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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