BONE METASTASES FROM BREAST CANCER A T T H E T I M E OF RADICAL MASTECTOMY AS

DETECTED BY BONE SCAN Eigli t - Yeay Follow-up

ROBERT €3. SKLAROFF, MD,* AND DAVID M. SKLAKOFF, A I D , F A C R ~

Sixty-four women with Stage I1 breast cancer who had Sr*5 bone scans at the time of radical mastectomy were followed for 8 years i n a prospective study. Those women with positive scans had a slight, but statistically significant, in- creased incidence of metastatic disease, particularly for metastases to bone. However, 40% of those women with positive bone scans and negative roent- genograms survived 8 years without evidence of any metastatic disease. There- fore, it has not been shown a t this time that bone scans should be obtained in order to exclude bone metastasis before regional therapy for breast cancer is instituted. Also, a significant percentage of women with negative bone scans developed both bone and soft tissue metastases. As many as 30% of asymptom- atic women with a history of breast cancer and positive bone scans and negative bone roentgenograms may still harbor disease i n bone after 8 years.

Cancer 38:107-111, 1976.

HE PRIMARY T H E R A P Y OF BREAST CANCER IS T essentially based upon the staging of the disease as either “local” or “systemic.” How- ever, most women with carcinoma presumably limited to the breast region (Stage I or Stage 11) subsequently prove to have had subclinical metastases at the time of diagnosis and treat- ment.

Because breast cancer commonly metas- tasizes to bones,7 and because bone scanning has been used successfully to diagnose meta- static cancer in bones,G bone scanning was proposed as a possible diagnostic procedure lor evaluation and staging of women with breast cancer.

Sixty-four women were examined in this manner 8 years ago.18 This paper will present

Presented at the Fourteenth Annual Conference on Detection and Treatment of Early Breast Cancer, San Juan, Puerto Rlco, March 10-14, 1955.

From the Albert Einstein Medical Center, No1 thern Division, York and Tabor Roads, Philadelphia, Penn- sylvania.

* Resident, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan.

t Chairman, Department of Radiation Therapy, Al- bert Einstein Medical Center, Philadelphia, Penn- sylvania.

Address for reprints: Department of Radiation Ther- apy, Albert Einstein Medical Center, Northern Divi- sion, York and Tabor Roads, Philadelphia, PA 19141.

Received foi publication August 15, 1975.

a follow-up report of this group of patients. An attempt was made to answer the follow- ing questions: 1) How reliable ia the bone scan as an indicator of prognosis? 2) Does a positive bone scan prove bone metastasis? and 3) Is the bone scan indicated in the pretreat- ment work-up of the asymptomatic patient?

METHODS

Sixty-four unselected women with Stage I1 breast cancer were examined by Sr85 bone scans shortly after primary tumor resection and immediately prior to prophylactic radia- tion therapy. These patients were followed for 8 years in a prospective manner.

Scans were made on an 8-in. sodium-iodide crystal scanner 48 hours following the injec- tion of 100 pCi of Srsj nitrate. Appropriate skeletal survey films were obtained. None of the patients had roentgenographic evidence of distant metastases to the bone or to the lung, and all were free from bone pain at the time of evaluation.

T h e charts of these patients were reviewed in May 1974. T h e data were studied for evi- dence ol any metastatic disease and specifically lor bone metastases. Those women who had been re-evaluated in the prior 4 months and were found to be free irom disease were

107

108 CANCER Ju ly 1976 Vol. 38

deemed “nonmetastatic.” Any deviation from a normal report on the initial bone scan of axial skeleton and pelvis was recorded as “positive.”

In every patient except one, a diagnosis of bone metastasis was made when the patient complained ot pain and the roentgenogram was positive. T h e one exception (case #38) will be presented here as a case history.

If bone metastases were not detected prior to death, the patient was said to be free of clinical evidence of metastasis, regardless ol whether bone involvement was lound at i i i i-

topsy.

KESUL?S

Table 1 shows the results of initial bone scan contrasted with the course of the breast cancer. Of the 64 women who were studied, 18 had positive bone scans and 46 had nega- tive bone scans. Of the 18 with positive bone scans, three h a d roentgenograms demonstrat- ing benign disease and 15 had negative roent- genograms. Therefore, 227, 01 the women (15 of 64) had positive bone scans which might have been due to bone metastases of breast cancer.

Of the 15 women with positive scans and negative roentgenograms, nine developed met- astatic disease and six did not. Of the 46 women with negative scans, 24 developed met- astatic disease and 22 did not. I t should be recalled that all of the women with negative bone scans had negative roentgenograms. More than half of both groups of patients developed metastases, as is usually the case.

Table 2 shows the site of metastases for each group of women. Of the 15 women with positive scans and negative roentgenograms, nine developed metastases and eight of these

had clinically evident bone metastases. Of the 46 with negative bone scans, 24 developed metastases and 13 of these had bone metns- tases and 11 developed soft tissue metastases.

When the subgroups in the study are com- pared, one might note an increased incidence of bone as a site of metastasis in those women with initially positive bone scans (887; vs. 547,). However, only eight of the 15 in the group ot women with positive scans and nega- tive roentgenograms developed bone metas- tases (537,), whereas 13 of 46 women with initially negative bone scans (287,) developed bone metastases.

Bone metastases were noted trom 2 to 56 months after the initiation of therapy. Of the 21 women who developed bone metastases (incidence, 337”) 12 women were diagnosed in the first 2 years (incidence, 587,).

T h e women with positive bone scans and positive roentgenograms for benign disease had osteoarthritis, osteoporosis and ostei tis condensans ilei.

In summary, of all the 64 patients, one- halt developed metastatic disease. Those wornen with positive bone scans and negative roentgenograms developed bone metastases more often than the others, but 407, survived 8 years with no evidence ol any metastatic disease. Moreover, a significant percentage (527,) of women with negative bone scans developed metastases either to bone or to soft tissue. Fully 287, of the women with initiallj negative bone scans developed bone metas- tases.

STATISTICAL ANALYSIS

Chi-square calculations were used to illus- trate conclusions drawn from each of the charts. Because the purpose of this study was

TABLE 1. Initial Bone Scan Results and Course of Breast Cancer-Eight-year Followrip of All Patients

Total no. patients No. of patients No. patients with (% patients with

-

Incidence of metastases

Population subgroup in subgroup with metastases no metastases metastases)

Positive bone scan and positive roentgenogram for benign disease 3 0 3 100 ( 3 / 3 )

Positive bone scan and negative roentgenogram 15 9 6 60 (9/15)

Negative bone scan 46 24 22 52 (24/46) TOTAL 64 33 31 52 (33/64)

so. 1 BONE METASTASES FROM BREAST CANCER * Sk la?.otf and S k Zrwofl 1 09 r . I ARI.T: 2. Iiiitial Bone Scan Results and Site of Subseqiient hletnst;ises--Eii.ht-year Fol lo \v i ip of I ’ ; i t i c i i t i

with Rletastases

,. 1 otal 110.

patients i n I’opulatioi~ subgroup subgroup

Positive bone scan and negative roentgenogram 1 5

Negative bone sciiii -16 61 -. 1 O’IAI,

9 1 8 88 (8/9) 5 3 (8;I.i)

2.2 11 1 3 5-1 (13124) 28 ( l h - 1 6 )

3 1 12 2 1 68 ( 2 1 1 3 1 ) 3 1 (21/61)

to contrast those patients having positive bone scans and negative roentgenograms with the others, each set ol results actually had but one degree of lreedom.

Consequently, our null hypotheses were: 1 ) ‘There is no difference in the incidence of Ineti1static breast cancer (to any site) between women with initially positive bone scans and negative roentgenograms antl those with either negative bone scans or positive roentgeno- grams; mt l 2) there is no difference in the in- cidence of metastatic breast cancer specifically to bone between women with initially posi- tive bone scans and negative roentgenograms antl those with either negative bone scans or positive roeii tgenograms.

For the first null hypothesis, chi square = 0.35 (p > 0.10) antl it is accepted. For the second null hypothesis, chi square = 24.3 (p < 0.001) and it is rejected.

Therefore, statistical analysis demonstrated that the slightly increased probability ol met- astatic disease in women who had positive bone scans antl negative roentgenograms was not statistically significant, as expected. How- ever, clearly demonstrated was an increased incidence ol bone as a site of metastasis in this group ol women, when compared with those who had either negative bone scans or positive rocn tgenograms.

CASE REPORT (Ca5e #38)

F.K. was a 28-year-old black woman who was first seen in the Department of Radiation Therapy in December 1965. The pathological diagnosis of the radical mastectomy specimen was “anaplastic duct-cell carcinoma probably arising as lobular carcinoma” with metastasis in two out of 20 axil- lary lymph nodes. At this time, the patient was asymptomatic and there was no evidence of resid- ual, recurrent, or metastatic disease. The bone scan was negative.

In April 1966, 4 month? later, following com-

plaints of pain and tenderness iii her lower back and inguinal region, repeat roentgenograms and bone scans were ordered. The roentgenograms were read as normal, but the bone scans revealed “abnormal isotope accumulation of the 3rd lumhar vertebra ;inti probably the 2nd a s well.” Cobalt therapy relieved her pain and she died ol l i \er metastases in June 1966. Autopsy revealed meta- static carcinoma in bones, lung, liver, lymph nodes, and thyroid gland.

h presumptive diagnosis ol metastatic tlis- ease to the lumbar spine was considered br- cause of the presence of pain, and was con- firmed by a positive bone scan which hat1 beeii negative only 4 months previously. l h i s w i s it Phase I pathological state7 in which “liisto- logically, one sees bone destruction, tumor invasion, and immature new bone. The reac- tive bone consists mainly ol poorly inineral- ized, pale-staining osteoitl, and prolileriiting osteoblasts.” However, the 30-500/:, bone tle- struction necessary for ;t positive rocnrgeno- gram‘ I~iitl not yet occurred.

‘lhis case demonstrated the accuracy of bone scanning used in the differential diag- nosis ol bone pain in patients with a history of carcinoma.’C For the purposes of this study, she was placed in the group of women with iiegati-i~e initial postoperative bone scans who did develop clinically significant bone metas- tases, despite the fact that a positive bone scan antedated the definitive diagnosis (made a t autopsy) arid despite the fact that ;I p s i t iye roentgenogram was never obtained.

Drsc:rrssioN

Preoperative staging procedures (using physical examination and laboratory studies) and postoperative staging procedures (using pathologic analysis) have been utilized lor prognosis a n d lor treatment p1;inning. To date, clinical staging procedures have been unsatisfactory.

110 CANCER J u l y 1976 Vol. 38

Before biopsy of a suspected malignancy and institution of therapy, some physicians order mammograms and thermograms, but such studies are properly used to detect occult disease in both breasts and to follow the con- tralateral breast. The results should not in- fluence the decision to operate.R

Some physicians use skeletal surveys, others, just chest roentgenograms. In 1967, the re- liability of the bone scan in the detection of bone metastasis in spite of negative roentgeno- grams was demonstrated.l7 Now, some physi- cians feel that only bone scans might be neces- sary to screen for metastatic disease. A recent study13 compared the results of Technecium scan with roentgenograms of 200 patients with biopsy-proven cancer in bone. T h e false yields for roentgenograms and scans were 9.1% and 0.47” respectively. This suggests that one might order only a bone scan initially, and evaluate roentgenographically just those area5 which are suspicioiis on scan.

Investigitors have noted hematogenous in- volvement with breast cancer cells in clinically early tumors, but this observation has had an effect not on the treatment of this disease, but on our concept of the malignant process4

The varied behavior of breast cancer has been well documented. Untreated tumors with no progression for as long as 20 years have been reported,2O and metastases have been noted as late as 8.1 years after primary ther- apy .19

Moreover, the natural history of untreated breast cancer shows an 18% 5-year and a 4% 10-year ~u rv iva l .~ Cellular activity has been used to explain such facts; doubling-time calculations have demonstrated that “early” breast cancer measuring 1 cm in diameter might be at least 2 years old, and possibly as much as 17.5 years old.11

The courses of the disease in this series were comparable to those in other series. One- third (21 of 64) developed bone metastases within 8 years of follow-up, all of them with Stage 2 disease. Bone metastases have been noted after 10 years of follow-up in 30% of Stage 2 cases and 9% of Stage 1 cases.

It should also be noted that the survival rate for 8 years recorded in this series is some- what better than that of Zimmerman et al.,21 whose figures have been quoted as being repre- sentative.16 In Stage 2 disease, he reported a 36% 5-year and a 22% 10-year survival. I n this series, 55% of all women (35 of 64) died

within 8 years of primary therapy, yielding A

survival rate of 45y0. I t must be emphasized that in analjsis of

this seiies of patients, “suivi\al late” is lers instructile t1ian the znczdenre of metastatic disease, regardless of the length of the time interval between the diagnosis of the primary and the diagnosis of the metastasis. In this way, we have conducted a “synchronous” study, as described by Collins and Adams,o in which the two groups of patients followed (those with positive and those with negative bone scans) were seen concurrently instead of serially.

T h e pitfalls of “nonsynchronous” studies, which might tend to cause increased survival rates in the group studied second, include: a) earlier diagnosis, b) errors in pathologic diagnosis causing the inclusion of benign tlis- edse in statistics, and c) more advanced pal- liation techniques. Therefore, in designing this study, attention was locused on the two Iactors described which mask the true course ot the disease: d) differing biological growth rates and e) presence of occult metastases at time of primary therapy. Consequently, the first three factors (a-c) did not influence the results and the fourth (d) was stressed in an- swering questions raised by the fifth (e).

T o illustrate the extremely variable course of this disease, both betore and after the ‘ip- pearance of bone metastases, Devitt’O has noted that in Stage I1 disease, bone metastases appear 2-1 20 months following initial ther- ‘ipy (median, 24 months) and survived after their diagnosis varies fiom 1-72 months (me- dian, 9 months).

In this series of patients followed lor 96 months, bone metastases appeared as early as 2 months and as late as 90 months following initial therapy. Fif ty-eight percent of them appeared within the first two postmastectomy years, compared with 47.57” in another

What is the significance of a positive bone scan in an asymptomatic woman with negative roentgenogram? I t has been shown that almost 90% of cancer patients with positive bone scans have biopsy-proven meta~tas i s .~ Yet, in 8 years, only 60% of the women in this series with positive scans have developed clinical or radiographic evidence of metastatic disease. Therefore, as many as 30’% of asymptomatic women with a history of breast cancer, posi- tive bone scans, and negative bone roentgeno- grams may still harbor disease in bone after 8 years.

study.14

No. 1 BONE METASTASES FROM BREAST

Bone-scanning techniques have been refined in the past 8 years. Consequently, although some may argue that the ability to differ- entiate benign from malignant disease may not have improved, the sensitivity of scanning is vastly improved.’l13 Therefore, it seems that another prospective study using more modern techniques would be in order-following both Stage I and Stage I1 patients.

Therefore, on the basis of this and other papers,”8.14 certain recommendations might be made.

T h e indications for bone scanning in the woman who has had breast cancer:

1. For examination of patients with per- sistent pain thought to be in bone despite equivocal or negative roentgenograms.

2. For determination of the extent of bony disease when roentgenographic changes are visible, particularly in the asymptomatic patient.

3. For evaluation 01 areas which are dif- ficult to study by conventional radio- graphic methods, such as the sternum and scapula.

4. For differentiation of pathologic from

CANCER * Sklaroff and Slclarofl 111

traumatic fracture by demonstrating other sites of involvement not appreciated on roentgenograms.

5. For planning x-ray treatment portals.

6. For determination of the response to hormonal, chemical, or radiation therapy.

Regardless of the contemplated primary therapy, the workup of a woman with sus- pected mammary carcinoma should include a mammogram, thermogram, chest radiograph, and a skeletal survey. The indication for bone scan is not yet established, before definitive therapy is given, although women who have bone pain or women who are borderline- operable might be considered.

In discussing regional vs. systemic control ol breast cancer, Nichinil‘ has concluded: “Present therapy for operable breast cancer fails to take into account the large number ol patients who have already developed oc- cult bloodborne metastases. Efforts should be directed to the establishment of more effective methods of identifying occult hematogenous metastases prior to surgery. T h e recognition of the patient with occult disseminated dis- ease would be the most effective prognostic index available.”

REFERENCES 1. Babaiantz, L.: Les osteopathies arthrophiques.

.J. Radiol. Electrol. Med. Nucl. 29:333-361, 1948. 2. Bell, E. G.: Nuclear medicine and skeletal disease.

Hosp . Prac. 7:49-60, 1972. 3. Bloom, H. J. G.: The natural history of untreated

breast cancer. Ann. N . Y . Acad. Sci. 114:747-754, 1964. 4. Bruce, J.: T h e enigma of breast cancer. Cancer

5. Charkes, N. D., and Sklaroff, D. M.: Detection of mcult metastases to bone by photoscanning with radio- isotopes of strontium. I n Progress in Clinical Cancer, vol. 1, 1st ed., I. Ariel, Ed. New York, Grune and Stratton, Inc., 1965; pp. 235-257.

6. Charkes, N. D., and Sklaroff, D. M.: The radio- active strontium photoscan as a diagnostic aid in pri- mary and metastatic cancer in bone. Radiol. Clin. h‘ortk A m . 3:499-509, 1965.

7. Charkes, N. D., Young, I., and Sklaroff, D. M.: The pathologic basis of the strontium bone scan. JAMA

8. Cohn, H. E.: Mammography in its proper per- spective. Surg. Gynecol. Obstet. 134:97-98, 1972.

9. Collins, V. P., and Adams, R. M.: The paradox of breast cancer. A m . .J. Roentgenol. Radium Zher. Nucl. Med. 99:965-972, 1967.

10. Devitt, J. E.: The enigmatic behavior of breast cancer. Cancer 27:12-17, 1971.

11. Gershon-Cohen, J., Berger, S. M., and Klickstein, H. S.: Roentgenography of breast cancer moderating concept of “biologic predeterminism.” Cancer 16:961- 964, 1963.

12. Nichini, F. M., and Tsien, K. C.: Distant me- tastases as an evaluation of the treatment of breast

24~1314-1318, 1969.

206:2482-2488, 1968.

cancer. A m . J . Roentgenol. Radium Ther. Nucl. Med. 11 1: 142-147, 1971.

13. Pistenma, D. A,, McDougall, I. R., and Kriss, 1. P.: Screening for bone metastases-Are only scans necessary? ,JAMA 231:46-50, 1975.

14. Quinn, J. L., Ed.: Yearbook of Nuclear Medicine 1973. Chicago, Yearbook Medical Publishers, Inc., 1973;

15. Rohbins, G. F., Knapper, W. H., Barrie, J., Kripalani, I., and Lawrence, J.: Metastatic bone dis- ease developing in patients with potentially curable breast cancer. Cancer 29:1702-1704, 1972.

16. Rubin, P., Ed.: Clinical Oncology for Medical Students and Physicians-A Multidisciplinary Approach, 3rd ed., 1970-1971. New York, American Cancer So- ciety, 1971; pp. 98-99.

17. Sklaroff, D. M., and Charkes, N. D.: Early detec- tion of bone lesions by photoscanning with radioactive strontium. Cancer 203734-737, 1967.

18. Sklaroff, D. M., and Charkes, N. D.: Bone me- tastases from breast cancer at the time of radical mastectomy. Surg. Gynecol. Obstet. 127:763-768, 1968.

19. Sklaroff, D. M., and Sterling, J. A,: Delayed ap- pearance of metastasis from carcinoma of breast. Sur- gery 37:838-839, 1955.

20. Steckler, R. M., and Martin, R . G.: Prolonged survival in untreated breast cancer. A m . J. Swg. 126: 111-113, 1973.

21. Zimmerman, K. W., Montdgue, E. D., and Fletcher, G. H.: Frequency anatomical distribution and management of local recurrences after definitive therapy for breast cancer. Cancer 19672, 1966.

pp. 372-373.