Inr. J. Radiation
Oncology
Biol.
Phys..
1976. Vol.
I. pp. 407-413
Pergamon
EWING’S
Press
Printed
m the U.S.A
SARCOMA
ADJUVANT TOTAL BODY IRRADIATION, CYCLOPHOSPHAMIDE AND VINCRISTINE RICHARD D. T. JENKIN, M.B.,* WALTER D. RIDER, M.B.$ and MARILYN J. SONLEY, M.D.5 The Faculty
of Medicine.
University
of Toronto.
Toronto,
Canada
For patients with Ewing’s Sarcoma treated from 1960 to 1973, the 5year survival and relapse free rates were: primary site irradiation without systemic treatment (16 patients) 25% and 12%: primary site irradiation with total body irradiation (13 patients) 3WG and 23%. The Cyear survival and relapse free rates for 12 patients treated from 1970 to 1973 by primary site irradiation, total body irradiation and one year of elective Cyclophosphamide and Vincristine were 40% and 30%. These data provide further evidence that systemic therapy may be effective in eradicating occult metastases in a moderate proportion of patients with Ewing’s Sarcoma. Ewing’s Sarcoma,
Adjuvant
total body irradiation,
INTRODUCTION
?Assistant Professor. and Pediatrics.
Departments
Vincristine.
evaluate systemic adjuvant therapy which we regarded as sequential, related, single institution pilot studies of Ewing’s Sarcoma. We shall review this experience and compare it with our former experience in 1%0-64 when no adjuvant therapy was used.
Classically most patients with Ewing’s Sarcoma develop overt bone and lung metastases
within the first year from diagnosis and rapidly succumb to their disease. Thus in a literature review of 944 patients Falk and Alpert gave only an 8% 5-year survival rate.’ At a single institution Pritchard et al. reported a 16% 5-year survival rate in a series of 229 patients treated from 1912 to 1968.” Therefore a clear need existed for an effective adjuvant treatment which would eradicate occult metastatic disease. During the last decade a number of studies, generally conducted in single institutions with small numbers of patients, have demonstrated that adjuvant chemotherapy will increase the relapse free survival rate during the first 2 years following diagnosis.3”.“.9.” This initial improvement may be maintained. Pomeroy and Johnson have reported a median survival in excess of 5 years in a series of 43 patients without gross metastatic disease at diagnosis who were treated with adjuvant chemotherapy.’ At The Princess Margaret Hospital (P.M.H.) during the period 1%5-73, two specific treatment protocols were used to
Cyclophosphamfde,
METHODS AND MATERIALS From 1960 to 1973, 54 consecutive patients with previously untreated Ewing’s Sarcoma were referred to P.M.H. The diagnosis was confirmed at this hospital clinically and histologically. An additional 3 patients were accepted initially as Ewing’s Sarcoma but their subsequent progress indicated that the correct diagnosis was primary malignant lymphoma of bone. In Toronto radiation therapy services are centralized in one hospital (P.M.H.). For this
reason we believe this series to be unselected and representative of this disease in the Metropolitan Toronto and Northern Ontario regions. The primary site involved, age and sex distribution are given in Figs. 1 ‘and 2. Demonstrable metastatic disease was present at diagnosis in 9 of the 54 patients. The
of Radioiogq
SAssociate Professor, Department of Radiology. PAssistant Professor, Department of Pediatrics. 407
Radiation Oncology 0 Biology ??Physics
408
March-April 1976. Vol. 1, Number 5 and Number 6
the whole of the affected bone together with all the soft tissues of that segment of the limb. The same principle of large volume irradiation was applied to other sites. The tumor dose was 5000 rad in 25 fractions in 5 weeks or a dose closely equivalent.’ 1%5-69 R + TBI Local treatment was unaltered but after completion of local irradiation total body irradiation (TBI) was given as adjuvant systemic therapy in a single dose of 300 rad in 20-30 min.’
Fig. 1. Ewing’s Sarcoma. Individual are indicated.
primary sites
0
9 (221
?? 8 (32) a”. Y.15,’
0-I
4-5 2-3
6-9 6-7
IO-11
Q-13 16-17 2U-21 24-25 14-15 16-19 22-23 26-27
Fig. 2. Ewing’s Sarcoma. Age and sex distribution. screening tests for metastatic disease included a skeletal survey and bone marrow in all
patients, with the addition of a skeletal scintogram in recent years. Three primary treatment programs to be compared are:
1970-73 R + TBI + CV After completion of local and total body irradiation and adequate bone marrow recovery, elective chemotherapy with Cyclophosphamide and Vincristine was commenced. These drugs were given as alternating weekly injections for 12 months. Cyclophosphamide, 15 mglkg i.v. and Vincristine, 0.05 mg/kg i.v. (maximum dose 2 mg). Treatment of relapse throughout these years was by local irradiation for localized disease in bone and whole lung f local irradiation for lung metastases. Chemotherapy, generally using sequential maintained single agents, was always given for generalized relapse, but during these years was utilized at a progressively earlier stage so that during 1%5-69 chemotherapy was usually given at the time of the first relapse together with local irradiation. Generally the single agents were used in the sequence Cyclophosphamide, Vincristine, Chlorambucil, Actinomycin-D and more recently Adriamycin. The detailed distribution of the primary treatments used during the intervals 1%0-64, 1%5-69 and 1970-73 is given in Table 1. We shall compare treatment results in the 16 patients treated by local irradiation alone; 13 patients treated by local irradiation and TBI and 12 treated by local irradiation, TBI and elective Cyclophosphamide and Vincristine. RESULTS
1%0-64 R Local irradiation alone. The volume irradiated for primary sites in the limbs included
(a) Sumiual The crude 5-year survival rates in the first two of these treatment programs were:
Ewing’s Sarcoma 0 R. D. T. JENKIN
Table 1. Variation in primary treatment R+TBI
R 1%~64 1965-69 1970-73
14 2
methods
during 1960-73
R+TBI+CV
Other
Totals
12
16
409
etal.
1
15 17 22 54
1
17
3 9
13
12
13
R Local irradiation only. R + TBI Local irradiation plus total body irradiation. R + TBI + CV Local irradiation plus total body irradiation Cyclophosphamide and Vincristine
and elective
1960-64 R 25% (4/16 patients) 1965-69 R + TBI 38% (5/13 patients). The projected Life Table 4-year rate for the most recent group is :
survival
1970-73 R+TBI +CV 40% (12 patients), Fig. 3. t
(b) Relapse free survival The 5-year relapse free rates were:
0
Fig. 4. Relapse
1960-64R
12% (2/16 patients)
1%5-69 R + TBI 23% (3/13 patients). and the projected
4-year relapse free rate:
1970-74 R + TBI + CV 30% (12 patients), Fig. 4. (c) Control of the primary tumor A first relapse by recurrence of the primary tumor alone was found in 6 of these 54 patients. An additional 6 relapsed synchronously at the primary site and with distant
2 3 Y‘ZOiS
4
free survival by primary method.
5
treatment
metastatic disease. The initial primary tumor relapse rate therefore was 22% (12/54). The addition of 300 rad TBI or 300 rad TBI with 1 year of Cyclophosphamide and Vincristine did not influence the primary tumor control rate as far as we can judge in this small series (Table 2). Conversely Fernandez et al. found that elective chemotherapy with pulsed Cyclophosphamide and Vincristine did increase the control rate at the primary site for a given method
IO0
I
of local
irradiation.’
1 '\
L s
I
2
3
4
5
Years
Fig. 3. Crude survival by primary treatment method. Numerals in brackets ( ) indicate number of patients treated
by each method.
DISCUSSION In comparing small groups of patients with Ewing’s Sarcoma we necessarily have to be very cautious since the different groups may not contain patients with equivalent prognosis. For example, reflecting our ignorance of the prognostic factors, we have no staging system for Ewing’s Sarcoma. The site of the primary tumor is related to prognosis. Tumors arising in the innominate bone do poorly and distal limb tumors fare better than proximal ones. Thus Pritchard et al. demon-
410
Radiation
Oncology
0
Biology 0 Physics
March-April 1976, Vol. 1, Number 5 and
Number
6
Table 2. The frequency of recurrence of the primary tumor at the time of first relapse is given for each treatment method Treatment method
No. recurrent 1”+2 1”
No. risk
Totals
R+TBI R+TBI+CV Other
16 13 12 13
3 1 2
1 2 2 1
4 2 3 3
Totals
54
6
6
12
R
1”Primary tumor recurrence alone. lo+ 2” Primary tumor recurrence + gross metastatic disease. strated in 229 patients a 22% 5-year survival rate for patients with limb tumors compared with 8% for patients with tumors at other sites.” Distribution of our patients according to primary site and treatment method is given in Table 3. We cannot exclude that these variations may mean there are important differences in the patients in the three compared groups. However, as a first approximation, the proportion of patients with “bad” tumors arising either in the innominate bones or the femurs is roughly the same in the three groups. The presence of overt systemic metastases at diagnosis is a bad prognostic sign. There were no such patients in Groups R or R + TBI + CV, whereas 3 of 13 patients in Group R + TBI were metastatic at diagnosis, although only to a single site in each patient. Since two of these 3 patients survived more
than 5 years their inclusion did not unfavorably bias this group. Of 54 consecutive patients, 41 were entered in three defined treatment regimens. The remaining 13 patients were a mixed group treated by a variety of methods; from 1960 to 1964 one patient with a distal tibia1 primary was treated by irradiation of only the distal one third of the limb. Subsequently the tumor recurred proximally in the tibia. The whole leg was then irradiated and she received TBI. She remained well 10 + years later. From 1%5-69 3 patients were treated by other methods: one boy with a primary tumor of the nasal bone was treated by surgical resection. Subsequently he required irradiation on two occasions for recurrence at the primary site. He remained well 8 + years after diagnosis; the second patient was the youngest in this series, being only 7 months old at diagnosis.
Table 3. The primary site distribution and incidence of systemic metastases at diagnosis is compared for patients within each treatment regimen Treatment Site
R
Pelvis Femur Tib + fib Humerus Radius-ulna Other
6 4 2 2 1 1
2 4 2 2 1 2
Total patients
16
13
-
R+TBI
Systemic 3
method
R+TBI+CV
Total
Other
6 1 2
2 2 4 2 3
16 11 10 6 3 8
13
54
1 2 12
patients
-
metastases at diagnosis 6
411
Ewing’s Sarcoma 0 R. D. T. JENKIN et al.
There was initial uncertainty concerning the diagnosis although it was confirmed at final autopsy. He was treated by local irradiation to the primary tibia1 tumor and for each of the next two relapses. The third patient was unsuitable for TBI due to widespread bone metastases at diagnosis. From 1970-73, nine patients were treated by other methods. Five had overt metastases at diagnosis and were considered unsuitable for TBI. All received Cyclophosphamide and Vincristine (CV) in various regimens. Only transient responses were obtained; 2 patients were given CV in other hospitals after primary tumor irradiation at P.M.H; 1 patient with a chronic tibia1 lesion was followed radiologically for 3 years before biopsy confirmed Ewing’s Sarcoma. He was treated by local irradiation in view of the chronicity but later developed metastases. While alive at 4 years he had uncontrolled disease. A final patient treated in 1973 electively received adjuvant treatment with Actinomycin-D, Cyclophosphamide and Vincristine. He remained in a first complete remission 1 year later. Thus the 13 patients treated by “other” methods were a very heterogeneous group, both in regard to natural history and to treatment methods employed. They cannot be compared with the “typical” patients included in the three specific treatment protocols. When we integrated the treatment results obtained in these subgroups into our total institutional experience, for all 54 consecutive patients, the 5-year survival rates were l%O64 27% (15 patients) and 1965-69 35% (17 patients) and the projected 4-year survival rate for 22 patients treated during 1970-73 is 49% (Fig. 5). Our baseline historical experi-
Table
Ewng'sSarcoma 1928-‘73
L..
I
Treatment R R+TBI R+TBI+CV *I of 12 patients
16 13 11*
2
not evaluable.
.
1928-'60(331
3
4
5
YWE
Fig. 5. Crude survival for each of the intervals 1960-64,1%5-69 and 1970-73. Numerals in brackets ( ) indicate number of patients in each interval. Our
prior experience 192~6Ois given. ence from 1928-60 was a 5-year survival rate of 9% (3/33).’ The changing pattern of these survival curves is the best evidence that systemic therapy has had an impact on the natural history of Ewing’s Sarcoma. Additional information is given by examining the median time from diagnosis to first relapse and from first relapse to death (Table 4). The median time to relapse for patients treated by R + TBI + CV will be not less than 20 months nor greater than 24 months, an improvement over 9.5 months for R and 12 months for R +TBI. Conversely when the disease broke through elective chemotherapy with Cyclophosphamide and Vincristine subsequent survival was brief with a median duration of 4 months compared with 13.5 months following relapse after treatment by R + TBI. Preliminary assessment of our experience with R + TBI in 1%9 indicated that while there might be a beneficial effect on long term
treatment
Median time (months) Diagnosis to First relapse first relapse to death 9.5 1’ 2&24
.
Pt3
‘---._
c
4. Variation of disease tempo with method in Ewing’s Sarcoma
Total patients
-(87
8 13.5 4
412
Radiation Oncology 0 Biology 0 Physics
survival, the early high relapse rate was similar to that found in the group of patients treated by local irradiation only.’ This result was expected and is now confirmed. During the middle and late 1960s others were demonstrating improved relapse free survival rates when combination chemotherapy was used electively with local irradiation of the primary tumor. Initially,3-6,R Cyclophosphamide and Vincristine were used with or without Actinomycin-D. For this reason, in 1970 we added Cyclophosphamide and Vincristine to systemic irradiation. While the median time to first relapse has increased, the disease broke through elective chemotherapy in 5/l 1 evaluable patients during the course of the first year, so that the initial siope of the relapse free survival curve remained steep and apparently the same as that associated with treatment by R or R+TBI. (Fig. 4). Markedly improved relapse free survival rates during the first two years have been Using an adjuvant reported recently. chemotherapy program combining Vincristine, Cyclophosphamide, Actinomycin-D and Adriamycin, Rosen et al. reported 12 of 12 children relapse free for intervals ranging from 10 to 37 months from diagnosis.” Of these 12 children, 4 had completed the 24 months program. Pomeroy and Johnson reported 14 of 15 patients relapse free for intervals ranging from 3 to 24 months from diagnosis. Their adjuvant program comprised of Adriamycin, Cyclophosfour cycles phamide and Vincristine combined with initial cranial irradiation and intrathecal Methotrexate.’ In the control of the primary tumor a dose of 5000 rad in 25 fractions is satisfactory. At this dose level acute and delayed combined therapy toxicity is acceptable. A first relapse at the primary site alone occurred in 11% of our patients, but there is no good data that higher doses of irradiation are more effective in primary tumor control, and above 5000 rad morbidity escalates rapidly. In only one patient in this series was the solitary primary recurrence in a limb, permitting salvage by amputation. When the primary tumor recurrence is associated with overt metastatic
March-April
1976, Vol. I. Number 5 and Number 6
disease moderate dose re-irradiation of the primary site usually will provide good symptomatic relief and adequate function through the final phase of the disease. In the initial irradiation of a primary limb tumor a rapid complete response with normal function is the rule. For this reason, in this era of improving results in the treatment of Ewing’s Sarcoma. irradiation remains the indicated treatment. However, it may be argued that immediate ablation of the limb would effectively eradicate the problem of primary tumor recurrence and the survival hazard that might be associated with this. Indeed, there is some evidence that in the absence of effective adjuvant therapy surgical treatment may be superior.“’ At the present time it seems best to reserve surgical treatment for the isolated recurrent primary tumor, for the functional and emotional price of initial amputation is currently much too high, considering the generally satisfactory results obtained with medical management.
CONCLUSIONS In our experience stepwise improvement in relapse free survival was obtained in Ewing’s Sarcoma when adjuvant therapy with TBI was added to local irradiation of the primary tumor and was again obtained when TBI+CV replaced TBI as adjuvant therapy. However, in these small series of not necessarily comparable patients we can attach no formal significance to these results. The gradual improvement of our overall survival rates in this unselected series during the period l%O-73 to levels not described prior to systemic therapy does suggest that in a small proportion of these patients our adjuvant treatment programs were eradicating micrometastases. We discontinued TBI + CV at the end of 1973 due to the unacceptable relapse rate during the Iirst year. In Ewing’s Sarcoma others have demonstrated that a complete remission may be induced rapidly and maintained in a high proportion throughout the first year by various combinations of adjuvant Cyclophosphamide, Vincristine, Actinomycin-D and Adriamycin,
Ewing’s Sarcoma 0 R. D. T. JENKINet nl.
together with primary tumor irradiation. Therefore it is now inappropriate to use a single high dose of TBI immediately following primary site irradiation since the consequent
413
pancytopenia delays effective combination chemotherapy for 4-6 weeks and TBI alone is not effective in preventing early relapse in a high proportion of patients.
REFERENCES radiotherapy. Proc. Am. Sot. Clin. Oncol. 15: 1. Baird. R.J., Krause, V.W.: Ewing’s tumor: a 1974, Abstract 800. review of 33 cases. Can. J. Surg. 6: 136-140, 7. Jenkin, R.D.T., Rider, W.D., Sonley, M.J.: 1963. 2. Falk, S., Alpert, M.: Five year survival of Ewing’s Sarcoma-a trial of adjuvant total body Surgery, irradiation. Radiation 96: 151-1.55. 1970. patients with Ewing’s Sarcoma. Gynaec. Obstet. 124: 319-324, 1%7. 8. Johnson, R.E., Pomeroy, T.C.: Integrated 3. Femandez, C.H., Lindberg, R.D., Sutow, W. W., therapy for Ewing’s Sarcoma., Am. J. RoentSamuels, M.L.: Localised Ewing’s Sarcoma. genol. 114: 532-535, 1972. Treatment and results. Cancer 34: 134-138, 9. Pomery, T.C., Johnson, R.E.: Combined modality therapy of Ewing’s Sarcoma. Cancer 35: 1974. 4. Freeman, AI., Sachatello, C., Gaeta, J., Shah, 3647, 1975. N.K., Wang, J.J., Sinks, L.F.: An analysis of 10. Pritchard, D.J., Dahlin, D.C., Dauphine, R.T., Ewing’s tumor in children at Roswell Park Taylor, W.F., Beabout, J.W.: Ewing’s Sarcoma. Memorial Institute. Cancer 29: 1563-1569. A clinico-pathological analysis of patients surviving five years or longer. J. Bone Joint 1972. Surg. 57A: 10-16, 1975. 5. Hustu, H.O., Pinkel, D., Pratt, C.B.: Treatment of clinically locahsed Ewing’s Sarcoma with 11. Rosen, G., Wollner, N., Tan, C., Wu. S.J., radiotherapy and combination chemotherapy. Hajdu, S.I., Chan, W., D’Angio, G.J., Mercy, Cancer 30: 1522-1527, 1972. M.L.: Disease free survival in Ewing’s Sarcoma 6. J&e, N., Sallan, S., Traggis, D., Cassady, R., treated with radiation therapy and adjuvant four Vawter, G.: Improved outlook for Ewing’s drug sequential chemotherapy. Cancer 33: Sarcoma with combination chemotherapy and 384-392, 1974.
Oncology
Biol.
Phys..
1976. Vol.
I. pp. 407-413
Pergamon
EWING’S
Press
Printed
m the U.S.A
SARCOMA
ADJUVANT TOTAL BODY IRRADIATION, CYCLOPHOSPHAMIDE AND VINCRISTINE RICHARD D. T. JENKIN, M.B.,* WALTER D. RIDER, M.B.$ and MARILYN J. SONLEY, M.D.5 The Faculty
of Medicine.
University
of Toronto.
Toronto,
Canada
For patients with Ewing’s Sarcoma treated from 1960 to 1973, the 5year survival and relapse free rates were: primary site irradiation without systemic treatment (16 patients) 25% and 12%: primary site irradiation with total body irradiation (13 patients) 3WG and 23%. The Cyear survival and relapse free rates for 12 patients treated from 1970 to 1973 by primary site irradiation, total body irradiation and one year of elective Cyclophosphamide and Vincristine were 40% and 30%. These data provide further evidence that systemic therapy may be effective in eradicating occult metastases in a moderate proportion of patients with Ewing’s Sarcoma. Ewing’s Sarcoma,
Adjuvant
total body irradiation,
INTRODUCTION
?Assistant Professor. and Pediatrics.
Departments
Vincristine.
evaluate systemic adjuvant therapy which we regarded as sequential, related, single institution pilot studies of Ewing’s Sarcoma. We shall review this experience and compare it with our former experience in 1%0-64 when no adjuvant therapy was used.
Classically most patients with Ewing’s Sarcoma develop overt bone and lung metastases
within the first year from diagnosis and rapidly succumb to their disease. Thus in a literature review of 944 patients Falk and Alpert gave only an 8% 5-year survival rate.’ At a single institution Pritchard et al. reported a 16% 5-year survival rate in a series of 229 patients treated from 1912 to 1968.” Therefore a clear need existed for an effective adjuvant treatment which would eradicate occult metastatic disease. During the last decade a number of studies, generally conducted in single institutions with small numbers of patients, have demonstrated that adjuvant chemotherapy will increase the relapse free survival rate during the first 2 years following diagnosis.3”.“.9.” This initial improvement may be maintained. Pomeroy and Johnson have reported a median survival in excess of 5 years in a series of 43 patients without gross metastatic disease at diagnosis who were treated with adjuvant chemotherapy.’ At The Princess Margaret Hospital (P.M.H.) during the period 1%5-73, two specific treatment protocols were used to
Cyclophosphamfde,
METHODS AND MATERIALS From 1960 to 1973, 54 consecutive patients with previously untreated Ewing’s Sarcoma were referred to P.M.H. The diagnosis was confirmed at this hospital clinically and histologically. An additional 3 patients were accepted initially as Ewing’s Sarcoma but their subsequent progress indicated that the correct diagnosis was primary malignant lymphoma of bone. In Toronto radiation therapy services are centralized in one hospital (P.M.H.). For this
reason we believe this series to be unselected and representative of this disease in the Metropolitan Toronto and Northern Ontario regions. The primary site involved, age and sex distribution are given in Figs. 1 ‘and 2. Demonstrable metastatic disease was present at diagnosis in 9 of the 54 patients. The
of Radioiogq
SAssociate Professor, Department of Radiology. PAssistant Professor, Department of Pediatrics. 407
Radiation Oncology 0 Biology ??Physics
408
March-April 1976. Vol. 1, Number 5 and Number 6
the whole of the affected bone together with all the soft tissues of that segment of the limb. The same principle of large volume irradiation was applied to other sites. The tumor dose was 5000 rad in 25 fractions in 5 weeks or a dose closely equivalent.’ 1%5-69 R + TBI Local treatment was unaltered but after completion of local irradiation total body irradiation (TBI) was given as adjuvant systemic therapy in a single dose of 300 rad in 20-30 min.’
Fig. 1. Ewing’s Sarcoma. Individual are indicated.
primary sites
0
9 (221
?? 8 (32) a”. Y.15,’
0-I
4-5 2-3
6-9 6-7
IO-11
Q-13 16-17 2U-21 24-25 14-15 16-19 22-23 26-27
Fig. 2. Ewing’s Sarcoma. Age and sex distribution. screening tests for metastatic disease included a skeletal survey and bone marrow in all
patients, with the addition of a skeletal scintogram in recent years. Three primary treatment programs to be compared are:
1970-73 R + TBI + CV After completion of local and total body irradiation and adequate bone marrow recovery, elective chemotherapy with Cyclophosphamide and Vincristine was commenced. These drugs were given as alternating weekly injections for 12 months. Cyclophosphamide, 15 mglkg i.v. and Vincristine, 0.05 mg/kg i.v. (maximum dose 2 mg). Treatment of relapse throughout these years was by local irradiation for localized disease in bone and whole lung f local irradiation for lung metastases. Chemotherapy, generally using sequential maintained single agents, was always given for generalized relapse, but during these years was utilized at a progressively earlier stage so that during 1%5-69 chemotherapy was usually given at the time of the first relapse together with local irradiation. Generally the single agents were used in the sequence Cyclophosphamide, Vincristine, Chlorambucil, Actinomycin-D and more recently Adriamycin. The detailed distribution of the primary treatments used during the intervals 1%0-64, 1%5-69 and 1970-73 is given in Table 1. We shall compare treatment results in the 16 patients treated by local irradiation alone; 13 patients treated by local irradiation and TBI and 12 treated by local irradiation, TBI and elective Cyclophosphamide and Vincristine. RESULTS
1%0-64 R Local irradiation alone. The volume irradiated for primary sites in the limbs included
(a) Sumiual The crude 5-year survival rates in the first two of these treatment programs were:
Ewing’s Sarcoma 0 R. D. T. JENKIN
Table 1. Variation in primary treatment R+TBI
R 1%~64 1965-69 1970-73
14 2
methods
during 1960-73
R+TBI+CV
Other
Totals
12
16
409
etal.
1
15 17 22 54
1
17
3 9
13
12
13
R Local irradiation only. R + TBI Local irradiation plus total body irradiation. R + TBI + CV Local irradiation plus total body irradiation Cyclophosphamide and Vincristine
and elective
1960-64 R 25% (4/16 patients) 1965-69 R + TBI 38% (5/13 patients). The projected Life Table 4-year rate for the most recent group is :
survival
1970-73 R+TBI +CV 40% (12 patients), Fig. 3. t
(b) Relapse free survival The 5-year relapse free rates were:
0
Fig. 4. Relapse
1960-64R
12% (2/16 patients)
1%5-69 R + TBI 23% (3/13 patients). and the projected
4-year relapse free rate:
1970-74 R + TBI + CV 30% (12 patients), Fig. 4. (c) Control of the primary tumor A first relapse by recurrence of the primary tumor alone was found in 6 of these 54 patients. An additional 6 relapsed synchronously at the primary site and with distant
2 3 Y‘ZOiS
4
free survival by primary method.
5
treatment
metastatic disease. The initial primary tumor relapse rate therefore was 22% (12/54). The addition of 300 rad TBI or 300 rad TBI with 1 year of Cyclophosphamide and Vincristine did not influence the primary tumor control rate as far as we can judge in this small series (Table 2). Conversely Fernandez et al. found that elective chemotherapy with pulsed Cyclophosphamide and Vincristine did increase the control rate at the primary site for a given method
IO0
I
of local
irradiation.’
1 '\
L s
I
2
3
4
5
Years
Fig. 3. Crude survival by primary treatment method. Numerals in brackets ( ) indicate number of patients treated
by each method.
DISCUSSION In comparing small groups of patients with Ewing’s Sarcoma we necessarily have to be very cautious since the different groups may not contain patients with equivalent prognosis. For example, reflecting our ignorance of the prognostic factors, we have no staging system for Ewing’s Sarcoma. The site of the primary tumor is related to prognosis. Tumors arising in the innominate bone do poorly and distal limb tumors fare better than proximal ones. Thus Pritchard et al. demon-
410
Radiation
Oncology
0
Biology 0 Physics
March-April 1976, Vol. 1, Number 5 and
Number
6
Table 2. The frequency of recurrence of the primary tumor at the time of first relapse is given for each treatment method Treatment method
No. recurrent 1”+2 1”
No. risk
Totals
R+TBI R+TBI+CV Other
16 13 12 13
3 1 2
1 2 2 1
4 2 3 3
Totals
54
6
6
12
R
1”Primary tumor recurrence alone. lo+ 2” Primary tumor recurrence + gross metastatic disease. strated in 229 patients a 22% 5-year survival rate for patients with limb tumors compared with 8% for patients with tumors at other sites.” Distribution of our patients according to primary site and treatment method is given in Table 3. We cannot exclude that these variations may mean there are important differences in the patients in the three compared groups. However, as a first approximation, the proportion of patients with “bad” tumors arising either in the innominate bones or the femurs is roughly the same in the three groups. The presence of overt systemic metastases at diagnosis is a bad prognostic sign. There were no such patients in Groups R or R + TBI + CV, whereas 3 of 13 patients in Group R + TBI were metastatic at diagnosis, although only to a single site in each patient. Since two of these 3 patients survived more
than 5 years their inclusion did not unfavorably bias this group. Of 54 consecutive patients, 41 were entered in three defined treatment regimens. The remaining 13 patients were a mixed group treated by a variety of methods; from 1960 to 1964 one patient with a distal tibia1 primary was treated by irradiation of only the distal one third of the limb. Subsequently the tumor recurred proximally in the tibia. The whole leg was then irradiated and she received TBI. She remained well 10 + years later. From 1%5-69 3 patients were treated by other methods: one boy with a primary tumor of the nasal bone was treated by surgical resection. Subsequently he required irradiation on two occasions for recurrence at the primary site. He remained well 8 + years after diagnosis; the second patient was the youngest in this series, being only 7 months old at diagnosis.
Table 3. The primary site distribution and incidence of systemic metastases at diagnosis is compared for patients within each treatment regimen Treatment Site
R
Pelvis Femur Tib + fib Humerus Radius-ulna Other
6 4 2 2 1 1
2 4 2 2 1 2
Total patients
16
13
-
R+TBI
Systemic 3
method
R+TBI+CV
Total
Other
6 1 2
2 2 4 2 3
16 11 10 6 3 8
13
54
1 2 12
patients
-
metastases at diagnosis 6
411
Ewing’s Sarcoma 0 R. D. T. JENKIN et al.
There was initial uncertainty concerning the diagnosis although it was confirmed at final autopsy. He was treated by local irradiation to the primary tibia1 tumor and for each of the next two relapses. The third patient was unsuitable for TBI due to widespread bone metastases at diagnosis. From 1970-73, nine patients were treated by other methods. Five had overt metastases at diagnosis and were considered unsuitable for TBI. All received Cyclophosphamide and Vincristine (CV) in various regimens. Only transient responses were obtained; 2 patients were given CV in other hospitals after primary tumor irradiation at P.M.H; 1 patient with a chronic tibia1 lesion was followed radiologically for 3 years before biopsy confirmed Ewing’s Sarcoma. He was treated by local irradiation in view of the chronicity but later developed metastases. While alive at 4 years he had uncontrolled disease. A final patient treated in 1973 electively received adjuvant treatment with Actinomycin-D, Cyclophosphamide and Vincristine. He remained in a first complete remission 1 year later. Thus the 13 patients treated by “other” methods were a very heterogeneous group, both in regard to natural history and to treatment methods employed. They cannot be compared with the “typical” patients included in the three specific treatment protocols. When we integrated the treatment results obtained in these subgroups into our total institutional experience, for all 54 consecutive patients, the 5-year survival rates were l%O64 27% (15 patients) and 1965-69 35% (17 patients) and the projected 4-year survival rate for 22 patients treated during 1970-73 is 49% (Fig. 5). Our baseline historical experi-
Table
Ewng'sSarcoma 1928-‘73
L..
I
Treatment R R+TBI R+TBI+CV *I of 12 patients
16 13 11*
2
not evaluable.
.
1928-'60(331
3
4
5
YWE
Fig. 5. Crude survival for each of the intervals 1960-64,1%5-69 and 1970-73. Numerals in brackets ( ) indicate number of patients in each interval. Our
prior experience 192~6Ois given. ence from 1928-60 was a 5-year survival rate of 9% (3/33).’ The changing pattern of these survival curves is the best evidence that systemic therapy has had an impact on the natural history of Ewing’s Sarcoma. Additional information is given by examining the median time from diagnosis to first relapse and from first relapse to death (Table 4). The median time to relapse for patients treated by R + TBI + CV will be not less than 20 months nor greater than 24 months, an improvement over 9.5 months for R and 12 months for R +TBI. Conversely when the disease broke through elective chemotherapy with Cyclophosphamide and Vincristine subsequent survival was brief with a median duration of 4 months compared with 13.5 months following relapse after treatment by R + TBI. Preliminary assessment of our experience with R + TBI in 1%9 indicated that while there might be a beneficial effect on long term
treatment
Median time (months) Diagnosis to First relapse first relapse to death 9.5 1’ 2&24
.
Pt3
‘---._
c
4. Variation of disease tempo with method in Ewing’s Sarcoma
Total patients
-(87
8 13.5 4
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survival, the early high relapse rate was similar to that found in the group of patients treated by local irradiation only.’ This result was expected and is now confirmed. During the middle and late 1960s others were demonstrating improved relapse free survival rates when combination chemotherapy was used electively with local irradiation of the primary tumor. Initially,3-6,R Cyclophosphamide and Vincristine were used with or without Actinomycin-D. For this reason, in 1970 we added Cyclophosphamide and Vincristine to systemic irradiation. While the median time to first relapse has increased, the disease broke through elective chemotherapy in 5/l 1 evaluable patients during the course of the first year, so that the initial siope of the relapse free survival curve remained steep and apparently the same as that associated with treatment by R or R+TBI. (Fig. 4). Markedly improved relapse free survival rates during the first two years have been Using an adjuvant reported recently. chemotherapy program combining Vincristine, Cyclophosphamide, Actinomycin-D and Adriamycin, Rosen et al. reported 12 of 12 children relapse free for intervals ranging from 10 to 37 months from diagnosis.” Of these 12 children, 4 had completed the 24 months program. Pomeroy and Johnson reported 14 of 15 patients relapse free for intervals ranging from 3 to 24 months from diagnosis. Their adjuvant program comprised of Adriamycin, Cyclophosfour cycles phamide and Vincristine combined with initial cranial irradiation and intrathecal Methotrexate.’ In the control of the primary tumor a dose of 5000 rad in 25 fractions is satisfactory. At this dose level acute and delayed combined therapy toxicity is acceptable. A first relapse at the primary site alone occurred in 11% of our patients, but there is no good data that higher doses of irradiation are more effective in primary tumor control, and above 5000 rad morbidity escalates rapidly. In only one patient in this series was the solitary primary recurrence in a limb, permitting salvage by amputation. When the primary tumor recurrence is associated with overt metastatic
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1976, Vol. I. Number 5 and Number 6
disease moderate dose re-irradiation of the primary site usually will provide good symptomatic relief and adequate function through the final phase of the disease. In the initial irradiation of a primary limb tumor a rapid complete response with normal function is the rule. For this reason, in this era of improving results in the treatment of Ewing’s Sarcoma. irradiation remains the indicated treatment. However, it may be argued that immediate ablation of the limb would effectively eradicate the problem of primary tumor recurrence and the survival hazard that might be associated with this. Indeed, there is some evidence that in the absence of effective adjuvant therapy surgical treatment may be superior.“’ At the present time it seems best to reserve surgical treatment for the isolated recurrent primary tumor, for the functional and emotional price of initial amputation is currently much too high, considering the generally satisfactory results obtained with medical management.
CONCLUSIONS In our experience stepwise improvement in relapse free survival was obtained in Ewing’s Sarcoma when adjuvant therapy with TBI was added to local irradiation of the primary tumor and was again obtained when TBI+CV replaced TBI as adjuvant therapy. However, in these small series of not necessarily comparable patients we can attach no formal significance to these results. The gradual improvement of our overall survival rates in this unselected series during the period l%O-73 to levels not described prior to systemic therapy does suggest that in a small proportion of these patients our adjuvant treatment programs were eradicating micrometastases. We discontinued TBI + CV at the end of 1973 due to the unacceptable relapse rate during the Iirst year. In Ewing’s Sarcoma others have demonstrated that a complete remission may be induced rapidly and maintained in a high proportion throughout the first year by various combinations of adjuvant Cyclophosphamide, Vincristine, Actinomycin-D and Adriamycin,
Ewing’s Sarcoma 0 R. D. T. JENKINet nl.
together with primary tumor irradiation. Therefore it is now inappropriate to use a single high dose of TBI immediately following primary site irradiation since the consequent
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pancytopenia delays effective combination chemotherapy for 4-6 weeks and TBI alone is not effective in preventing early relapse in a high proportion of patients.
REFERENCES radiotherapy. Proc. Am. Sot. Clin. Oncol. 15: 1. Baird. R.J., Krause, V.W.: Ewing’s tumor: a 1974, Abstract 800. review of 33 cases. Can. J. Surg. 6: 136-140, 7. Jenkin, R.D.T., Rider, W.D., Sonley, M.J.: 1963. 2. Falk, S., Alpert, M.: Five year survival of Ewing’s Sarcoma-a trial of adjuvant total body Surgery, irradiation. Radiation 96: 151-1.55. 1970. patients with Ewing’s Sarcoma. Gynaec. Obstet. 124: 319-324, 1%7. 8. Johnson, R.E., Pomeroy, T.C.: Integrated 3. Femandez, C.H., Lindberg, R.D., Sutow, W. W., therapy for Ewing’s Sarcoma., Am. J. RoentSamuels, M.L.: Localised Ewing’s Sarcoma. genol. 114: 532-535, 1972. Treatment and results. Cancer 34: 134-138, 9. Pomery, T.C., Johnson, R.E.: Combined modality therapy of Ewing’s Sarcoma. Cancer 35: 1974. 4. Freeman, AI., Sachatello, C., Gaeta, J., Shah, 3647, 1975. N.K., Wang, J.J., Sinks, L.F.: An analysis of 10. Pritchard, D.J., Dahlin, D.C., Dauphine, R.T., Ewing’s tumor in children at Roswell Park Taylor, W.F., Beabout, J.W.: Ewing’s Sarcoma. Memorial Institute. Cancer 29: 1563-1569. A clinico-pathological analysis of patients surviving five years or longer. J. Bone Joint 1972. Surg. 57A: 10-16, 1975. 5. Hustu, H.O., Pinkel, D., Pratt, C.B.: Treatment of clinically locahsed Ewing’s Sarcoma with 11. Rosen, G., Wollner, N., Tan, C., Wu. S.J., radiotherapy and combination chemotherapy. Hajdu, S.I., Chan, W., D’Angio, G.J., Mercy, Cancer 30: 1522-1527, 1972. M.L.: Disease free survival in Ewing’s Sarcoma 6. J&e, N., Sallan, S., Traggis, D., Cassady, R., treated with radiation therapy and adjuvant four Vawter, G.: Improved outlook for Ewing’s drug sequential chemotherapy. Cancer 33: Sarcoma with combination chemotherapy and 384-392, 1974.
