yr)S Table 13:$ N+ pts Prcmenopausal Postmenopausal
aloneor surgeryandirradiation
Frequeoeyt of disease by 5 yr in N + patients receiving postoperative irradiation compared with operation only postop inad.
+ 14% -2%
+ 16% +346
N.S.A.B.P. Table 6 (5 ycars):$ N+ pts l-3 +Nodes ~4 +Nodesl Table 7 (5 years):$ Nr pts Premenopausal Postmenopausal
Placebo
N/A N/A N/A 62.1% 50.9% 71.6%
67.7% s7.6% 78.1%
43.0% (23’) 50.0%
49.0% (35’) 51.0%
Increased frequency of disease in the lhcebo group N/A 5.6% 6.5% 7.5% 6.0% 1.0%
patients with lymph nodes positive for tumor. tStjemsward.Y *Fisher et al.” 785% in TSPA (S-Thio-Tepa) patients. “Number of patients. BNational Surgical Adjuvant Breast Project. N+:
Table 8. Ten-year survival ratest in two radical mastectomy series at M.D.AndersonHospital(Jan. 1955-D=. 1967)
Radical mastectomy only* Irradiation (peripheral lymphatics and breast) iRadical mastectomy
No. of patients
% of axillary nodes histologically positive
%
246
9
63
419
299
62
tAge adjusted survival rate-Berkson
Gage.’ *These patients had primary lesions located in the outer half of the breast with histologically negative axilla. The 9% who had positive axillary nodes should have had postoperative irradiation, but, for a variety of reasons, did not. M-50% of the patients would have been expected to have positive axillary nodes if preoperative irradiation had not been given?” Modified from: Fletcher, G. H.,” courtesy of Lea & Febiger. positive axillary nodes) who were treated with 4000 rad (1000 rad per week) given preoperatively. In the latter group, 40-M% of the patients would have been expected to have positive axillary nodes if preoperative irradiation had not been given.‘*” The fact that the lo-year survival rates are the same despite a marked difference in the percentages of patients with positive axillary nodes using the same technique of examination of the axillary specimen, indicates that irradiation cured
some patients. If the alleged immunosuppression let microscopic foci of cancer cells grow it is outweighed by the benefits of irradiating the disease locally and in the peripheral lymphatics. STATlSTICS AND REALITY In the NSABP trial of thioTEPA versus placebo, the results are not consistent between Phase I (patients treated from 1958 to l%l) and Phase II (patients treated from 1%1
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Radiation Oncology ??Biology 0 Physics
1976, Vol. 1, Number 7 and Number 8
the protocol staying identical. Quoting from the 1%8 report” on the Phase I clinical trial of thio’TEPA versus placebo: “A plot for premenopausal patients with four or more positive nodes revealed, however, a difference in the TSPA (5Thio-Tepa) and placebo groups which was greatest (approximately 4%) between the eighteenth and thirty-sixth postoperative months. Subsequently, increased numbers of recurrences in the TSPA treated patients gradually lessened the difference so that by 48 months the dissimilarity had diminished to below the level of statistical significance for groups of this size “.
received thioTEPA than in those who had a placebo (Table 9). The 1975 report, analyzing only the Phase I patients, shows favorable results in favor of the thioTEPA patients (Table 9).” A statistically significant difference in results in premenopausal patients with 4 ot more positive nodes has been emphasized and utilized in a publication without any positive statement that the subset results do not affect the overall results in all patients treated (Table lo).” The NSABP clinical trial of thioTEPA
and
1970 (Table 6)t
to 1968).
“Whereas in Phase I at 18 months after operation there was a 38% diflerence in recurrence rate, in Phase II this difference was less impressive, being only 21%“. In the 1970 report on the Phase II NSABP (National Surgical Adjuvant Breast Project) trial,” the failure rates at 5 years are worse (although without statistical signifkance) in the patients with 4 or mote positive nodes who Table 10. Faihue
Table 9. Failure rates at 5 years in all patients with four or more positive nodes Phase II patients (1961-68) 1975 (Table 2)$ Phase I patients (1958-61)
TSPA
85%
(34/40)
Placebo
78%
(25132)
TSPA Placebo
72%
@Opts)0
7%
(90 pts)0
wisher et fd.‘2 *Fisher et ul.” BSample size and percentage from life table calculations for plots of probability of treatment failure. The tables do not have any numerators.
rates and survival rates at 5 and 10 years following radical mastectomy with or without thioTEPA 10yr
5yr thioTEPA %
placebo %
thioTEPA %
placebo %
63.5 (406)
45.8 (397)
45.9 (390)
60.0 68.2t
(23)
45.8 86.1t (37)
(22)
56.5 88.9t (36)
38.74 62.80 74.6
51.7$ 60.66 74.1
57.1$ 36.19 89.1
67.94 32.80 84.3
90 (No.)
All patients Survival rates
(2:) Premenopausal Failure rates Failure rates
+ Nodes 1-3 r4
Postmenopausal Faihtre rates Survival rates Faihrre rates
+ Nodes l-3 l-3 r4
52.4 65.2t
() Number of patients. There are no numerators. The percentages are calculated from life table plots of probability of survival or failure. tp = 0.06 at 5 yr and 0.05 at 10 yr. More effective with primary 53 cm in diameter. Sp = 0.13 at 5 yr and 0.23 at 10 yr. More effective with primary 53 cm in diameter. Op = 0.8 at 5 yr and 0.7 at 10 yr. From: Fisher et al.,” by permission of Surg., Gynecol. & Obstet.
Reflections on breast cancer 0 G. H. FLETCHER
versus placebo is replete with internal biological inconsistencies.‘4 Antitumor agents are known to be more effective when the tumor burden is less. Only 56.5% of the premenopausal placebo patients with l-3 positive nodes experience a failure by 10 years as compared to 88.9% in the patients with 4 or more positive nodes (Table 10). The patients with l-3 positive nodes clearly have a lesser tumor burden and, therefore, thioTEPA should have been effective in that group of patients. Premenopausal women with negative nodes, and therefore, a lesser tumor burden, experienced a 24% failure rate at 10 years. ThioTEPA should also be effective in this group but is not. A trend in effectiveness of thioTEPA in postmenopausal women with l-3 positive nodes is present at 5 years, but this is not sustained at 10 years (Table 10). In the premenopausal women with 4 or more positive nodes and in the postmenopausal women with l-3 positive nodes, if the size of the tumor in the breast is no more than 3 cm in diameter, there is a trend to effectiveness of thioTBPA at 5 years.14 Since the primary tumor has been removed by the radical mastectomy, its size should have no bearing on the effectiveness of thioTEPA which should relate only to the tumor burden existing after the mastectomy when the chemotherapy is initiated. There is a current tendency to report results, not by comparison of percentages obtained by the simple arithmetic of successes
771
or failures
over the sample size but by using sophisticated statistical techniques, with the numerator not given. Statistically significant differences in survival rates obtained by sophisticated statistical techniques may be very impressive. However, with a small sample size if one calculates from the percentages the actual number of patients alive with one method of treatment compared with another, the numbers may be miniscule. This is well illustrated in the NSABP trial, in which 5 of 414 patients who received the drug were statistically cured at 10 years (Table 11). Similarly, the conclusion that bilateral adrenalectomy is effective in postmenopausal patients with 4 or more positive nodes is based on the statistical cure of 2-3 patients.’ DISCUSSION AND SUMMARY (1) Breast cancer is a very elusive disease, one which is biologically fragile and easily influenced, at least for some periods of time, by a variety of agents. Ten years survival rates are essential for final evaluation of any method of treatment. (2) Treatment of the supraclavicular and internal mammary chain nodes, either by surgical dissection or irradiation, in addition to the radical mastectomy, can only cure those patients who have disease in one or both of these areas but who do not have occult distant metastases. Patients who do not have disease in these nodal areas do not require treatment to these areas and those who have occult
Table 11. Numbert of patients cured by the thioTEPA in 414t patients who received the drug At 5 years Premenopausal
2 4 + Nodes
56.5%t of 23 patients survived Only 24.3%t of 23 patients would have survived without thioTEPA Number of patients surviving at 5 yr because of thioTEPA At 10 years Premenopausal 2: 4 + Nodes 34.8%t of 23 patients survived Only 13.5%t of 23 patients would have survived without thioTEPA Number of patients surviving at 10 yr because of thioT’EPA
= 13 = 5 = 8 I 8 = 3 =5
IThere are no numerators in Table 3 of the report. The percentages are calculated from life table plots of probability of survival. From:
Fisher
et al.,” by permission
of Surg. Glynecol.
& Obstet.
778
RadiationOncology??Biology0 Physics
distant metastases will not be cured by the extra treatment. Therefore, it is understandable that there is no evidence of improved overall survival rates by treatment of the peripheral lymphatics since only a small subset of the patient population can benefit from the additional treatment. (3) Close to 100% locoregional control of disease is secured by combining 4500-5000 rad (1000 rad per week) to the chest wall and peripheral lymphatics with radical mastectomy or simple mastectomy. Since the majority of locoregional failures appear earlier than do distant metastases, the longest possible initial period free of disease is of great psychological value to the patients. (4) Speculation has been made that irradia-
1976,Vol. 1, Number7 and Number 8
tion is deleterious because of a decrease in the T lymphocytes. There are no data on lo-year survival rates, to substantiate this speculation. (5) It does not seem warranted to use the fragile information from the thioTEPA trial as evidence that the preliminary results in the recent L-PAM study with an average followup period of 9 months will be maintained.‘” At present, all that can be said about the elective use of L-PAM after radical mastectomy is that it is associated with a delay in the appearance of disease failures. The data from the Instituto Nazionale Tumori in Milan also are very preliminary.’ Whether elective chemotherapy wiIl be shown to be curative and if so, in what percentage of the patients, remains to be determined by IO-year survival rates.
REFFXtF+NCES 1. Berkson, J., Gage, R.P.: Calculation of survival
rates for caucer, Proc. stag M&r., Mayo clinic 2!!: 270-286.1950.
2. Bloom, HJ.E., Richardson, W.W., Harries, E J.: Natural history of untreated breast cancer (1805-1933): Comparison of untreated and treated cases according to histological grade of malignancy. Br. Med. J. 2: 213-221, 1962.
R.O., Vermund, H.: Postoperative irradiation in breast cancer. RadioLogy 93: %5-913.1969. Il. Fisher, B., Ravdin, R.G., Ausman, R.K. et al.: Surgical adjuvant chemotherapy in cancer of the breast; results of a decade of cooperative investigation. Ann. Surg. 168:337-356, 1%8.
12. Fisher, B., Slack, N.H., Cavanaugh, P J. et al.:
Postoperative radiotherapy in the treatment of 3. Bonadonna, G., BNS~UXIO~~I~~. P.. Valagussa, breast cancer: Results of the NSABP clinical P., Verone, U.: Adjuvant study with combinatrial. Ann. Surg. 172: 711-732, 1970. tion chemotherapy in operable breast cancer. 13. Fisher, B., Carbone, P., Economou, S.G. et al.: Proc. Am. Assoc. Cancer Res. 16: 254, May L-Phenylalanine mustard (L-PAM) in the man1975. agement of primary breast cancer: A report of 4. BNCe, J.: The enigma of breast cancer. Cancer early findings. N. Engl. J. Med. 292: 117-122, 24: 1314-1318, 1%9. 1975. 5. Bucalossi, P., Veronesi, U., Ziiog, L., Cantu, 14. Fisher, B., Slack, N., Katrych, D.. Wohnark, C.: Enlarged mastectomy for breast cancerN.: Ten-year follow-up results of patients with review of 1213 cases. Am. J. Roentgen. 111: carcinomas of the breast in a cooperative 115-118, 1971. clinical trial evaluating surgical adjuvant 6. Caceres, E.: An evaluation of extended radical chemotherapy. Surg. Gynec. t Obstet. 140: mastectomy in the treatment of breast cancer. 528-534, 1975. In Breast Cancer, Early and Late, Chicago, 15. Fletcher, G.H.: Textbook of Radiotherapy, 2nd Year Book Medical Publishers, 1970, pp. Edn, Philadelphia, Lea & Febiger, 1973, pp.
125-134. 7. Chu, F.C.H.. Lucas, J.C.. Farrow, J.H.,Nickerson, JJ.: Doses prophylactic radiation therapy
given for cancer of the breast predispose to metastasis? Am. J. Roentgen. 99: !387-!394,1%7. 8. Dao, T.L., Nemoto, T., Chamberlain, A., Bross, I.: Adrenalectomy with radical mastectomy in the treatment of high-risk breast cancer. Cancer 35: 47-2, 1975. Schryver, A.: La radiothbrapie 9. de pr6operatorie dans le cancer du sein: Description d’un protocole d’essai clinique et premiers r&ultats. Bull. du Cancer 62: 1975-182, 1975. 10. Edland. R.W., Maldonado, L.G., Johnson,
457-493. 16. Fletcher, G.H.: Indications for combination of irradiation and surgery. J. Radio/. Electrol. in
press. 17. Gallager, H.S.: Treatment selection in primary breast cancer: Pathologic considerations. Am. J. Roentgen. 126: 135-138, 1976. 18. Ghossein, N., Stacey, P.. Alpert, S., Ager, P., Krishnaswamy, V.: Local control of breast cancer treated either by tumorectomy and radiotherapy or by radiotherapy alone, Radio1 ogy in press. 19. Greenwood, M: Report on the natural duration of cancer, Reports on Public Health and
Reflections on breast camcer 0 G. H. FLETCHER
20.
21.
22.
23.
24.
25.
26. 27.
28.
Medical Subjects, 33, London Ministry of Health, 1926. Haagensen, C.D.: Diseases of the Breast, 2nd Edn, Philadelphia, W. B. Saunders, 1971, pp. 669-733. Haagensen, C.D., Stout, A.P.: Carcinoma of the breast-I Results of Treatment Ann. Surg. 116: 801-815. 1942. Hamilton, T., Langlands, A.O., Prescott, R.J.: The treatment of operable cancer of the breast: a clinical trial in the south-east region of Scotland. Br. J. Surg. 61: 758-761, 1974. Kaae, S., Johansen, H.: Simple mastectomy plus postoperative irradiation by the method of McWhirter for mammary carcinoma. Ann. Surg. 6: 895-899, 1%9. Lacour,J., Bucalossi, P., Caceres, E., Jacobelli, G. et al.: Radical mastectomy versus radical mastectomy plus internal mammary dissection-five year results of an internal 1976. cooperative study. Cancer 37: 26214, Madoc-Jones, H., Nelson, A.J., III, Montague, E.D.: Evaluation of the effectiveness of radiotherapy in the management of early nodal recurrences from adenocarcinoma of the breast. Breast 2: 31-34, 1976. McKinnon, N.E.: Breast cancer. Can. J. Pub. Health 42: 88-94, 1951. Nathanson, LT., Welch, C.E.: Life expectancy and incidence of malignant disease: carcinoma of the breast. Am. J. Cancer 28: 40-53, 1936. Park, W.W., Lees, J.C.: The absolute curability of cancer of the breast. Surg. Gynec. & Obstet. 93: 129-152. 1951.
779
29. Paterson, R., Russell, M.H.: Clinical trials in malignant disease: Part II-Breast cancer: Value of irradiation of the ovaries. J. Fat. Radiol. (Lond.) 10: 130-133, 1959. 30. Paterson, R., Russell, M-H.: Clinical trials in malignant disease. Part III-Breast cancer: Evaluation of postoperative radiotherapy. J. Fat. Radial. (Land). 10: 175-180, 1959. 31. Robbins, G.C., Lucas, J.C., Fracchia, A.A. et al.: An evaluation of postoperative prophylactic radiation therapy in breast cancer. Surg. Gynec. & Obstet. 122: 979-982, 1966. 32. Romsdahl, M.M., Sears, M.E., Eckles, N.: Post treatment evaluation of breast cancer. In Breast Cancer, Early and Late, Chicago, Illinois, Year Book Medical Publishers, 1970, pp. 291-299. 33. Sprat& J.S.: Locally recurrent cancer after Cancer 20: 1051-1053. radical mastectomy. 1%7. 34. Stjemsward, J.: Decreased survival related to irradiation postoperatively in early operable breast cancer. Lancer 2: 1285-1286, 1974. 35. Urban, J.A.: Radical mastectomy in continuity with en bloc resection of internal mammary lymph node chain; new procedure for primary operable cancer of the breast. Cancer 5: 992-1008, 1952. 36. Urban, J.A., Marjani, M.A.: Significance of internal mammary lymph node metastases in breast cancer. Am. J. Roentgen. 111: 130-136, 1971.
_I. Radiation
Oncology
Bid.
Phys..
1976, Vol.
1, pp. 769279.
Pcrgamon
Press.
Printed
in the U.S.A.
REFLECTIONS ON BREAST CANCER? GILBERT
H.
FLETCHER,
M.D.4
Department of Radiotherapy, The University of Texas System Cancer Center, hf. D. Anderson Hospital and Tumor Institute at Houston, Houston, TX 77030, U.S.A. Breast~isavery~~ediseaaerurdlOyePrwvvivalrstesPreessentiPlfor~ evahmtfon of any method of treamt. Treatme!nt of the supradavkular and internal ~mammaryychafnnodes,eftherbysnrgkafdiaeectionorirrsdktim,haddftfontotheradfcal mrrstectoray,cenonlycprethose~whoheve~~norbothaftheseprepsbut IneWtBs.Thereaore,ufs~tbattbcreisno wbodonotlmveoa!ultd&Btant evidence of improved overall mrvfval rates by treatment of the perfpheral lymphatks sfnce onlyamaUsubeetdtbepatkntpopmWoncanbemefitframthe--t. Close to MO55lomqfoaal control of d&ease is secured by combining 45fML!50@0 rad (1000 rad per week) to the chest wall and peripheral lymphatfcs wftb radical m&e&my or simple IMStWtoElIy. Spamlathfutsbeenmadethatfrradia~fsdbeaweofadecrease &UtheT lymphocgte&Thaepre~o~on1oyeuwrviorrl~~,to~this~. Whetbuekche ~py~be~~tobecarptiveurdifso,inwhptpemntpge ofthepatfmts,remafnstobedeWmfned by1Oyearsuwivalrates.
Breast cancer, Irrad&&n, Immanoeuppression, Cbemotberapy.
INTRODUCTION A curative attack against breast cancer started with the radical mastectomy some 80 years ago. As of today, there is no convincing evidence that this radical procedure yields higher survival rates than any one of the more conservative procedures. This is perhaps the most outstanding example of how elusive the management of breast cancer remains. In around 1950, epidemiologistsmade an impressive argument that no evidence existed that any treatment actually cured patients with breast cancer. All treatments to that time had been essentially locoregional, although ovarian ablation, either by oophorectomy or by irradiation, had been used either electively or to manage disseminated disease. However, elective castration had not been undertaken systematically. The inability to improve survival rates is ascribed to the fact that the fate of patients with occult distant metastases is not influenced by any form of locoregional treatment. Presently, there is great enthusiasm for
elective chemotherapy or immunotherapy after the initial mastectomy, leading breast oncologists to overlook the benefits of locoregional therapy. In addition, in evahmting elective chemotherapy, there is a trend to abandon the M-year follow-up in favor of short periods of observation, some series utilizing less than l-year median follow-up. It is timely, therefore, to review the present status of the art with various treatment modalities-surgery, irradiation, chemotherapy and immunotherapy.
tThis investigation was supported in part by Public Health Service Research Grants CA06294
and CA05654 from the National Cancer Institute. $Professor and Head.
NATURAL HISTORY OF BREAST CANCER The evaluation of the management of breast cancer is made elusive by the natural history of the disease. This is the only malignant disease in which there are well-documented data on long survivals in untreated patients (Fig. 1). Any physician who has had many year’s association with a large oncology practice has seen patients with tumor replacing the whole breast, the disease unquestiona-
769
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Radiation Oncology 0 Biology ??Physics
1976. Vol. 1, Number 7 and Number 8
survival rates in patients with breast cancer are meaningless because a significant percentage of the patients are alive with disease and an additional significant percentage will experience clinical activation of disease between 5 and 10 years after the initial treatment. After 10 years, disease will develop only in 5% of the patients.
Duration, in Years. of Life from Onset of Symptoms
Fig.
1. Survival of untreated breast cancer. (Curves: Bloom et al.;f Greenwood;‘9 Nathanson and Welchn) Courtesy of British Medical Journal.
bly having been present for 15-20 years. Often these patients will have neither palpable axillary nor supraclavicular nodes nor evidence of distant metastases. Breast cancer is also the only malignant disease where a local recurrence (skin nodules on the chest wall) may appear 20 or more years after the initial surgical excision. In the squamous cell carcinomas, at least 95% of locoregional recurrences are clinically manifest by 2 years, whereas in breast cancer after radical mastectomy, only 75% of locoregional failures have appeared by 3 years.“*‘2 From the standpoint of cure, j-year
Locoregional failures Patients who are at a high risk of locoregional failures have been well defined by several studies. Positive axillary nodes and the location of the tumor in the breast correlate with infestation of the supraclavicular and internal mammary chain nodes.zo3s Advanced disease in the breast and/or heavy infestation of the axilla are associated with a high incidence of chest wall recurrences after radical mastectomy (Table 1).20V33 The infestation of the lymphatics of the dermis is so diffuse that it cannot be resected even with wide excision of the breast requiring skin grafting. Distant metastases The size of the primary tumor in the breast and the grave signs of Haagensen” can be correlated to some degree with survival rates, although there is no universal agreement in all the series reported. The survival rates in all
Table 1. Patients exposed to a high risk of locoregional failure in breast cancer Supraclavicular
Axilla positive in surgical specimen 20-26% (Paterson and Russell,M Robbins et ak3’)
Parastemal
Axilla positive in surgical specimen 9% W/264) central or inner quadrant (Urba#
Chest wall
Radical mastectomy only Extensive axillary involvement only 45% (Sprattt)-” 35-40% (Haagensen#’ Locally advanced breast lesion 33% (Spmtt)” 47% (Haagensen and Stout)”
tNumber
of nodes involved not specified. Sin 17 Stage A and 33 Stage B with 8 or more positive axillary nodes. From: Fletcher,16 courtesy of Masson & Cie, Paris.
Reflections on breast cancer 0 G. H. FLETCHER
series correlate closely with the percentage of patients with positive axillary nodes. The prognosis also is related to the percentage of nodes involved. One must keep in mind that finding disease in the axilla depends on the intensity and meticulousness of the search for it. For instance, with the clearing technique used at Columbia-Presbyterian Center more patients with positive axillary nodes and a higher percentage of nodes involved will be found than with an ordinary study of the axillary contents. EVALUATION OF TEE EFFECTIVENESS OF IRRADIATION WITH MASTECTOMY For approximately 50 years, irradiation has been used in combination with radical mastectomy. Techniques have varied considerably both in the anatomical areas covered and in
the doses given. It was not until around 1950 that the internal mammary nodes specifically were identified in the tissues to be irradiated after radical mastectomy. Both improved and nonimproved survival rates have been reported in innumerable articles on the results of postoperative irradiation. Perhaps the most publicized data comes from the Manchester randomized trial which showed that survival rates were not improved despite some diminution in locoregional failures.W There are a few series in which postoperative irradiation has increased survival rates in a subset of patients.‘.” Elective irradiation of the supraclavicdar area and of the internal mammary chain secures almost 100% freedom from disease in these areas (Table 2). In a randomized trial of preoperative irradiation versus primary
Table 2. Results of combined surgery and irradiation in patients exposed to a high risk of locoregional recurrences Site of recurrence
Supraclavicular
Parastemal
Extent of disease and method of treatment Axilla positive in the surgical specimen Radical mastectomy and postop. irrad. Recurrence rate to the peripheral lymphatics 1.5% 4500-5000 rad/5 weeks (Fletchert)” Axilla positive in the surgical specimen and central tumor or in the inner quadrant Recurrence Radical mastectomy and postop. in-ad. rate to the peripheral lymphatics 0% 4SOO-SOOOrad/5weeks (MDAHjM. D. Anderson Hospital (O/204)
> 20% Positive axillary nodes and/or grave signs Recurrence Radical mastectomy plus 5OOOrad/5weeks rate to the peripheral lymphatics and Chest wall
771
chest wall (MDAH)-M. D. Anderson Hospital 10% Locally advanced and/or extensive axillary involvements+ Simple mastectomy plus SOOOrad/Sweeks Recurrence to peripheral lymphatics and chest 3.5%0 wall (MDAHj-M. D. Anderson Hospital
tFletcher, G. H.15 SThe lesions were technically suitable for radical mastectomy. At least one of the following clinical features were present: Primary: >5 cm-less than 0.5 breast Edema or peau d’orunge or wheals CO.5 breast Central satellite nodules Erythema CO..5 breast Axillary nodes: Multiple or chain 23 cm. $In 89 patients, 1 axillary recurrence and 1 parasternal nodule. From: Fletcher,16 courtesy of Masson & Cie, Paris.
772
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Radiation Oncology 0 Biology 0 Physics
45OOrad (875 rad per week)
to the
axilla cuts in half the incidence of patients with positive axillary nodes and almost by two-thirds the incidence of patients with extranodal disease (Table 3). The effectiveness of irradiation to eradicate subclinical disease in the breast is well established in a study in which one recurrence only appeared in 18 patients who had had a tumorectomy with the margins of surgical resection involved by tumor on microscopic examination.” In the patients who are exposed to a high risk of chest wall recurrence, elective irradiation of the chest wall drastically diminishes the appearance of recurrences (Table 2). Simple mastectomy followed by 5000 rad in 5 weeks produces excellent control on the chest wall in patients with advanced
1976. Vol. 1. Number 7 and Number 8
disease, of the same order as in the series of Haagensen and StouP and Spratt3’ EFFECT OF EXTRNDRD RADICAL MASTECTOMY ON SURVIVAL RATES That patients are cured by the dissection of the internal mammary chain is shown in Table 4.sA)6 From 1953 to 1968 an International group collected 1580 cases of breast cancer randomized into two therapeutic groupsradical mastectomy and extended radical mastectomy.” The results (Table 5) show that there is no dilIerence in the overall survival rates and that only those patients with T1 and T2 lesions located in the inner or medial quadrants and with positive axillary nodes benefit by the extended procedure. This subset being only 13% of the overall group of
Table 3. Eifect of preoperative irradiation on the incidence of metastatic disease in the axillarynodes as shown at the histopathological examinationof the surgicalspecimen Incidence of
Preoperative hadiation primnry surgery
positive axihrynodes No. %
Incidence of extranodal disease No. %
21t 39t
19* (4121) 52.S (40176)
(21/99) (76/l%)
tx’ = 9.266 p c 0.005. S$ = 7.499 p < 0.010. From: de Schryver,’ courtesy of Masson & Cie, Paris.
Table 4. Survival rates by nodal involvement Intemal malmnary cllain only
National Cancer Institute Milan, Italy’ 610 patients 5 years National Institute of Neoplastic Diseases Lima, Peru6 548 patients 5Years Memorial Hospital (NYC)= 315 patients 10 years
Internal mammary chain + axilla
%
No. patients
%
No. patients
78.6
(28)
27.8
(126)
53.3
(15)
29.2
(89)
52.0
(23)
21.0
(75)
Reflectionson breast cancer 0 G. H. FLETCHER
773
Table 5. Five year survival rates by type of operation
All patients 1%366
Patients with T, + T2 lesions of inner and medial quadrants and N + 1963-68
Cw
Halsted Halsted and internal mammary dissection
543t 5061
70 70
52% \_ ,p
- 0.01
71%
tThe incidence of patients with positive axillary nodes (N +) is 58% in the Halsted group and 55% in the Halsted and internal mammary dissection group. In the years 1%7 and 1968 the incidence of patients with positive axillary nodes is 60% in 205 patients in the Hal&d group and 50% in 195 patients in the Halsted and internal mammary dissection group (p = 0.02) and, therefore, these two groups are not comparable. From: Lacour et al.,” courtesy of Cancer. patients, it is expected that the overall survival rates would not be affected. HORMONAL THEEAPY All experienced breast oncologists have seen patients with considerable tumor burden treated with hormonal therapy who are free from disease 10 years or more after the treatment. Presumably these patients are cured. Irradiation of the ovaries with 450rad improved survival rates in a Manchester clinical trial.2g In a recent trial, bilateral adrenalectomy has been carried out in postmenopausal women with 4 or more positive axillary nodes.’ Of 17 patients who were followed from 10 to 69 months, 3 patients have experienced a recurrence. Using historical controls according to the life table plots of probability of recurrence, between 5.2 and 15.07 nonadrenalectomixed patients should have experienced a recurrence,8 a difference significant at the 1% level.’ IMMUNE RESPONSE It is not in the scope of this paper to review the experimental and laboratory data on the immune response. Following irradiation, because of a depression in lymphocyte count, predominantly the 7’ lymphocytes, there has
been speculation that irradiation is deleterious. Before concluding that diminution of the lymphocyte count promotes the growth of cancer in patients with cancer of the breast, one must have evidence that more patients having had inadiation combined with a surgical procedure have recurrent disease at 5 and 10 years than those who had the same surgical procedure alone. There is as yet no single series which shows statistically significant difFerences in survival rates in patients who had surgery alone versus surgery and irradiation. In a recent publieation, using the Mantel-Haenxel statistical technique, it was concluded by combining several randomized trials of surgery alone versus surgery and irradiation, that irradiation increases the overall mortality rates.y Since the publication is quoted widely, the series utilized must be reviewed critically. (1) The Edinburgh and Copenhagen randomized trials which are included, cpmpare radical mastectomy with simple mastectomy plus irradiation (Table 6). An evaluation of postoperative irradiation can be made only if the same surgical procedure has been utilized in both series. Furthermore, the survival rates are identical in the Copenhagen trial and a difference of 76 and 66% in survival rates used for the statistical technique came from a
774
Radiation Oncology 0 Biology 0 Physics
1976, Vol. 1, Number 7 and Number 8
Table 6. Comparison of results in patients treated with surgery alone or surgery and irradiation Survival ratest
Frequent y of disease by
5 years+. Survival
rate (o/o) Study Mancheste? “Quadrate” Technique Radical mastectomy with or without postop irrad. “Peripheral” Technique Radical mastectomy with or without postop irrad. Copenhagenz) Extended radical mastectomy versus simple mastectomy and lrracl.
Years Surg. + postop. irrad.
Surg. only
Increased mortality in irradiated groups (%)6
Postop in-ad.
Placebo
5 10
55.0 42.7
56.5 44.0
1.5 1.3
N/A N/A
N/A N/A
5 10
56.5 44.2
61.0 47.5
4.5 3.3
N/A N/A
N/A N/A
5
66.0
67.0
1.0
N/A
N/A
10.0 (3%li)
N/A N/A
N/A N/A
6.0
49.4
50.4
EdinburghV Badical mastectomy versus simple mastectomy and irrad.
5
N.S.A.B.P.’ 1970” Badical mastectomy with postop Grad. or placebo
5
56.0
62.0
tStjemsward, J.w *Fisher, B.‘* QComparing surg. only against surg. +irrad. by the Mantel-HaenzeI procedure gives x2 = 4.22 (p = 0.04). llIn a recent evaluation the j-year survival rate is 72% for simple mastectomy + irradiation and 74% for radical mastectomy alone. Hamilton, et aLP ‘National Surgical Adjuvant Breast Project. preliminary analysis of the Edinburgh trial. This difference has narrowed to 74 and 72% in a recent publication.a (2) If, in the NSABP trial of radical mastectomy alone versus radical mastectomy and irradiation, instead of comparing survival rates at 5 years, one compares failure rates, one sees (Table 6) that 49.4% of patients receiving postoperative irradiation had recurrent disease by 5 years, whereas there is a 50.4% failure receiving the placebo, i.e. an increase of 1% in the placebo-treated group.‘* (3) Concerning the subset of patients with positive azillary nodes, if, instead of comparing mortality rates at 3 years in the patients with positive axillary nodes (Table 7) one compares the frequency of disease by 5 years
one sees that the frequency of disease in the placebo-treated patients is increased in relation to either nodal involvement or menopausal status.‘* Only the Manchester data remain for utilization of the Mantel-Haenzel combination procedure. It becomes apparent that the alleged statistically valid proof of the deleteriousness of postoperative irradiation was created artilkally and that one cannot conclude that postoperative irradiation has promoted the growth of cancer. Table 8 shows IO-year survival rates at the M. D. Anderson Hospital in a group of patients (9% histologically positive axiBary nodes) who were treated with radical mastectomy alone and a group (2% histologically
775
Reflections on breast cancer 0 G. H. FLETCHER
Table7. Comparisonof resultsinpatientstreatedwithsurgery Increasedmortality7
after postop. irrad. in breast caocer patients as compared with operation only in relation to age or menstrual status Mauchesta4 (5 yr) age s45 Age=-65 N.S.A.B.P.5 (3 yr)S Table 13:$ N+ pts Prcmenopausal Postmenopausal
aloneor surgeryandirradiation
Frequeoeyt of disease by 5 yr in N + patients receiving postoperative irradiation compared with operation only postop inad.
+ 14% -2%
+ 16% +346
N.S.A.B.P. Table 6 (5 ycars):$ N+ pts l-3 +Nodes ~4 +Nodesl Table 7 (5 years):$ Nr pts Premenopausal Postmenopausal
Placebo
N/A N/A N/A 62.1% 50.9% 71.6%
67.7% s7.6% 78.1%
43.0% (23’) 50.0%
49.0% (35’) 51.0%
Increased frequency of disease in the lhcebo group N/A 5.6% 6.5% 7.5% 6.0% 1.0%
patients with lymph nodes positive for tumor. tStjemsward.Y *Fisher et al.” 785% in TSPA (S-Thio-Tepa) patients. “Number of patients. BNational Surgical Adjuvant Breast Project. N+:
Table 8. Ten-year survival ratest in two radical mastectomy series at M.D.AndersonHospital(Jan. 1955-D=. 1967)
Radical mastectomy only* Irradiation (peripheral lymphatics and breast) iRadical mastectomy
No. of patients
% of axillary nodes histologically positive
%
246
9
63
419
299
62
tAge adjusted survival rate-Berkson
Gage.’ *These patients had primary lesions located in the outer half of the breast with histologically negative axilla. The 9% who had positive axillary nodes should have had postoperative irradiation, but, for a variety of reasons, did not. M-50% of the patients would have been expected to have positive axillary nodes if preoperative irradiation had not been given?” Modified from: Fletcher, G. H.,” courtesy of Lea & Febiger. positive axillary nodes) who were treated with 4000 rad (1000 rad per week) given preoperatively. In the latter group, 40-M% of the patients would have been expected to have positive axillary nodes if preoperative irradiation had not been given.‘*” The fact that the lo-year survival rates are the same despite a marked difference in the percentages of patients with positive axillary nodes using the same technique of examination of the axillary specimen, indicates that irradiation cured
some patients. If the alleged immunosuppression let microscopic foci of cancer cells grow it is outweighed by the benefits of irradiating the disease locally and in the peripheral lymphatics. STATlSTICS AND REALITY In the NSABP trial of thioTEPA versus placebo, the results are not consistent between Phase I (patients treated from 1958 to l%l) and Phase II (patients treated from 1%1
776
Radiation Oncology ??Biology 0 Physics
1976, Vol. 1, Number 7 and Number 8
the protocol staying identical. Quoting from the 1%8 report” on the Phase I clinical trial of thio’TEPA versus placebo: “A plot for premenopausal patients with four or more positive nodes revealed, however, a difference in the TSPA (5Thio-Tepa) and placebo groups which was greatest (approximately 4%) between the eighteenth and thirty-sixth postoperative months. Subsequently, increased numbers of recurrences in the TSPA treated patients gradually lessened the difference so that by 48 months the dissimilarity had diminished to below the level of statistical significance for groups of this size “.
received thioTEPA than in those who had a placebo (Table 9). The 1975 report, analyzing only the Phase I patients, shows favorable results in favor of the thioTEPA patients (Table 9).” A statistically significant difference in results in premenopausal patients with 4 ot more positive nodes has been emphasized and utilized in a publication without any positive statement that the subset results do not affect the overall results in all patients treated (Table lo).” The NSABP clinical trial of thioTEPA
and
1970 (Table 6)t
to 1968).
“Whereas in Phase I at 18 months after operation there was a 38% diflerence in recurrence rate, in Phase II this difference was less impressive, being only 21%“. In the 1970 report on the Phase II NSABP (National Surgical Adjuvant Breast Project) trial,” the failure rates at 5 years are worse (although without statistical signifkance) in the patients with 4 or mote positive nodes who Table 10. Faihue
Table 9. Failure rates at 5 years in all patients with four or more positive nodes Phase II patients (1961-68) 1975 (Table 2)$ Phase I patients (1958-61)
TSPA
85%
(34/40)
Placebo
78%
(25132)
TSPA Placebo
72%
@Opts)0
7%
(90 pts)0
wisher et fd.‘2 *Fisher et ul.” BSample size and percentage from life table calculations for plots of probability of treatment failure. The tables do not have any numerators.
rates and survival rates at 5 and 10 years following radical mastectomy with or without thioTEPA 10yr
5yr thioTEPA %
placebo %
thioTEPA %
placebo %
63.5 (406)
45.8 (397)
45.9 (390)
60.0 68.2t
(23)
45.8 86.1t (37)
(22)
56.5 88.9t (36)
38.74 62.80 74.6
51.7$ 60.66 74.1
57.1$ 36.19 89.1
67.94 32.80 84.3
90 (No.)
All patients Survival rates
(2:) Premenopausal Failure rates Failure rates
+ Nodes 1-3 r4
Postmenopausal Faihtre rates Survival rates Faihrre rates
+ Nodes l-3 l-3 r4
52.4 65.2t
() Number of patients. There are no numerators. The percentages are calculated from life table plots of probability of survival or failure. tp = 0.06 at 5 yr and 0.05 at 10 yr. More effective with primary 53 cm in diameter. Sp = 0.13 at 5 yr and 0.23 at 10 yr. More effective with primary 53 cm in diameter. Op = 0.8 at 5 yr and 0.7 at 10 yr. From: Fisher et al.,” by permission of Surg., Gynecol. & Obstet.
Reflections on breast cancer 0 G. H. FLETCHER
versus placebo is replete with internal biological inconsistencies.‘4 Antitumor agents are known to be more effective when the tumor burden is less. Only 56.5% of the premenopausal placebo patients with l-3 positive nodes experience a failure by 10 years as compared to 88.9% in the patients with 4 or more positive nodes (Table 10). The patients with l-3 positive nodes clearly have a lesser tumor burden and, therefore, thioTEPA should have been effective in that group of patients. Premenopausal women with negative nodes, and therefore, a lesser tumor burden, experienced a 24% failure rate at 10 years. ThioTEPA should also be effective in this group but is not. A trend in effectiveness of thioTEPA in postmenopausal women with l-3 positive nodes is present at 5 years, but this is not sustained at 10 years (Table 10). In the premenopausal women with 4 or more positive nodes and in the postmenopausal women with l-3 positive nodes, if the size of the tumor in the breast is no more than 3 cm in diameter, there is a trend to effectiveness of thioTBPA at 5 years.14 Since the primary tumor has been removed by the radical mastectomy, its size should have no bearing on the effectiveness of thioTEPA which should relate only to the tumor burden existing after the mastectomy when the chemotherapy is initiated. There is a current tendency to report results, not by comparison of percentages obtained by the simple arithmetic of successes
771
or failures
over the sample size but by using sophisticated statistical techniques, with the numerator not given. Statistically significant differences in survival rates obtained by sophisticated statistical techniques may be very impressive. However, with a small sample size if one calculates from the percentages the actual number of patients alive with one method of treatment compared with another, the numbers may be miniscule. This is well illustrated in the NSABP trial, in which 5 of 414 patients who received the drug were statistically cured at 10 years (Table 11). Similarly, the conclusion that bilateral adrenalectomy is effective in postmenopausal patients with 4 or more positive nodes is based on the statistical cure of 2-3 patients.’ DISCUSSION AND SUMMARY (1) Breast cancer is a very elusive disease, one which is biologically fragile and easily influenced, at least for some periods of time, by a variety of agents. Ten years survival rates are essential for final evaluation of any method of treatment. (2) Treatment of the supraclavicular and internal mammary chain nodes, either by surgical dissection or irradiation, in addition to the radical mastectomy, can only cure those patients who have disease in one or both of these areas but who do not have occult distant metastases. Patients who do not have disease in these nodal areas do not require treatment to these areas and those who have occult
Table 11. Numbert of patients cured by the thioTEPA in 414t patients who received the drug At 5 years Premenopausal
2 4 + Nodes
56.5%t of 23 patients survived Only 24.3%t of 23 patients would have survived without thioTEPA Number of patients surviving at 5 yr because of thioTEPA At 10 years Premenopausal 2: 4 + Nodes 34.8%t of 23 patients survived Only 13.5%t of 23 patients would have survived without thioTEPA Number of patients surviving at 10 yr because of thioT’EPA
= 13 = 5 = 8 I 8 = 3 =5
IThere are no numerators in Table 3 of the report. The percentages are calculated from life table plots of probability of survival. From:
Fisher
et al.,” by permission
of Surg. Glynecol.
& Obstet.
778
RadiationOncology??Biology0 Physics
distant metastases will not be cured by the extra treatment. Therefore, it is understandable that there is no evidence of improved overall survival rates by treatment of the peripheral lymphatics since only a small subset of the patient population can benefit from the additional treatment. (3) Close to 100% locoregional control of disease is secured by combining 4500-5000 rad (1000 rad per week) to the chest wall and peripheral lymphatics with radical mastectomy or simple mastectomy. Since the majority of locoregional failures appear earlier than do distant metastases, the longest possible initial period free of disease is of great psychological value to the patients. (4) Speculation has been made that irradia-
1976,Vol. 1, Number7 and Number 8
tion is deleterious because of a decrease in the T lymphocytes. There are no data on lo-year survival rates, to substantiate this speculation. (5) It does not seem warranted to use the fragile information from the thioTEPA trial as evidence that the preliminary results in the recent L-PAM study with an average followup period of 9 months will be maintained.‘” At present, all that can be said about the elective use of L-PAM after radical mastectomy is that it is associated with a delay in the appearance of disease failures. The data from the Instituto Nazionale Tumori in Milan also are very preliminary.’ Whether elective chemotherapy wiIl be shown to be curative and if so, in what percentage of the patients, remains to be determined by IO-year survival rates.
REFFXtF+NCES 1. Berkson, J., Gage, R.P.: Calculation of survival
rates for caucer, Proc. stag M&r., Mayo clinic 2!!: 270-286.1950.
2. Bloom, HJ.E., Richardson, W.W., Harries, E J.: Natural history of untreated breast cancer (1805-1933): Comparison of untreated and treated cases according to histological grade of malignancy. Br. Med. J. 2: 213-221, 1962.
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