Stage II

Complete gross resection with microscopic residual disease

PRETEXT II

One or two sections are involved, and two contiguous sections are free of tumour

Stage III

Biopsy only or Incomplete resection nodal involvement or tumour spill

PRETEXT III

Two or three sections are involved, and no two contiguous sections are free of tumour

Stage IV

Metastatic disease

PRETEXT IV

All four sections are involved

The following definitions are used to assess outcome:

• Complete remission (CR) – complete disappearance of all lesions and normalisation of α-FP for at least 4 weeks

• Disease progression – children with persistent lesion(s) or an abnormal α-FP level at the end of treatment, or both

• Event-free survival (EFS) – period to occurrence of event (could be disease or symptom or discontinuation of treatment – if toxic perhaps).

• Overall survival (OS) – period to death (from any cause)

20.2.2.1  SIOPEL PROTOCOLS

The benefits of neoadjuvant chemotherapy are the early elimination of occult, microscopic metastatic foci; shrinkage of the primary tumour that facilitates curative resection while preserving the maximum liver parenchyma; and the opportunity to assess the histological response to chemotherapeutic agents.

Neoadjuvant chemotherapy has been given to all patients in SIOPEL protocols as compared with other protocols, such as COG or GPOH, although this may change in the future.

• SIOPEL 1 and 2 showed the efficacy of cisplatin alone in standard-risk groups and the combination of cisplatin + doxorubicin (PLADO) in high-risk groups [5]. The 5-year EFS was 66% and OS 75%.

• SIOPEL 3 (2003–2006) confirmed that three preoperative cycles plus two postoperative cycles of cisplatin (as monotherapy) were both equivalent to and less cardiotoxic than cisplatin + doxorubicin for standard-risk patients [6].

• SIOPEL 3 HR (Super PLADO) (Figure 20.1) showed that OS for metastatic patients increased from 28% to 56% [7].

• SIOPEL 4 addressed only high-risk patients, with treatment consisting of preoperative chemotherapy (cycles A1–A3, followed by surgical removal of all remaining tumours if feasible and including liver transplantation [LT] and metastasectomy). Patients for which tumour remained unresectable received additional preoperative chemotherapy (cycle B). After surgery, postoperative chemotherapy was given (cycle C) to patients who did not receive cycle B (Figure 20.1). This treatment proved to be more effective on high-risk patients (metastatic, multifocal PRETEXT IV, α-FP < 100 ng/mL) [8]. The main drawbacks of this treatment were increased otoxicity and haematologic toxicity, which could lead to death or delays before surgery. In this protocol, 16 of 62 (25%) children were transplanted. None of those with microscopic residual tumour relapsed.

Table 20.3 PRETEXT staging system: Additional criteria

Source: Roebuck DJ, et al., Pediatric Radiology 2007, 37: 123–132.

Note: The PRETEXT used in the COG central review is slightly different for vascular invasion since P refers to the main portal trunk invasion and V all three hepatic vein invasions [4].

Table 20.4 Risk stratification in current SIOPEL studies

Source: Maibach R, et al., European Journal of Cancer 2012; 48: 1543–1549.

Note: SCUD, small cell undifferentiated.

Table 20.5 Current COG stratification group and chemotherapy regimens

Source: Meyers RL, et al., Pediatric Blood & Cancer 2012, 59: 800–808.

Note: PFH, pure fetal histology; SCU, small cell undifferentiated; C5V ± D, cisplatin, 5-fluorouracil, vincristin ± doxorobucin.

• SIOPEL 5 is a protocol for cases of HCC occurring in those <30 years of age.

• The ongoing SIOPEL 6 study assesses both efficacy and safety of sodium thiosulfate in preventing ototoxicity and renal toxicity in standard-risk patients, without compromising efficacy (Figure 20.1).

20.2.3  Reported outcomes

Standard risk – the complete resection rate after both chemotherapy and surgery should be 94%–99% with a 3-year EFS and OSs of 83% and 95%, respectively [6].

High risk – complete resection rate should be 74% with a 3-year EFS and OSs of 76% and 84%, respectively [8]. Among this group, metastatic patients have a 3-year EFS and OSs of 77% and 79% with the SIOPEL 4 HR protocol compared with 56% and 62% with SIOPEL 3 HR.

Those children who underwent LT with clearance of lung metastases have had a much better outcome than those in SIOPEL 3 HR. These results are consistent with PLUTO^* reports of 83% survival in those patients who cleared their metastases before LT [9]. Conversely, for nonmetastatic PRETEXT IV patients, the EFS and OS are the same in both studies, and given the toxicity of the SIOPEL 4 treatment, the current recommendations by the SIOPEL group are to give the less toxic SIOPEL 3 HR treatment to nonmetastatic PRETEXT IV patients. Patients with low α-FP still have a dismal prognosis, with a 3-year EFS and OS of about 33% [8]. Treatments and prognosis according to risk stratifications in the current SIOPEL group are displayed in Table 20.4.

20.2.3.1  RELAPSES

Treatment strategy for recurrent HB has not been standardised, but relapses can be managed with carboplatin, doxorobucin, irinotecan and high doses of cyclophosphamide. Surgical removal of detectable tumour foci is recommended whenever feasible, either after the diagnosis of relapse or following chemotherapy for patients with unresectable disease at time of relapse. The decision to administer postoperative chemotherapy and the choice of drugs were at the discretion of the treating physicians. A recent paper from the SIOPEL group, compiling SIOPEL 1–3 studies, showed that relapse was local in 36%, metastatic in 55%, and combined in 9% of children. The site of metastases was lungs, peritoneum and central nervous system. The median interval between the initial diagnosis and the date of documented relapse was shorter in patients with a local relapse (10 months) than in patients with metastases (20 months). Some patients suffered from a late relapse (>3 years after diagnosis). These late relapses were in the liver in most cases and occurred in older children (median age at first diagnosis 5.5 years). Fifty-two children achieved a second CR, and 58% of them were alive after a median of 84 (range 3–175) months, and 32% were alive in CR after a second relapse, proving that treatment of relapse combining surgery and chemotherapy is useful [10].

Table 20.6 Chemotherapies used in European or American protocols for liver tumours

Note: ++, likely/intense; +, less likely/intense; CDDP, cis-dichlorodiammino-platine; HR, high risk; CNS, central nervous system; GI, gastrointestinal; HB, hepatoblastoma; UES, undifferentiated embryonal sarcoma; BM, bone marrow.

Currently, the main thrust of trials is to reduce the toxicity of chemotherapy, and the COG approach of up-front resection of PRETEXT I–II tumours with pure fetal histology may be used in future SIOPEL studies.

20.2.4  Chemotherapy: North American experience

COG protocols evolved from a surgery-first strategy, a clear difference from the European experience. Thus, those with PRETEXT I and II and pure fetal histology on diagnostic biopsy undergo an up-front surgical resection. With this, 100% EFS can be achieved without any postoperative chemotherapy [11]. Unfortunately, this represents only 6% of the overall cohort.

Results from various trials of the North American Cooperative Study Group showed that children with localised disease achieve long-term survival following treatment with a combination of cisplatin, 5-fluorouracil and vincristine (C5V) ± doxorubucin^* (C5VD), therefore avoiding the toxicities of PLADO chemotherapy. The current COG trial is AHEP0731, begun in 2009 and expected to end in 2016. The chemotherapy regimens according to different groups of treatments are displayed in Table 20.5.

20.2.5  Late effects of chemotherapy

Cisplatin-induced ototoxicity and doxorobucin-related cardiac toxicity are the main late effects of treatments. COG investigators failed to prevent platinum-induced hearing loss by the use of the otoprotectant, amifostine.^† Currently, SIOPEL investigators are conducting a randomised study for standard-risk patients to receive therapy with cisplatin with or without sodium thiosulfate (SIOPEL 6). Second tumours (mainly acute myeloid leukaemia) have been reported [12].

Figure 20.1 Current SIOPEL protocols. (a) SIOPEL 6 protocol for standard risk. CDDP, cisplatin; STS, sodium thiosulfate (ear protection). (b) Super PLADO protocol in SIOPEL 3. C, cisplatin; D, doxorobucin; CA, carboplatin. 1 arrow = 2 weeks. (c) High-risk protocol in SIOPEL 4. C, cisplatin; D, doxorobucin; CA, carboplatin.

20.3  LIVER TUMOURS: HEPATOCELLULAR CARCINOMA

HCC is the second most common and accounts for about 30% of primitive malignant liver tumours in children and young adults of <20 years in age, with an incidence of 0.5–1 per million population. There are two types of HCCs:

• Classic HCC (with two subtypes), which resembles the adult common type and is associated with chronic liver disease in 33% of cases [13] (Table 20.7)

• FL-HCC, which usually occurs in a noncirrhotic liver

20.3.1  Pathology

There are two histologic subtypes of classic HCC, the most common resembling the adult pattern but occurring in the first decade of life in those with cholestatic or metabolic disease. Histologically, there is cyto megaly, nuclear pleiomorphism, tumour giant cells and broad trabeculae. The second one occurs in adolescents without any underlying liver disease, which may show a morphological spectrum sometimes overlapping with HB.

There is another subtype in which consensus between pathologists has still not been reached, now called hepatocellular neoplasm not otherwise specified (NOS). This last entity includes transitional liver cell tumour based on the hypothesis that these may represent a new type, with a putative cell of origin situated at a transition between the hepatoblast and hepatocyte lineages. In contrast to FL-HCC, classic HCC has a raised α-FP.

Table 20.7 Chronic liver diseases in which HCC occurs

Note: PFIC, progressive familial intrahepatic cholestasis

20.3.2  Treatment

20.3.2.1  SIOPEL 2 AND 3 EXPERIENCE

Thirty-five percent of HCC were metastatic, 22% had extra-hepatic disease and 35% were PRETEXT IV. of these, 14% underwent primary resection, 84% had neoadjuvant chemotherapy according to the Super PLADO protocol (SIOPEL 2 and 3 HR) and only a half of them were resectable. This protocol showed a 53% rate of chemosensitivity, which is higher than its adult counterpart, but did not impact the overall complete resection rate of only 18%. An important point is that children who responded to chemotherapy had a better outcome [13,14].

20.3.2.2  COG EXPERIENCE

Seventeen percent were resectable at diagnosis and 3% more after chemotherapy. In COG studies, children with HCC were assigned randomly to treatment regimens that consisted either of cisplatin, vincristine and fluorouracil or of cisplatin and continuous infusion doxorubicin.

20.3.2.3  LIVER TRANSPLANTATION

For patients with chronic liver disease and an ‘incidental’ finding of a small HCC without extrahepatic or metastatic extension, liver resection and placement on a waiting list for transplant, or simply transplantation according to the underlying liver disease, are warranted. Nonetheless, due to the shortage of liver donors, such children could wait for a long time before getting access to a graft – unless they are small enough to get a graft from a split.

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