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Chemotherapy can convert unresectable hepatoblastoma
Chemotherapy
Can Convert Unresectable
By M. Reynolds, Chicago, Illinois; Memphis,
E.C. Douglass,
M. Finegold,
A. Cantor, and A. Glicksman
Tennessee; Houston, Texas; Gainesville, Florida; and Providence, Rhode Island
@The surgical evaluation and management of children with hepatoblastoma has changed with recent advances in imaging modalities and preoperative chemotherapy. Pediatric Oncology Group (POG) Study no. 8697 has followed 63 patients with hepatoblastoma from 1986 to 1991. Twenty-six patients underwent primary tumor resection followed by chemotherapy consisting of cisplatin, vincristine, and 5-fluorouracil (group I). Thirty-seven patients with “unresectable” tumors received preoperative chemotherapy. Twenty-nine of these patients responded to chemotherapy and 26 underwent delayed surgical resection (group II). Eight patients had an inadequate response to chemotherapy; two have had successful liver transplantation and six are dead of disease progression. “Unresectable tumor” involved both liver lobes (25 patients), encased the inferior vena cava (2). involved adjacent tissues (l), involved the hepatic veins (2). or was deemed too large for safe resection (7). Two patients had distant metastases. The reason for an unresectable designation was not reported in five patients. The determination for an unresectable designation included exploratory laparotomy in 14 patients, angiogram in 7, computed tomography scan in 20, and magnetic resonance imaging in 3 patients. Operative times and transfusion requirements were similar in both groups. Perioperative complications were higher in patients in group II. There was no mortality and only minor morbidity associated with chemotherapy in each group. In both groups 77% of the patients are in complete remission after 13 to 54 months. Preoperative chemotherapy can allow successful resection of initially “unresectable” hepatoblastoma. Primary resection that may result in exsanguination should be postponed and chemotherapy given. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Hepatoblastoma, tive chemotherapy.
Hepatoblastoma
unresectable,
preopera-
C
OMPLETE surgical resection offers the only hope for cure of hepatoblastoma. At the time of diagnosis some children have unresectable tumors or distant metastases that preclude total resection. Adjuvant chemotherapy can be used to convert an “unre-
sectable” tumor to a “resectable” tumor and improve the outcome for these children. Analysis of data collected for 63 patients participating in the Pediatric Oncology Group (POG) Study no. 8697 serves as the basis of this report. MATERIALS
AND METHODS
POG Study no. 8697 was opened in June 1986 and closed in September 1989. The surgical evaluation of all children participating in this study included review of operative dictations, surgical checklists, and pre and postoperative complication checklists. Data collected for this study included methods of determining resectability, criteria for determining resectability, type of surgical resection, transfusion requirements, duration of operation, intraoperative and postoperative complications, and complications of chemotherapy. The POG Statistical Office provided all outcome data. Follow-up ranged from 17 to 54 months. Sixty-three children are included in the study. Twenty-six patients (group I) underwent primary tumor resection. Postoperative chemotherapy included a single course of Cisplatin (DDP) (90 mg/m2), followed by four courses of DDP, Vincristin (VCR) (1.5 mg/m2), and 5-fluorouracil(5FU) (600 mg/m2). Thirty-seven patients had unresectable tumors and received three courses of the same chemotherapy and reevaluation. Six patients had an inadequate response to chemotherapy. Two patients had liver transplantation after chemotherapy because of an inadequate response to chemotherapy. In two patients the tumor disappeared after chemotherapy. Another patient received a combination of chemotherapy and radiation with complete response of the tumor. Twenty-six patients had significant tumor reduction and went on to have complete surgical resection of the tumor (group II). Tumors were initially unresectable because there was involvement of both lobes (25) tumor surrounding the inferior vena cava (2), tumor too large (7), contiguous spread (l), involvement of the hepatic veins (2), and distant metastases (2). In five cases the reason for an unresectable designation was not reported. Preoperative evaluation included computed tomography (CT) scans in 20 children, magnetic resonance imaging (MRI) in 3, and angiography in 7. Preoperative imaging studies were not reported in 13 patients. Fourteen patients underwent exploratory laparotomy to determine resectability and/or biopsy the tumor. The types of surgical resections in each group are detailed in Table 1.
From the Children’s Memorial Hospital, Chicago, IL; St Jude Children’s Hospital, Memphis, TN; Texas Children’s Hospital, Houston, TX; Pediatric Oncology Group Statistical office, Gainesville, FL; and the New England Pediatric Oncology Consortium, Providence, RI. Supported in part by grants from the National Cancer Institute and the National Institutes of Health (CA-30969, CA-29139, CA-07431, CA-31566, CA-03161, and CA-29293). Presented at the 43rd Annual Meeting of the Surgical Section of the American Academy of Pediatrics, New Orleans, Louisiana, October 26-27, 1991. Address reprint requests to Marleta Reynolds, MD, POG Protocol no. 8697, Pediatric Oncology Group, 4949 WPine Blvd, St Louis, MO 63108. Copyrtgh t o I992 by W B. Saunders Company 0022-3468/92/2708-0029$03.00/O
Twenty patients in group I are in complete remission following primary surgical resection and postoperative chemotherapy. Tumor spill did not appear to affect outcome as one patient in this group had preoperative tumor rupture and another minor intraoperative spill. Six patients who underwent primary surgical resection are dead. One died of unknown causes. One patient with known metastatic disease at the time of resection died of tumor progression. Another patient with multifocal disease was trans-
1080
JournalofPediatric
RESULTS
Surgery, Vol27,
No 8 (August),
1992:
pp 1080-1084
CHEMOTHERAPY
FOR UNRESECTABLE HEPATOBLASTOMA
1081
Table 1. Types of Hepatic Resection
Groupl Right trisegmentectomy Right lobectomy
GroupI
8
5
12
3
Right lateral lobectomy
1
Left trisegmentectomy
5
Left lobectomy
5
10
Leh lateral segmentectomy
1
1
Caudate lobectomy
1
Total
26
26
planted for tumor recurrence and has since died of progression of disease. The other three are dead from tumor recurrence (Fig 1). In three patients the tumor “disappeared” after preoperative chemotherapy. One patient is stiIl in complete remission. At exploratory laparotomy two patients had no viable tumor identified. One of these patients has since relapsed (Fig 2). Twenty-six patients with unresectable tumor had partial response to chemotherapy and subsequent resection of the primary tumor. Twenty of these patients are in complete remission. Six patients have relapsed. One patient died of infection following liver transplantation. Three patients died of tumor recurrence. Another patient developed recurrent disease and has died of unknown causes. One patient is alive following thoracotomy for resection of pulmonary metastases. Eight patients had an inadequate response to chemotherapy. Two have undergone successful liver transplantation. Six patients have died of progression of disease. Four of these patients had metastatic disease at the time of diagnosis (Fig 3). Preoperative chemotherapy did not reduce operative morbidity. In group I 23 of 26 patients received Primary Remotion 126
Ccapiete Rariamlon
(20)
patientm)
Fig 2.
Outcome for patients treated with preoperative chemother-
apy.
red cell transfusions in the perioperative period. Volumes of blood ranged from 55 to 1,500 mL (mean, 300 mL). Thirteen of 26 patients in group II received red cell transfusions. The volumes ranged from 95 to 2,000 mL (mean, 517 mL). Operating time for hepatic resection with group I patients averaged 5.2 hours and with group II patients averaged 6.0 hours. Minor postoperative complications developed in 4 patients in group I and 3 patients in group II. No major postoperative complications developed in group I patients. Three patients in group II returned to the operating room for control of hemorrhage. Three patients in group II were treated for bile duct injury (Table 2). One patient in group I presented with metastatic disease and is dead of tumor progression. Seven other patients in the study presented with metastatic disease. Four of these patients had an inadequate response to chemotherapy and died without operative intervention. One patient has had disease recurrence after an abdominal exploration showed no evidence of tumor. Two patients have had surgical resection after chemotherapy reduced tumor size and Inadequate Response to Preoperative Chemotherapy (8)
Di$eeae
Progression (6)
Transplant (2)
Dead of Disease (61 Fig 1.
Outcome for patients treated with primary resection.
Disease Progression ( I
I
1 Dead of Disease (6)
Complete Remission (2) Fig 3. Outcome chemotherapy.
for patients
with
an inadequate
response
to
1082
REYNOLDS ET AL
Table 2. Surgical Morbidity Group I (n = 23) Mean red cell transfusions (mL)
300
Group II (n = 13) 517
Mean operative time (h)
5.2
6.0
Minor postoperative complications
4
3
0
3
Major postoperative complications Bleeding Bile duct damage
3
irradicated the metastases. One is in complete remission and the other is dead of recurrent disease. Five children had multifocal tumors. One child in group I treated with primary resection and tumorectomy has since died following transplantation and tumor progression. Four children in group II presented with multifocal lesions. Preoperative chemotherapy resulted in tumor reduction in all four patients who then went on to successful resection of unifocal tumors, Three of these children have survived and the fourth has died of unknown causes. Four children have had liver transplantation. One child from group I with bilobar disease at presentation is now dead of recurrent tumor. Two children from group II are alive and the third died of posttransplant infection. DISCUSSION
Complete surgical resection has been the most effective form of curative therapy for children with hepatoblastoma. l At least 50% of children present with tumors that are not amenable to primary resection.* Prior to the 1980s success with adjunctive chemotherapy for the treatment of hepatoblastoma was anecdotal. In 1982 Evans et al reported from the Childrens Cancer Study Group (CCSG) and the Southwest Oncology Group a significant improvement in survival with use of combined chemotherapy (VCR, Doxurubicin, 5-FU, and Cyclophosphamide) and surgery.3 In several small series preoperative chemotherapy using a variety of agents resulted in sufficient tumor reduction to allow surgical resection-4-g Fifty-nine percent of patients treated with preoperative chemotherapy for unresectable hepatoblastoma in the recent large series from the CCSG responded with significant tumor reduction and had secondary tumor resection.‘O Gauthier et al have gone one step further and since 1982 have treated all patients with hepatoblastoma with preoperative chemotherapy.ll Black et al recently recommended preoperative high-dose DDP to all patients with hepatoblastoma.l* The present study from POG confirms the efficacy of preoperative chemotherapy in patients with “unresectable” hepatoblastoma. Survival of patients in this study with primary and secondary
resection is identical and perioperative morbidity is low. Proponents of preoperative chemotherapy have focused on operative safety as a reason for preoperative treatment.7 Significant operative mortality has been reported with patients treated with and without preoperative chemotherapy.6J1J2 Improvements in surgical technique, instruments, anesthesia, and preoperative and postoperative care should reduce perioperative morbidity and mortality. No patient in this series died as a result of surgical therapy. Morbidity was higher in the group of patients that received preoperative chemotherapy. Some surgeons reported in their operative dictations that an increase in fibrous tissue in areas of previous tumor increased the risk of technical mishaps. An increase in operative morbidity was also found in the group of patients treated with preoperative chemotherapy in the CCSG study.‘O Toxicity from chemotherapy has been significant in some series. Evans et al reported severe toxicity in their early reports of successful chemotherapy.3 Andrassy et al reported one of six children treated with preoperative chemotherapy who died of cardiotoxicity from Doxorubicin.4 Black et al reported nephrotoxicity related to high-dose DDP.‘* Ninane et al reported the most comprehensive evaluation of toxicity with Doxorubicin and DDP in their group of patients with hepatoblastoma treated in the SIOP Study (The International Society of Pediatric Oncology).‘3 In our series the toxicity related to chemotherapy is minimal. Careful monitoring is essential to prevent lifethreatening complications in all of these patients. The two questions this study does not answer are: what constitutes an “unresectable” tumor, and how does one determine that a tumor is unresectable? Children with distant metastases and tumors with multifocal and bilobar disease at presentation do not have resectable disease. A tumor that is “too large” or “involves both lobes” may be resectable by trisegmentectomy in another surgeon’s hands. It is impossible to judge which tumor with these characteristics is truly unresectable because preoperative evaluations are not uniform. In the CCSG study only 85% of patients had the recommended abdominal exploration for assessment of resectability.‘O Only 14 patients in group II of the present study underwent pretreatment laparotomy and most did not have a formal exploration to determine resectability. Assessment of resectability using modern imaging modalities is not 100% accurate. Because the results with preoperative chemotherapy are so promising a study designed to answer these questions may not be possible. Children with multifocal bilobar disease should be
CHEMOTHERAPY
FOR UNRESECTABLE
HEPATOBLASTOMA
1083
aggressively treated. All four of the present patients treated with preoperative chemotherapy responded with sufficient tumor reduction to allow surgical resection of a single lesion. Tsuchida et al reported a case of a child with bilobar multifocal disease that responded favorably to chemotherapy delivered through a catheter placed in the hepatic artery.r4 Golladay et al have successfully utilized this form of therapy in a child with hepatoblastoma who did not respond to preoperative chemotherapy.15 The role of liver transplantation in children with hepatoblastoma is evolving. In 1988, Ringe et al included two children with hepatoblastoma in their large series of patients transplanted with hepatobiliary malignancy. l6 One child was alive 6 years after transplant and the other died of sepsis. More recently Koneru et al reported 12 children with hepatoblastoma who had liver transplantation; 6 are living.r7 Three children died of tumor recurrence and three died of complications of transplantation. Children
with multifocal and metastatic disease did not do as well as children with unifocal disease and the authors recommend that transplantation be offered to only those children with nonmetastatic unresectable disease. Pretransplant and posttransplant chemotherapy may be beneficial but there are insufficient data to support its use at this time. Both the CCSG and POG study strongly support preoperative chemotherapy for children with unresectable hepatoblastoma. The absence of operative mortality and fewer major postoperative complications following primary resection in both series supports the recommendations of both groups that primary resection be performed for all resectable tumors. Preoperative chemotherapy can convert an unresectable tumor to a resectable tumor. The indiscriminate use of preoperative chemotherapy cannot be recommended in light of the complications related to chemotherapy that have been reported and that may still be discovered.
REFERENCES 1. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in a particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section survey, 1974. J Pediatr Surg 10:329-337,1974 2. Giacomantonio M, Ein SH, Mancer K, et al: Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg 19523-526, 1984 3. Evans AE, Land VJ, Newton WA, et al: Combination chemotherapy (Vincristine, Adriamycin, Cyclophosphamide, and 5Fluorouracil) in the treatment of children with malignant hepatoma. Cancer 50:821-826,1982 4. Andrassy RJ. Brennan P, Siegel MM, et al: Preoperative chemotherapy for hepatomablastoma in children. Report of six cases. J Pediatr Surg 15:517-522, 1980 5. Ikeda K, Suita S, Nakagawara A, et al: Preoperative chemotherapy for initially unresectable hepatoblastoma in children. Arch Surg 114:203-207,1979 6. Mahour GH, Wogu GU, Siegal SE, et al: Improved survival in infants and children with primary malignant liver tumors. Am J Surg 146:236-240.1983 7. Pierro A, Langevin AM, Filler RM, et al: Preoperative chemotherapy in “unresectable” hepatoblastoma. J Pediatr Surg 24124-29, 1989 8. Quinn JJ, Altman AJ. Robinson HT, et al: Adriamycin and Cisplatin for hepatoblastoma. Cancer 56:1926-1929,1985 9. Weinblatt ME, Siegel SE, Siegel MM, et al: Preoperative
chemotherapy for unresectabler primary hepatic malignancies in children. Cancer 50:1061-1064,1982 10. King DR, Ortega J, Campbell J, et al: The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy. J Pediatr Surg 26:1074-1081. 1991 11. Gauthier F, Valayer J, Thai BL, et al: Hepatoblastoma and hepatocarcinoma in children: Analysis of a series of 29 cases. J Pediatr Surg 21:424-429, 1986 12. Black CT, Cangir A, Choroszy M, et al: Marked response to preoperative high-dose cis-platinum in children with unresectable hepatoblastoma. J Pediatr Surg 26:1070-1073,199l 13. Ninane J, Perilongo G, Stalens JP, et al: Effectiveness and toxicity of Cisplatin and Doxorubicin (PLADO) in childhood hepatoblastoma and hepatocellular carcinoma: A SIOP pilot study. Med Pediatr Oncol 19:199-203, 1991 14. Tsuchida Y, Bastos JC, Honna T, et al: Treatment of disseminated hepatoblastoma involving bilateral lobes. J Pediatr Surg25:1253-1255.1990 15. Golladay ES, Mollitt DL, Osteen PK, et al: Conversion to resectability by intra-arterial infusion chemotherapy after failure of systemic chemotherapy. J Pediatr Surg 20:715-717, 1985 16. Ringe B, Wittekind C, Bechstein WO, et al: The role of liver transplantation in hepatobiliary malignancy. Ann Surg 209:88-98, 1989 17. Koneru B, Flye MW, Busuttil RW. et al: Liver transplantation for hepatoblastoma. Ann Surg 213:118-121, 1991
Discussion Patricia Donahoe (Boston, MA): For those of us who have been around long enough to watch the evolution of surgery for hepatoblastoma, this represents a rather dramatic change.
I think there are a number of rather outstanding things that were said in this paper. One was that no patient died as a result of surgery. The other was that toxicity-related chemotherapy was minimal. And the
1084
third was that half those had liver transplantation. So I think this series represents some rather outstanding accomplishments. The fact is that preoperative chemotherapy can salvage what was previously unsalvageable. Would the authors comment on whether they would recommend preoperative chemotherapy for all patients with hepatoblastoma, and would you indeed be able to reduce the mortality or at least morbidity of those patients in the group that had primary resection if they all had chemotherapy preoperatively? Thorn Lobe (Memphis, TN): Since you mentioned it, I feel obligated to comment on laparoscopy and these tumors. As you know, for all tumors now, at least at St Jude, we have been doing laparoscopy at the time of laparotomy or before. Two cases come to mind. One was in a child who by all imaging modalities had a tumor. At laparoscopy it looked more like an inflammatory mass, or infection, and we stuck a needle in it, directed by laparoscopy. It turned out to be an infection, and we saved him a laparotomy. Another child had a tumor that by imaging modalities was thought to be unresectable. He was pretreated with chemotherapy but had no response. He then underwent laparoscopy, to discover that he was resectable and performed a successful trisegmentectomy. So I think laparoscopy does play a role, and we will continue to laparoscope these patients. We will sort out in the future how it exactly helps us. I have a question that is unrelated. Is there a role for debulking tumors that are minimally responsive to chemotherapy? We have been asked to do this in several instances thinking that if we get rid of 90% or 85% of the tumor, more chemotherapy and/or radiation might play a role. Should we attempt this? Or should we, in patient without metastases, just throw our hands up and call the liver transplant service? Robert Filler (Toronto, Ontario): I have several questions for Dr Reynolds and I want to tell you of our own experience. Did you give adjuvant chemotherapy to the children who had a primary resection? Did you look at the histology of these and the responders? We found that if the tumors are anaplastic, they do not respond to our chemotherapy regimen, but other histological type tumors did. In 1986 we began to use a different chemotherapy protocol (adriamycin and cisplatin) for inoperable cases. Since 1988 we have used preoperative chemotherapy in all cases. We now have 17 patients treated
REYNOLDS ET AL
by this protocol. We recently reported on 15 of them and the report will be published in Surgery this month. We had no significant chemotherapy complications, and 10 of those 15 were “unresectable; 6 had pulmonary metastases. Of these 15, one was an operative death. There are 12 that are alive and well, many of them up to 4 years posttreatment. Eugene Wiener (Pittsburgh, PA): At the May APSA meeting, we presented Pittsburgh data on hepatoblastoma; we had 6 such patients who were transplanted with likewise an 80% survival. This is obviously a good approach to those patients who don’t respond to conventional therapy. I would ask you, in your review of these data, do you have any idea at what point one should say that chemotherapy isn’t working and place the patient on the donor list? Marleta Reynolds (response): Dr Donahoe, we do not recommend that all patients be treated with preoperative chemotherapy. Our study and the CCSG study show that there were more intraoperative and postoperative complications in those patients who were treated with preoperative chemotherapy. Dr Lobe, thank you for your information about laparoscopy. The CCSG study that was presented here last year showed that partial debulking of these tumors was beneficial. We did not have any patients that underwent debulking procedures. Based on this study, I would have to recommend that those patients be referred for transplantation. I think this study and the CCSG study show that transplantation is definitely a viable option. The reports from Pittsburgh and Los Angeles are very good in a selected group of patients. Dr Filler, all patients with primary resection were treated postoperative with chemotherapy. The histology was reviewed by our pathologist. There were no patients with hepatocellular carcinoma, and there was no significant difference in the pathology for the different groups of patients that I have described. The present CCSG/POG study actually addressed the issue of different chemotherapeutic agents. In the next several years we may have some more information about the efficacy and toxicity of Adriamycin and Cisplantin. Dr Weiner, I don’t know which patients should go on to transplantation. Based on this study and the CCSG study, transplantation is a good option. Data on the ideal time for transplantation are not available.
Can Convert Unresectable
By M. Reynolds, Chicago, Illinois; Memphis,
E.C. Douglass,
M. Finegold,
A. Cantor, and A. Glicksman
Tennessee; Houston, Texas; Gainesville, Florida; and Providence, Rhode Island
@The surgical evaluation and management of children with hepatoblastoma has changed with recent advances in imaging modalities and preoperative chemotherapy. Pediatric Oncology Group (POG) Study no. 8697 has followed 63 patients with hepatoblastoma from 1986 to 1991. Twenty-six patients underwent primary tumor resection followed by chemotherapy consisting of cisplatin, vincristine, and 5-fluorouracil (group I). Thirty-seven patients with “unresectable” tumors received preoperative chemotherapy. Twenty-nine of these patients responded to chemotherapy and 26 underwent delayed surgical resection (group II). Eight patients had an inadequate response to chemotherapy; two have had successful liver transplantation and six are dead of disease progression. “Unresectable tumor” involved both liver lobes (25 patients), encased the inferior vena cava (2). involved adjacent tissues (l), involved the hepatic veins (2). or was deemed too large for safe resection (7). Two patients had distant metastases. The reason for an unresectable designation was not reported in five patients. The determination for an unresectable designation included exploratory laparotomy in 14 patients, angiogram in 7, computed tomography scan in 20, and magnetic resonance imaging in 3 patients. Operative times and transfusion requirements were similar in both groups. Perioperative complications were higher in patients in group II. There was no mortality and only minor morbidity associated with chemotherapy in each group. In both groups 77% of the patients are in complete remission after 13 to 54 months. Preoperative chemotherapy can allow successful resection of initially “unresectable” hepatoblastoma. Primary resection that may result in exsanguination should be postponed and chemotherapy given. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Hepatoblastoma, tive chemotherapy.
Hepatoblastoma
unresectable,
preopera-
C
OMPLETE surgical resection offers the only hope for cure of hepatoblastoma. At the time of diagnosis some children have unresectable tumors or distant metastases that preclude total resection. Adjuvant chemotherapy can be used to convert an “unre-
sectable” tumor to a “resectable” tumor and improve the outcome for these children. Analysis of data collected for 63 patients participating in the Pediatric Oncology Group (POG) Study no. 8697 serves as the basis of this report. MATERIALS
AND METHODS
POG Study no. 8697 was opened in June 1986 and closed in September 1989. The surgical evaluation of all children participating in this study included review of operative dictations, surgical checklists, and pre and postoperative complication checklists. Data collected for this study included methods of determining resectability, criteria for determining resectability, type of surgical resection, transfusion requirements, duration of operation, intraoperative and postoperative complications, and complications of chemotherapy. The POG Statistical Office provided all outcome data. Follow-up ranged from 17 to 54 months. Sixty-three children are included in the study. Twenty-six patients (group I) underwent primary tumor resection. Postoperative chemotherapy included a single course of Cisplatin (DDP) (90 mg/m2), followed by four courses of DDP, Vincristin (VCR) (1.5 mg/m2), and 5-fluorouracil(5FU) (600 mg/m2). Thirty-seven patients had unresectable tumors and received three courses of the same chemotherapy and reevaluation. Six patients had an inadequate response to chemotherapy. Two patients had liver transplantation after chemotherapy because of an inadequate response to chemotherapy. In two patients the tumor disappeared after chemotherapy. Another patient received a combination of chemotherapy and radiation with complete response of the tumor. Twenty-six patients had significant tumor reduction and went on to have complete surgical resection of the tumor (group II). Tumors were initially unresectable because there was involvement of both lobes (25) tumor surrounding the inferior vena cava (2), tumor too large (7), contiguous spread (l), involvement of the hepatic veins (2), and distant metastases (2). In five cases the reason for an unresectable designation was not reported. Preoperative evaluation included computed tomography (CT) scans in 20 children, magnetic resonance imaging (MRI) in 3, and angiography in 7. Preoperative imaging studies were not reported in 13 patients. Fourteen patients underwent exploratory laparotomy to determine resectability and/or biopsy the tumor. The types of surgical resections in each group are detailed in Table 1.
From the Children’s Memorial Hospital, Chicago, IL; St Jude Children’s Hospital, Memphis, TN; Texas Children’s Hospital, Houston, TX; Pediatric Oncology Group Statistical office, Gainesville, FL; and the New England Pediatric Oncology Consortium, Providence, RI. Supported in part by grants from the National Cancer Institute and the National Institutes of Health (CA-30969, CA-29139, CA-07431, CA-31566, CA-03161, and CA-29293). Presented at the 43rd Annual Meeting of the Surgical Section of the American Academy of Pediatrics, New Orleans, Louisiana, October 26-27, 1991. Address reprint requests to Marleta Reynolds, MD, POG Protocol no. 8697, Pediatric Oncology Group, 4949 WPine Blvd, St Louis, MO 63108. Copyrtgh t o I992 by W B. Saunders Company 0022-3468/92/2708-0029$03.00/O
Twenty patients in group I are in complete remission following primary surgical resection and postoperative chemotherapy. Tumor spill did not appear to affect outcome as one patient in this group had preoperative tumor rupture and another minor intraoperative spill. Six patients who underwent primary surgical resection are dead. One died of unknown causes. One patient with known metastatic disease at the time of resection died of tumor progression. Another patient with multifocal disease was trans-
1080
JournalofPediatric
RESULTS
Surgery, Vol27,
No 8 (August),
1992:
pp 1080-1084
CHEMOTHERAPY
FOR UNRESECTABLE HEPATOBLASTOMA
1081
Table 1. Types of Hepatic Resection
Groupl Right trisegmentectomy Right lobectomy
GroupI
8
5
12
3
Right lateral lobectomy
1
Left trisegmentectomy
5
Left lobectomy
5
10
Leh lateral segmentectomy
1
1
Caudate lobectomy
1
Total
26
26
planted for tumor recurrence and has since died of progression of disease. The other three are dead from tumor recurrence (Fig 1). In three patients the tumor “disappeared” after preoperative chemotherapy. One patient is stiIl in complete remission. At exploratory laparotomy two patients had no viable tumor identified. One of these patients has since relapsed (Fig 2). Twenty-six patients with unresectable tumor had partial response to chemotherapy and subsequent resection of the primary tumor. Twenty of these patients are in complete remission. Six patients have relapsed. One patient died of infection following liver transplantation. Three patients died of tumor recurrence. Another patient developed recurrent disease and has died of unknown causes. One patient is alive following thoracotomy for resection of pulmonary metastases. Eight patients had an inadequate response to chemotherapy. Two have undergone successful liver transplantation. Six patients have died of progression of disease. Four of these patients had metastatic disease at the time of diagnosis (Fig 3). Preoperative chemotherapy did not reduce operative morbidity. In group I 23 of 26 patients received Primary Remotion 126
Ccapiete Rariamlon
(20)
patientm)
Fig 2.
Outcome for patients treated with preoperative chemother-
apy.
red cell transfusions in the perioperative period. Volumes of blood ranged from 55 to 1,500 mL (mean, 300 mL). Thirteen of 26 patients in group II received red cell transfusions. The volumes ranged from 95 to 2,000 mL (mean, 517 mL). Operating time for hepatic resection with group I patients averaged 5.2 hours and with group II patients averaged 6.0 hours. Minor postoperative complications developed in 4 patients in group I and 3 patients in group II. No major postoperative complications developed in group I patients. Three patients in group II returned to the operating room for control of hemorrhage. Three patients in group II were treated for bile duct injury (Table 2). One patient in group I presented with metastatic disease and is dead of tumor progression. Seven other patients in the study presented with metastatic disease. Four of these patients had an inadequate response to chemotherapy and died without operative intervention. One patient has had disease recurrence after an abdominal exploration showed no evidence of tumor. Two patients have had surgical resection after chemotherapy reduced tumor size and Inadequate Response to Preoperative Chemotherapy (8)
Di$eeae
Progression (6)
Transplant (2)
Dead of Disease (61 Fig 1.
Outcome for patients treated with primary resection.
Disease Progression ( I
I
1 Dead of Disease (6)
Complete Remission (2) Fig 3. Outcome chemotherapy.
for patients
with
an inadequate
response
to
1082
REYNOLDS ET AL
Table 2. Surgical Morbidity Group I (n = 23) Mean red cell transfusions (mL)
300
Group II (n = 13) 517
Mean operative time (h)
5.2
6.0
Minor postoperative complications
4
3
0
3
Major postoperative complications Bleeding Bile duct damage
3
irradicated the metastases. One is in complete remission and the other is dead of recurrent disease. Five children had multifocal tumors. One child in group I treated with primary resection and tumorectomy has since died following transplantation and tumor progression. Four children in group II presented with multifocal lesions. Preoperative chemotherapy resulted in tumor reduction in all four patients who then went on to successful resection of unifocal tumors, Three of these children have survived and the fourth has died of unknown causes. Four children have had liver transplantation. One child from group I with bilobar disease at presentation is now dead of recurrent tumor. Two children from group II are alive and the third died of posttransplant infection. DISCUSSION
Complete surgical resection has been the most effective form of curative therapy for children with hepatoblastoma. l At least 50% of children present with tumors that are not amenable to primary resection.* Prior to the 1980s success with adjunctive chemotherapy for the treatment of hepatoblastoma was anecdotal. In 1982 Evans et al reported from the Childrens Cancer Study Group (CCSG) and the Southwest Oncology Group a significant improvement in survival with use of combined chemotherapy (VCR, Doxurubicin, 5-FU, and Cyclophosphamide) and surgery.3 In several small series preoperative chemotherapy using a variety of agents resulted in sufficient tumor reduction to allow surgical resection-4-g Fifty-nine percent of patients treated with preoperative chemotherapy for unresectable hepatoblastoma in the recent large series from the CCSG responded with significant tumor reduction and had secondary tumor resection.‘O Gauthier et al have gone one step further and since 1982 have treated all patients with hepatoblastoma with preoperative chemotherapy.ll Black et al recently recommended preoperative high-dose DDP to all patients with hepatoblastoma.l* The present study from POG confirms the efficacy of preoperative chemotherapy in patients with “unresectable” hepatoblastoma. Survival of patients in this study with primary and secondary
resection is identical and perioperative morbidity is low. Proponents of preoperative chemotherapy have focused on operative safety as a reason for preoperative treatment.7 Significant operative mortality has been reported with patients treated with and without preoperative chemotherapy.6J1J2 Improvements in surgical technique, instruments, anesthesia, and preoperative and postoperative care should reduce perioperative morbidity and mortality. No patient in this series died as a result of surgical therapy. Morbidity was higher in the group of patients that received preoperative chemotherapy. Some surgeons reported in their operative dictations that an increase in fibrous tissue in areas of previous tumor increased the risk of technical mishaps. An increase in operative morbidity was also found in the group of patients treated with preoperative chemotherapy in the CCSG study.‘O Toxicity from chemotherapy has been significant in some series. Evans et al reported severe toxicity in their early reports of successful chemotherapy.3 Andrassy et al reported one of six children treated with preoperative chemotherapy who died of cardiotoxicity from Doxorubicin.4 Black et al reported nephrotoxicity related to high-dose DDP.‘* Ninane et al reported the most comprehensive evaluation of toxicity with Doxorubicin and DDP in their group of patients with hepatoblastoma treated in the SIOP Study (The International Society of Pediatric Oncology).‘3 In our series the toxicity related to chemotherapy is minimal. Careful monitoring is essential to prevent lifethreatening complications in all of these patients. The two questions this study does not answer are: what constitutes an “unresectable” tumor, and how does one determine that a tumor is unresectable? Children with distant metastases and tumors with multifocal and bilobar disease at presentation do not have resectable disease. A tumor that is “too large” or “involves both lobes” may be resectable by trisegmentectomy in another surgeon’s hands. It is impossible to judge which tumor with these characteristics is truly unresectable because preoperative evaluations are not uniform. In the CCSG study only 85% of patients had the recommended abdominal exploration for assessment of resectability.‘O Only 14 patients in group II of the present study underwent pretreatment laparotomy and most did not have a formal exploration to determine resectability. Assessment of resectability using modern imaging modalities is not 100% accurate. Because the results with preoperative chemotherapy are so promising a study designed to answer these questions may not be possible. Children with multifocal bilobar disease should be
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aggressively treated. All four of the present patients treated with preoperative chemotherapy responded with sufficient tumor reduction to allow surgical resection of a single lesion. Tsuchida et al reported a case of a child with bilobar multifocal disease that responded favorably to chemotherapy delivered through a catheter placed in the hepatic artery.r4 Golladay et al have successfully utilized this form of therapy in a child with hepatoblastoma who did not respond to preoperative chemotherapy.15 The role of liver transplantation in children with hepatoblastoma is evolving. In 1988, Ringe et al included two children with hepatoblastoma in their large series of patients transplanted with hepatobiliary malignancy. l6 One child was alive 6 years after transplant and the other died of sepsis. More recently Koneru et al reported 12 children with hepatoblastoma who had liver transplantation; 6 are living.r7 Three children died of tumor recurrence and three died of complications of transplantation. Children
with multifocal and metastatic disease did not do as well as children with unifocal disease and the authors recommend that transplantation be offered to only those children with nonmetastatic unresectable disease. Pretransplant and posttransplant chemotherapy may be beneficial but there are insufficient data to support its use at this time. Both the CCSG and POG study strongly support preoperative chemotherapy for children with unresectable hepatoblastoma. The absence of operative mortality and fewer major postoperative complications following primary resection in both series supports the recommendations of both groups that primary resection be performed for all resectable tumors. Preoperative chemotherapy can convert an unresectable tumor to a resectable tumor. The indiscriminate use of preoperative chemotherapy cannot be recommended in light of the complications related to chemotherapy that have been reported and that may still be discovered.
REFERENCES 1. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in a particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section survey, 1974. J Pediatr Surg 10:329-337,1974 2. Giacomantonio M, Ein SH, Mancer K, et al: Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg 19523-526, 1984 3. Evans AE, Land VJ, Newton WA, et al: Combination chemotherapy (Vincristine, Adriamycin, Cyclophosphamide, and 5Fluorouracil) in the treatment of children with malignant hepatoma. Cancer 50:821-826,1982 4. Andrassy RJ. Brennan P, Siegel MM, et al: Preoperative chemotherapy for hepatomablastoma in children. Report of six cases. J Pediatr Surg 15:517-522, 1980 5. Ikeda K, Suita S, Nakagawara A, et al: Preoperative chemotherapy for initially unresectable hepatoblastoma in children. Arch Surg 114:203-207,1979 6. Mahour GH, Wogu GU, Siegal SE, et al: Improved survival in infants and children with primary malignant liver tumors. Am J Surg 146:236-240.1983 7. Pierro A, Langevin AM, Filler RM, et al: Preoperative chemotherapy in “unresectable” hepatoblastoma. J Pediatr Surg 24124-29, 1989 8. Quinn JJ, Altman AJ. Robinson HT, et al: Adriamycin and Cisplatin for hepatoblastoma. Cancer 56:1926-1929,1985 9. Weinblatt ME, Siegel SE, Siegel MM, et al: Preoperative
chemotherapy for unresectabler primary hepatic malignancies in children. Cancer 50:1061-1064,1982 10. King DR, Ortega J, Campbell J, et al: The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy. J Pediatr Surg 26:1074-1081. 1991 11. Gauthier F, Valayer J, Thai BL, et al: Hepatoblastoma and hepatocarcinoma in children: Analysis of a series of 29 cases. J Pediatr Surg 21:424-429, 1986 12. Black CT, Cangir A, Choroszy M, et al: Marked response to preoperative high-dose cis-platinum in children with unresectable hepatoblastoma. J Pediatr Surg 26:1070-1073,199l 13. Ninane J, Perilongo G, Stalens JP, et al: Effectiveness and toxicity of Cisplatin and Doxorubicin (PLADO) in childhood hepatoblastoma and hepatocellular carcinoma: A SIOP pilot study. Med Pediatr Oncol 19:199-203, 1991 14. Tsuchida Y, Bastos JC, Honna T, et al: Treatment of disseminated hepatoblastoma involving bilateral lobes. J Pediatr Surg25:1253-1255.1990 15. Golladay ES, Mollitt DL, Osteen PK, et al: Conversion to resectability by intra-arterial infusion chemotherapy after failure of systemic chemotherapy. J Pediatr Surg 20:715-717, 1985 16. Ringe B, Wittekind C, Bechstein WO, et al: The role of liver transplantation in hepatobiliary malignancy. Ann Surg 209:88-98, 1989 17. Koneru B, Flye MW, Busuttil RW. et al: Liver transplantation for hepatoblastoma. Ann Surg 213:118-121, 1991
Discussion Patricia Donahoe (Boston, MA): For those of us who have been around long enough to watch the evolution of surgery for hepatoblastoma, this represents a rather dramatic change.
I think there are a number of rather outstanding things that were said in this paper. One was that no patient died as a result of surgery. The other was that toxicity-related chemotherapy was minimal. And the
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third was that half those had liver transplantation. So I think this series represents some rather outstanding accomplishments. The fact is that preoperative chemotherapy can salvage what was previously unsalvageable. Would the authors comment on whether they would recommend preoperative chemotherapy for all patients with hepatoblastoma, and would you indeed be able to reduce the mortality or at least morbidity of those patients in the group that had primary resection if they all had chemotherapy preoperatively? Thorn Lobe (Memphis, TN): Since you mentioned it, I feel obligated to comment on laparoscopy and these tumors. As you know, for all tumors now, at least at St Jude, we have been doing laparoscopy at the time of laparotomy or before. Two cases come to mind. One was in a child who by all imaging modalities had a tumor. At laparoscopy it looked more like an inflammatory mass, or infection, and we stuck a needle in it, directed by laparoscopy. It turned out to be an infection, and we saved him a laparotomy. Another child had a tumor that by imaging modalities was thought to be unresectable. He was pretreated with chemotherapy but had no response. He then underwent laparoscopy, to discover that he was resectable and performed a successful trisegmentectomy. So I think laparoscopy does play a role, and we will continue to laparoscope these patients. We will sort out in the future how it exactly helps us. I have a question that is unrelated. Is there a role for debulking tumors that are minimally responsive to chemotherapy? We have been asked to do this in several instances thinking that if we get rid of 90% or 85% of the tumor, more chemotherapy and/or radiation might play a role. Should we attempt this? Or should we, in patient without metastases, just throw our hands up and call the liver transplant service? Robert Filler (Toronto, Ontario): I have several questions for Dr Reynolds and I want to tell you of our own experience. Did you give adjuvant chemotherapy to the children who had a primary resection? Did you look at the histology of these and the responders? We found that if the tumors are anaplastic, they do not respond to our chemotherapy regimen, but other histological type tumors did. In 1986 we began to use a different chemotherapy protocol (adriamycin and cisplatin) for inoperable cases. Since 1988 we have used preoperative chemotherapy in all cases. We now have 17 patients treated
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by this protocol. We recently reported on 15 of them and the report will be published in Surgery this month. We had no significant chemotherapy complications, and 10 of those 15 were “unresectable; 6 had pulmonary metastases. Of these 15, one was an operative death. There are 12 that are alive and well, many of them up to 4 years posttreatment. Eugene Wiener (Pittsburgh, PA): At the May APSA meeting, we presented Pittsburgh data on hepatoblastoma; we had 6 such patients who were transplanted with likewise an 80% survival. This is obviously a good approach to those patients who don’t respond to conventional therapy. I would ask you, in your review of these data, do you have any idea at what point one should say that chemotherapy isn’t working and place the patient on the donor list? Marleta Reynolds (response): Dr Donahoe, we do not recommend that all patients be treated with preoperative chemotherapy. Our study and the CCSG study show that there were more intraoperative and postoperative complications in those patients who were treated with preoperative chemotherapy. Dr Lobe, thank you for your information about laparoscopy. The CCSG study that was presented here last year showed that partial debulking of these tumors was beneficial. We did not have any patients that underwent debulking procedures. Based on this study, I would have to recommend that those patients be referred for transplantation. I think this study and the CCSG study show that transplantation is definitely a viable option. The reports from Pittsburgh and Los Angeles are very good in a selected group of patients. Dr Filler, all patients with primary resection were treated postoperative with chemotherapy. The histology was reviewed by our pathologist. There were no patients with hepatocellular carcinoma, and there was no significant difference in the pathology for the different groups of patients that I have described. The present CCSG/POG study actually addressed the issue of different chemotherapeutic agents. In the next several years we may have some more information about the efficacy and toxicity of Adriamycin and Cisplantin. Dr Weiner, I don’t know which patients should go on to transplantation. Based on this study and the CCSG study, transplantation is a good option. Data on the ideal time for transplantation are not available.