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Preoperative irradiation and chemotherapy for initially unresectable hepatoblastoma
Preoperative Irradiation and Chemotherapy for Initially Unresectable Hepatoblastoma By Alan D. Shafer
l 1hree cases of hepatoblartoma that were deemed unresectable, both by angiographic study and exploration, became re-
and Paul M. Selinkoff sectable following combined therapy of dactinomycin, vincristine, and irradiation. INDEX WORDS: Hepatoblastoma.
H
EPATOBLASTOMA is a highly malignant tumor which primarily attacks infants, and if not treated by surgical extirpation, is uniformly fatal.lm4 In recent years, it has become evident to pediatric surgeons that if resection is done for cure, survival rates are approximately 60%.‘J8 However, even in experienced hands, operative mortality for major liver resections in infants and children is still quite high, ranging up to 33~~.‘~4~‘o Because only 50x-60% of hepatoblastomas are considered resectable for cure at the time of initial presentation,’ any therapeutic modality that could theoretically increase the percentage of tumors resected could increase the number of infants salvaged. Since the initial report of Hermann and Lonsdale in 1970,3 only five other cases of an initially unresectable hepatoblastoma becoming resectable following chemotherapy and radiotherapy have been reported in the English literature.‘19,” We present two additional cases, and discuss the rationale for the increased utilization of preoperative adjunctive therapy in the treatment of hepatoblastoma. CASE
REPORTS
Case 1 A.C. was admitted to Children’s Medical Center, Dayton, on January 7, 1976, at the age of 16 mo, for evaluation of anemia and hepatomegaly. Two mo previously, he was hospitalized elsewhere for evaluation of fever, cough, and vomiting, and was noted by his pediatrician to have hepatomegaly. Physical examination was normal except for a bulging liver palpable 7 cm below the right costal margin. Laboratory findings included a hemoglobin of 9.7 gm/lOO ml, normal liver function tests, and a positive test for a-fetoprotein. The liver scan showed a large filhng defect in the right lobe (Fig. IA). Abdominal angiograms showed a large vascular right hepatic mass supplied by the right hepatic artery, and a small branch from the left hepatic via the left gastric. Chest x-ray, bone scan, and marrow aspirate were normal. Laparotomy on January 13, 1976, revealed a 20 cm tumor in the right hepatic lobe displacing all intra-abdominal structures to the left. Liver biopsy was performed, and the biopsy site covered with a Silon patch to prevent peritoneal seeding of the tumor. Histologic examination of the tumor revealed an epithelial type hepatoblastoma. One wk later, he was started on dactinomycin, irradiation, and then vincristine. Over the next mo, he received 1200 rads to the right lobe of the liver, and a follow-
From the Children’s Medical Center and Wright State University School of Medicine, Dayton. and the Cleveland Clinic Foundation. Cleveland, Ohio. Presented before the 8th Annual Meeting of the American Pediatric Surgical Association, Acapulco Mexico, April 20-23, 1977. Address reprints request to Alan D. Shafer, M.D., Children’s Medical Center, 1725 Chapel Street, Dayton, Ohio 45404. G I977 bv Grune & Stratton. Inc. ISSN 0022-3468.
Journal of Pediofric Surgery, Vol. 12, No. 6 (December), 1977
1001
1002
SHAFER
AND SELINKOFF
Fig. 1. (A) Pretreatment liver scan shows huge filling defect taking up entire right lobe. (B) Approximately 50% reduction of tumor mass is seen after course of irradiation and chemotherapy.
up liver scan showed a 50% reduction in the size of the tumor (Fig. 1B). On March 5, 1976. after 6 wk of combined therapy and IO days after his last irradiation, an extended right hepatic lobectomy was carried out without difficulty, the tumor having shrunk to about one-half its former size. The specimen weighed 3 IO gm and measured I2 x 1 I x 6 cm. Microscopic sections confirmed the diagnosis of hepatoblastoma, epithelial type, with massive fibrosis. The postoperative course was uneventful, and he was given an additional 1800 rads to the right upper quadrant of the abdomen. Vincristine, adriamycin. and cyclophosphamide were continued for 1 yr, and at the most recent follow-up, 13 mo after surgery, he is without evidence of disease. The a-fetoprotein determinations remain negative, and the liver scan shows no filling defects.
Case 2 T.H. was a 12-mo-old girl admitted to Children’s Medical Center on May 6, 1976, for evaluation of an abdominal mass found by her pediatrician on routine examination. She was totally asymptomatic, and the remainder of her history was unremarkable. Physical examination revealed only a firm mass in the epigastrium. Laboratory studies included a normal hemogram, a WBC of 19,000/
Fig. 2. (A) Selective ongiogmm anterioposterior view shows both left lobe and medial segment of right lobe involved with tumor. (B) After irradiation and chemotherapy repeat angiograms show 50% reduction of tumor and less tortuosity of vessels.
PREOPERATIVE
Fig. shows ing
3.
IRRADIATION
Case
marked
2
1003
specimen
fibrosis
chemotherapy
AND CHEMOTHERAPY
followand
ir-
radiation.
normal mn13,
liver function tests except for an elevated cholesterol and a negative assay for showed marked enlargement of the left lobe of the A plain film of the abdomen liver. Chest x-ray and bone scan were normal. Radioisotopic and ultrasound scanning revealed a large solid mass in the left hepatic lobe. Abdominal angiograms showed a large vascular mass supplied by a single large hepatic artery arising from the superior mesenteric and by a large branch of the ieft gastric artery (Fig. 2A). At laparotomy on May 13, 1976, a 20 cm central tumor involving predominantly the left lobe was biopsied and oversewn with a Silon patch. Histologic examination documented the diagnosis of hepatoblastoma, mixed type. Dactinomycin and vincristine were started, and she received 2375 rads to the tumor over a period of 8 wk. Repeat angiograms on July 15, 1976, showed a definite decrease in the size and vascularity of the tumor (Fig. 2B). which no longer displaced the stomach, celiac axis, or aorta. On July 22, 1976, I5 days following her last irradiation, she underwent an anatomic left hepatic lobectomy through a thoracoabdominal incision with minimal blood loss. The specimen weighed 245 gm and measured 12 x IO x 5 cm. The pathologist reported a mixed hepatoblastoma with marked fibrosis and multiple foci of osteoid tissue (Fig. 3). Her postoperative course was complicated by a persistent biliary fistula requiring reoperation on September 8, 1976. She continues on vincristine. adriamycin, and cyclophosphamide, and remains asymptomatic 8 mo postoperatively with a normal liver scan. a-fetoprotein.
DISCUSSION
Although no hepatoblastomas have been cured with irradiation and chemotherapy alone, several recent reports have documented significant reductions in tumor bulk using these modes of treatment. *.4,9~”In each of our cases, the tumor was deemed unresectable at initial exploration because of apparent involvement of both lobes by a large tumor mass. In each case, preoperative combined adjunctive therapy led to a demonstrable decrease in tumor size and vascularity. such that standard anatomic lobectomy became feasible. Preoperative conversion of initially unresectable tumors to resectability is by no means unique to hepatoblastoma, and indeed, may be performed in many other childhood malignancies, particularly in those of primitive cell origin. Kumar and associates” have reported such conversion in 36 children, the majority of whom had a Wilms’ tumor, but also included neuroblastomas, em-
SHAFER
1004
AND SELINKOFF
bryonal carcinomas, various sarcomas, and a single incompletely resected hepatoblastoma, with long term survival in over 50% of their cases including the hepatoblastoma. Filler and associates” have reported clinical and experimental evidence that irradiation and actinomycin may cause serious adverse reactions in various organ systems when administered following hepatic lobectomy, and may interfere with hepatic regeneration following major resection. This has not proven to be a problem in our cases, and has not been mentioned in other reports of combined preoperative attack on hepatoblastoma. The ease with which resection is carried out following preoperative shrinkage of these liver tumors has led us to consider the use of adjunctive therapy in all cases of hepatoblastoma, not merely those initially thought to be unresectable. In a survey of the Surgical Section of the American Academy of Pediatrics in 1974, Exelby, Filler and Grosfeld’ reported the nationwide experience of pediatric surgeons with this tumor. There were 25 intra- and postoperative deaths among 85 children in whom resection was attempted. By far the most common causes of death were related to intraoperative blood loss and cardiac arrest. Ein and Stephans in 1974 reported 11 liver resections for malignant disease in children, and in seven of their cases, operative blood loss exceeded the patient’s blood volume. Although we realize that much study is still needed to ascertain the long term effects of chemotherapy and irradiation in small children, we feel that the preoperative use of these modalities in the treatment of hepatoblastoma will increase the percentage of cases in which resection may be undertaken with the intent to cure the disease, decrease the operative mortality, and thereby greatly increase the overall salvage of children who present to us with this highly malignant tumor. In view of the relatively small number of cases seen in any single institution, we would suggest a cooperative study to test our hypothesis. ADDENDUM
A third December
patient with hepatoblastoma, mixed type, presented 28, 1976 after this paper was written.
herself to us on
Case 3 A. P. was a Y-mo-old and causing respiratory
girl with a enormous tumor of the right lobe extending to the pelvic brim embarrassment (Fig. 4). On exploration on January 3, 1977, the tumor was
thought to be unresectable. After biopsy an attempt was made to shrink the tumor with dactinomytin, irradiation, and vincristine. After 2000 rads, however, the tumor had not appreciably shrunk. Therefore, another 1000 rads of irradiation were given to the tumor along with another course of dactinomycin. Both courses of dactinomycin consisted of 12 pg/kg/day for 5 days, while the two previous patients were given 15 rg/kg. (Both previous cases became very ill after dactinomycin and irradiation.) The tumor responded and diminished to about two-thirds the original size. This combined therapy extended over an 8-wk period. She underwent an extended right lobectomy on March 18, 1977, I I days after her last irradiation treatment. The tumor was still very large, and the liver substance at the site of resection was quite friable, making the control of bleeding unmanageable compared with the relative ease of the other two cases. The patient, with a known patent ductus, had a cardiac arrest as the skin was being closed. Although she was resuscitated, bleeding problems persisted, associated with low platelets, acidosis, and high serum potassium.
PREOPERATIVE
IRRADIATION
ig. 4. Gigantic It hepatic Idbe, ;sure on diaphrag
AND CHEMOTHERAPY
1005
in is 3‘ causi ing
She died 5 hr postoperatively despite the administration of fresh frozen plasma, platelets, and other resuscitative efforts. The specimen weighed 430 gm and measured 15 x 9 x 8 cm. Microscopic pathology showed mixed hepatoblastoma with much osteoid and acute necrosis. The bulk of this tumor did not shrink as much as the other two, partly because of the large amount of calcium and bony deposits in the tumor. However, there was very little active tumor left at the time of resection. Besides the very large size of this tumor, another factor affecting the fatal outcome may well have been the timing of resection. The radiotherapist though that a longer interval (i.e., 4 ~6 wk) should have elapsed before resection was attempted, since the liver had been irradiated to the point of tissue tolerance (3000 rads). The cut edge of the normal liver parenchyma did indeed show acute radiation changes with edema, congestion, and polymorphonuclear infiltration, as compared to the mild fibrosis in the other two cases.
REFERENCES I. Fish JC, McCary RG: Primary cancer of the liver in childhood. Arch Surg 93:355, 1966 2. Grosfeld JL, Ballentine TVN, Lowe D. et al: Benign and malignant teratomas in children: Analysis of 85 patients. Surgery 80:297, 1976 3. Hermann RE, Lonsdale D: Chemotherapy, radiotherapy and hepatic lobectomy for hepatoblastoma in an infant: Report of a survival. Surgery 68:383, 1970
4. Holten CP, Burrington JD. Hatch EI: A multiple chemotherapeutic approach to the management of hepatoblastoma. Cancer 35: 1085. 1975 5. Ein SH, Stephans CA: Malignant liver tumors in children. J Pediatr Surg 9:491, 1974 6. Exelby PR, El-Domeri A, Huvos AC. et al: Primary malignant tumors of the liver in children. J Pediatr Surg 6:272, 197 1 7. Exelby PR, Filler RM, Grosfeld JL: Liver
SHAFER
1006
tumors in children in particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey-1974. J Pediatr Surg 10:329, 1975 8. Sinniah D, Campbell PE, Colebatch JH: Primary hepatic cancer in childhood. Arch Dis Child 49:496 9. Howat JM: Major hepatic resections in infancy and childhood. Gut 12:212, 1971 10. Clatworthy HW, Schiller M, Grosfeld
AND SELINKOFF
JL: Primary liver tumors in infancy and childhood. Arch Surg 109:143, 1974 11. Kumar APM, Wrenn EL, Fleming D, et al: Preoperative therapy for unresectable malignant tumors in children. J Pediatr Surg 10:657, 1975 12. Filler RM, Tefft M, Vawter GF, et al: Hepatic lobectomy in childhood: EtTects of X-ray and chemotherapy. J Pediatr Surg 4:31, 1969
Discussion J. Weirzntan
(Los Angeles):
We have had two similar
cases
managed
in a different
way.
The
first is an 8-yr-old boy who had an unresectable hepatoblastoma of the right lobe of the liver. Following biopsy of the tumor, the patient was treated with a monthly course of adriamycin, vincristine, cytoxin, and decarbazine. No radiotherapy was employed. A repeat angiogram 6 mo later showed a 2Oo,b-300,, reduction in the size of the tumor. A successful extended right hepatic lobectomy was performed. Chemotherapy was discontinued 1 I mo after surgery. The patient is doing well with no evidence of disease 18 mo since surgery. The second case involved a 14-yr-old girl with an enormous hepatoblastoma of the right lobe of the liver who also had evidence of pulmonary metastases. Following biopsy she was placed on adriamycin, 5-FU. and cytoxin for 7 mo, and then actinomycin-D was substituted for the adriamycin. Three mo later, after an angiogram showed a remarkable reduction in tumor size and there was no evidence of pulmonary metastases. a successful extended right hepatic lobectomy was performed. Chemotherapy was continued for 10 mo. The patient is now 1 yr postoperative and shows no evidence of disease. R. Telonder(Rocitester, M&I.): We share with you a similar case. Approximately 14 mo ago we saw a child also in a terminal state with a massive tumor involving the liver. The left lobe was totally replaced by a huge tumor, and interestingly enough, the right lobe had about a halfdozen nodules 2-3 cm in diameter. We placed this child on adriamycin. Within weeks there was remarkable resolution of the tumor. We explored the child 6 mo later; the tumor nodules which had been present in the right lobe were visible only in the sense of some white scar that revealed no tumor present. The massive tumor which appeared to be the primary tumor of the left lobe was now a resectable lesion, and by doing an extended left hepatic lobectomy, all gross tumor was removed. She is now 8 mo postresection and CT scans and other studies of the child reveal no tumor to be present. if bleeding is a major problem T. Boles (Columbus): With respect to bleeding, however. (and obviously it is); it can be completely controlled with a thoracoabdominal incision, either the usual oblique type or a vertical midline incision going into the chest. Control of the vena cava above and below the liver can then be secured with tapes. Of course. control of the vessels in the porta hepatis during the period of resection can also be obtained. Question: do you use hypothermia or moderate hypothermia? R. Swank (Tampa): Heaney wrote up a description of using a simple little incision in the left side of the diaphragm, without entering the chest. through a vertical midline incision-initially in trauma but it can be applied to tumors-where he isolates the vena cava within the pericardium just by passing a right angle clamp around it. If you’re in a big hurry to take out a tumor or to repair a laceration of the hepatic veins, you put a catheter into the inferior vena cava from the abdomen. isolating the cava below the renal veins, have side holes in that catheter, and then clamp the porta. You’ll have complete isolation of the liver from any vascular supply with no retrograde bleeding and no occlusion of renal veins. J. Burrington (Chicago): I would like to ask Dr. Selinkotf whether or not they used adriamycin. In the abstract they don’t mention it, but in the oral presentation they did. It is very important to be specific on this point since adriamycin is slowly emerging as a very valuable drug for therapy of many sarcomas.
PREOPERATIVE
IRRADIATION
AND CHEMOTHERAPY
1007
P. Selinkofl(C/osing)c I’d like to thank Drs. Weitzman and Telander for adding their cases to our small series. To Dr. Boles and Dr. Swank regarding the last case with the excessive hemorrhage, this was oozing. There was no major site of bleeding. The operative field was dry at the time of closure. Apparently, the patient had a form of disseminated intravascular coagulation. We have considered the use of cardiopulmonary bypass in cases where there is a very large tumor, as in our third case, in which one would anticipate bleeding problems. We would also like to suggest a resurvey of the membership in a few years, since it seems that the survival will be improved over the last survey in 1974.
l 1hree cases of hepatoblartoma that were deemed unresectable, both by angiographic study and exploration, became re-
and Paul M. Selinkoff sectable following combined therapy of dactinomycin, vincristine, and irradiation. INDEX WORDS: Hepatoblastoma.
H
EPATOBLASTOMA is a highly malignant tumor which primarily attacks infants, and if not treated by surgical extirpation, is uniformly fatal.lm4 In recent years, it has become evident to pediatric surgeons that if resection is done for cure, survival rates are approximately 60%.‘J8 However, even in experienced hands, operative mortality for major liver resections in infants and children is still quite high, ranging up to 33~~.‘~4~‘o Because only 50x-60% of hepatoblastomas are considered resectable for cure at the time of initial presentation,’ any therapeutic modality that could theoretically increase the percentage of tumors resected could increase the number of infants salvaged. Since the initial report of Hermann and Lonsdale in 1970,3 only five other cases of an initially unresectable hepatoblastoma becoming resectable following chemotherapy and radiotherapy have been reported in the English literature.‘19,” We present two additional cases, and discuss the rationale for the increased utilization of preoperative adjunctive therapy in the treatment of hepatoblastoma. CASE
REPORTS
Case 1 A.C. was admitted to Children’s Medical Center, Dayton, on January 7, 1976, at the age of 16 mo, for evaluation of anemia and hepatomegaly. Two mo previously, he was hospitalized elsewhere for evaluation of fever, cough, and vomiting, and was noted by his pediatrician to have hepatomegaly. Physical examination was normal except for a bulging liver palpable 7 cm below the right costal margin. Laboratory findings included a hemoglobin of 9.7 gm/lOO ml, normal liver function tests, and a positive test for a-fetoprotein. The liver scan showed a large filhng defect in the right lobe (Fig. IA). Abdominal angiograms showed a large vascular right hepatic mass supplied by the right hepatic artery, and a small branch from the left hepatic via the left gastric. Chest x-ray, bone scan, and marrow aspirate were normal. Laparotomy on January 13, 1976, revealed a 20 cm tumor in the right hepatic lobe displacing all intra-abdominal structures to the left. Liver biopsy was performed, and the biopsy site covered with a Silon patch to prevent peritoneal seeding of the tumor. Histologic examination of the tumor revealed an epithelial type hepatoblastoma. One wk later, he was started on dactinomycin, irradiation, and then vincristine. Over the next mo, he received 1200 rads to the right lobe of the liver, and a follow-
From the Children’s Medical Center and Wright State University School of Medicine, Dayton. and the Cleveland Clinic Foundation. Cleveland, Ohio. Presented before the 8th Annual Meeting of the American Pediatric Surgical Association, Acapulco Mexico, April 20-23, 1977. Address reprints request to Alan D. Shafer, M.D., Children’s Medical Center, 1725 Chapel Street, Dayton, Ohio 45404. G I977 bv Grune & Stratton. Inc. ISSN 0022-3468.
Journal of Pediofric Surgery, Vol. 12, No. 6 (December), 1977
1001
1002
SHAFER
AND SELINKOFF
Fig. 1. (A) Pretreatment liver scan shows huge filling defect taking up entire right lobe. (B) Approximately 50% reduction of tumor mass is seen after course of irradiation and chemotherapy.
up liver scan showed a 50% reduction in the size of the tumor (Fig. 1B). On March 5, 1976. after 6 wk of combined therapy and IO days after his last irradiation, an extended right hepatic lobectomy was carried out without difficulty, the tumor having shrunk to about one-half its former size. The specimen weighed 3 IO gm and measured I2 x 1 I x 6 cm. Microscopic sections confirmed the diagnosis of hepatoblastoma, epithelial type, with massive fibrosis. The postoperative course was uneventful, and he was given an additional 1800 rads to the right upper quadrant of the abdomen. Vincristine, adriamycin. and cyclophosphamide were continued for 1 yr, and at the most recent follow-up, 13 mo after surgery, he is without evidence of disease. The a-fetoprotein determinations remain negative, and the liver scan shows no filling defects.
Case 2 T.H. was a 12-mo-old girl admitted to Children’s Medical Center on May 6, 1976, for evaluation of an abdominal mass found by her pediatrician on routine examination. She was totally asymptomatic, and the remainder of her history was unremarkable. Physical examination revealed only a firm mass in the epigastrium. Laboratory studies included a normal hemogram, a WBC of 19,000/
Fig. 2. (A) Selective ongiogmm anterioposterior view shows both left lobe and medial segment of right lobe involved with tumor. (B) After irradiation and chemotherapy repeat angiograms show 50% reduction of tumor and less tortuosity of vessels.
PREOPERATIVE
Fig. shows ing
3.
IRRADIATION
Case
marked
2
1003
specimen
fibrosis
chemotherapy
AND CHEMOTHERAPY
followand
ir-
radiation.
normal mn13,
liver function tests except for an elevated cholesterol and a negative assay for showed marked enlargement of the left lobe of the A plain film of the abdomen liver. Chest x-ray and bone scan were normal. Radioisotopic and ultrasound scanning revealed a large solid mass in the left hepatic lobe. Abdominal angiograms showed a large vascular mass supplied by a single large hepatic artery arising from the superior mesenteric and by a large branch of the ieft gastric artery (Fig. 2A). At laparotomy on May 13, 1976, a 20 cm central tumor involving predominantly the left lobe was biopsied and oversewn with a Silon patch. Histologic examination documented the diagnosis of hepatoblastoma, mixed type. Dactinomycin and vincristine were started, and she received 2375 rads to the tumor over a period of 8 wk. Repeat angiograms on July 15, 1976, showed a definite decrease in the size and vascularity of the tumor (Fig. 2B). which no longer displaced the stomach, celiac axis, or aorta. On July 22, 1976, I5 days following her last irradiation, she underwent an anatomic left hepatic lobectomy through a thoracoabdominal incision with minimal blood loss. The specimen weighed 245 gm and measured 12 x IO x 5 cm. The pathologist reported a mixed hepatoblastoma with marked fibrosis and multiple foci of osteoid tissue (Fig. 3). Her postoperative course was complicated by a persistent biliary fistula requiring reoperation on September 8, 1976. She continues on vincristine. adriamycin, and cyclophosphamide, and remains asymptomatic 8 mo postoperatively with a normal liver scan. a-fetoprotein.
DISCUSSION
Although no hepatoblastomas have been cured with irradiation and chemotherapy alone, several recent reports have documented significant reductions in tumor bulk using these modes of treatment. *.4,9~”In each of our cases, the tumor was deemed unresectable at initial exploration because of apparent involvement of both lobes by a large tumor mass. In each case, preoperative combined adjunctive therapy led to a demonstrable decrease in tumor size and vascularity. such that standard anatomic lobectomy became feasible. Preoperative conversion of initially unresectable tumors to resectability is by no means unique to hepatoblastoma, and indeed, may be performed in many other childhood malignancies, particularly in those of primitive cell origin. Kumar and associates” have reported such conversion in 36 children, the majority of whom had a Wilms’ tumor, but also included neuroblastomas, em-
SHAFER
1004
AND SELINKOFF
bryonal carcinomas, various sarcomas, and a single incompletely resected hepatoblastoma, with long term survival in over 50% of their cases including the hepatoblastoma. Filler and associates” have reported clinical and experimental evidence that irradiation and actinomycin may cause serious adverse reactions in various organ systems when administered following hepatic lobectomy, and may interfere with hepatic regeneration following major resection. This has not proven to be a problem in our cases, and has not been mentioned in other reports of combined preoperative attack on hepatoblastoma. The ease with which resection is carried out following preoperative shrinkage of these liver tumors has led us to consider the use of adjunctive therapy in all cases of hepatoblastoma, not merely those initially thought to be unresectable. In a survey of the Surgical Section of the American Academy of Pediatrics in 1974, Exelby, Filler and Grosfeld’ reported the nationwide experience of pediatric surgeons with this tumor. There were 25 intra- and postoperative deaths among 85 children in whom resection was attempted. By far the most common causes of death were related to intraoperative blood loss and cardiac arrest. Ein and Stephans in 1974 reported 11 liver resections for malignant disease in children, and in seven of their cases, operative blood loss exceeded the patient’s blood volume. Although we realize that much study is still needed to ascertain the long term effects of chemotherapy and irradiation in small children, we feel that the preoperative use of these modalities in the treatment of hepatoblastoma will increase the percentage of cases in which resection may be undertaken with the intent to cure the disease, decrease the operative mortality, and thereby greatly increase the overall salvage of children who present to us with this highly malignant tumor. In view of the relatively small number of cases seen in any single institution, we would suggest a cooperative study to test our hypothesis. ADDENDUM
A third December
patient with hepatoblastoma, mixed type, presented 28, 1976 after this paper was written.
herself to us on
Case 3 A. P. was a Y-mo-old and causing respiratory
girl with a enormous tumor of the right lobe extending to the pelvic brim embarrassment (Fig. 4). On exploration on January 3, 1977, the tumor was
thought to be unresectable. After biopsy an attempt was made to shrink the tumor with dactinomytin, irradiation, and vincristine. After 2000 rads, however, the tumor had not appreciably shrunk. Therefore, another 1000 rads of irradiation were given to the tumor along with another course of dactinomycin. Both courses of dactinomycin consisted of 12 pg/kg/day for 5 days, while the two previous patients were given 15 rg/kg. (Both previous cases became very ill after dactinomycin and irradiation.) The tumor responded and diminished to about two-thirds the original size. This combined therapy extended over an 8-wk period. She underwent an extended right lobectomy on March 18, 1977, I I days after her last irradiation treatment. The tumor was still very large, and the liver substance at the site of resection was quite friable, making the control of bleeding unmanageable compared with the relative ease of the other two cases. The patient, with a known patent ductus, had a cardiac arrest as the skin was being closed. Although she was resuscitated, bleeding problems persisted, associated with low platelets, acidosis, and high serum potassium.
PREOPERATIVE
IRRADIATION
ig. 4. Gigantic It hepatic Idbe, ;sure on diaphrag
AND CHEMOTHERAPY
1005
in is 3‘ causi ing
She died 5 hr postoperatively despite the administration of fresh frozen plasma, platelets, and other resuscitative efforts. The specimen weighed 430 gm and measured 15 x 9 x 8 cm. Microscopic pathology showed mixed hepatoblastoma with much osteoid and acute necrosis. The bulk of this tumor did not shrink as much as the other two, partly because of the large amount of calcium and bony deposits in the tumor. However, there was very little active tumor left at the time of resection. Besides the very large size of this tumor, another factor affecting the fatal outcome may well have been the timing of resection. The radiotherapist though that a longer interval (i.e., 4 ~6 wk) should have elapsed before resection was attempted, since the liver had been irradiated to the point of tissue tolerance (3000 rads). The cut edge of the normal liver parenchyma did indeed show acute radiation changes with edema, congestion, and polymorphonuclear infiltration, as compared to the mild fibrosis in the other two cases.
REFERENCES I. Fish JC, McCary RG: Primary cancer of the liver in childhood. Arch Surg 93:355, 1966 2. Grosfeld JL, Ballentine TVN, Lowe D. et al: Benign and malignant teratomas in children: Analysis of 85 patients. Surgery 80:297, 1976 3. Hermann RE, Lonsdale D: Chemotherapy, radiotherapy and hepatic lobectomy for hepatoblastoma in an infant: Report of a survival. Surgery 68:383, 1970
4. Holten CP, Burrington JD. Hatch EI: A multiple chemotherapeutic approach to the management of hepatoblastoma. Cancer 35: 1085. 1975 5. Ein SH, Stephans CA: Malignant liver tumors in children. J Pediatr Surg 9:491, 1974 6. Exelby PR, El-Domeri A, Huvos AC. et al: Primary malignant tumors of the liver in children. J Pediatr Surg 6:272, 197 1 7. Exelby PR, Filler RM, Grosfeld JL: Liver
SHAFER
1006
tumors in children in particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey-1974. J Pediatr Surg 10:329, 1975 8. Sinniah D, Campbell PE, Colebatch JH: Primary hepatic cancer in childhood. Arch Dis Child 49:496 9. Howat JM: Major hepatic resections in infancy and childhood. Gut 12:212, 1971 10. Clatworthy HW, Schiller M, Grosfeld
AND SELINKOFF
JL: Primary liver tumors in infancy and childhood. Arch Surg 109:143, 1974 11. Kumar APM, Wrenn EL, Fleming D, et al: Preoperative therapy for unresectable malignant tumors in children. J Pediatr Surg 10:657, 1975 12. Filler RM, Tefft M, Vawter GF, et al: Hepatic lobectomy in childhood: EtTects of X-ray and chemotherapy. J Pediatr Surg 4:31, 1969
Discussion J. Weirzntan
(Los Angeles):
We have had two similar
cases
managed
in a different
way.
The
first is an 8-yr-old boy who had an unresectable hepatoblastoma of the right lobe of the liver. Following biopsy of the tumor, the patient was treated with a monthly course of adriamycin, vincristine, cytoxin, and decarbazine. No radiotherapy was employed. A repeat angiogram 6 mo later showed a 2Oo,b-300,, reduction in the size of the tumor. A successful extended right hepatic lobectomy was performed. Chemotherapy was discontinued 1 I mo after surgery. The patient is doing well with no evidence of disease 18 mo since surgery. The second case involved a 14-yr-old girl with an enormous hepatoblastoma of the right lobe of the liver who also had evidence of pulmonary metastases. Following biopsy she was placed on adriamycin, 5-FU. and cytoxin for 7 mo, and then actinomycin-D was substituted for the adriamycin. Three mo later, after an angiogram showed a remarkable reduction in tumor size and there was no evidence of pulmonary metastases. a successful extended right hepatic lobectomy was performed. Chemotherapy was continued for 10 mo. The patient is now 1 yr postoperative and shows no evidence of disease. R. Telonder(Rocitester, M&I.): We share with you a similar case. Approximately 14 mo ago we saw a child also in a terminal state with a massive tumor involving the liver. The left lobe was totally replaced by a huge tumor, and interestingly enough, the right lobe had about a halfdozen nodules 2-3 cm in diameter. We placed this child on adriamycin. Within weeks there was remarkable resolution of the tumor. We explored the child 6 mo later; the tumor nodules which had been present in the right lobe were visible only in the sense of some white scar that revealed no tumor present. The massive tumor which appeared to be the primary tumor of the left lobe was now a resectable lesion, and by doing an extended left hepatic lobectomy, all gross tumor was removed. She is now 8 mo postresection and CT scans and other studies of the child reveal no tumor to be present. if bleeding is a major problem T. Boles (Columbus): With respect to bleeding, however. (and obviously it is); it can be completely controlled with a thoracoabdominal incision, either the usual oblique type or a vertical midline incision going into the chest. Control of the vena cava above and below the liver can then be secured with tapes. Of course. control of the vessels in the porta hepatis during the period of resection can also be obtained. Question: do you use hypothermia or moderate hypothermia? R. Swank (Tampa): Heaney wrote up a description of using a simple little incision in the left side of the diaphragm, without entering the chest. through a vertical midline incision-initially in trauma but it can be applied to tumors-where he isolates the vena cava within the pericardium just by passing a right angle clamp around it. If you’re in a big hurry to take out a tumor or to repair a laceration of the hepatic veins, you put a catheter into the inferior vena cava from the abdomen. isolating the cava below the renal veins, have side holes in that catheter, and then clamp the porta. You’ll have complete isolation of the liver from any vascular supply with no retrograde bleeding and no occlusion of renal veins. J. Burrington (Chicago): I would like to ask Dr. Selinkotf whether or not they used adriamycin. In the abstract they don’t mention it, but in the oral presentation they did. It is very important to be specific on this point since adriamycin is slowly emerging as a very valuable drug for therapy of many sarcomas.
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IRRADIATION
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P. Selinkofl(C/osing)c I’d like to thank Drs. Weitzman and Telander for adding their cases to our small series. To Dr. Boles and Dr. Swank regarding the last case with the excessive hemorrhage, this was oozing. There was no major site of bleeding. The operative field was dry at the time of closure. Apparently, the patient had a form of disseminated intravascular coagulation. We have considered the use of cardiopulmonary bypass in cases where there is a very large tumor, as in our third case, in which one would anticipate bleeding problems. We would also like to suggest a resurvey of the membership in a few years, since it seems that the survival will be improved over the last survey in 1974.