Frontiers in Anti-Cancer Drug Discovery Volume 10 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Cancer Drug Discovery
- Sprache: Englisch
Frontiers in Anti-Cancer Drug Discovery is a book series devoted to publishing the latest advances in anti-cancer drug design and discovery. In each volume, eminent scientists contribute reviews relevant to all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The book series should prove to be of interest to all pharmaceutical scientists involved in research in anti-cancer drug design and discovery. The book series is essential reading to all scientists involved in drug design and discovery who wish to keep abreast of rapid and important developments in the field.
The tenth volume of the series features chapters covering the following topics:
- Challenges in the Management of Hepatoblastoma
- The Emerging Role of Monocarboxylate Transporter-1 in Cancer
- In-vitro Anti-Proliferative Assays and Techniques Used in Pre-Clinical Anti-Cancer Drug Discovery
- Recent Advances in the Development of Mesoporous Anti-Cancer Drug Nanocarriers
- Polyphenols and Cancer
- Glioblastoma Multiforme
- Cutting Edge Targeting Strategies Utilizing Nanotechnology in Breast Cancer Therapy
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Veröffentlichungsjahr: 2019
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Frontiers in Anti-Cancer Drug
Discovery
(Volume 10)
Edited by
Atta-ur-Rahman, FRS
&
M. Iqbal Choudhary
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
Cancers are among the most fearful human diseases. This has attracted the attention of scientists, policy makers, media, and general publica alike. There are dozens of different types of cancers, with complex etiologies, heterogenicities and complex risk factors. This makes the treatment of cancer a major challenge. Recent advances in the field of anti-cancer drug discovery and development is largely based on a better understanding of cancer biology and molecular genetics. This book series entitled, “Frontiers in Anti-Cancer Drug Discovery” is regularly publishing excellent articles in this field and has gained reputation of being thorough, up-to-date and inclusive.
The present 10th volume contains seven excellent chapters focusing on various aspects of cancer biology, and advances in anti-cancer drug development. Ziogas and Tsoulfas have focused their article on general characteristics of hepatoblastoma, the third most common pediatrics tumor of the abdomen. They have reviewed various treatment options in different stages of the disease. The review by Gangarapu et al., is focused on the importance of monocarboxylate transporters (MCT) as a novel anti-cancer drug target. They summarize the recent developments in the field of MCT inhibitors, a new class of drugs against various cancers.
Biological screenings play an important role in initial drug discovery process. For pre-clinical anticancer drug lead discovery, a large number of in vitro cell-based anti-proliferative assays have been developed which are critically reviewed in the next chapter by Ediriweera et al. The nexus between diet and the onset of malignancies is the central theme of the article by Rajendran et al., They have reviewed the anticancer effects of major polyphenolic compounds found in common foods, in the context of their molecular mechanisms. Glioblastoma multiforme (GBM) is an aggressive lethal form of brain tumor, with poor prognosis. The chapter Review of Gabrani et al., is focused on recent development of synergistic combinations various classes of drugs with temozolomide, which provide substantial survival advantages to GBM patients. The central theme of the last two reviews is recent developments of anti-cancer drug delivery systems by using nanocarriers. Mendez-Rojas et al have reviewed recent progress on the development of mesoporous nanocarriers as efficient systems for controlled transport and delivery of various anti-cancer drugs, whereas the last review by Saraf et al., mainly deals with the active targeting of anti-breast cancer drugs by using various kinds of nanomaterials, and the challenges faced in these processes.
We are grateful to all contributors for their excellent scholarly contributions, and for the timely submissions of their reviews. We would like to express our gratitude to the excellent coordination of Ms. Fariya Zulfiqar (Manager Publications), Mr. Shehzad Naqvi (Editorial Manager Publications) and Mr. Mahmood Alam (Director Publications) of Bentham Science Publishers for the timely completion of the volume in hand. We sincerely hope that the efforts of the authors and the production team will help readers in a better understanding of the subject and motivate them to conduct further good quality research.
Prof. Dr. Atta-ur-Rahman, FRS Honorary Life Fellow, Kings College, University of Cambridge, Cambridge UKList of Contributors
Challenges in the Management of Hepatoblastoma
Ioannis A. Ziogas1,Georgios Tsoulfas2,*Abstract
Hepatoblastoma is the third most common pediatric tumor of the abdomen with an incidence of about 1.2-1.5 cases/million population/year. It has been associated with various genetic conditions, such as familial adenomatous polyposis, Beckwith-Wiedemann syndrome and Edwards syndrome, while genetic mutations of the Wnt signaling pathway are also frequently seen. The different staging systems and treatment approaches of the four hepatoblastoma study groups, International childhood liver tumors strategy group, Children’s Oncology Group, German Society for Pediatric Oncology, and Japanese Study Group for Pediatric Liver Tumors, led to different outcomes among the various trials published over the years. Some groups tended to follow a protocol of an upfront surgical resection, while others suggested neoadjuvant chemotherapy to all patients. Now these groups try to come on the same page by initiating an international collaborative attempt to pool previously published data, as well as to classify future patients into risk-stratified groups that would determine treatment options and facilitate improved survival outcomes. The aim of this chapter is to review the general characteristics of hepatoblastoma, the various treatments implemented over the last years, as well as the challenges in management that its rarity and discrepancies among the study groups pose.
INTRODUCTION
Hepatoblastoma (HB) is the third most frequently reported solid tumor of the abdominal cavity in very young children and the most common pediatric malignancy of the liver [1]. In fact, currently the incidence is 1.2-1.5 cases/million population/year [2], thus representing around 1% of the malignant tumors in childhood. HB usually presents in children between 6 months and 4 years old with a median age of 18 months [3]. It is an embryonal malignancy, thought to be
derived from the hepatoblast (precursor of hepatocyte) during embryogenesis of the liver [4]. Many factors have been accused of increasing the risk of HB development, such as low birth weight, prematurity, oxygen therapy, total parenteral nutrition, medication (furosemide) and radiation, but the exact pathogenetic mechanisms are yet to be unveiled [2]. Additionally, parental exposure to tobacco or metals, increased maternal weight before pregnancy, preeclampsia, previous treatment for infertility and either poly- or oligohydramnios can be such risk factors [5].
GENETICS & PROGNOSIS
Although HB mostly presents in a sporadic manner, it has been associated with familial adenomatous polyposis, Beckwith-Wiedemann syndrome and Edwards syndrome [6]. These associations indicate that genes in chromosomes 5, 11 and 18 may pose important assets in the development of HB. At the same time, the Wnt signaling pathway, and the beta-catenin gene in particular, is the cascade exhibiting the highest rate of genetic mutations (70-80%) [7]. Those aberrations result in the accumulation of beta-catenin inside the nucleus, which has been linked to poorly differentiated cellular components [7]. The same finding has been demonstrated in other liver malignancies (i.e. cholangiocarcinoma) and appears to have an association with the status of differentiation [8]. Alterations in the beta-catenin gene can also lead to the overexpression of some target genes, such as cyclin D and fibronectin [7]. Telomerase, a reverse transcriptase enzyme, prevents the shortening of telomeres hence rendering normal stem cells, as well as cancer cells, immortal. This process is closely regulated by the expression of TERT (human telomerase reverse transcriptase) [9]. Notably, MYC, a target gene of the Wnt pathway, upregulates the expression of TERT, while the latter one simultaneously participates in the activation process of the Wnt signaling cascade. Together, active TERT and MYC signaling tends to be found in more aggressive HB phenotypes [10, 11]. Hippo, a tumor-suppressor signaling pathway, and one of its downstream effectors called Yes-associated protein (Yap) also play a vital role in cell growth and differentiation. Even though the implications about its oncogenic properties have only recently been described, it has already been found that it intersects with the Wnt cascade, thus leading to tumorigenesis in general [12], but also in HB specifically [13]. Further evaluation of the genetic features of HB, may lead to more solid conclusions regarding the genetic associations of HB, while by intervening in those pathways we may be able to improve overall prognosis.
HISTOPATHOLOGY & PROGNOSIS
Another important factor associated with prognosis is histopathology. To elaborate this, there are two HB subtypes, the epithelial one and the epithelial mixed with mesenchymal tissues, such as skeletal muscle, bone or cartilage [14]. The epithelial group can be further subclassified into well-differentiated fetal (WDF), crowded or mitotically active fetal, embryonal, macrotrabecular (fetal or embryonal), small cell undifferentiated (SCU) and cholangioblastic. 30-60% of the HB cases are mixed fetal and embryonal with the rest of the epithelial group comprising less than 10% of the total cases [15]. On the other hand, the epithelial mixed with mesenchymal elements group accounts for 20-56% of the specimens [16, 17]. In terms of prognosis, it has been reported by the Children’s Oncology Group (COG) that when complete resection was facilitated prior to chemotherapy, children with WDF histology and low mitotic activity could be solely treated with surgical resection without the need for chemotherapy [18]. Although those patients represented only 7% of the cases, their event-free survival (EFS) was 100%. Additionally, the SCU histopathology, which usually presents with low alpha-fetoprotein (AFP) levels and is nonresponsive to chemotherapy, has been linked to worse prognosis [2, 19]. Limited data from immunohistochemical staining showed that INI1 nuclear negative SCU HBs are linked to more unfavorable prognosis [20], but on the same time classical HB SCU cells retain the INI1 stain [21]. A study reported that the SCU HBs that retained INI1 may be not be linked to poor prognosis [22]. Unfortunately, due to the rarity of HB and the scarcity of prechemotherapy resections, histopathology data were not commonly implemented in the management plan of HB, hence compromising the importance of biologic studies. Recently, consensus has been reached on the importance of HB sampling before the initiation of chemotherapy, thus facilitating diagnosis based on histopathological analysis, as well as HB classification [21]. Nevertheless, clinical data, such as patient age, AFP levels at diagnosis, underlying liver disease and liver reserve and results of imaging studies, should be provided to those reviewing the specimen [21].
PRETREATMENT EXTENT OF DISEASE & RISK STRATIFICATION
As in most pathologic entities, management varies according to risk stratification. Consequently, the therapeutic approach is determined not only by imaging and histopathology results, as well as by the presence or not of distant metastasis. Another crucial factor, apart from the tumor itself, is the extent of the liver remaining unaffected, as the vast majority of HBs require surgical resection. The four major study groups, International childhood liver tumors strategy group (SIOPEL), COG, German Society for Pediatric Oncology (GPOH), and Japanese Study Group for Pediatric Liver Tumors (JPLT), used to follow different risk stratification stages, hence rendering it impossible to pool cumulative data on the outcomes. Auspiciously, most US and European centers follow the presurgical extent of disease (PRETEXT) grading system to predict tumor resectability established by SIOPEL, which is based on imaging data. According to that, stage I is defined as one involved section and three free adjoining sections, while stage II is defined as one or two involved sections, but two free adjoining sections. Furthermore, stage III is described as two or three involved sections, while no two adjoining sections are free and in stage IV all sections are involved [23]. As adjuvant chemotherapy may usually afflict the anatomy of the area, the PRETEXT classification system is also used about 10 days after every two cycles of chemotherapy to reevaluate the anatomy (post-treatment extent/POST-TEXT). Even though the above-mentioned groups have launched many trials based on PRETEXT grading system, they still had many differences in terms of the annotation factors, which define involvement of the vena cava (V) or the portal vein (P), contiguous extrahepatic intra-abdominal tumor extension (E), multifocal liver tumor (F), rupture of the tumor at diagnosis (R), and metastasis (M). It was the Children’s Hepatic tumors International Collaboration (CHIC) that tried to pool the data from all those trials, follow a standardization process and conclude to the most useful individual prognostic factors regarding EFS [3]. They also utilized multivariate analyses in order to hierarchically prioritize prognostic factors, and as a result come up with a more accurate risk stratification system [24]. CHIC takes into consideration the PRETEXT radiologic groups and annotation factors, in combination with age and AFP levels, so as to define treatment groups for the ongoing “Paediatric Hepatic International Tumour Trial (PHITT) (NCT03017326)” [25]. It is therefore profound that dealing with HB is a real challenge and although its management has been through different approaches, the future seems promising based on collaborative initiatives.
SURGICAL RESECTION
As previously stated HB is a malignant tumor, and as such resection is the cornerstone of treatment. In fact, complete surgical resection determines the prognosis of the HB patients. Unfortunately, only one-third of the tumors are resectable at the time of diagnosis [26]. However, the great challenge of effectively treating HB laid for many years on the discrepancies between the different study groups. The most historically significant was the one between COG and SIOPEL in terms of the endeavor to completely resect HB at the time of diagnosis. The SIOPEL group followed a protocol of four neoadjuvant chemotherapy sessions before attempting surgical resection [27]. On the contrary, the COG collaboration group used to pursue complete surgical resection if possible upfront based on the Evan’s system and limit the administration of chemotherapy, if this goal was achieved [28, 29]. According to this staging system, surgeons would perform an exploratory laparotomy and, if the tumor could be resected, it was classified as stage I and IIwith microscopically negative and positive margins, respectively. If the tumor was considered unresectable, it was classified at stage III and IV without and with metastasis, respectively. At the same time, GPOH and JPLT used their own hybrid refined staging systems to determine tumor resectability [30]. Subsequently, COG also abandoned the exploratory surgery protocol at the time of diagnosis and implemented their own PRETEXT-based hybrid system (current COG protocol, AHEP0731) [27]. They suggested performing surgery upfront at diagnosis only in PRETEXT I or II HBs with more than 1 cm free margin, which were not concerning for macrovascular involvement. Apparently, JPLT multicenter studies followed the same rule for early stage HB (PRETEXT I and II) complete resection at diagnosis, but according to their protocols the majority of HBs should be treated not only with resection but also with liver transplantation (LT) and neoadjuvant chemotherapy [31-33]. In the same manner, COG also suggested that PRETEXT III (or POST-TEXT, V and P: negative) patients should be treated with neoadjuvant chemotherapy before resection, while PRETEXT IV (and POST-TEXT III with V and P: positive) may require either radical resection or liver transplant [27]. The need for referral to an LT center for PRETEXT IV was also highlighted by SIOPEL [1]. On the other hand, the upfront complete resection adopted by the COG group led to the identification of the WDF HBs, for which resection is enough [18]. Fortunately, it was reported that complete resection contributes significantly in non-WDF HBs as well, by decreasing the necessity for adjuvant chemotherapy [18, 29].
The resectability of the HB is not only stage-dependent, but also technique-dependent. Top-notch expertise is required in order to yield optimal outcomes. The only acceptable surgical resection techniques are the non-extended lobectomy and segmentectomy, so that complete tumor resection is achieved. On the same wavelength, according to the two trials launched by GPOH (HB89 and HB94), near 40% of the patients receiving an atypical resection can have residual tumor postoperatively [16]. Obviously, residual disease is associated with worse outcomes and this may be due to the fact that atypical resection leads to dissemination of tumor cells in the liver [34]. It is clearly articulated, therefore, that atypical, wedge and non-anatomic resections should be abandoned when it comes to surgical resection of HB. They could be considered appropriate only in multifocal HB, and particularly when metastases and lack of donor graft render LT unfeasible. The utilization of intraoperative ultrasonography is useful in identifying those multiple foci, as well as in achieving 1 cm resection margins. Biopsy and marginal resection should be attempted if residual macroscopic lesions are present [27]. The surgeons should be accustomed to liver anatomy and vessel variations, as well as follow the basic principles of surgical oncology. The technological advances in surgical equipment, such as Ligasure, harmonic scalpel, argonbeam and infrared coagulator, ultrasonic cavitron ultrasonic surgical aspirator (CUSA)-type dissector, and water knife (Hydrojet, ERBE), are also occasionally implemented during operations for HB [35].
As mentioned above, it is widely known that there were many discrepancies in terms of the different protocols and approaches followed by SIOPEL, COG, GPOH and JPLT. Their current collaborative initiative, also faced many challenges in terms of extracting and pooling the data thought of being related to prognosis, so as to stratify patients in very low-, low-, intermediate- and high-risk backbone groups [24]. According to this model, very low- and low risk patients are separated only by tumor resectability at diagnosis as per the surgical guidelines for PHITT. Interestingly, older age seems to override low PRETEXT, hence yielding worse prognostic outcomes. Even though at first there were three age groups: a) <3, b) 3-7, and c) ≥ 8 years old, children falling into the 3-7 years’ age group with PRETEXT I/II present with resectable HBs at the time of diagnosis, so they should still be perceived as low-risk patients. This decision is reasonable on the basis of resecting potentially chemo-resistant tumors. So, except for the case of PRETEXT IV, in which children between 3 and 7 years old have equally poor prognosis as those ≥ 8 years old, the authors suggest a simplification such that of <8 years and ≥8 years, but yet future trials may determine better age cut-offs [24]. The results of PHITT are awaited in suspense, as they may retrospectively validate the approaches utilized, as well as determine when surgical resection should be implemented.
CHEMOTHERAPY
Over the years, although overall survival (OS) seems to be on the rise, a common pattern observed in all of the study groups was the administration of a more or less modified combination of cisplatin chemotherapy and complete surgical resection. The contribution of chemotherapy in these improved survival outcomes is unquestionable. In fact, up until a few decades ago, only 20-30% of HB patients would usually survive [36], but the introduction of neoadjuvant and adjuvant chemotherapy raised those percentages up to 70-80% [37].
The North American cooperative group studies for the management of pediatric liver malignancies were firstly carried out in the 1970s. Initially, the chemotherapeutic regimens consisted of either vincristine, cyclophosphamide, and actinomycin D or vincristine, cyclophosphamide, doxorubicin, and 5-fluorouracil if a more aggressive approach was necessary [38]. Nevertheless, cisplatin (CDDP) skyrocketed survival rates and, according to the Children’s Cancer Study Group (CCCG), when used with continuous infusion doxorubicin (DOXO), a combined therapy named PLADO, for patients with unresectable or metastatic HB (stage III and IV) showed an improved 3-year disease-free survival up to 55 and 30%, respectively [39]. Moreover, when the regimen of CDDP, 5-fluorouracil, and vincristine (C5V) was implemented, the EFS for stage I/II HB patients was 90%, for stage III HB patients 67%, and for those with stage IV HB 12.5% (POG8697 trial) [40]. The INT-0098 trial was carried out in order to compare those two chemotherapeutic schemas [26]. Six courses of PLADO showed lower rates of disease progression, but higher rates of toxicity versus six courses of C5V, and as 5-year EFS was not significantly different between the two regimens, C5V was adopted by the COG trials due to its lower toxicity. The SIOPEL-1 trial (1989-1994) also assessed the PLADO schema by administering it as a 4 triweekly preoperative course, followed by two postoperative courses [37]. The results showed a 66% EFS and a 75% 5-year OS, while it also achieved downstaging in around 28% of the patients. However, the outcomes for patients with PRETEXT-IV or metastatic disease were poor.
In order to improve those disappointing outcomes in patients with metastatic and unresectable HB, as well as to decrease the chemotherapy-associated toxicity, the P9645 trial was carried out [41]. Intensified platinum therapy, specifically alternating cisplatin and carboplatin, was compared to C5V with or without amifostine and the study showed that a 1-year EFS of 37% vs 57%, respectively. As a result, the study was discontinued based on the results of the interim analysis and patients were continued on C5V with or without amifostine. Nonetheless, the potential protective role of amifostine could not be elucidated, as patients with stage I or II stage HB showed no reduced hemato- or ototoxicity [42]. Concomitantly, the SIOPEL-2 study was designed in order to evaluate the adequacy of CDDP monotherapy in comparison to the addition of DOXO for standard-risk patients, so as to prevent DOXO’s toxicity. On the other hand, high-risk patients were treated with alternating CDDP and carboplatin/DOXO [43]. The investigators reported that CDDP monotherapy is adequate for standard-risk patients, but for high-risk patients the outcomes were not yet promising. Therefore, the SIOPEL group designed the SIOPEL-3 trial, in which they initiated all standard-risk patients on CDDP monotherapy and then randomized them on either continuing with CDDP monotherapy or switching to PLADO [44]. The results showed equal rates of survival and complete surgical resection between the two groups, hence suggesting the safe abandonment of DOXO from the treatment plan of those patients. However, for high-risk patients, they implemented 7 preoperative and 3 postoperative courses of alternating CDDP and carboplatin/ DOXO [45], and according to the results 3-year EFS was 65%, and 3-year OS was 69% for all patients, thus indicating that intensification of CDDP therapy may improve survival. Consequently, the single-arm SIOPEL-4 trial [46] was designed and patients were initiated on preoperative treatment with PLADO (cycle A), followed by surgical removal of the remaining malignant lesions if possible. If the tumor was still unresectable, a second cycle of preoperative chemotherapy with carboplatin and DOXO was administered (cycle B), while a postoperative regimen of carboplatin and DOXO (cycle C) was given to those that did not receive cycle B. The investigators reported complete resection in 74% of the patients with a 3-year EFS and OS of 76% and 83%, respectively, therefore reporting the highest survival rates ever even in metastatic HB. However, this was a single-arm study comparing the recruited patients with historical cohorts, and in addition to the high rates of toxicity, such as hematologic complications, ototoxicity and toxic deaths, it is profound that further evaluation with a randomized controlled trial is needed. Hopefully, the ongoing PHITT may come up with more meaningful outcomes.
The JPLT group also designed two trials in order to elucidate the optimal treatment approach for HB. Their first one, JPLT-1 study (1989-1999), used a regimen consisting of CDDP and pirarubicin instead of DOXO (CITA regimen) postoperatively in early-stage HB and both pre- and postoperatively in advanced-stage HB with the CDDP dose in the latter group being double than that of the first one [32]. The outcomes for the first group were acceptable, but the EFS among the patients with advanced disease was less than 50%, thus further proving the challenging management of unresectable and metastatic HB. Therefore, in the same manner as SIOPEL, the group from Japan designed a second multi-institutional trial, JPLT-2 (1999-2008), so as to improve the outcomes in patients with HB [31]. This was by the time that the different groups started coming on the same page as per using the same staging systems, such as the PRETEXT classification. Patients with PRETEXT 1 HB were treated with upfront resection followed by postoperative CITA, while the rest of the cases were treated with preoperative CITA and surgery, followed by postoperative chemotherapy. As the results of JPLT-1 were not promising for advanced HB, they followed two different approaches for that stage in their second trial. To elaborate this, patients without even partial response to CITA received a salvage regimen called ITEC (ifosfamide, pirarubicin, etoposide and carboplatin), while those with metastatic disease received high-dose chemotherapy with autologous hematopoietic stem cell transplantation. Based on the interim analysis, the OS rates for non-metastatic PRETEXT I, II, III, and IV were 100%, 87.1%, 89.7%, and 78.3%, respectively. Unfortunately, the OS for metastatic disease was only 43.9%, even though one-third of them was treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation. In these cases, intensifying chemotherapy in the neoadjuvant setting may be efficacious, as reported by the SIOPEL-4 trial [46]. The real challenge lays on the fact that the vast majority of these patients can sufficiently be treated with standard instead of intensified CDDP monotherapy, according to the SIOPEL-3 study [47]. Generally, the outcomes for PRETEXT I-III in JPLT-2 were similar to those from other multi-institutional studies, while in comparison to JPLT-1 the survival outcomes in patients with PRETEXT III and IV HB were improved [31]. In those non-metastatic HBs, the intensified regimen ITEC, partial hepatectomy thereafter transarterial chemoembolization (TACE), and LT played a vital role in these improved results. Another controversy lays on the appropriate intensity for the locally advanced HBs (PRETEXT IV). This is because on the one hand many of those patients will eventually require LT so we should prevent the toxic effects of intensive chemotherapy, while on the other hand preoperative chemotherapy can downstage around 30-50% of the tumors, which will then require partial hepatectomy instead of LT [23].
The rarity of HB poses a great challenge to investigators when it comes to designing and carrying out phase 1 and 2 trials and to date no novel efficacious drugs have come to light [48]. Also, despite the promising results of SIOPEL-4 the toxicities of CDDP and DOXO are significant. So, the need for novel agents has emerged, especially in the context of refractory or recurrent HB. The best way to evaluate response to these drugs are the AFP levels, as well as the Response Evaluation Criteria in Solid Tumors (RECIST). A recent SIOPEL study assessed the monotherapy with irinotecan and reported partial responses as per the two above mentioned methods in about 25% of the patients with recurrent or refractory HB [49]. With the intent of further assessing potential agents for high-risk HB patients, the COG group designed the AHEP0731 study to evaluate the use of irinotecan and vincristine [50]. Specifically, patients with metastatic HB and AFP less than 100 ng/mL received two cycles of vincristine and irinotecan, while response was defined either as 30% decrease in tumor burden based on RECIST criteria or a 90% decrease in AFP levels. If patients responded, they received two additional cycles of vincristine and irinotecan mixed with six cycles of C5V and DOXO (C5VD), while if they did not respond, they received only six cycles of C5VD. It was shown that even though this regimen did not fulfill the predetermined criteria for adequate control of the disease, these agents have substantial activity against high-risk HB. Nevertheless, more studies are required to further assess this combination. Around 33% of the patients with disease progression or recurrence after initial therapy without anthracyclines can still be rescued with DOXO regimens and surgery [42]. Carboplatin, etoposide and ifosfamide, have been used not only as rescue regimens, but as upfront treatment in high-risk patients as well [42, 51, 52]. Small groups of patients with relapse have also been tested on irinotecan and oxaliplatin [49, 52, 53]. In an attempt to decrease the toxicity of CDDP, the SIOPEL-6 study was designed in order to evaluate the potential protective effect of sodium thiosulfate for CDDP-induced ototoxicity. Its result showed that if it is administered 6 hours after CDDP, it can reduce the CDDP-induced hearing loss, while concomitantly preserving the OS and EFS [54]. When it comes to the implementation of chemotherapy in the LT context, it is controversial if there is a potential advantage prior to LT. Specifically, for the management of pulmonary metastases, many surgeons will still request surgical exploration before LT, so it is unclear if chemotherapy has something to add in this setting. As far as administering chemotherapy post-transplantation, although there may be a risk for higher rates of LT-related complications, more and more LT centers seem to adopt this approach. Current data suggest equal outcomes with either administering or not chemotherapeutic regimens in the post-transplant setting [55-57].
TRANSARTERIAL CHEMOEMBOLIZATION (TACE) & HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU)
In the cases of relapsed or progressive HB, apart from LT, other non-chemotherapy modalities have been proven to be efficacious. The need for these therapies is immense, as chemotherapy can be associated with numerous side effects, like myelosuppression, cardiotoxicity, and secondary malignancies [54, 58-61]. TACE aptly represents this group by efficiently decreasing tumor burden, hence facilitating complete tumor resection after initial management with chemotherapy [62, 63]. The rate of complete surgical resection is around 81% without any morbidity [64]. Its efficiency is based on the higher drug concentrations accumulated, hence destroying tumor cells, a process otherwise impossible with systemic chemotherapy. However, laparotomy is needed, so as to facilitate catheter access to the artery [65, 66]. Data showed an 87.5% 1-year OS, 68.7% 3-year OS and 50% 5-year OS, as well as a 75%, 62.5% and 43.7% 1-, 3- and 5-year EFS, respectively [64]. Regardless if the tumor is resectable or not, TACE can be the initial and sole preoperative treatment in patients with no distant metastases, while for patients with distant metastases, systemic chemotherapy before the implementation of TACE is essential [63]. Additionally, it can facilitate the transition of a tumor from the unresectable status to resectable, especially in patients without distant metastases, without the severe side effects of liver or renal failure, myelosuppression or cardiac damage [67]. On the other hand, a “postembolization syndrome” comprising of fever, abdominal pain, nausea, vomiting, and hepatitis, and increased CRP levels can afflict the vast majority of patients, even though these symptoms are temporary and clinically insignificant [64].
High-intensity focused ultrasound (HIFU) has also been used in combination with TACE and its ability to directly target tumor cells and enhance their death is impressive. In a trial assessing HIFU ablation plus TACE versus C5V chemotherapy reported an increased rate of complete resection and a decreasedrate of serious adverse events in comparison to C5V treatment in advanced pediatric HB [68]. Presuming that HIFU ablation is as efficacious as surgery in the management of HB, it was used after TACE in stage III and IV HBs and achieved complete ablation in all of the cases with the significant percentages of tumor size reduction by 50-60% [69]. At this point, it is essential to highlight the importance of administering HIFU ablation after TACE. This lays on the fact that TACE interferes with tumor blood flow, which may result in heat loss during HIFU, by reducing it. At the same time, TACE leads to iodinated oil deposition in the HB itself, hence not only increasing the acoustic impendence, but also providing synergistic thermogenic effects up to those of HIFU [69]. Further research is warranted before introducing those techniques to first-line treatment protocols.
LIVER TRANSPLANTATION (LT)
LT is supposed to be the last curative treatment resort for unresectable and metastatic HB. In fact, from the low rate of 5% in 1990, LT was performed as frequently as 43% in 2013 [70]. Even though HB’s frequency has increased four times over a 32-year period, LT is performed significantly twenty times more frequently [71]. Interestingly, in the 1990s only half of the recipients of primary LT were expected to survive [72], while nowadays the rate is about 80-90% [70, 73]. However, data suggest that surgeons with high expertise may be able to resect otherwise unresectable tumors. As such, many controversies exist as per which is the optimal treatment for very large or critically positioned HBs that impinge on vital vessels or multifocal HBs in all four sectors of the liver before neoadjuvant chemotherapy [37, 74-77].
Current indications for LT in HB are the unifocal POST-TEXT IV HBs and/or POST-TEXT III or IV that are multifocal in nature or invade the vasculature [35, 78]. The presence of active extrahepatic HB sites, both regional spread and metastases, that have not been completely treated either surgically or with chemotherapy, poses a contraindication to LT. As mentioned before, pulmonary metastases and their management specifically is a controversial topic. Nevertheless, even partial response by HB size reduction and fall of AFP levels constitute good prognostic factors. Remnants of extrahepatic disease before LT, even if cleared on computed tomography (CT) scan before LT, is a significant risk factor for HB recurrence after LT [79]. Similar outcomes have been observed in terms of disease clearance and recurrence rates between surgery and chemotherapy [35, 70, 80].
There is an ongoing debate regarding the best method for the management of multifocal HB, between LT versus conventional surgical resection after clearance of intrahepatic lesions with neoadjuvant chemotherapy [27, 76, 79, 80]. At least for POST-TEXT IV HBs with multifocal spread that present without metastases post neoadjuvant chemotherapy, the reasonable management is LT [81]. Studies have shown that the exact extent of the disease may be overestimated in about 40% of the patients, if staging is based solely on imaging findings [76, 82]. So many surgeons, especially in liver centers with high expertise in extensive liver cancer resections, suggest exploratory laparotomy upfront prior to listing for LT, so as to determine the actual extent of the disease. However, the vast majority of liver surgeons agree that radiographic findings are enough for listing for LT, before exploratory surgical procedure. If intraoperatively the tumor presents to be unresectable, LT if necessary and usually from a living donor, can be carried out at the same time [77, 78, 83]. On the contrary, the COG guidelines clearly state that referral to LT centers for LT should be timely for unresectable tumors [27, 35]. This was based on the optimal outcomes observed after primary LT for these patients (80% survival) versus rescue LT after failure of primary surgical resection due to recurrence (30-40%) [47, 75, 84, 85]. Actually, on multivariate analysis, it was seen that the only factor affecting OS was macroscopic venous invasion. In general, long-lasting preoperative chemotherapy protocols in HBs that remain unresectable should be avoided, as not only may the effects on treating the tumor decrease with prolonged therapy, but resistance in chemotherapeutic agents can also be seen. In fact, continuing the anticancer regimen for more than four chemotherapy cycles has no impact in increasing the rates of conventional tumor resectability [86, 87]. So, in that context when local control is needed, especially after four cycles of chemotherapy, LT is the best possible option [27]. The ongoing trial by COG (AHEP0731) is about to assess the feasibility and outcomes of early referral for LT versus primary extreme surgical resection [88]. However, the scarcity of liver grafts poses another real therapeutic challenge, which may afflict survival of HB patients (waiting time for LT ranges from 1 to 50 days, with a median of 16 days) [80]. Living donor LT can be a potential solution to this problem by increasing the liver graft pool. Notably, the rates of recurrence were higher in patients waiting for a cadaveric graft (mean 31 versus 15 days in patients with and without recurrence, respectively) [70].
In contrast, it is actively advocated that liver resection can provide similar oncologic outcomes without the disadvantages of post-LT immunosuppression and of the absence of liver donors and cadaveric livers, especially in countries like Egypt where cadaveric livers are not culturally acceptable [89, 90]. Another argument of those vouching for liver resection over LT is that the latter is supposed to carry some serious complications, as it is a significant operation. These include but are not limited to malfunction, hepatic artery and portal vein thrombosis, long-lasting immunosuppression, lymphoproliferative disease and chronic rejection [35], while data from large registries (like the PLUTO registry) indicate lack of hepatic artery thrombosis [91]. Another study reported a 10% hepatic artery or portal vein thrombosis requiring a second LT operation [70]. Post-LT chemotherapy and immunosuppression can also lead to either a secondary malignancy, like Burkitt lymphoma [80], or infection, such as CMV [92].
Overall, a recent study assessing the long-term outcomes in a 14-year period of LT reported a 1-, 3-, and 5-year graft survival rate of 96%, 87%, and 80%, respectively with even 66% of the patients that received salvage LT surviving for a 1.5 year now postoperatively [93]. Generally, it is really difficult to pool the data of previous studies and reach solid conclusions about the actual survival of HB patients receiving LT over the years, because of the discordances in age, staging systems, chemotherapy schemas, the presence of metastatic disease pre-LT and the implementation of chemotherapy post-LT among the individual studies. A worth mentioning review article gathered the data from 292 HB patients who received LT and showed that, at the time of each individual paper’s publication, 41% of the patients that underwent a rescue LT were alive, while the percentage was 85% for those that received primary LT [81]. Another recently published study from Japan reported that primary LT is superior to liver resection for advanced HB with an OS of 100% vs 91.7%, respectively [94]. Thus, primary LT is the suggested treatment for advanced stage HB, at least until the AHEP0731 trial elucidates those controversies.
THE ROLE OF AFP
Serum AFP levels tend to somehow correlate with HB, thus have been defined as a sensitive prognostic marker. AFP levels are usually increased in children with HB, while in around 5-10% of the cases they can be either normal or low [95].The actual number is not that significant for prognosis, but there are two other ways that AFP levels can be found useful. Firstly, AFP levels are related to the tumor extent and biologic nature, so they can be helpful at the time of diagnosis. Secondly, they can also be monitored after administering chemotherapy to evaluate response to treatment. Actually, the SIOPEL stratified children with HB into two groups, as standard-risk and high-risk, as per the AFP levels. Levels lower than 100 ng/mL are thought of carrying a higher risk of a worse response to chemotherapy and poorer prognosis [95, 96]. High-risk were the tumors confined in all four liver sectors or even those presenting with distant metastases. Standard-risk were the HBs limited to the liver and not involving more than three liver sectors [96]. However, recently the CHIC is making attempts to re-stratify patients based on more accurate prognostic factors, and AFP plays a vital role in this process [24]. As previously mentioned, they divide patients into five backbone groups and, when it comes to AFP, in the first four backbone groups AFP is defined as over 100 ng/mL, while the level of AFP ≤100 ng/mL is set for the fifth backbone group, while in general groups are defined based on PRETEXT and the presence or not of metastatic disease. In terms of the outcomes of this attempt to pool the data of previous trials, children in the backbone 5 group exhibited a poor prognosis and low AFP did not seem to be as predictive of a poor outcome, because children with PRETEXT I and low AFP (≤100 ng/mL) did not show such a bad prognosis. Consequently, AFP levels are useful prognostic factors, but the resectability of the tumor seems to outweigh AFP in terms of significance. They also introduced a new category as per the AFP levels (≤100, 100–1000 and >1000 ng/mL) based on the notion that infants younger than 6 months of age present with a broader range of normal AFP levels, which does not coalesce with the predetermined “adult” normal values at least until they become 6-12 months old, after reviewing previously published work in this topic [97]. It was shown that patients with AFP >1000 ng/mL exhibited improved survival regardless of being positive for one of the annotation factors. Additionally, patients with AFP ranging between 100 and 1000 ng/mL, even though being PRETEXT III, <8 years of age, and without metastasis, had a relatively worse 5-year EFS. Besides, it is known based on data that patients that not survive of HB tend to have a lower median AFP at presentation [93].
When it comes to response to chemotherapy, previous studies pointed towards the perception that the level of decrease in AFP levels was more predictive for survival than the actual numerical value [98], while more recent data suggest that the actual AFP levels after neoadjuvant chemotherapy and before surgical resection are more predictive [99]. Moreover, AFP levels tend to increase postoperatively when a relapse occurs with less than 1% of relapses thought of being AFP-negative [96]. So instead of utilizing imaging for post-treatment relapse surveillance, it is recommended that AFP levels are routinely monitored and imaging studies are reserved for patients with increased risk of relapse, such as the older ones and those presenting with a low AFP value or a SCU histopathology result [99]. Nevertheless, further trials are needed to solidify the currently available data regarding the prognostic significance of AFP in HB, but the recent collaborative approaches seem promising.
CONCLUSION
HB is a one of the most commonly intraabdominal solid tumors of childhood, and presents occasionally with several genetic associations, such as familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and various genetic mutations. The discrepancies among the grouping systems and treatment approaches among the four study groups dealing with this entity posed a real challenge for many years in terms of determining the best possible risk-stratification system and therapeutic plan that would lead to the most favorable prognosis. The different modalities implemented are neoadjuvant chemotherapy, surgical resection and adjuvant chemotherapy, especially for low-risk tumors, while high-risk patients are mostly favored by pre- and/or postoperative chemotherapy and LT or liver resection. Future studies evaluating TACE and HIFU may drastically alter the current first-line treatment protocols. The ongoing work of the current international collaborative initiative, which consists of the four major HB study groups, seems really promising and the PHITT that is now still recruiting patients may further elucidate foggy areas and result into better survival outcomes for children afflicted by HB.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
Declare None.
