- Email: [email protected]
Vincristine in children with malignant solid tumors
534
T h e J o u r n a l of P E D I A T R I C S
Vincristine in children n4th solid tumors Vincristine, an alkaloid o[ the periwinkle plant, was administered intravenously to 19 children with inoperable malignant solid tumors. Tumor regression was observed in 2 o[ 3 children with Hodgkin's disease, 3 o[ 7 with neuroblastoma, 2 with Wilms' tumor, and 1 each with lymphosarcoma, neurofibrosarcoma, Ewing's sarcoma, malignant teratoma, and retinoblastoma. One child with a localized inoperable neuroblastoma responded to vincristine therapy, [oUowed by ionizing radiation, to such an extent that the localized tumor could be excised completely. The fndings o[ this study suggest that a sale and effective vincristine dose [or children is 1.5 rag. per square meter per week.
David MEMPHIS,
H.
James,
Jr., M.D., ~
and Phillip George, M . D .
TENN.
is an indole-indoline alkaloid derived from the common periwinkle plant, V i n c a rosea L i n n . Its chemical structure has been partially elucidated by Neuss and co-workers1 and is shown in Fig. 1. Following the observation that this compound h a d - , m a r k e d activity against the
V i N c RIS TIN E
From the St. Jude Hospital and the Department o[ Pediatrics, College o[ Medicine, University of Tennessee. This study was supported by the American Lebanese Syrian Associated Charities ( A L S A C ) and by Grants CA-06660-01 and CPD-16022 [rom the National Cancer Institute o[ the National Institutes o[ Health, United States Public Health Service. Presented in part at the annual meeting o[ the American Association [or Cancer Research, May, 1963, Toronto, Ont., Canada. X'Address: St. Jude Hospital, 332 N. Lauderdale, Memphis, Tenn.
P-1534 leukemia in DBA/2 mice, 2' a it was made available for clinical trials in man. The mechanism of action of vincristine is not known at this time. However, in studies of its effect on normal bone marrow and leukemic cells of DBA/2 mice 4 it has been shown to produce mitotic arrest at the metaphase stage. This effect is similar to that produced by the closely related alkaloid, vinblastine, and by colchicine. Recently, Hunter 5 has observed that vincristine produces a marked stimulation of aerobic acid production without significant inhibition of respiration in thioguanine-resistant L1210 leukemia cells. H e suggests that vincristine, as well as vinblastine, inhibits the Pasteur effect and may interfere with cell energy production required for mitosis.
Volume 64 Number 4
COOCH3
Vincristine in malignant tumors
CH30
~ CH
0
H3
COOCH 3
Fig. 1. Vincristine structure. Although considerable data have been accumulated concerning the use of this drug for the treatment of acute leukemia, ~-I~ little has been mentioned in the literature concerning its effect on childhood solid tumors. Recently Selawry and H a n a n i a n 1~ reported on its use in 13 children with a variety of solid tumors. Objective tumor regression was observed in 2 children with Hodgldn's disease, 1 with reticulum ceil sarcoma, 1 of 3 with neuroblastoma, 1 of 2 with rhabdomyosarcoma, 1 with Wilms' tumor, and 1 with Ewing's sarcoma. T w o children with osteogenic sarcoma and 1 With an ovarian dysgerminona failed to show any response to the drug. SUBJECTS
The present report is based on a study of the effects of vincristine administration to nineteen children with inoperable malignant solid tumors. Their ages ranged from 1 to 15 years. Three children had Hodgkin's disease, 7 had neuroblastoma, and 2 had Wilms' tumor. One each had lymphosarcoma, Ewing's sarcoma, malignant teratoma, neurofibrosarcoma, osteogenic sarcoma, and lymphoepithelioma. METHODS
Vincristine sulfate ~ was obtained as a powder in sterile vials. Each milligram of the drug was dissolved in 2 ml. of isotonic saline immediately prior to use. This was injected intravenously in single weekly doses ranging from 0.8 to 2.5 mg. per square meter. *The vincristine sulfate used in this study was supplied by Dr. J. G. Armstrong of Eli Lilly Company, Indianapolis, Ind.
535
The patient was considered to have an objective tumor regression if there was a 50 per cent or greater reduction, lasting 1 month or more, in the size of a palpable Or radiographically demonstrable tumor. The tumor size was defined as the product of the two greatest perpendicular diameters of the mass. RESULTS
A summary of the results obtained in this study is presented in Table I. T u m o r regression occurred in two of three children with Hodgkin's disease. One of these was a 13-year-old boy with widespread involvement. After receiving 4 weekly injections of vincristine, all signs and symptoms subsided. H e remains free of overt disease 17 months later. The other was a 15year-old girl with disease involving the cervical and superior mediastinal nodes. After 2 weekly injections of vincristine there was marked regression of all the involved areas (Fig. 2). Following chemotherapy she was treated with ionizing radiation (tumor dose 3,000 r) to the mediastinum and cervical regions. This was administered through eight separate ports over an 8 week period. During the past 10 months she has been asymptomatic and the chest roentgenogram remains normal. A 10-year-old boy with a large, inoperable neuroblastoma filling the entire right upper quadrant of the abdomen was given 6 weekly injections of vincristine. This produced more than 50 per cent reduction in the size of the mass (Fig. 3). Following chemotherapy he received a course of ionizing radiation (tumor dose 4,000 r) over a 6 week period. H a l f of the tumor dose (2,000 r) was administered through an anterior port (13 by 16 cm.) to the right upper quadrant of the abdomen and the other half (2,000 r) was administered to the same area through a posterior port (13 by 16 cm.). In November, 1962, the residual mass was excised. Histologic examination of this specimen revealed only fibrous and necrotic tissue (Fig. 4). No t u m o r cells were observed. Eleven months later there are no signs or symptoms of disease.
5 3 6 ,]ames and George
April 1964
Fig. 2. Hodgkin's disease involving cervical and superior mediastinal regions. A, Prior to vincristine (Sept. 26, 1962). B, After treatment (Oct. 16, 1962).
Fig. 3. Localized neuroblastoma filling right upper quadrant of the abdomen. A, Prior to vlncristlne. B, After treatment. A 13-year-01d girl was referred to St. Jude Hospital with a large Ewing's sarcoma arising from the left ilium. There were multiple pulmonary and-bony metastases. Six weekly injections of vincristine produced marked regression of the pulmonary lesions (Fig. 5). This response lasted only 6 weeks, however, and subsequently she developed further widespread metastases which could not be controlled by any type of therapy. A 2-year-old child with bony metastases from a retinoblastoma was treated with 5 -injections of vincristine over a 56 day period. On this treatment there was definite evidence of healing of' the bony lesions as demonstrated by roentgenographic examination
(Fig. 6). However, the intracranial metastases could not be controlled by chemotherapy. A 9-year-old b o y w i t h a neurofibrosarcoma of the cervical area was referred with signs of spinal cord compression and roentgenographic evidence of a tumor mass in the right anterior mediastinum. After 4 weekly injections of vincristine the signs of cord compression were relieved and the thoracic mass decreased in size. This response lasted for 3 months, during which time vincristine therapy was continued. Subsequently, however, there developed signs and symptoms of progressive disease. In the 19 patients treated with vincristine
Volume 64 Number 4
the only serious a n d dose-limiting type of toxicity was t h a t r e l a t e d to the nervous system. M i l d or m o d e r a t e neurotoxicity was c h a r a c t e r i z e d by paresthesias a n d depressed or absent d e e p t e n d o n reflexes. Severe neur o t o x i c i t y was manifested by wrist or foot drop and m a r k e d muscle weakness. These side effects g r a d u a l l y subsided after vin-
Vincristine in malignant tumors
537
cristine t h e r a p y was discontinued. Complete d i s a p p e a r a n c e of m i l d or m o d e r a t e neurotoxic effects usually r e q u i r e d only a few weeks. However, in 1 p a t i e n t w i t h severe involvement, the neurotoxicity d i d not clear completely until 10 m o n t h s after the drug h a d been stopped. T h e relation of neurotoxicity to total dose
B
A Fig. 4. Histologic appearance of surgical specimens to vincristine. Note diffuse infiltration of malignant ment with vincristine and ionizing radiation (tumor No malignant cells are observed. (Hematoxylin and
from child with localized neuroblastoma. A, Prior cells. (Hematoxylin and eosin • B, After treatdose 4,000 r). Note areas of fibrosis and necrosis. eosin •
A
B
Fig. 5. Ewing's sarcoma of left ilium with pulmonary metastases. A, Prior to vlncristlne. B, After treatment.
538
]ames and George
April 1964
in 1. These symptoms began within 24 hours after vincristine administration and subsided in 24 to 48 hours. Transient leukopenia, unrelated to duration of treatment, was noted in 5 children. This was not associated with serious infection. In this group of children vincristine treatment did not produce alopecia, oral ulceration, diarrhea, hypertension, convulsion, visual disturbance, personality change, or cranial nerve palsy. These toxic effects have been reported by others ~~ and have been observed by us in patients treated for acute leukemia. DISCUSSION
B
Fig. 6. Retinoblastoma with bony metastases. A, Prior to vincristine. Note destructive lesions at proximal end of tibia. B, After treatment. Note periosteal thickening and reealcification of destructive lesions. of vincristine and duration of treatment was examined graphically, as shown in Fig. 7. It can be seen that severe neurotoxicity occurred only at doses equivalent to 2 mg. per square meter per week or greater. T h e relation of tumor response to total dose of vincristine and d u r a t i o n of treatment is shown in Fig. 8. I t can be seen that 4 out of 6 children who received the equivalent of less than 2.0 rag. per square meter per week had objective response to treatment with vincristine. This compares favorably with the 8 out of 13 children who had tumor regression at doses higher than 2.0 mg. per square meter per week. I n 1 patient there was extravasation of vincristine into the subcutaneous tissue at the time of an intravenous injection. This produced marked pain, erythema, edema, and blister formation which subsided slowly over several weeks' duration. Nausea and vomiting occurred in 4 patients, abdominal pain in 2, and constipation
As noted in a previous report, 1~ vincristine has been found again to be active against a wide variety of malignant neoplasms of children. In adults, on the other hand, significant tumor regressions have been observed primarily in patients with Hodgkin's disease and lymphosarcoma, n, x2 In this group of children vincristine produced marked palliation of signs and symptoms in 2 of 3 with Hodgkin's disease and in a single patient with lymphosarcoma. This is comparable to the results reported b y others, both in adults ~, 1~ and in children. ~0 In 1 patient with an inoperable abdominal neuroblastoma it was possible to reduce the tumor size, first by vincristine administration and then by radiation therapy, to allow total excision of the residual tumor. This approach to treatment of localized inoperable tumors has previously been described by Pinkel for single patients treated with ChlorambuciP a and actinomycin D. 1~ As new cancer chemotherapeutic agents become available there should be a greater possibility of producing tumor reduction to such an extent that localized inoperable tumors become operable. Marked tumor regression was observed in 1 patient with Hodgkin's disease involving the cervical and superior mediastinal nodes following vincristine administration. Subsequent radiation therapy was given in an effort to prolong the remission. A similar
Volume 64 Number 4
Vincristine in malignant tumors
5 39
T h e t u m o r regression in the child with the neurofibrosarcoma was m a r k e d a n d resulted in relief of all signs of spinal cord compression. T h i s t u m o r has shown n o response to other cancer c h e m o t h e r a p e u t i c agents, to the authors' knowledge. T h e relation of total d r u g dose to neurotoxicity was e x a m i n e d in o r d e r to define a safe a n d effective dosage for children. I n this g r o u p of children n o serious neurotoxic effects were seen at doses less t h a n 2.0 mg. p e r square m e t e r per week. O n the other hand, the percentage of children having t u m o r regression a p p e a r e d to be as high at
approach, use of a cancer c h e m o t h e r a p e u t i c agent followed by r a d i a t i o n therapy, has previously resulted in p r o l o n g e d remissions in 1 child with Ewing's s a r c o m a m e t a s t a t i c to t h e lung a n d p l e u r a a n d a n o t h e r w i t h undifferentiated sarcoma of the axilla a n d pleural effusion? 5 T h e r a p i d recalcification of bone i n v a d e d by t u m o r in the child w i t h w i d e s p r e a d reti n o b l a s t o m a represents a result of t h e r a p y with vincristine t h a t has n o t been described previously. F u r t h e r clinical trials in patients with this p a r t i c u l a r type of t u m o r w o u l d a p p e a r to be indicated.
/ 1
169
/
14-
~"
f
/ /
g
10-
o
4-
Fig. 7. Relation of neurotoxicity to vincristine dose. Note that no severe neurotoMcity wag observed at dosages less than 9.0 mg. per square meter per week.
2-
/. o / t
or Moderafe xo Mild Severe ToxJcirt~ te -- 2,0 mg/m=/wk
9
i I
t 2
/ 3
i 4
i 5
i 6
Toxicity Toxicity
i 7
i S
Weeks
/ 169
f
/ f
/
/ x
./sXx
f2"
f/
E
X//TjJ
9 o
X
g o
o
Fig. B. Relation of tumor response to vincristine dosage. Note that 4 out of 6 children who received less than 9.0 nag. per square meter per week had objective response to vincristlne treatment.
oX
f~j
cz /
6-
"4"
J / / ' ~ l
9I"/'
I
/"
J
~
f
~
~
o Moderate Response @p~Marked i eP ! nO! Response x ---- 20 mg/m / w k
9
2-
I
2
3
I 4 Weeks
z 5
6
7
8
540
]ames and George
April 1964
T a b l e I. Effects of vincristine in children with m a l i g n a n t solid t u m o r s
Age Patient Diagnosis 1 Hodgkin's disease 2 Hodgkin's disease 3 Hodgkin's disease
(years) 13 15 15
Neuroblastoma, localized
Sex M F F
10
Previous treatment Chlorambucil: no effect; radiation: no effect Nolle
Cyclophosphamide: regression; blastine: no effect
tLN~: regression; vin.
M
Nolle
F F M M F F M
Cyclophosphamide: no effect; radiation: regression Cyclophosphamide: no effect; radiation: regression None Cyelophosphamide: regression; radiation: regression Cyclophosphamide: regression; radiation: regression Radiation : regression
13
F
Cyclophosphamide: regression; radiatlon: regression Nephrectomy; radiation, cyclophosphamide, and actin0mycin D after operation Nephrectomy; radiation after'operation; actinomycin D: regressmn Excision of primary tumor; radiation: regression Enucleatio~ of left eye; cyclophosphamide: regression Radiation : regression Left midthigh amputation; cyclophosphamide: no effect Radiation : regression ; chlorambucil : no effect; cyelophos. phamide an d prednisone: no effect
5 6 7 8 9 10 11
Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Lymphosarcoma, generalized
1 ~2 1% 3 1% 3 2 5
12
Ewing's sarcoma
13
Wilms' tumor
6
M
14
Wilms' tumor
2
M
15 16 17 18 19
Malignant teratoma Retinobtastoma, metastatic Neurofibrosarcoma Osteogenic sarcoma Lymphoepithelioma
2 2 9 11 10
M M M M M
None
~Milligrams per square meter of body surface.
this lower dose as w h e n a dose of 2.0 mg. p e r square m e t e r per week or greater was employed. It is therefore suggested t h a t a dose of 1.5 mg. p e r square m e t e r per week is safe a n d as effective for children as are h i g h e r doses. SUMMARY
Vincristine was a d m i n i s t e r e d intravenously to 19 children with i n o p e r a b l e malign a n t solid tumors. O b j e c t i v e t u m o r regression was observed in 2 of 3 children with H o d g k i n ' s disease, 3 of 7 w i t h neuroblastoma, 2 with Wilms' tumor, a n d 1 each w i t h lymphosardoma, neurofibrosarcoma, Ewing's sarcoma, m a l i g n a n t t e r a t o m a , a n d retinoblastoma. O n e child with osteogenic sarcoma a n d 1 with a l y m p h o e p l t h e l i o m a failed to respond to the drug. O n e child with a localized inoperable n e u r o b l a s t o m a responded to vincristine therapy, followed by ionizing radiation, to such a n extent that the localized t u m o r could be excised com~Ietelv. II
T h e relation-of neurotoxicity to total dose of vincristine a n d d u r a t i o n of t r e a t m e n t was e x a m i n e d graphicMiy. I t was observed t h a t severe n e u r o t o x i c i t y was seen only at doses equivalent to 2.0 mg. p e r square m e t e r per week or greater. F o u r out of 6 children who received the e q u i v a l e n t of less t h a n 2.0 rag. per squar e m e t e r per week h a d objective response to t r e a t m e n t with this agent. T h e findings of this study suggest t h a t a safe a n d effective vincristine dosage for children is 1.5 mg. p e r square m e t e r p e r week.
Acknowledgment is made to Donald Pinkel, M.D., Professor of Pediatrics, Coiiege of Medicine, University of Tennessee, and Medical Director, St. Jude Hospital, for his helpful suggestions and critical review of this paper. Appreciation is expressed to Sister M. Luciana and the members of the nursing staff, St. Jude Hosnital. for their assistance in these studies.
Volume 64 Number 4
~Vincristine treatment ~] Duration Total dose* (days) ,I---
Vincristine in malignant tumors
Tumor response
54 1
Neurotoxic effect
10.0 3.9 2.3
28 14 21
Marked regression, 17 months+ Marked regression, followed by radiation None
Bilateral wrist and foot drop Marked depression of deep tendon reflexes None
12.0
42
None
11.0 4.0 6.0 6.0 10.0 4.2 12.0
49 14 21 21 42 21 42
Marked regression followed by radiation and complete excision None None Moderate regression, 2 months None Moderate regression, 2 months None Marked regression, 2 months
12.0
42
Marked regression, 6 weeks
14.1
49
8.0
28
Marked regression, followed by radiation and excision Moderate regression, 6 weeks
6.0 10.4 8.0 12.5 15.2
56 28 42 42
Marked regression of 1 lesion Healing of metastatic bone lesions Marked regression, 3 months None None
None None Marked None Loss of Marked Marked severe Marked severe None
depression of deep tendon reflexes deep tendon reflexes depression of deep tendon reflexes depression of deep tendon reflexes, weakness depression of deep tendon reflexes, weakness
Loss of deep tendon reflexes Marked depression of deep tendon reflexes None None None None
REFERENCES
I. Neuss, N., Gorman, M., Boaz, It. E., and Cone, N. J.: Vinea alkaloids. XI. Structures of leurocristine (LCR) and vincaleukoblastine " (VLB), J. Am. Chem. Soc. 84: 1509, 1962. 2. Svoboda, G. H., Johnson, I. S., Gorman, M.. and Neuss, N.: Current status of research on the alkaloids of Vinca rosea Linn (Catharanthus roseus G. Don), J. Pharm. Soc. 51: 707, 1962. 3. Johnson, I. S., Svoboda, G. H., and Wright, H. F.: Experimental basis for clinical evaluation of two new alkaloids from Vinca rosea Linn, Proc. Am. A. Cane. Res. 3: 331, 1962. 4. Cardinali, G., Cardinali, G., and Enein, M. A.: Studies on the antimitotie activity of Ieurocristine (vincristine), Blood 21: 102, 1963. 5. Hunter, J. C.: Effects of vincaleukoblastine sulfate on metabolism of thioguanine-resistant L1210 leukemia cells, Biochem. Pharmacol. 12: 283, 1963. 6. Karon, M. R., Freireich, E. J., and Frei, E., III: A preliminary report on vincristine sulfate. A new active agent for the treatment of acute leukemia, Pediatrics 30: 791, 1962. 7. Evans, A. E., Mariano, P., and Brunet, S.: Vincristine in the treatment of children with
8.
9.
10. 11. 12.
13. 14. 15.
acute leukemia, Proc. Am. A. Canc. Res. 4: 18, 1963. Bohannon, R. A., Miller, D. G., and Diamond, H. D.: Leurocristine in the treatment of lymphomas and leukemias, Proc. Am. A. Canc. Res. 3: 305, 1962. Tan, C., and Aduna, N. S.: Preliminary clinical experience with leurocristine in children, Proe. Am. Ass. Cane. Res. 3: 367, 1962. Selawry, O. S., and Hananlan, J.: Vincristine treatment of cancer in children, J. A. M. A. 183: 741, 1963. Carbone, P. P., Bono, V., Frei, E., III, and Brindley, C. O.: Clinical studies with vincristine, Blood 21: 640, I963. Costa, G., Hreshchyshyn, M. M., and Holland, J. F.: Initial clinical studies with vincristine, Canc. Chemotherap. Reports 24: 39, 1962. Pinkel, D.: Chlorambucil in childhood cancer, Cancer 14: 36, 1961. Pinkel, D.: Actinomycin D in childhood cancer. A preliminary report, Pediatrics 23: 342, 1959. Pinkel, D.: Cyclophosphamide in children with cancer, Cancer 15: 42, 1962.
T h e J o u r n a l of P E D I A T R I C S
Vincristine in children n4th solid tumors Vincristine, an alkaloid o[ the periwinkle plant, was administered intravenously to 19 children with inoperable malignant solid tumors. Tumor regression was observed in 2 o[ 3 children with Hodgkin's disease, 3 o[ 7 with neuroblastoma, 2 with Wilms' tumor, and 1 each with lymphosarcoma, neurofibrosarcoma, Ewing's sarcoma, malignant teratoma, and retinoblastoma. One child with a localized inoperable neuroblastoma responded to vincristine therapy, [oUowed by ionizing radiation, to such an extent that the localized tumor could be excised completely. The fndings o[ this study suggest that a sale and effective vincristine dose [or children is 1.5 rag. per square meter per week.
David MEMPHIS,
H.
James,
Jr., M.D., ~
and Phillip George, M . D .
TENN.
is an indole-indoline alkaloid derived from the common periwinkle plant, V i n c a rosea L i n n . Its chemical structure has been partially elucidated by Neuss and co-workers1 and is shown in Fig. 1. Following the observation that this compound h a d - , m a r k e d activity against the
V i N c RIS TIN E
From the St. Jude Hospital and the Department o[ Pediatrics, College o[ Medicine, University of Tennessee. This study was supported by the American Lebanese Syrian Associated Charities ( A L S A C ) and by Grants CA-06660-01 and CPD-16022 [rom the National Cancer Institute o[ the National Institutes o[ Health, United States Public Health Service. Presented in part at the annual meeting o[ the American Association [or Cancer Research, May, 1963, Toronto, Ont., Canada. X'Address: St. Jude Hospital, 332 N. Lauderdale, Memphis, Tenn.
P-1534 leukemia in DBA/2 mice, 2' a it was made available for clinical trials in man. The mechanism of action of vincristine is not known at this time. However, in studies of its effect on normal bone marrow and leukemic cells of DBA/2 mice 4 it has been shown to produce mitotic arrest at the metaphase stage. This effect is similar to that produced by the closely related alkaloid, vinblastine, and by colchicine. Recently, Hunter 5 has observed that vincristine produces a marked stimulation of aerobic acid production without significant inhibition of respiration in thioguanine-resistant L1210 leukemia cells. H e suggests that vincristine, as well as vinblastine, inhibits the Pasteur effect and may interfere with cell energy production required for mitosis.
Volume 64 Number 4
COOCH3
Vincristine in malignant tumors
CH30
~ CH
0
H3
COOCH 3
Fig. 1. Vincristine structure. Although considerable data have been accumulated concerning the use of this drug for the treatment of acute leukemia, ~-I~ little has been mentioned in the literature concerning its effect on childhood solid tumors. Recently Selawry and H a n a n i a n 1~ reported on its use in 13 children with a variety of solid tumors. Objective tumor regression was observed in 2 children with Hodgldn's disease, 1 with reticulum ceil sarcoma, 1 of 3 with neuroblastoma, 1 of 2 with rhabdomyosarcoma, 1 with Wilms' tumor, and 1 with Ewing's sarcoma. T w o children with osteogenic sarcoma and 1 With an ovarian dysgerminona failed to show any response to the drug. SUBJECTS
The present report is based on a study of the effects of vincristine administration to nineteen children with inoperable malignant solid tumors. Their ages ranged from 1 to 15 years. Three children had Hodgkin's disease, 7 had neuroblastoma, and 2 had Wilms' tumor. One each had lymphosarcoma, Ewing's sarcoma, malignant teratoma, neurofibrosarcoma, osteogenic sarcoma, and lymphoepithelioma. METHODS
Vincristine sulfate ~ was obtained as a powder in sterile vials. Each milligram of the drug was dissolved in 2 ml. of isotonic saline immediately prior to use. This was injected intravenously in single weekly doses ranging from 0.8 to 2.5 mg. per square meter. *The vincristine sulfate used in this study was supplied by Dr. J. G. Armstrong of Eli Lilly Company, Indianapolis, Ind.
535
The patient was considered to have an objective tumor regression if there was a 50 per cent or greater reduction, lasting 1 month or more, in the size of a palpable Or radiographically demonstrable tumor. The tumor size was defined as the product of the two greatest perpendicular diameters of the mass. RESULTS
A summary of the results obtained in this study is presented in Table I. T u m o r regression occurred in two of three children with Hodgkin's disease. One of these was a 13-year-old boy with widespread involvement. After receiving 4 weekly injections of vincristine, all signs and symptoms subsided. H e remains free of overt disease 17 months later. The other was a 15year-old girl with disease involving the cervical and superior mediastinal nodes. After 2 weekly injections of vincristine there was marked regression of all the involved areas (Fig. 2). Following chemotherapy she was treated with ionizing radiation (tumor dose 3,000 r) to the mediastinum and cervical regions. This was administered through eight separate ports over an 8 week period. During the past 10 months she has been asymptomatic and the chest roentgenogram remains normal. A 10-year-old boy with a large, inoperable neuroblastoma filling the entire right upper quadrant of the abdomen was given 6 weekly injections of vincristine. This produced more than 50 per cent reduction in the size of the mass (Fig. 3). Following chemotherapy he received a course of ionizing radiation (tumor dose 4,000 r) over a 6 week period. H a l f of the tumor dose (2,000 r) was administered through an anterior port (13 by 16 cm.) to the right upper quadrant of the abdomen and the other half (2,000 r) was administered to the same area through a posterior port (13 by 16 cm.). In November, 1962, the residual mass was excised. Histologic examination of this specimen revealed only fibrous and necrotic tissue (Fig. 4). No t u m o r cells were observed. Eleven months later there are no signs or symptoms of disease.
5 3 6 ,]ames and George
April 1964
Fig. 2. Hodgkin's disease involving cervical and superior mediastinal regions. A, Prior to vincristine (Sept. 26, 1962). B, After treatment (Oct. 16, 1962).
Fig. 3. Localized neuroblastoma filling right upper quadrant of the abdomen. A, Prior to vlncristlne. B, After treatment. A 13-year-01d girl was referred to St. Jude Hospital with a large Ewing's sarcoma arising from the left ilium. There were multiple pulmonary and-bony metastases. Six weekly injections of vincristine produced marked regression of the pulmonary lesions (Fig. 5). This response lasted only 6 weeks, however, and subsequently she developed further widespread metastases which could not be controlled by any type of therapy. A 2-year-old child with bony metastases from a retinoblastoma was treated with 5 -injections of vincristine over a 56 day period. On this treatment there was definite evidence of healing of' the bony lesions as demonstrated by roentgenographic examination
(Fig. 6). However, the intracranial metastases could not be controlled by chemotherapy. A 9-year-old b o y w i t h a neurofibrosarcoma of the cervical area was referred with signs of spinal cord compression and roentgenographic evidence of a tumor mass in the right anterior mediastinum. After 4 weekly injections of vincristine the signs of cord compression were relieved and the thoracic mass decreased in size. This response lasted for 3 months, during which time vincristine therapy was continued. Subsequently, however, there developed signs and symptoms of progressive disease. In the 19 patients treated with vincristine
Volume 64 Number 4
the only serious a n d dose-limiting type of toxicity was t h a t r e l a t e d to the nervous system. M i l d or m o d e r a t e neurotoxicity was c h a r a c t e r i z e d by paresthesias a n d depressed or absent d e e p t e n d o n reflexes. Severe neur o t o x i c i t y was manifested by wrist or foot drop and m a r k e d muscle weakness. These side effects g r a d u a l l y subsided after vin-
Vincristine in malignant tumors
537
cristine t h e r a p y was discontinued. Complete d i s a p p e a r a n c e of m i l d or m o d e r a t e neurotoxic effects usually r e q u i r e d only a few weeks. However, in 1 p a t i e n t w i t h severe involvement, the neurotoxicity d i d not clear completely until 10 m o n t h s after the drug h a d been stopped. T h e relation of neurotoxicity to total dose
B
A Fig. 4. Histologic appearance of surgical specimens to vincristine. Note diffuse infiltration of malignant ment with vincristine and ionizing radiation (tumor No malignant cells are observed. (Hematoxylin and
from child with localized neuroblastoma. A, Prior cells. (Hematoxylin and eosin • B, After treatdose 4,000 r). Note areas of fibrosis and necrosis. eosin •
A
B
Fig. 5. Ewing's sarcoma of left ilium with pulmonary metastases. A, Prior to vlncristlne. B, After treatment.
538
]ames and George
April 1964
in 1. These symptoms began within 24 hours after vincristine administration and subsided in 24 to 48 hours. Transient leukopenia, unrelated to duration of treatment, was noted in 5 children. This was not associated with serious infection. In this group of children vincristine treatment did not produce alopecia, oral ulceration, diarrhea, hypertension, convulsion, visual disturbance, personality change, or cranial nerve palsy. These toxic effects have been reported by others ~~ and have been observed by us in patients treated for acute leukemia. DISCUSSION
B
Fig. 6. Retinoblastoma with bony metastases. A, Prior to vincristine. Note destructive lesions at proximal end of tibia. B, After treatment. Note periosteal thickening and reealcification of destructive lesions. of vincristine and duration of treatment was examined graphically, as shown in Fig. 7. It can be seen that severe neurotoxicity occurred only at doses equivalent to 2 mg. per square meter per week or greater. T h e relation of tumor response to total dose of vincristine and d u r a t i o n of treatment is shown in Fig. 8. I t can be seen that 4 out of 6 children who received the equivalent of less than 2.0 rag. per square meter per week had objective response to treatment with vincristine. This compares favorably with the 8 out of 13 children who had tumor regression at doses higher than 2.0 mg. per square meter per week. I n 1 patient there was extravasation of vincristine into the subcutaneous tissue at the time of an intravenous injection. This produced marked pain, erythema, edema, and blister formation which subsided slowly over several weeks' duration. Nausea and vomiting occurred in 4 patients, abdominal pain in 2, and constipation
As noted in a previous report, 1~ vincristine has been found again to be active against a wide variety of malignant neoplasms of children. In adults, on the other hand, significant tumor regressions have been observed primarily in patients with Hodgkin's disease and lymphosarcoma, n, x2 In this group of children vincristine produced marked palliation of signs and symptoms in 2 of 3 with Hodgkin's disease and in a single patient with lymphosarcoma. This is comparable to the results reported b y others, both in adults ~, 1~ and in children. ~0 In 1 patient with an inoperable abdominal neuroblastoma it was possible to reduce the tumor size, first by vincristine administration and then by radiation therapy, to allow total excision of the residual tumor. This approach to treatment of localized inoperable tumors has previously been described by Pinkel for single patients treated with ChlorambuciP a and actinomycin D. 1~ As new cancer chemotherapeutic agents become available there should be a greater possibility of producing tumor reduction to such an extent that localized inoperable tumors become operable. Marked tumor regression was observed in 1 patient with Hodgkin's disease involving the cervical and superior mediastinal nodes following vincristine administration. Subsequent radiation therapy was given in an effort to prolong the remission. A similar
Volume 64 Number 4
Vincristine in malignant tumors
5 39
T h e t u m o r regression in the child with the neurofibrosarcoma was m a r k e d a n d resulted in relief of all signs of spinal cord compression. T h i s t u m o r has shown n o response to other cancer c h e m o t h e r a p e u t i c agents, to the authors' knowledge. T h e relation of total d r u g dose to neurotoxicity was e x a m i n e d in o r d e r to define a safe a n d effective dosage for children. I n this g r o u p of children n o serious neurotoxic effects were seen at doses less t h a n 2.0 mg. p e r square m e t e r per week. O n the other hand, the percentage of children having t u m o r regression a p p e a r e d to be as high at
approach, use of a cancer c h e m o t h e r a p e u t i c agent followed by r a d i a t i o n therapy, has previously resulted in p r o l o n g e d remissions in 1 child with Ewing's s a r c o m a m e t a s t a t i c to t h e lung a n d p l e u r a a n d a n o t h e r w i t h undifferentiated sarcoma of the axilla a n d pleural effusion? 5 T h e r a p i d recalcification of bone i n v a d e d by t u m o r in the child w i t h w i d e s p r e a d reti n o b l a s t o m a represents a result of t h e r a p y with vincristine t h a t has n o t been described previously. F u r t h e r clinical trials in patients with this p a r t i c u l a r type of t u m o r w o u l d a p p e a r to be indicated.
/ 1
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f
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g
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Fig. 7. Relation of neurotoxicity to vincristine dose. Note that no severe neurotoMcity wag observed at dosages less than 9.0 mg. per square meter per week.
2-
/. o / t
or Moderafe xo Mild Severe ToxJcirt~ te -- 2,0 mg/m=/wk
9
i I
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/ 3
i 4
i 5
i 6
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i 7
i S
Weeks
/ 169
f
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/
/ x
./sXx
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f/
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9 o
X
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o
Fig. B. Relation of tumor response to vincristine dosage. Note that 4 out of 6 children who received less than 9.0 nag. per square meter per week had objective response to vincristlne treatment.
oX
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9
2-
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2
3
I 4 Weeks
z 5
6
7
8
540
]ames and George
April 1964
T a b l e I. Effects of vincristine in children with m a l i g n a n t solid t u m o r s
Age Patient Diagnosis 1 Hodgkin's disease 2 Hodgkin's disease 3 Hodgkin's disease
(years) 13 15 15
Neuroblastoma, localized
Sex M F F
10
Previous treatment Chlorambucil: no effect; radiation: no effect Nolle
Cyclophosphamide: regression; blastine: no effect
tLN~: regression; vin.
M
Nolle
F F M M F F M
Cyclophosphamide: no effect; radiation: regression Cyclophosphamide: no effect; radiation: regression None Cyelophosphamide: regression; radiation: regression Cyclophosphamide: regression; radiation: regression Radiation : regression
13
F
Cyclophosphamide: regression; radiatlon: regression Nephrectomy; radiation, cyclophosphamide, and actin0mycin D after operation Nephrectomy; radiation after'operation; actinomycin D: regressmn Excision of primary tumor; radiation: regression Enucleatio~ of left eye; cyclophosphamide: regression Radiation : regression Left midthigh amputation; cyclophosphamide: no effect Radiation : regression ; chlorambucil : no effect; cyelophos. phamide an d prednisone: no effect
5 6 7 8 9 10 11
Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Neuroblastoma, generalized Lymphosarcoma, generalized
1 ~2 1% 3 1% 3 2 5
12
Ewing's sarcoma
13
Wilms' tumor
6
M
14
Wilms' tumor
2
M
15 16 17 18 19
Malignant teratoma Retinobtastoma, metastatic Neurofibrosarcoma Osteogenic sarcoma Lymphoepithelioma
2 2 9 11 10
M M M M M
None
~Milligrams per square meter of body surface.
this lower dose as w h e n a dose of 2.0 mg. p e r square m e t e r per week or greater was employed. It is therefore suggested t h a t a dose of 1.5 mg. p e r square m e t e r per week is safe a n d as effective for children as are h i g h e r doses. SUMMARY
Vincristine was a d m i n i s t e r e d intravenously to 19 children with i n o p e r a b l e malign a n t solid tumors. O b j e c t i v e t u m o r regression was observed in 2 of 3 children with H o d g k i n ' s disease, 3 of 7 w i t h neuroblastoma, 2 with Wilms' tumor, a n d 1 each w i t h lymphosardoma, neurofibrosarcoma, Ewing's sarcoma, m a l i g n a n t t e r a t o m a , a n d retinoblastoma. O n e child with osteogenic sarcoma a n d 1 with a l y m p h o e p l t h e l i o m a failed to respond to the drug. O n e child with a localized inoperable n e u r o b l a s t o m a responded to vincristine therapy, followed by ionizing radiation, to such a n extent that the localized t u m o r could be excised com~Ietelv. II
T h e relation-of neurotoxicity to total dose of vincristine a n d d u r a t i o n of t r e a t m e n t was e x a m i n e d graphicMiy. I t was observed t h a t severe n e u r o t o x i c i t y was seen only at doses equivalent to 2.0 mg. p e r square m e t e r per week or greater. F o u r out of 6 children who received the e q u i v a l e n t of less t h a n 2.0 rag. per squar e m e t e r per week h a d objective response to t r e a t m e n t with this agent. T h e findings of this study suggest t h a t a safe a n d effective vincristine dosage for children is 1.5 mg. p e r square m e t e r p e r week.
Acknowledgment is made to Donald Pinkel, M.D., Professor of Pediatrics, Coiiege of Medicine, University of Tennessee, and Medical Director, St. Jude Hospital, for his helpful suggestions and critical review of this paper. Appreciation is expressed to Sister M. Luciana and the members of the nursing staff, St. Jude Hosnital. for their assistance in these studies.
Volume 64 Number 4
~Vincristine treatment ~] Duration Total dose* (days) ,I---
Vincristine in malignant tumors
Tumor response
54 1
Neurotoxic effect
10.0 3.9 2.3
28 14 21
Marked regression, 17 months+ Marked regression, followed by radiation None
Bilateral wrist and foot drop Marked depression of deep tendon reflexes None
12.0
42
None
11.0 4.0 6.0 6.0 10.0 4.2 12.0
49 14 21 21 42 21 42
Marked regression followed by radiation and complete excision None None Moderate regression, 2 months None Moderate regression, 2 months None Marked regression, 2 months
12.0
42
Marked regression, 6 weeks
14.1
49
8.0
28
Marked regression, followed by radiation and excision Moderate regression, 6 weeks
6.0 10.4 8.0 12.5 15.2
56 28 42 42
Marked regression of 1 lesion Healing of metastatic bone lesions Marked regression, 3 months None None
None None Marked None Loss of Marked Marked severe Marked severe None
depression of deep tendon reflexes deep tendon reflexes depression of deep tendon reflexes depression of deep tendon reflexes, weakness depression of deep tendon reflexes, weakness
Loss of deep tendon reflexes Marked depression of deep tendon reflexes None None None None
REFERENCES
I. Neuss, N., Gorman, M., Boaz, It. E., and Cone, N. J.: Vinea alkaloids. XI. Structures of leurocristine (LCR) and vincaleukoblastine " (VLB), J. Am. Chem. Soc. 84: 1509, 1962. 2. Svoboda, G. H., Johnson, I. S., Gorman, M.. and Neuss, N.: Current status of research on the alkaloids of Vinca rosea Linn (Catharanthus roseus G. Don), J. Pharm. Soc. 51: 707, 1962. 3. Johnson, I. S., Svoboda, G. H., and Wright, H. F.: Experimental basis for clinical evaluation of two new alkaloids from Vinca rosea Linn, Proc. Am. A. Cane. Res. 3: 331, 1962. 4. Cardinali, G., Cardinali, G., and Enein, M. A.: Studies on the antimitotie activity of Ieurocristine (vincristine), Blood 21: 102, 1963. 5. Hunter, J. C.: Effects of vincaleukoblastine sulfate on metabolism of thioguanine-resistant L1210 leukemia cells, Biochem. Pharmacol. 12: 283, 1963. 6. Karon, M. R., Freireich, E. J., and Frei, E., III: A preliminary report on vincristine sulfate. A new active agent for the treatment of acute leukemia, Pediatrics 30: 791, 1962. 7. Evans, A. E., Mariano, P., and Brunet, S.: Vincristine in the treatment of children with
8.
9.
10. 11. 12.
13. 14. 15.
acute leukemia, Proc. Am. A. Canc. Res. 4: 18, 1963. Bohannon, R. A., Miller, D. G., and Diamond, H. D.: Leurocristine in the treatment of lymphomas and leukemias, Proc. Am. A. Canc. Res. 3: 305, 1962. Tan, C., and Aduna, N. S.: Preliminary clinical experience with leurocristine in children, Proe. Am. Ass. Cane. Res. 3: 367, 1962. Selawry, O. S., and Hananlan, J.: Vincristine treatment of cancer in children, J. A. M. A. 183: 741, 1963. Carbone, P. P., Bono, V., Frei, E., III, and Brindley, C. O.: Clinical studies with vincristine, Blood 21: 640, I963. Costa, G., Hreshchyshyn, M. M., and Holland, J. F.: Initial clinical studies with vincristine, Canc. Chemotherap. Reports 24: 39, 1962. Pinkel, D.: Chlorambucil in childhood cancer, Cancer 14: 36, 1961. Pinkel, D.: Actinomycin D in childhood cancer. A preliminary report, Pediatrics 23: 342, 1959. Pinkel, D.: Cyclophosphamide in children with cancer, Cancer 15: 42, 1962.