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Chemotherapy of skeletal metastases
Int. J. Radiation
Bid.
Oncology
Phys.,
1976, Vol.
1, pp. 1211-1215.
CHEMOTHERAPY
of Medicine
Bone metastases,
Chemotherapy,
Fellow.
in the U.S.A.
METASTASES
and Pharmacology, Yale University Haven, CT 06510, U.S.A.
School of Medicine,
New
Radiotherapy.
Eiupported by training grant CA-05138 from the Oncology
Printed
and JOSEPH R. BERTINO, M.D.S
INTRODUCTION Metastatic cancer to bone is the most common bone cancer,23 unlike primary bone tumors, occurs at multiple sites 90% of the time.13 The axial skeleton is most often affected; the extremities rarely. Neoplasms of the breast, lung, prostate, kidney and thyroid account for nearly 80% of bone metastases. Skeletal metastases from the colon, pancreas and stomach are uncommon, occurring in less than 10% of patients with these tumors.‘.‘333 Radiographic appearance of the bone metastases aids in the identification of the primary source. Osteoblastic lesions in males most frequently will be of prostatic origin, rarely from pancreas, colon, lung, carcinoid tumor, Hodgkin’s disease, or myeloma. _41though the majority of skeletal breast lesions are lytic, the most common source of blastic bony metastases in women is breast cancer. Lytic bone lesions generally are without characteristic identifying features which would help in the identification of the primary cancer, with the exception of kidney, which often presents as a solitary radiolucent expansile bone lesion. Radiotherapy is the treatment of choice for skeletal metastases which are painful and few in number or located in strategic areas of skeletal support. However, many bone lesions, can be expected to respond favorably to chemotherapy. The effectiveness of chemotherapy on various skeletal metastases is reviewed. THYROID Thyroid carcinomas characteristically have many long term survivors following surgical
USPHS.
Press.
OF SKELETAL
ED. CADMAN, M.D.? Department
Pergamon
therapy, 80-90% live 10 years or greater. The small number that succumb to ‘their disease often have bone or pulmonary metastases or both.1%1834Papillary carcinoma occurs in approximately 66% of patients and tends to metastasize to local lymph nodes. Follicular carcinoma occurs in 20% of patients with a predilection for vessel invasion and subsequent bone and lung metastases. Treatment other than surgery has resided consistently with oral 13’1administration. The dose is generally lOO-300mCi given repeatedly over 2 years for a total dose of 500 mCi.” I31I has been documented to accumulate in bone metastases and to have a favorable effect on survival. In one study, all of 10 patients lived 5 years, with 3 patients living 6, 15 and 25 years after ‘9 therapy.” There is even documentation of roentgenograms returning to normal in 5 of 30 patients, with total regression of pain in all patients.” Other chemotherapeutic agents used in metastatic thyroid cancer without success are 5-fluorouracil, methotrexate, actinomycin D, cyclophosphamide, phenylaline mustard, and others.” The use of bleomycin has had conflicting reports.‘6 Adriamycin (75 mglm’ q3 week) achieved 4 partial remissions in 12 patients with bone involvement, it was documented as 50% radiographic regression for 1 month. One patient had relief of pain.‘O 13’1appears to be the agent of choice when metastases are small and capable of concentrating 1311.Thus far, adriamycin is the only chemotherapeutic agent shown to be effective in advanced bone metastases. SSupported by USPHS Grant CA-08341. Piofessor of Medicine and Pharmacology.
121I
1212
Radiation Oncology 0 Biology 0 Physics PROSTATE
Prostatic carcinoma metastasizes frequently to bones (see Table 1). Estrogens relieve pain in 75% of patients, but rarely with evidence of bone healing.” To date chemotherapeutic agents have not been used systematically in prostatic cancer. In one reported series only a few of the 88 patients treated with either nitrogen mustard + 5fluorouracil, or S-fluorouracil, or cyclophosphamide, or aniline mustard appeared to respond.40 The most dramatic response of prostatic bone metastases has been to PSZ. Tong and Finkelstein3’ administered parathyroid hormone (PTH) 300 units x 7 days; on days 9, 10 and 11,2 mCi of PpI were given and then twice weekly x 2 followed by 1 mCi twice weekly x 3 for a total dose of 21 mCi. All of the I5 patients who were treated, and who had failed on estrogens, had pain relief beginning at two weeks and lasting up to 3.5 years. In 8 patients, bone repair was demonstrated radiographically; in 2 patients with pathological fractures, there was evidence of healing. All acid and alkaline phosphatase levels which were elevated prior to treatment, fell to within the normal range. Merrin and Bakshi26 treated 8 patients with bone metastases who also were refractory to estrogens; the patients received only 1 dose of 10 mCi PS2,24 hr after 6 days of PTH at 300 units per day. In 5 patients, pain totally disappeared for a duration of l-8 months. There was no bone healing. In neither study was toxicity reported. Whether P,, extends survival of patients with prostatic skeletal metastases has not been Table 1. Per cent bone metastases
from
various
primary sites
% Patients with bone metastases (Ref.) Ref. % Ref. % Ref. % Ref.
Primary
%
Breast Prostate Lung
49 (23) 47 (23) 23 (23)
57 (13) 55 (13) 44 (13)
Kidney Thyroid
32 (23) 32 (23)
37 (2) 40 (34)
84 (8) 62 (40) 35 (39) 19 (29) 27 (11)
73 (1) 84 (1) 33 (1) 24 (1) 50 (1)
References: Autopsy series+, 13, 23, 34, 39); Advanced disease-(2, 11, 29, 40); Bone scan in advanced disease-@).
November-December
1976, Vol. 1. No. 11 and No. 12
established because of the small numbers and uncontrolled nature of the studies to date. The palliation is dramatic, however, and appears worthy of further study. BREAST
Breast cancer affects 5% of all women and accounts for 25% of all cancer in women.3Z The most common site of metastases is to the skeletal system, occurring in 49-84% of patients who have metastatic breast cancer (Table 1). The bone lesions often are painful and the source of much disability. Corticosteroids seldom are used as primary therapy in breast carcinoma except when hypercalcemia, brain metastases or pulmonary lymphangetic spread is evident. When used, it does provide relief from painful skeletal metastases in 15-30% of patients; healing is rare, however.‘*” Although estrogens achieve a slightly higher response rate than do androgens for the palliation of soft tissue breast cancer metastasis in postmenopausal women, this advantage is not observed for the palliation of skeletal metastases when both response rates are around 25%.” The comparative antitumor effect of the various androgen preparations has not shown any individual drug superiority. The newest androgenic hormone, calusterone (7P-17a-dimethyltestosterone), has produced bone healing or a 50% decrease in the size of skeletal metastases in 50% of postmenopausal women when used as a primary form of therapy. When used as a secondary form of treatment after prior hormonal or chemotherapy, however, the response was no different from other androgens -25%.’ Androgens are effective in breast cancer in premenopausal women; however they are not warranted because of the superior results from castration. The addition of androgens to the oophorectomized women adds very little and, in fact, may be deleterious since the androgen metabolites include estrogenic products.*’ The most commonly used agents in breast cancer have been cyclophosphamide (cytoxan) and 5-fluorouracil (5-FU). Their effect on skeletal metastases has been reported inconsistently in the literature (see
Chemotherapy of skeletal metastasesOE.
Table 2) mainly because of unstandardized and highly variable criteria for response. Some authors require bone recalcification and healing, while others insist only on nonprogression of bone lesions. Of the 676 breast cancer patients treated with 5-FU who were reviewed by Ansfield: 227 had osseous metastases as their dominant lesion. 30% had 50% regression in their bony disease, 27% were unchanged, while 43% progressed. The median survival of the improved and unchanged groups were identical-32 months. In the progressive disease group it was 13 months. In Johnston’s group of patients who were treated with either agent, skeletal disease was stabilized and pain relieved in 37%; no lesions regressed.14 Two conclusions can be inferred: (1) there need only be stabilization of the osseous lesion for an effect on survival, (2) pain relief occurs much more frequently than objective regression of osseous- lesions. Combination therapy utilizing cyclophosphamide, vincristine, prednisone, methotrexate and 5-fluorouracil (COMP-FU) has produced a much higher response rate for all metastatic sites when compared to single agents (see Table 2). In 16 patients with bone metastases, Cooper noted 14 complete responses, i.e. total disappearance of disease.6 Spigel et al. demonstrated complete responses in 4 of 7 patients.35 However, other authors
Table 2. Response of breast carcinoma skeletal metastases % Response
Reference
Cyclophosphamide
23 (10/49) 24 (8/30) 31 (5/16)
25 30 37
S-FU
18 19 37 42 56 57 87
5 3 37 30 19 35 6
Drug
Cyclophosphamide, vincristine methotrexate, prednisone and 5-FU Adriamycin L-DOPA
(9/51) (67/227) (6/16) (8/19) (9/16) (4/7) (16/19)
19 (4/21) 33 (10/30)
(I) = (pts. responding/total
pts. treated).
12 27
CADMANand J. R. BERTINO
1213
have reported a similar percentage of partial responses with only rare complete remissions of bone metastases.4.‘gp Adriamycin (75 mg/m’ q 3 week) produced a 19% partial response rate when it was used in patients with osseous lesions who had failed on conventional chemotherapeutic agents.*2 The response rate was higher for all other metastatic foci. The impressive fact is that these patients had all been treated with a multitude of hormonal and chemotherapeutic agents. Adriamycin currently is being tested as a first-line drug alone or in combination . with other chemotherapeutic agents. L-Dopa has recently been added to the armamentarium against skeletal involvement in breast cancer. Of 30 patients treated with 250-500 mg p.o. q 4 hr 10 experienced total relief of pain.” Of the 10 patients 9 were free of pain 3 months or longer. More significantly, in 5 of 8 patients with abnormal bone scans repeat scars became normal during therapy. Three responders had a subsequent oophorectomy with a complete response. The predictive value of a response to L-DOPA for a subsequent oophorectomy response had been observed previously.= The use of L-DOPA in patients indeed may prove to be useful with skeletal breast cancer metastases, especially since the pain relief often occurs within hours and certainly within days.
RENAL Skeletal metastases occur in approximately one-third of all patients with metastatic renal cell cancer (see Table 1). An isolated metastasis masquerading as a primary bone tumor is not an uncommon occurrence. Chemotherapy of metastatic disease has not altered the survival rates significantly,2.36 nor has it consistently altered bone metastases either subjectively or objectively. Multiple agents have been used without successprogestogens, androgens, alkylating agents, antimetabolites (5-FU, 6-mercaptopurine, cytosine arabinoside, methotrexate, and hydroxyurea), antimitotic agents (vincristine and vinblastine), adriamycin and the investigational drugs dimethylimidazole carboxamide and the nitrosoureas.%
1214
Radiation Oncology 0 Biology 0 Physics
LUNG If it is not cured surgically at an early stage, lung cancer is palliated only minimally with chemotherapy.33.4’ Small cell carcinoma (oat cell) occurs with a frequency of nearly 20% in patients with lung cancer; usually, it is widely disseminated at the time of diagnosis, often involving the bone marrow, liver and brain.‘.15 This histological type of lung carcinoma is the most responsive to chemotherapy, with response rates ranging from 50 to 88%.‘.33The responses generally are partial and for a period of only a few months. Adequate documentation of the effect of chemotherapy on the skeletal involvement is limited, however, primarily because of the rapid demise.of the patients from their primary lung cancer or metastases in the liver or brain. Chemotherapy has not been as efficacious for the other histological types of lung cancer. Reports of beneficial effects of chemotherapy on bone lesions from these other histological categories of lung cancer are lacking. MULTIPLE MYELOMA When they are treated with intermittent courses of melphalan and prednisone,3’ 30% of myeloma patients with characteristic
1.
November-December
1976, Vol. I. No. II and No. I2
“punched” out bony lesions will have demonstrable radiographic bone repair. SUMMARY Of all the carcinomas which frequently metastasize to bones, breast carcinoma is the most responsive to chemotherapeutic agents, especially if drugs are given in combination. Adriamycin and L-DOPA also have been reported to be efficacious in the treatment of osseous metastases of bone cancer: further investigation is warranted with these agents. 13’1continues to be the agent of choice in osseous thyroid cancer. Adriamycin is effective in the advanced stages of the disease when “‘I has little or no effect, and may be found to be of greater utility if used earlier. After priming with PTH, P,, has produced dramatic pain relief in patients with prostatic cancer who have failed on hormonal therapy. Additional studies are required before its general use can be recommended, however. Thus far, chemotherapy has had little or no effect on the skeletal metastases from renal cell carcinoma or those from lung cancer, with the exception of oat cell carcinoma. Melphalan and prednisone do produce bone healing in 30% of multiple
myeloma
patients.
REFERENCES Abrams, H.L.: Skeletal metastases in car8. Galasko, C.S.B.: Skeletal metastases and mamcinema. Radiology 55: 534-538, 1950. mary cancer. Ann. Royal Coil. Surg. Engl. SO,
2. Alberto, P., Senn, H.J.: Hormonal therapy of renal carcinoma alone and in association with cytostatic drugs. Cancer 33: 12261229, 1974. 3. Ansfield, F.J.: A ten-year study of 5fluorouracil in disseminated breast cancer with clinical results and survival times. Cancer Res. 29: 1062-1066, 1%9. 4. Ansfield, F.J., et al.: Five-drug therapy for advanced breast cancer: A phase I study. Cancer Chemo. Repts 55: 183-187, 1971. 5. Brennan, M.J., Talley, R.W.: Implications of treatment sequence effects on responsiveness to 5-fluorouracil and cytoxan. In Concepts in Breasf Cancer, ed. by Segaloff A., Meyer K., Debakey S. Baltimore, Williams & Wilkins, 1967, pp. 225-239. 6. Cooper, R.G.: Combination chemotherapy in hormone resistant breast cancer. Proc. Am. Assoc. Cancer Res. 10: 15, 1%9 (appears on one page only). 7. Eagan, R.T., et al.: Small cell carcinoma of the lung: Staging, paraneoplastic syndromes, treatment and survival. Cancer 33: 527-532, 1974.
3-27, 1972. 9. Gordan, G.S., et al.: Calusterone as primary and secondary therapy of advanced breast cancer. Oncology 28: 138-146, 1973. 10. Gottlieb, J.A., Hill, Jr., C.S.: Chemotherapy of thyroid cancer with adriamycin. New Engl. J. Med. 290: 193-197, 1974. 11: Gottlieb, J.A., et al.: Chemotherapy of thyroid cancer. Cancer SO: M-853, 1972. 12. Gottlieb, J.A., et al.: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma. Cancer 33: 519-526, 1974. 13. Johnston, A.D.: Pathology of metastatic tumors in bone. Clin. Orthoped. 73: 8-32,197O. 14. Johnston, M.J., Lipsett, J.A., Donovan, A.J.: Osseous metastasis in mammary cancer. Arch. $rg. 101: 578-581, 1970. 15. Hansen, H.H., Muggia, F.M.: Staging of inoperable patients with bronchogenic carcinema with special reference to bone marrow examination and peritoncoscopy. Cancer 30: 1395-1401, 1970.
Chemotherapy
1215
of skeletal metastases 0 E. CADMAN and J. R. BERTINO
16. Harada, T., et al.: Bleomycin treatment for cancer of the thyroid. Am. J. Surg. 122: 53-57, 1971. 17. Harness, J.K., et al.: Differentiated thyroid carcinomas-treatment of distant metastases. Arch. Surg. 108: 410-419, 1974. 18. Haynie, T.P., Nofal, M.M., Beierwalters, W.H.: Treatment of thyroid carcinoma with ‘“‘I. J.A.M.A. 183: 303-306, 1%3. 19. Kaufman, S., Goldstein, M.: Combination chemotherapy in disseminated carcinoma of the breast. Surg. Gynecol. & Obstet. 137: 83-87, 1973. 20. Kelley, R.W.: Hormones and chemotherapy in breast cancer. Cancer 28: 1686-1691, 1971. 21. Kennedy, B.J.: Hormonal therapies in breast cancer; Seminars in Oncol. 1: 119-130, 1974. 22. Lee, J.M., et al.: An evaluation of five-drug combination chemotherapy in the management of recurrent carcinoma of the breast. Surg Gynecol. & Obstet. 138: 77-81, 1974. 23. Meissner, W., Warren, S.: Distribution of metastases in 4012 cancer patients. Pathology ed. by Anderson, W.A.D. 6th Edn, Chap. 16, 1971, p. 538. 24. Mellette, S.: Management of malignant disease metastatic to bone by hormonal alterations. Clin. Orthoped. 73: 73-88, 1970. 25. Menoto, T., Dao, T-L.: 5-Fluorouracil and cyclophosphamide in disseminated breast cancer. NY State J. Med. 71: 554-558, 1971. 26. Merrin, C., Bakshi, S.: Treatment of metastatic carcinoma of the prostate to bone with parahormone and radioactive phosphorous. J. Surg. Oncol. 6: 67-72, 1974. 27. Minton, J. P.: The response of breast cancer patients with bone pain to L-DOPA. Cancer 33: 358-363, 1974. 28. Minton, J.P., Dickey, R.P.: Levo-dopa test to predict response of carcinoma of the breast to surgical ablation of endocrine glands. Surg. Gynecol. 62 Obstet. 136: 971-974, 1973. 29. Rafla, S.: Renal cell carcinoma-natural history and results of treatment. Cancer 25: 26-40, 1970. 30. Rauden, R.G., Eisman, S.H.: Disseminated breast cancer: relationship of response to
31.
32.
33.
34.
35.
manipulation, and endocrine cytoxan, fluorouracil. In Current Concepts in Breast ed. by Segaloff, A., Meyer, K., Cancer, Debakey, S. Baltimore, Williams & Wilkins, 1%7, pp. 200-207. Rodriguez, L.H., et al.: Bone healing in multiple myeloma with melphalan chemotherapy. Ann. Intern. Med. 76: 551-556, 1972. Ross, W.L.: The magnitude of the breast cancer problem in the U.S.A. Cancer 24: 1106-l 108, 1%9. Selawry, O.S.: Monochemotherapy of bronchogenie carcinoma with special reference to cell type. Cancer Chemo. Reps. Vol. 4. 177-188, 1973. Silverberg, S.G., Hutter, R.V., Foote, F.W.: Fatal carcinoma of the thyroid: Histology, metastases and causes of death. Cancer 25: 792-802, 1970. Spigel, S.C., Coltman, C.A., Costanzi, J.J.: Disseminated breast carcinomtreatment with combination chemotherapy. Arch. Intern. Med.
132: 575-577, 1973. R.W.: Chemotherapy 36. Talley. cinema of the kidney. Cancer
of
adenocar-
34: 1062-1065,
1973. 37. Talley, R.W., Vaitkevicius, V.K., Leighton, G.A.: Comparison of cyclophosphamide and 5-fluorouracil in the treatment of patients with metastatic breast cancer. Clin. Pharmacol. Ther. 6: 74&748, 1%5. 38. Tong, E.C., Finkelstein, P.: The treatment of prostatic bone metastases with parahormone and radioactivephosphorus. J. Ural. 109: 71-75, 1973. 39. Watsen, W.L. (ed.): Lung Cancer-A Study of 5000 Memorial Hospital Cases. Baltimore, Mosby, 1968, p. 507 (appears on one page only). 40. Yagoda, A.: Non-hormonal cytotoxic agents in the treatment of prostatic adenocarcinoma. Cancer 32: 1131-1139, 1973. 41. Zelen, M.: Keynote address on biostatics and data retrieval. Cancer Chemo. Reps. 4: 31-42, 1973.
Bid.
Oncology
Phys.,
1976, Vol.
1, pp. 1211-1215.
CHEMOTHERAPY
of Medicine
Bone metastases,
Chemotherapy,
Fellow.
in the U.S.A.
METASTASES
and Pharmacology, Yale University Haven, CT 06510, U.S.A.
School of Medicine,
New
Radiotherapy.
Eiupported by training grant CA-05138 from the Oncology
Printed
and JOSEPH R. BERTINO, M.D.S
INTRODUCTION Metastatic cancer to bone is the most common bone cancer,23 unlike primary bone tumors, occurs at multiple sites 90% of the time.13 The axial skeleton is most often affected; the extremities rarely. Neoplasms of the breast, lung, prostate, kidney and thyroid account for nearly 80% of bone metastases. Skeletal metastases from the colon, pancreas and stomach are uncommon, occurring in less than 10% of patients with these tumors.‘.‘333 Radiographic appearance of the bone metastases aids in the identification of the primary source. Osteoblastic lesions in males most frequently will be of prostatic origin, rarely from pancreas, colon, lung, carcinoid tumor, Hodgkin’s disease, or myeloma. _41though the majority of skeletal breast lesions are lytic, the most common source of blastic bony metastases in women is breast cancer. Lytic bone lesions generally are without characteristic identifying features which would help in the identification of the primary cancer, with the exception of kidney, which often presents as a solitary radiolucent expansile bone lesion. Radiotherapy is the treatment of choice for skeletal metastases which are painful and few in number or located in strategic areas of skeletal support. However, many bone lesions, can be expected to respond favorably to chemotherapy. The effectiveness of chemotherapy on various skeletal metastases is reviewed. THYROID Thyroid carcinomas characteristically have many long term survivors following surgical
USPHS.
Press.
OF SKELETAL
ED. CADMAN, M.D.? Department
Pergamon
therapy, 80-90% live 10 years or greater. The small number that succumb to ‘their disease often have bone or pulmonary metastases or both.1%1834Papillary carcinoma occurs in approximately 66% of patients and tends to metastasize to local lymph nodes. Follicular carcinoma occurs in 20% of patients with a predilection for vessel invasion and subsequent bone and lung metastases. Treatment other than surgery has resided consistently with oral 13’1administration. The dose is generally lOO-300mCi given repeatedly over 2 years for a total dose of 500 mCi.” I31I has been documented to accumulate in bone metastases and to have a favorable effect on survival. In one study, all of 10 patients lived 5 years, with 3 patients living 6, 15 and 25 years after ‘9 therapy.” There is even documentation of roentgenograms returning to normal in 5 of 30 patients, with total regression of pain in all patients.” Other chemotherapeutic agents used in metastatic thyroid cancer without success are 5-fluorouracil, methotrexate, actinomycin D, cyclophosphamide, phenylaline mustard, and others.” The use of bleomycin has had conflicting reports.‘6 Adriamycin (75 mglm’ q3 week) achieved 4 partial remissions in 12 patients with bone involvement, it was documented as 50% radiographic regression for 1 month. One patient had relief of pain.‘O 13’1appears to be the agent of choice when metastases are small and capable of concentrating 1311.Thus far, adriamycin is the only chemotherapeutic agent shown to be effective in advanced bone metastases. SSupported by USPHS Grant CA-08341. Piofessor of Medicine and Pharmacology.
121I
1212
Radiation Oncology 0 Biology 0 Physics PROSTATE
Prostatic carcinoma metastasizes frequently to bones (see Table 1). Estrogens relieve pain in 75% of patients, but rarely with evidence of bone healing.” To date chemotherapeutic agents have not been used systematically in prostatic cancer. In one reported series only a few of the 88 patients treated with either nitrogen mustard + 5fluorouracil, or S-fluorouracil, or cyclophosphamide, or aniline mustard appeared to respond.40 The most dramatic response of prostatic bone metastases has been to PSZ. Tong and Finkelstein3’ administered parathyroid hormone (PTH) 300 units x 7 days; on days 9, 10 and 11,2 mCi of PpI were given and then twice weekly x 2 followed by 1 mCi twice weekly x 3 for a total dose of 21 mCi. All of the I5 patients who were treated, and who had failed on estrogens, had pain relief beginning at two weeks and lasting up to 3.5 years. In 8 patients, bone repair was demonstrated radiographically; in 2 patients with pathological fractures, there was evidence of healing. All acid and alkaline phosphatase levels which were elevated prior to treatment, fell to within the normal range. Merrin and Bakshi26 treated 8 patients with bone metastases who also were refractory to estrogens; the patients received only 1 dose of 10 mCi PS2,24 hr after 6 days of PTH at 300 units per day. In 5 patients, pain totally disappeared for a duration of l-8 months. There was no bone healing. In neither study was toxicity reported. Whether P,, extends survival of patients with prostatic skeletal metastases has not been Table 1. Per cent bone metastases
from
various
primary sites
% Patients with bone metastases (Ref.) Ref. % Ref. % Ref. % Ref.
Primary
%
Breast Prostate Lung
49 (23) 47 (23) 23 (23)
57 (13) 55 (13) 44 (13)
Kidney Thyroid
32 (23) 32 (23)
37 (2) 40 (34)
84 (8) 62 (40) 35 (39) 19 (29) 27 (11)
73 (1) 84 (1) 33 (1) 24 (1) 50 (1)
References: Autopsy series+, 13, 23, 34, 39); Advanced disease-(2, 11, 29, 40); Bone scan in advanced disease-@).
November-December
1976, Vol. 1. No. 11 and No. 12
established because of the small numbers and uncontrolled nature of the studies to date. The palliation is dramatic, however, and appears worthy of further study. BREAST
Breast cancer affects 5% of all women and accounts for 25% of all cancer in women.3Z The most common site of metastases is to the skeletal system, occurring in 49-84% of patients who have metastatic breast cancer (Table 1). The bone lesions often are painful and the source of much disability. Corticosteroids seldom are used as primary therapy in breast carcinoma except when hypercalcemia, brain metastases or pulmonary lymphangetic spread is evident. When used, it does provide relief from painful skeletal metastases in 15-30% of patients; healing is rare, however.‘*” Although estrogens achieve a slightly higher response rate than do androgens for the palliation of soft tissue breast cancer metastasis in postmenopausal women, this advantage is not observed for the palliation of skeletal metastases when both response rates are around 25%.” The comparative antitumor effect of the various androgen preparations has not shown any individual drug superiority. The newest androgenic hormone, calusterone (7P-17a-dimethyltestosterone), has produced bone healing or a 50% decrease in the size of skeletal metastases in 50% of postmenopausal women when used as a primary form of therapy. When used as a secondary form of treatment after prior hormonal or chemotherapy, however, the response was no different from other androgens -25%.’ Androgens are effective in breast cancer in premenopausal women; however they are not warranted because of the superior results from castration. The addition of androgens to the oophorectomized women adds very little and, in fact, may be deleterious since the androgen metabolites include estrogenic products.*’ The most commonly used agents in breast cancer have been cyclophosphamide (cytoxan) and 5-fluorouracil (5-FU). Their effect on skeletal metastases has been reported inconsistently in the literature (see
Chemotherapy of skeletal metastasesOE.
Table 2) mainly because of unstandardized and highly variable criteria for response. Some authors require bone recalcification and healing, while others insist only on nonprogression of bone lesions. Of the 676 breast cancer patients treated with 5-FU who were reviewed by Ansfield: 227 had osseous metastases as their dominant lesion. 30% had 50% regression in their bony disease, 27% were unchanged, while 43% progressed. The median survival of the improved and unchanged groups were identical-32 months. In the progressive disease group it was 13 months. In Johnston’s group of patients who were treated with either agent, skeletal disease was stabilized and pain relieved in 37%; no lesions regressed.14 Two conclusions can be inferred: (1) there need only be stabilization of the osseous lesion for an effect on survival, (2) pain relief occurs much more frequently than objective regression of osseous- lesions. Combination therapy utilizing cyclophosphamide, vincristine, prednisone, methotrexate and 5-fluorouracil (COMP-FU) has produced a much higher response rate for all metastatic sites when compared to single agents (see Table 2). In 16 patients with bone metastases, Cooper noted 14 complete responses, i.e. total disappearance of disease.6 Spigel et al. demonstrated complete responses in 4 of 7 patients.35 However, other authors
Table 2. Response of breast carcinoma skeletal metastases % Response
Reference
Cyclophosphamide
23 (10/49) 24 (8/30) 31 (5/16)
25 30 37
S-FU
18 19 37 42 56 57 87
5 3 37 30 19 35 6
Drug
Cyclophosphamide, vincristine methotrexate, prednisone and 5-FU Adriamycin L-DOPA
(9/51) (67/227) (6/16) (8/19) (9/16) (4/7) (16/19)
19 (4/21) 33 (10/30)
(I) = (pts. responding/total
pts. treated).
12 27
CADMANand J. R. BERTINO
1213
have reported a similar percentage of partial responses with only rare complete remissions of bone metastases.4.‘gp Adriamycin (75 mg/m’ q 3 week) produced a 19% partial response rate when it was used in patients with osseous lesions who had failed on conventional chemotherapeutic agents.*2 The response rate was higher for all other metastatic foci. The impressive fact is that these patients had all been treated with a multitude of hormonal and chemotherapeutic agents. Adriamycin currently is being tested as a first-line drug alone or in combination . with other chemotherapeutic agents. L-Dopa has recently been added to the armamentarium against skeletal involvement in breast cancer. Of 30 patients treated with 250-500 mg p.o. q 4 hr 10 experienced total relief of pain.” Of the 10 patients 9 were free of pain 3 months or longer. More significantly, in 5 of 8 patients with abnormal bone scans repeat scars became normal during therapy. Three responders had a subsequent oophorectomy with a complete response. The predictive value of a response to L-DOPA for a subsequent oophorectomy response had been observed previously.= The use of L-DOPA in patients indeed may prove to be useful with skeletal breast cancer metastases, especially since the pain relief often occurs within hours and certainly within days.
RENAL Skeletal metastases occur in approximately one-third of all patients with metastatic renal cell cancer (see Table 1). An isolated metastasis masquerading as a primary bone tumor is not an uncommon occurrence. Chemotherapy of metastatic disease has not altered the survival rates significantly,2.36 nor has it consistently altered bone metastases either subjectively or objectively. Multiple agents have been used without successprogestogens, androgens, alkylating agents, antimetabolites (5-FU, 6-mercaptopurine, cytosine arabinoside, methotrexate, and hydroxyurea), antimitotic agents (vincristine and vinblastine), adriamycin and the investigational drugs dimethylimidazole carboxamide and the nitrosoureas.%
1214
Radiation Oncology 0 Biology 0 Physics
LUNG If it is not cured surgically at an early stage, lung cancer is palliated only minimally with chemotherapy.33.4’ Small cell carcinoma (oat cell) occurs with a frequency of nearly 20% in patients with lung cancer; usually, it is widely disseminated at the time of diagnosis, often involving the bone marrow, liver and brain.‘.15 This histological type of lung carcinoma is the most responsive to chemotherapy, with response rates ranging from 50 to 88%.‘.33The responses generally are partial and for a period of only a few months. Adequate documentation of the effect of chemotherapy on the skeletal involvement is limited, however, primarily because of the rapid demise.of the patients from their primary lung cancer or metastases in the liver or brain. Chemotherapy has not been as efficacious for the other histological types of lung cancer. Reports of beneficial effects of chemotherapy on bone lesions from these other histological categories of lung cancer are lacking. MULTIPLE MYELOMA When they are treated with intermittent courses of melphalan and prednisone,3’ 30% of myeloma patients with characteristic
1.
November-December
1976, Vol. I. No. II and No. I2
“punched” out bony lesions will have demonstrable radiographic bone repair. SUMMARY Of all the carcinomas which frequently metastasize to bones, breast carcinoma is the most responsive to chemotherapeutic agents, especially if drugs are given in combination. Adriamycin and L-DOPA also have been reported to be efficacious in the treatment of osseous metastases of bone cancer: further investigation is warranted with these agents. 13’1continues to be the agent of choice in osseous thyroid cancer. Adriamycin is effective in the advanced stages of the disease when “‘I has little or no effect, and may be found to be of greater utility if used earlier. After priming with PTH, P,, has produced dramatic pain relief in patients with prostatic cancer who have failed on hormonal therapy. Additional studies are required before its general use can be recommended, however. Thus far, chemotherapy has had little or no effect on the skeletal metastases from renal cell carcinoma or those from lung cancer, with the exception of oat cell carcinoma. Melphalan and prednisone do produce bone healing in 30% of multiple
myeloma
patients.
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