1111.f. Radiation
Oncology Biof. Phys.,
1977, Vol. 2, pp
261-266
Pergamon Press.
Printed in the U.S.A.
??Original Contribution
THE ROLE OF HIGH-DOSE METHOTREXATE WITH CITROVORUM FACTOR “RESCUE” IN THE TREATMENT OF OSTEOGENIC SARCOMA?
NORMAN
JAFFE,
J. ROBERTCASSADY, HUGH
M.D.,
WATTS,
DEMETRIUS
M.D.,
M.D.
ROBERT
EMIL
TRAGGIS, M.
FREI,
M.D.,
FILLER, III,
M.D.,
M.D.
Children’s Hospital Medical Center, Divisions of Orthopedic Surgery and General Surgery, Sidney Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, U.S.A. Osteogenic sarcoma has been shown to be responsive to adriamycin (ADR) and vincristine-high-dose methotrexate with citrovorum factor “rescue” (VCR-MTX-CF). Both regimens have produced responses in patients with established disease. These experiences prompted utilization of these forms of chemotherapy in adjuvant programs. The VCR-MTX-CF regimen was also utilized in combination with radiation therapy to treat patients with inoperable tumors and those with presumed residual microscopic tumor in the lungs or elsewhere following surgical resection. More recently, chemotherapy was utilized in pre-treatment programs to facilitate local en bloc resection and insertion of internal prostheses to achieve useful functioning limbs. The evolution of these programs at the Sidney Farber Cancer Institute from January 1971, is documented and the results are updated to June 1976. Osteogenic sarcoma,
High dose methotrexate,
Adriamycin,
Radiation
METHODS
INTRODUCTION
therapy.
AND MATERIALS
Therapeutic research during the past five years has demonstrated that osteogenic sarcoma no longer should be considered a chemoresistant tumor. Thus, adriamycin (ADR) and vincristine-high-dose methotrexate with citrovorum factor “rescue” (VCR-MTXCF) have eradicated overt metastases,‘,5,6,8,‘3 improved survival in patients after ablative surgery2,7.‘6 and permitted local en bloc resection with preservation of useful functioning limbs.“,‘2 This report describes the evolution of the treatment programs initiated at the Sidney Farber Cancer Institute in January 1971, and updates the results to June 1976.
The basic VCR-MTX-CF program (Fig. 1) involves the admistration of VCR (2 mg/m*maximum 2 mg) followed 0.5 hr later by a 6-hr infusion of MTX (3 g/m’, 6 g/m’ and 7.5 g/m’ at 2-3 weekly intervals). Two hours after the completion of the MTX infusion, CF is administered over 72 hr. During the first 24 hours, it is administered intravenously at 3-hourly intervals and during the subsequent 48 hr at 6-hourly intervals by the oral route. The first oral dose commences 3 hr after the last intravenous dose. In this review, this therapeutic approach is designated Regimen 1. In June 1974, adriamycin (ADR) was incor-
tSupported in part by a research grant (CA06516) from the National Cancer Institute and by a grant (RR-05526) from the Division of Research Facilities and Resources, National Institutes of Health.
Reprint requests to: Sidney Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, U.S.A. 261
262
Radiation
Oncology
0 Biology 0 Physics
VCR-MTX-CF MTX i 0 5 hrs
I
YTX
I
~lv~
6hrs
V = VINCRISTINE
72 hrs
2 mg/M’
MTX=METHOTREXATE
3gms/M2;
CF = CITROVORUM FACTOR
Fig. 1. Basic
c-FrA
2 hrs
high-dose
6gms/MZ;75gms/M2
l5mg q3h 15mgq6h
I v.
methotrexate
program.
VCR-MTX-CF
2
mg/M*
MTX = METHOTREXATTE 3gms/M’, 6gms/MZ, CF = CiTROVORuM FACTOR 15mg q3h V 15mgq6h PO ALU?= ADRIAMYCIN 75 mg/M’
Fig. 2. Basic high-dose
methotrexate tin program.
1977, Volume
2, No.
3 and No. 4
of treatment. The cardiac status of each patient was monitored at regular intervals prior to administration of ADR by electrocardiographic studies, presystolic ejection time intervals and heart size by radiographic examination. Liver function studies and hemograms were also obtained immediately prior to the administration of ADR.
PO
porated into the treatment protocol (Fig. 2). It was administered 4 days after the completion of CF at a dose of 75 mg/m*. In view of possible myelosuppression which may be induced by ADR, Regimen 1 courses were extended to a 4 week cycle. After a cumulative dose of 450 mg/m* of ADR had been administered, the tri-weekly schedule for 1 was re-instated. The duration of Regimen treatment was 18 months. This therapeutic program is designated Regimen 2. With increasing experience and with the availability of pharmacologic monitoring to measure serum MTX levels, investigations were conducted to determine the efficacy of administration of Regimen 1 on a weekly basis. Generally, 4-8 weekly courses were administered. This weekly administration is designated Regimen 3. Prior to each course of MTX treatment, creatinine clearances were obtained and daily serum creatinine and MTX levels during the course. If a value in excess of 1 X lo-’ molar at 72 hours was detected, CF was continued until a result below this level was obtained. Leukocyte and platelet counts and liver function studies were obtained at semi-weekly intervals. Radiographs of the chest were obtained every 2-3 weeks prior to each course
” = “INCRlSTlNE
March-April
75gms/M’
and adriamy-
Radiation therapy In the early experience, radiation therapy was added to the treatment of Regimen 1 in patients with overt pulmonary metastases after apparent failure of response to the chemotherapy regimen. Patients were irradiated with a 4 or 8 Mev linear accelerator in all instances. They generally received 1500 rad/ 10 fractions/ 12 days.” More recently, radiation therapy was administered with increasing frequency in combination with Regimen 3. Patients with presumed residual microscopic tumor in the lungs following thoracotomy received I500 rad, administered in 150 rad fractions to both whole lung fields. One patient with residual tumor in the right pericardial area received an additional 1800 rad/9 fractions/ 11 days (total 3300 rad in 32 days). Similar “cone down” irradiation was administered following pulmonary nodule resection when surgical margins were questionable or positive. Radiation therapy was also administered in several patients to tumor located in extra pulmonary sites. Following incomplete resection of inguinal node metastases, I patient received 5200 rad/27 fractions/57 days to the left pelvis and inguinal femoral region. Treatment was interrupted after the second weekly course of chemotherapy because of drug toxicity, but was resumed 2 weeks later. A second patient received 4000 rad/20 fractions/28 days for an inoperable osteogenic sarcoma of the pelvis. He had previously received less than 3000 rad to the tumor concurrently with ADR at another institution. Patients Regimen 1. This was administered initially to 14 patients with pulmonary metastases (updated from original reports).3.h It was also utilized as adjuvant treatment after primary
The treatment
of osteogenic
definitive surgical therapy: there were 12 patients with the “classical” variety of osteogenic sarcoma with local control and 8 with other types, including 4 with the parosteal variety.’ To determine the efficacy of the adjuvant treatment, the incidence of pulmonary metastases was analyzed in 78 patients with “classical” osteogenic sarcoma and local control previously treated at the Sidney Farber Cancer Institute and Children’s Hospital Medical Center. Regimen 2. This was administered to 22 patients with “classical” osteogenic sarcoma following local control achieved by surgery. The incidence of pulmonary metastases in the historical control group outlined earlier, and in the treated patients, was also utilized to determine the efficacy of the treatment program. Regimen 3. This was administered to 3 groups of patients: Group I-15 patients with pulmonary metastases. Six had not received prior MTX treatment and 9 had previously received treatment with Regimen 1. Group 2-10 patients after resection of pulmonary metastases, one after incomplete resection of inguinal node metastases and one with a primary inoperable osteogenic sarcoma of the pelvis (see above). Five of the patients had been treated previously with Regimen 1 but still had residual lesions.” Following surgical residual microscopic resection, disease was considered to be present. These patients received radiation therapy, as outlined earlier. Group 3-7 patients were treated preoperatively with chemotherapy with intent to perform a limited resection of the primary tumor rather than limb ablation. Four to 8 weekly courses of treatment were administered. Two patients also received intraarterial ADR following the last course of MTX therapy. RESULTS Among the 14 patients treated with Regimen 1, 2 complete and 2 partial responses were obtained. One of these patients in whom a complete response was obtained remained alive and well, free of disease, 5 years later.
sarcoma 0 N.
JAFFE
et
al.
263
She recently delivered a live, normal baby who was without evidence of congenital abnormalities. Additionally, responses were also obtained in 4 patients with a combination of radiation therapy and Regimen 1.5.6 Seven of the 12 patients with “classical” osteogenic sarcoma treated with Regimen 1 as adjuvant therapy have remained free of pulmonary metastases for 2-4.5 yr (Fig. 3). The last patient who developed pulmonary metastases was free of disease at the time treatment was discontinued at 18 months. One month later, however, another lesion (? new primary tumor) was detected in the contralateral non-amputated femur. This was followed one month later by pulmonary metastases. Although it is possible that the metastases were derived from the “new” tumor, she was classified as a failure of adjuvant treatment. Two of the patients who developed pulmonary metastases were subOSTEOGENIC SARCOMA
100 90
LUNG MEYSTASES MTX-“CR-W ~/I
MONTHS
TO METASTASES
Fig. 3. Cumulative incidence of pulmonary metastases in historical and study groups. LCA represents local control achieved. The arrows represent the time of the last follow-up examination for individual patients. In the study group, the upper curve represents 12 patients with “classical” osteogenic sarcoma in whom local control was achieved. The lower curve represents the total experience.‘.‘”
264
Radiation
Oncology
0 Biology
0 Physics
sequently rendered free of disease by surgical resection. Five of the 8 other patients with different forms of osteogenic sarcoma also remain free of pulmonary metastases. Results in the patients with “classical” osteogenic sarcoma and local control and in the total experience are presented in Fig. 3. When compared to the historical control group, the difference in the incidence of metastases in the “local control” group and in the total study is highly significant (p < 0.001). Six of the 22 patients treated with Regimen 2 have developed pulmonary metastases. The remaining 16 have been free of disease for 8+ to 24+ months. This is outlined in Fig. 4 which also depicts the incidence of pulmonary metastases in the 12 patients with “classical” osteogenic sarcoma treated with Regimen 1. When compared to the historical control group, the difference in the incidence of pulmonary metastases is also highly significant (p < 0.001). Therefore, the results of both adjuvant programs are very similar to date. OSTEOGENIC PULMONARY
SARCOMA LCA METASTASES
loo-
go-
V-YTX-CFI N. 12) v-YTX-CF-A( w22, HlSTQnC COW‘KXS~N=
76)
SO-
TOz C601 !Fl = 50c 2 0 40: 2 $
JO-
O
I6
12 TIME-MONTHS
IS
24
+
March-April
1977, Volume
2, No. 3 and No. 4
With respect to Regimen 3, among the 6 patients in Group 1 who had not received prior MTX treatment, complete responses were obtained in 3 and a partial response in one. Additionally, 3 partial responses were obtained in patients who had received prior MTX treatment.” Nine of the 10 patients in Group 2 treated with Regimen 3 and radiation therapy remained free of recurrent disease for 6+ to 18+ months. Similarly, the patient with inguinal node metastases remained free of recurrent disease for 6+ months at the time of writing. A partial response was obtained in the patient receiving Regimen 3 and radiation therapy for the inoperable osteogenic sarcoma of the pelvis. Regimen 3 administered as a component of primary definitive therapy in the 7 patients (Group 3) produced partial responses in 4 and complete responses in 2. An amputation was performed in one of these patients because of complications induced by adriamycin. One patient failed to demonstrate a response. In 5 of the patients who responded, and 1 who failed to respond, a local en bloc resection was performed followed by insertion of an internal prosthesis. This resulted in preservation of the limb with a potential for useful function. Pulmonary metastases developed 6 months after diagnosis in the patient who failed to respond at the time of writing. The poor result in this patient was only demonstrated pathologically after examination of the resected specimen. The rest remain free of recurrent disease for 5+ to 18+ months. Toxicity The incidence of side effects with various regimens was less than lo%.” It comprised stomatitis, disturbances in liver function studies, transient renal abnormalities and myelosuppression. There was no exaggeration in the incidence of toxicity with Regimen 3. The major side effect encountered with the weekly schedule was weight loss.*
TO HETASTASES
Fig. 4. Cumulative incidence of pulmonary metastases in historical control group, 12 patients with “classical” osteogenic sarcoma in whom local control was achieved (see Fig. 2) and 22 patients treated with V-MTX-CF and adriamycin.
DISCUSSION The demonstration that various regimens may cause destruction of bulk tumor in patients with pulmonary metastases and in
The treatment
of osteogenic
patients with primary lesions is of signal importance. It justifies the administration of these regimens as adjuvant treatment as a means of eradicating pulmonary micrometastases. These are presumed to be present in over 80% of patients at diagnosis.’ Such metastases generally are more vulnerable to the action of effective chemotherapy than the primary tumor from which they were derived.15 Thus, approximately 60% of the patients treated with Regimen 1 failed to develop metastases and are probably cured. This contrasts with historical control patients where pooled data reveal that approximately 20% of patients survive.4 The addition of ADR to the basic regimen, Regimen 2, does not appear to have changed the results to date. However, the experience still is preliminary and further periods of observation are warranted. In patients who relapsed on adjuvant therapy, the number and time of appearance of pulmonary metastases appeared limited and delayed. This permitted more aggressive surgical intervention, rendering additional patients free of disease. These patients were also treated with radiation therapy and chemotherapy (Regimen 3) since they were considered to be at high risk for recurrence.” Methotrexate potentiates the action of radiation therapy5.6.14.‘7 and contrary to the ex-
sarcoma
0 N. JAFFE et al.
265
treatment does perience of others, I4 combined not appear to have produced inordinate degrees of pulmonary fibrosis. Regimen 3 represents a major advance in the application of high-dose MTX for osteogenic sarcoma. Utilizing this approach, a response rate of 88% was obtained in patients with pulmonary metastases or primary lesions who had not received prior MTX therapy.8 In several instances, complete tumor eradiation was noted. This was demonstrated by radiographic examination and confirmed by histologic studies.’ The experiences with high-dose MTX and ADR demonstrate that the regimens should be incorporated as a major component in the treatment of osteogenic sarcoma. Patients with the disease should be approached with curative intent. The results of combined treatment with radiation therapy and chemotherapy (Regimen 3) are preliminary but encouraging. Should permanent control of disease be achieved, they may provide justification for the “prophylactic” administration of such treatment to the lungs in future patients. Similarly, the preliminary exciting results achieved with the limb preservation program have prompted consideration to extending the study to an increasing number of selected patients.
REFERENCES 1. Cortes, E.P., Holland,
2.
3.
4.
5.
J.F., Wang, J.J., Sinks, L.F.: Doxorubicin in disseminated osteosarcoma. J. Am. Med. Assoc. 221: 1132-1138, 1972. Cortes, E.P., Holland, J.F., Wang, J.J., Sinks, L.F., et al.: Amputation and adriamycin in primary osteosarcoma. N. Engl. .I. Med. 291: 998-1000, 1974. Frei, E., III, Jaffe, N., Tattersall, M.H.N., Pitman, S., Parker, L.: New approaches to cancer chemotherapy with methotrexate. N. Engl. J. Med. 292: 846-851, 1975. Freidman, M.A., Carter, SK.: The therapy of osteogenic sarcoma: current status and thoughts for the future. J. Surg. Oncol. 4: 482-S 10, 1972. Jaffe, N.: Progress report on high-dose methotrexate (NSC-740) with citrovorum rescue in the treatment of metastatic bone tumors. Cancer Chemother. Rep. 58: 275-280, 1974.
6. Jaffe, N., Farber, S., Traggis, D., Geiser, C., et al.: Favorable response of osteogenic sarcoma to high dose methotrexate with citrovorum rescue and radiation therapy. Cancer 31: 1-4, 1973. 7. Jaffe, N., Frei, E., III, Traggis, D., Bishop, Y.: factor Ad juvant methotrexate-citrovorum treatment of osteogenic sarcoma. N. Engl. J. Med. 291: 994-997, 1974. 8. Jaffe, N., Frei, E., III, Traggis, D., Watts, H.: Weekly high-dose methotrexate-citrovorum factor in osteogenic sarcoma: pre-surgical treatment of primary tumor and of overt pulmonary metastases. Cancer 39: 45-50, 1977. 9. Jaffe, N., Traggis, D.: Toxicity of high-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother. Rep. 6: 31-36, 1975. 10. Jaffe, N., Traggis, D., Cassady, J.R., Filler,
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0 Physics
March-April
1977. Volume
2, No. 3 and No. 4
R.M., Watts, H., Frei, E., III: Advances in the treatment of osteogenic sarcoma. To be published. 11. Jaffe, N., Traggis, D., Cassady, J.R., Filler. R.M., Watts, H., Frei, E., III: Multidisciplinary treatment for macrometastic osteogenic sarcoma. Br. Med. J. 2: 1039-1041, 1976. 12. Rosen, G., Murphy, M.L., Huvos, A.G., Gutierrez, M., Marcove, R.C.: Chemotherapy, en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37: l-l 1, 1976. S., Kwon, C., Tan, C., 13. Rosen, G., Suwansirikul, Wu, S.J., Beattie, E.J., Jr., Murphy, M.L.: High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer 33: 115 l-l 163, 1974.
14. Rosen, G., Tefft, M., Martinez, A., Cham, W., Murphy, M.L.: Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma. Cancer 35: 622-630, 1975. 15. Schabel, F.M., Jr.: Concepts for systemic treatment of micrometastases. Cancer 35: 15-24, 1975. D.J.,, 16. Sutow, W.W., Sullivan, M.P., Fernbach, Cangir, A., George, S.L.: Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. Cancer 36: 15981602, 1975. 17. Wilbur, J.R., Etcubanas, E., Long, T., Glatstein, E., Leavitt, T.: 4 drug therapy and irradiation in primary and metastic osteogenic sarcoma. Proc. AACR/ASCO,I Houston, Texas, 1974, Vol. 15, page 188, Abstract No. 816.
I-AACR = American Research.
ASCO = American cology.
Association
for
Cancer
Society
for
Clinical
On-
Oncology Biof. Phys.,
1977, Vol. 2, pp
261-266
Pergamon Press.
Printed in the U.S.A.
??Original Contribution
THE ROLE OF HIGH-DOSE METHOTREXATE WITH CITROVORUM FACTOR “RESCUE” IN THE TREATMENT OF OSTEOGENIC SARCOMA?
NORMAN
JAFFE,
J. ROBERTCASSADY, HUGH
M.D.,
WATTS,
DEMETRIUS
M.D.,
M.D.
ROBERT
EMIL
TRAGGIS, M.
FREI,
M.D.,
FILLER, III,
M.D.,
M.D.
Children’s Hospital Medical Center, Divisions of Orthopedic Surgery and General Surgery, Sidney Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, U.S.A. Osteogenic sarcoma has been shown to be responsive to adriamycin (ADR) and vincristine-high-dose methotrexate with citrovorum factor “rescue” (VCR-MTX-CF). Both regimens have produced responses in patients with established disease. These experiences prompted utilization of these forms of chemotherapy in adjuvant programs. The VCR-MTX-CF regimen was also utilized in combination with radiation therapy to treat patients with inoperable tumors and those with presumed residual microscopic tumor in the lungs or elsewhere following surgical resection. More recently, chemotherapy was utilized in pre-treatment programs to facilitate local en bloc resection and insertion of internal prostheses to achieve useful functioning limbs. The evolution of these programs at the Sidney Farber Cancer Institute from January 1971, is documented and the results are updated to June 1976. Osteogenic sarcoma,
High dose methotrexate,
Adriamycin,
Radiation
METHODS
INTRODUCTION
therapy.
AND MATERIALS
Therapeutic research during the past five years has demonstrated that osteogenic sarcoma no longer should be considered a chemoresistant tumor. Thus, adriamycin (ADR) and vincristine-high-dose methotrexate with citrovorum factor “rescue” (VCR-MTXCF) have eradicated overt metastases,‘,5,6,8,‘3 improved survival in patients after ablative surgery2,7.‘6 and permitted local en bloc resection with preservation of useful functioning limbs.“,‘2 This report describes the evolution of the treatment programs initiated at the Sidney Farber Cancer Institute in January 1971, and updates the results to June 1976.
The basic VCR-MTX-CF program (Fig. 1) involves the admistration of VCR (2 mg/m*maximum 2 mg) followed 0.5 hr later by a 6-hr infusion of MTX (3 g/m’, 6 g/m’ and 7.5 g/m’ at 2-3 weekly intervals). Two hours after the completion of the MTX infusion, CF is administered over 72 hr. During the first 24 hours, it is administered intravenously at 3-hourly intervals and during the subsequent 48 hr at 6-hourly intervals by the oral route. The first oral dose commences 3 hr after the last intravenous dose. In this review, this therapeutic approach is designated Regimen 1. In June 1974, adriamycin (ADR) was incor-
tSupported in part by a research grant (CA06516) from the National Cancer Institute and by a grant (RR-05526) from the Division of Research Facilities and Resources, National Institutes of Health.
Reprint requests to: Sidney Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, U.S.A. 261
262
Radiation
Oncology
0 Biology 0 Physics
VCR-MTX-CF MTX i 0 5 hrs
I
YTX
I
~lv~
6hrs
V = VINCRISTINE
72 hrs
2 mg/M’
MTX=METHOTREXATE
3gms/M2;
CF = CITROVORUM FACTOR
Fig. 1. Basic
c-FrA
2 hrs
high-dose
6gms/MZ;75gms/M2
l5mg q3h 15mgq6h
I v.
methotrexate
program.
VCR-MTX-CF
2
mg/M*
MTX = METHOTREXATTE 3gms/M’, 6gms/MZ, CF = CiTROVORuM FACTOR 15mg q3h V 15mgq6h PO ALU?= ADRIAMYCIN 75 mg/M’
Fig. 2. Basic high-dose
methotrexate tin program.
1977, Volume
2, No.
3 and No. 4
of treatment. The cardiac status of each patient was monitored at regular intervals prior to administration of ADR by electrocardiographic studies, presystolic ejection time intervals and heart size by radiographic examination. Liver function studies and hemograms were also obtained immediately prior to the administration of ADR.
PO
porated into the treatment protocol (Fig. 2). It was administered 4 days after the completion of CF at a dose of 75 mg/m*. In view of possible myelosuppression which may be induced by ADR, Regimen 1 courses were extended to a 4 week cycle. After a cumulative dose of 450 mg/m* of ADR had been administered, the tri-weekly schedule for 1 was re-instated. The duration of Regimen treatment was 18 months. This therapeutic program is designated Regimen 2. With increasing experience and with the availability of pharmacologic monitoring to measure serum MTX levels, investigations were conducted to determine the efficacy of administration of Regimen 1 on a weekly basis. Generally, 4-8 weekly courses were administered. This weekly administration is designated Regimen 3. Prior to each course of MTX treatment, creatinine clearances were obtained and daily serum creatinine and MTX levels during the course. If a value in excess of 1 X lo-’ molar at 72 hours was detected, CF was continued until a result below this level was obtained. Leukocyte and platelet counts and liver function studies were obtained at semi-weekly intervals. Radiographs of the chest were obtained every 2-3 weeks prior to each course
” = “INCRlSTlNE
March-April
75gms/M’
and adriamy-
Radiation therapy In the early experience, radiation therapy was added to the treatment of Regimen 1 in patients with overt pulmonary metastases after apparent failure of response to the chemotherapy regimen. Patients were irradiated with a 4 or 8 Mev linear accelerator in all instances. They generally received 1500 rad/ 10 fractions/ 12 days.” More recently, radiation therapy was administered with increasing frequency in combination with Regimen 3. Patients with presumed residual microscopic tumor in the lungs following thoracotomy received I500 rad, administered in 150 rad fractions to both whole lung fields. One patient with residual tumor in the right pericardial area received an additional 1800 rad/9 fractions/ 11 days (total 3300 rad in 32 days). Similar “cone down” irradiation was administered following pulmonary nodule resection when surgical margins were questionable or positive. Radiation therapy was also administered in several patients to tumor located in extra pulmonary sites. Following incomplete resection of inguinal node metastases, I patient received 5200 rad/27 fractions/57 days to the left pelvis and inguinal femoral region. Treatment was interrupted after the second weekly course of chemotherapy because of drug toxicity, but was resumed 2 weeks later. A second patient received 4000 rad/20 fractions/28 days for an inoperable osteogenic sarcoma of the pelvis. He had previously received less than 3000 rad to the tumor concurrently with ADR at another institution. Patients Regimen 1. This was administered initially to 14 patients with pulmonary metastases (updated from original reports).3.h It was also utilized as adjuvant treatment after primary
The treatment
of osteogenic
definitive surgical therapy: there were 12 patients with the “classical” variety of osteogenic sarcoma with local control and 8 with other types, including 4 with the parosteal variety.’ To determine the efficacy of the adjuvant treatment, the incidence of pulmonary metastases was analyzed in 78 patients with “classical” osteogenic sarcoma and local control previously treated at the Sidney Farber Cancer Institute and Children’s Hospital Medical Center. Regimen 2. This was administered to 22 patients with “classical” osteogenic sarcoma following local control achieved by surgery. The incidence of pulmonary metastases in the historical control group outlined earlier, and in the treated patients, was also utilized to determine the efficacy of the treatment program. Regimen 3. This was administered to 3 groups of patients: Group I-15 patients with pulmonary metastases. Six had not received prior MTX treatment and 9 had previously received treatment with Regimen 1. Group 2-10 patients after resection of pulmonary metastases, one after incomplete resection of inguinal node metastases and one with a primary inoperable osteogenic sarcoma of the pelvis (see above). Five of the patients had been treated previously with Regimen 1 but still had residual lesions.” Following surgical residual microscopic resection, disease was considered to be present. These patients received radiation therapy, as outlined earlier. Group 3-7 patients were treated preoperatively with chemotherapy with intent to perform a limited resection of the primary tumor rather than limb ablation. Four to 8 weekly courses of treatment were administered. Two patients also received intraarterial ADR following the last course of MTX therapy. RESULTS Among the 14 patients treated with Regimen 1, 2 complete and 2 partial responses were obtained. One of these patients in whom a complete response was obtained remained alive and well, free of disease, 5 years later.
sarcoma 0 N.
JAFFE
et
al.
263
She recently delivered a live, normal baby who was without evidence of congenital abnormalities. Additionally, responses were also obtained in 4 patients with a combination of radiation therapy and Regimen 1.5.6 Seven of the 12 patients with “classical” osteogenic sarcoma treated with Regimen 1 as adjuvant therapy have remained free of pulmonary metastases for 2-4.5 yr (Fig. 3). The last patient who developed pulmonary metastases was free of disease at the time treatment was discontinued at 18 months. One month later, however, another lesion (? new primary tumor) was detected in the contralateral non-amputated femur. This was followed one month later by pulmonary metastases. Although it is possible that the metastases were derived from the “new” tumor, she was classified as a failure of adjuvant treatment. Two of the patients who developed pulmonary metastases were subOSTEOGENIC SARCOMA
100 90
LUNG MEYSTASES MTX-“CR-W ~/I
MONTHS
TO METASTASES
Fig. 3. Cumulative incidence of pulmonary metastases in historical and study groups. LCA represents local control achieved. The arrows represent the time of the last follow-up examination for individual patients. In the study group, the upper curve represents 12 patients with “classical” osteogenic sarcoma in whom local control was achieved. The lower curve represents the total experience.‘.‘”
264
Radiation
Oncology
0 Biology
0 Physics
sequently rendered free of disease by surgical resection. Five of the 8 other patients with different forms of osteogenic sarcoma also remain free of pulmonary metastases. Results in the patients with “classical” osteogenic sarcoma and local control and in the total experience are presented in Fig. 3. When compared to the historical control group, the difference in the incidence of metastases in the “local control” group and in the total study is highly significant (p < 0.001). Six of the 22 patients treated with Regimen 2 have developed pulmonary metastases. The remaining 16 have been free of disease for 8+ to 24+ months. This is outlined in Fig. 4 which also depicts the incidence of pulmonary metastases in the 12 patients with “classical” osteogenic sarcoma treated with Regimen 1. When compared to the historical control group, the difference in the incidence of pulmonary metastases is also highly significant (p < 0.001). Therefore, the results of both adjuvant programs are very similar to date. OSTEOGENIC PULMONARY
SARCOMA LCA METASTASES
loo-
go-
V-YTX-CFI N. 12) v-YTX-CF-A( w22, HlSTQnC COW‘KXS~N=
76)
SO-
TOz C601 !Fl = 50c 2 0 40: 2 $
JO-
O
I6
12 TIME-MONTHS
IS
24
+
March-April
1977, Volume
2, No. 3 and No. 4
With respect to Regimen 3, among the 6 patients in Group 1 who had not received prior MTX treatment, complete responses were obtained in 3 and a partial response in one. Additionally, 3 partial responses were obtained in patients who had received prior MTX treatment.” Nine of the 10 patients in Group 2 treated with Regimen 3 and radiation therapy remained free of recurrent disease for 6+ to 18+ months. Similarly, the patient with inguinal node metastases remained free of recurrent disease for 6+ months at the time of writing. A partial response was obtained in the patient receiving Regimen 3 and radiation therapy for the inoperable osteogenic sarcoma of the pelvis. Regimen 3 administered as a component of primary definitive therapy in the 7 patients (Group 3) produced partial responses in 4 and complete responses in 2. An amputation was performed in one of these patients because of complications induced by adriamycin. One patient failed to demonstrate a response. In 5 of the patients who responded, and 1 who failed to respond, a local en bloc resection was performed followed by insertion of an internal prosthesis. This resulted in preservation of the limb with a potential for useful function. Pulmonary metastases developed 6 months after diagnosis in the patient who failed to respond at the time of writing. The poor result in this patient was only demonstrated pathologically after examination of the resected specimen. The rest remain free of recurrent disease for 5+ to 18+ months. Toxicity The incidence of side effects with various regimens was less than lo%.” It comprised stomatitis, disturbances in liver function studies, transient renal abnormalities and myelosuppression. There was no exaggeration in the incidence of toxicity with Regimen 3. The major side effect encountered with the weekly schedule was weight loss.*
TO HETASTASES
Fig. 4. Cumulative incidence of pulmonary metastases in historical control group, 12 patients with “classical” osteogenic sarcoma in whom local control was achieved (see Fig. 2) and 22 patients treated with V-MTX-CF and adriamycin.
DISCUSSION The demonstration that various regimens may cause destruction of bulk tumor in patients with pulmonary metastases and in
The treatment
of osteogenic
patients with primary lesions is of signal importance. It justifies the administration of these regimens as adjuvant treatment as a means of eradicating pulmonary micrometastases. These are presumed to be present in over 80% of patients at diagnosis.’ Such metastases generally are more vulnerable to the action of effective chemotherapy than the primary tumor from which they were derived.15 Thus, approximately 60% of the patients treated with Regimen 1 failed to develop metastases and are probably cured. This contrasts with historical control patients where pooled data reveal that approximately 20% of patients survive.4 The addition of ADR to the basic regimen, Regimen 2, does not appear to have changed the results to date. However, the experience still is preliminary and further periods of observation are warranted. In patients who relapsed on adjuvant therapy, the number and time of appearance of pulmonary metastases appeared limited and delayed. This permitted more aggressive surgical intervention, rendering additional patients free of disease. These patients were also treated with radiation therapy and chemotherapy (Regimen 3) since they were considered to be at high risk for recurrence.” Methotrexate potentiates the action of radiation therapy5.6.14.‘7 and contrary to the ex-
sarcoma
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265
treatment does perience of others, I4 combined not appear to have produced inordinate degrees of pulmonary fibrosis. Regimen 3 represents a major advance in the application of high-dose MTX for osteogenic sarcoma. Utilizing this approach, a response rate of 88% was obtained in patients with pulmonary metastases or primary lesions who had not received prior MTX therapy.8 In several instances, complete tumor eradiation was noted. This was demonstrated by radiographic examination and confirmed by histologic studies.’ The experiences with high-dose MTX and ADR demonstrate that the regimens should be incorporated as a major component in the treatment of osteogenic sarcoma. Patients with the disease should be approached with curative intent. The results of combined treatment with radiation therapy and chemotherapy (Regimen 3) are preliminary but encouraging. Should permanent control of disease be achieved, they may provide justification for the “prophylactic” administration of such treatment to the lungs in future patients. Similarly, the preliminary exciting results achieved with the limb preservation program have prompted consideration to extending the study to an increasing number of selected patients.
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J.F., Wang, J.J., Sinks, L.F.: Doxorubicin in disseminated osteosarcoma. J. Am. Med. Assoc. 221: 1132-1138, 1972. Cortes, E.P., Holland, J.F., Wang, J.J., Sinks, L.F., et al.: Amputation and adriamycin in primary osteosarcoma. N. Engl. .I. Med. 291: 998-1000, 1974. Frei, E., III, Jaffe, N., Tattersall, M.H.N., Pitman, S., Parker, L.: New approaches to cancer chemotherapy with methotrexate. N. Engl. J. Med. 292: 846-851, 1975. Freidman, M.A., Carter, SK.: The therapy of osteogenic sarcoma: current status and thoughts for the future. J. Surg. Oncol. 4: 482-S 10, 1972. Jaffe, N.: Progress report on high-dose methotrexate (NSC-740) with citrovorum rescue in the treatment of metastatic bone tumors. Cancer Chemother. Rep. 58: 275-280, 1974.
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1977. Volume
2, No. 3 and No. 4
R.M., Watts, H., Frei, E., III: Advances in the treatment of osteogenic sarcoma. To be published. 11. Jaffe, N., Traggis, D., Cassady, J.R., Filler. R.M., Watts, H., Frei, E., III: Multidisciplinary treatment for macrometastic osteogenic sarcoma. Br. Med. J. 2: 1039-1041, 1976. 12. Rosen, G., Murphy, M.L., Huvos, A.G., Gutierrez, M., Marcove, R.C.: Chemotherapy, en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37: l-l 1, 1976. S., Kwon, C., Tan, C., 13. Rosen, G., Suwansirikul, Wu, S.J., Beattie, E.J., Jr., Murphy, M.L.: High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer 33: 115 l-l 163, 1974.
14. Rosen, G., Tefft, M., Martinez, A., Cham, W., Murphy, M.L.: Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma. Cancer 35: 622-630, 1975. 15. Schabel, F.M., Jr.: Concepts for systemic treatment of micrometastases. Cancer 35: 15-24, 1975. D.J.,, 16. Sutow, W.W., Sullivan, M.P., Fernbach, Cangir, A., George, S.L.: Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. Cancer 36: 15981602, 1975. 17. Wilbur, J.R., Etcubanas, E., Long, T., Glatstein, E., Leavitt, T.: 4 drug therapy and irradiation in primary and metastic osteogenic sarcoma. Proc. AACR/ASCO,I Houston, Texas, 1974, Vol. 15, page 188, Abstract No. 816.
I-AACR = American Research.
ASCO = American cology.
Association
for
Cancer
Society
for
Clinical
On-
