JPLT Mission Statement
Pediatric liver tumors are rare malignant tumors which occur in livers
of children. A high proportion is hepatoblastoma which are specific to
children, with occasional occurrence as adult-type hepatocellular carcinoma.
In Japan there are 30 to 40 cases yearly. Complete excision was the only
therapeutic procedure until the 1980s. In the 1990s, recovery from (formerly)
inoperable tumors, and tumors with metastasis was reported with the use
of antineoplastic drugs post-surgery and the recurrence rate after radical
surgery decreased. However, as only 30 to 40 cases are reported annually
across the country, that means only 1 or 2 cases are seen yearly per facility.
This low generation frequency tumor had been treated in each facility independently,
which meant that treatments had been carried out without the analysis of
nationwide data on long-term treatment results and related issues.Therefore,
taking the view that research by study groups is indispensable to improving
treatment results in this kind of tumor, in June, 1989, a few enthusiastic
pediatric surgeons with strong interest in this field got together and
decided to lay the foundation for this study group. In the meantime, Japan
got an invitation to participate in a SIOP group. This request was carefully
considered however in the end it was agreed that the protocol should be
specific to Japan. In 1991, the Japanese Study Group for Pediatric Liver
Tumor (JPLT) was formed nationwide, centering around Hokkaido University
(Representative Manager: Dr. Junichi UCHINO), with the aim of improving
the treatment of pediatric liver tumor.
In the U.S., randomized clinical trials of phase III using Cisplatin, Vincristine
and Fluorouracil on the case of postoperative hepatoblastoma by COG (Children
Oncology Group), are ongoing. Also in Europe, SIOPEL (Liver Tumor Strategy
Group) advocates staging called PRETEXT by the location of the tumor site
in the liver, while conducting a comparative study between cisplatin single
agent and cisplatin + doxorubicin (PLADO), and continues studying the effectiveness
of preoperative chemotherapy on advanced cases. In this way, while the
treatment results have been improved by combined treatment with chemotherapy
abroad, in this country JPLT-1 started in 1991 and the treatment results
of the group study have been collated every year. Results have been reported
at academic conferences and in academic journals and so forth 2) 3), and
collated results have also been reported. 4) Among the collated results
from 1991 to December, 1995, 103 cases of malignant hepatic tumor were
registered and 95 of them were hepatoblastoma. The eligible search cases
were 74 cases and the two year survival rates in each stage were I:100%,
II:95.5%, III A:85.5%, III B: 58.3 % and IV: 55.6%. The overall two year
survival rate was 81% and it was a treatment result in no way inferior
to that of SIOPEL 5) such as 79 % or of CCG 6) such as 71%.
However, from the analysis of the contents of the
treatment,
1)In case of both T1 and T2, if excised, the cure rate is almost 100%,
and JPLT 1-91A1 and 91A2 are the most satisfactory protocols. However intraarterial
injection cases are rare and the effect of the tumor regression has been
inconclusive.
2）The two year survival rates of response cases to 91B1 and 91B2 are both
favorable, approximately 90%, therefore it is not necessary to change the
present treatment protocol. Although there is no difference in the survival
rate between 91B1 and 91B2, it must be said that few cases of 91B1 were
registered to the study.
3）Stratified cases are rare due to the fact that it is difficult to explain
the procedure to families. And that preparation for intraarterial injection
takes time although most patients and families want to start the treatment
as soon as possible.
4）Cases of residual tumors, un-resectionable cases and casse of pulmonary
metastasis are intractable.
It became necessary to revise the protocol based on these results, and
after discussion at a meeting of JPLT organizers and the board of directors,
in December 1996, the following points were modified as follows:
1）91A remains the same. Since preoperative intraarteial injection treatment
is provided at the same time as angiography in many cases, this protocol
remains the same. At present, the survival rate is 100% therefore, the
chemotherapy can be reduced in the future.
2）91B will be restricted to the intravenous injection chemotherapy group.
The intraarterial chemotherapy group shall be used as a reference group.
3）Cases of relapse, resistance to 91A and 91B, and adult-type cases will
be treated by the protocols of each facility. The results will be considered
at a later date.
Because of the replacement of JPLT representative manager (Dr. Naomi OHNUMA),
the revision of the protocol was started in April 1998, based on the modifications
of 1996 mentioned above. From March 18th to 20th 1999, the second international
conference of pediatric liver tumor was held in Bern, Switzerland, sponsored
by SIOP Liver Tumor Study Group and representatives of SIOP, CCG, POG,
Intergroup (U.S.A.), Germany, Norway and Poland took part in discussions.
JPLT also participated in this meeting and the following issues became
clear.
1）In Western countries, especially SIOP, not only pediatric surgeons but
also oncologists, pathologists and radiologists were actively involved
in decisions on treatment, with (adult) liver surgeons also being called
in when necessary. Oncologists take a leading role and the main roles of
surgeons are liver excision and debating the necessity of liver transplant.
2）On the other hand, pediatric surgeons take a central role in Japan and
the Japanese characteristic protocol with interraterial treatment is based
on a surgeon’s prespective. Although the results might have been worthy
of attention, but in practice the protocol was not carried out widely enough
in Japan and accordingly it did not have an impact in other countries.
3）The treatment protocol of JPLT is simple and easy to adopt, concerning
the intravenous injection treatment. However, it has not indicated any
specific method for cases which are not resectable (the most important
point) and the design of the treatment and the study purposes are vague
comparing with the Western protocols.
4）The treatment protocol of JPLT is simple and easy to adopt, concerning
the intravenous injection treatment. However, it has not indicated any
specific method for cases which are not resectable (the most important
point) and the design of the treatment and the study purposes are vague
comparing with the Western protocols.
5）The medical treatment method of Japan for adult liver cancer contributes
significantly to the world. The method of determining surgical indication
of adult liver cancer and treatment, such as TACE (Trans-Arterial Chemo
Embolization), PEIT (Percutaneous Ethanol Injection Therapy) and so forth,
have been presented internationally and CCG has already started a trial
study with TACE. Moreover, the hematopoietic stem cell transplant for pediatric
liver tumor which has been performed at some facilities in Japan has also
been brought up internationally.
6）Basic research for pediatric liver tumors is topical and sporadic, and
although some of it has been outstanding (such as the high rate modification
of b-catenin gene), none of it has been linked directly to the clinical
practice yet. Our group study was the first that showed that the manifestation
of telomerase activity and telomerase enzyme protein (hTERT) is interrelated
to prognosis.
7) The shortage of tumor samples is a major cause of delay in research.
Analyzing the registration cases (follow-ups for one-year or more) of JPLT1
from 1991 to 1997, it has been considered that the following cases are
difficult to cure and accordingly, new treatment programs are necessary.
1）The rate of complete excision in stage IIIB is no more than 55%. In inoperable
cases, there were no cases of patients surviving with no tumor. Therefore,
in cases which do not respond to initial chemotherapy, an alternative salvage
therapy should be recommended, and the specific treatment for these cases
needs to be specified.
2）In the case of stage IIIA and IIIB, the prognosis for cases which metastasize
during treatment is extremely unsatisfactory and the chances of recovery
with ordinary chemotherapy are considered slim. Therefore, introducing
of a new kind of chemotherapy, as well as resection of metastatic lesions
and postoperative hematopoietic stem cell transplant (SCT) combined chemotherapy
are recommended for cases with metastatic recurrence.
3）For stage IV patients, the disease-free survival rate in both Japan and
the West is unsatisfactory at a little less than 30. Therefore, to improve
the treatment results, it was suggested that ultra-high-dose chemotherapy
combined with hematopoietic stem cell transplant may be necessary in stage
IV cases.
Based on the results above, many revisions and
improvements were made to our protocol, to improve the results of treatment for
children with pediatric liver tumors in Japan as well as in order to contribute
to health and welfare of child patients, and also to contribute to the
treatment of pediatric liver tumors abroad.
JPLT2 which introduced PRETEXT was proposed based on this. It is currently
in use and at present, this clinical trial is about to start reduction
of side effects by using smaller dose of chemotherapy in early stage cases
and to verify the effectiveness of preoperative chemotherapy in advanced
cases. Moreover, in recent years, the effectiveness of high-dose chemotherapy
combined stem cell transplant with advanced hepatoblastoma has been reported,
so we introduced regimen, which tried stem cell transplant in advanced
cases. On the other hand, with the prevalence of liver transplants, in
pediatric liver tumor cases in which local excision is impossible, for
recurrence cases, liver transplant therapy has been listed as the new treatment
strategy.
At present, treatment in Japan obtains equal results compared with the
U.S. and European countries, especially in early stage tumors, with more
than 90% survival rates using half the amount of antineoplastic drugs they
use. However, the treatment results for tumors which occupy all 4 hepatic
sections (PRETEXT IV) are not satisfactory and there are still a lot of
problems to solve, such as the necessity of chemotherapy in Stage II cases.
This study aims to evaluate the JPLT2 protocol, which
verifies in cases of pediatric liver tumor nationwide, the reduction of therapy
in early stage cases and the efficacy and safety of high-dose chemotherapy
combined with stem cell transplant in advanced cases, in order to improve the
treatment of pediatric liver tumors in Japan. Furthermore, if the treatment
method needs improvement based on the results, we will plan new treatment protocols,
make guidelines for surgical treatment including liver transplant, and create
new protocols to establish more effective and safer treatment. Also, since
treatment results are not only influenced by progression, by studying the
biochemical characteristics of tumors, identifying prognostic factors and
factors to relating to malignancy, and formulating the treatment options or
clarifying the responsiveness to medicine by the stratification of malignancy, we
aim to develop more effective and safer treatment.
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