 |
 |
 |
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
|
 |
 |
 |
 |
 |
 |
|
 |
|
 |
Review LIVER CANCER IN CHILDREN - NOW USUALLY CURABLE
In Volume 2, Issue 2 of "NETWORK", an article compared the outcome of two infants with hepatoblastoma recently diagnosed in the same city. These two children reflect the improvement in prognosis for infants with this rare tumor (median age 18-24 months) over the past 20 years.(1) Until the early 1980s, most patients with hepatoblastoma were considered incurable because in only 20-30% were the tumors considered to be "resectable" at diagnosis, and only half of these children (10-20% of the total) survived. The remainder died of progressive disease. Chemotherapy was not considered particularly useful and Transplant Centres were unwilling to accept children with hepatoblastoma for orthotopic liver transplantation (OLT) because the risk of recurrence was so high. Treatment of the "Hospital A" patient, who died of progressive tumor, represents this "old-fashioned" approach, whilst the patient managed by "Hospital B" benefited from two major recent advances and survived. First, in the early 1980s, Cisplatin and Doxorubicin (PLADO), were recognised to be the most active available agents for hepatoblastoma. Second, it seemed more logical to give chemotherapy prior to as well as after surgery—as in the case of most solid paediatric tumors—rather than only afterwards. Pre-operative PLADO was recognised to make tumors (a) smaller, (b) less vascular and (c) more "discrete," thereby making surgical removal considerably safer (Figure 1).
The rarity of primary liver cancer in children—only 1 in 30,000
are affected—means that national and international collaboration
is essential if treatment is to be improved via the conduct of clinical
trials. Only three national groups - the USA/Canada (Intergroup),
Japan and Germany/Austria (GPOG)—were sufficiently large to set
up independent studies. Many of the remainder have joined trials
coordinated by the International Society of Pediatric Oncology Liver
Cancer (SIOPEL) Group. For example, in SIOPEL 1, a single-arm study
of children with hepatoblastoma in which the PLADO combination and
delayed surgery were used, a total of 91 Centres in 30 countries—representing
all five inhabited continents—recruited 154 patients with hepatoblastoma
in just over four years (35-40 There were both surgical and chemotherapy considerations for the SIOPEL Group as they planned their next studies. The "delayed surgery" strategy was successful in that, unlike the situation in the other three collaborative groups, no patient needed a second surgical resection with its attendant complications; SIOPEL surgeons unanimously agreed that delayed surgery was also much less risky than surgery "up front" because of tumor shrinkage. This was consistent with the finding of a high percentage of necrosis (100% in some specimens) in the resected tumors. With respect to the chemotherapy regimen, the fact that 5-FU and Vincristine had not been notably "active" against hepatoblastoma in studies performed in the 1960's and 1970's, and the equivalence of two Intergroup regimens suggested that Cisplatin was the crucial element of PLADO. Moreover, whereas the Doxorubicin dose and dose intensity could not be readily increased, for fear of the higher incidence of cardiotoxicity noted in the Intergroup PLADO regime (in which the dose of Cisplatin was 80 mg/m² over 4 days, compared with 60 mg/m² over 2 days in the equivalent SIOPEL regime), Cisplatin could be intensified because there had been little nephrotoxicity or ototoxity in SIOPEL 1.
Analysis of the SIOPEL 1 results indicated that two "risk groups" could be delineated(7) [Table 2]. On the one hand, there were patients with no evident metastases and tumors limited to 1, 2 or 3 sectors of the liver (designated "standard risk" patients) and on the other, those with either all four sectors involved or extra-hepatic tumor, usually lung metastases. Patients in these two latter categories were combined as a "high risk" group [see Table 2]). In the SIOPEL 2 study, using these criteria, patients were stratified into two risk groups. All patients again had delayed surgery, including OLT if tumours responded to chemotherapy but all 4 hepatic sectors remained involved. "Standard risk" children (70% of the total) received single agent but more intensive Cisplatin at 2-weekly, rather than 3-weekly intervals, with careful auditory and renal monitoring. "High risk" patients (30% of the patients) received Doxorubicin, Carboplatin and Cisplatin in an alternating myelotoxic/non-myelotoxic sequence, a regime sometimes referred to as "Super PLADO". A total of 140 patients were recruited to this "pilot" trial over 3 years - a higher recruitment rate than for SIOPEL 1. The results are reassuring since "good risk" patients in SIOPEL 2 appeared to have a similar prognosis to those in SIOPEL 1 [Table 3]. This finding greatly influenced the design of the third SIOPEL trial (SIOPEL 3), now in progress. In SIOPEL 3, "good risk" patients are randomised to receive either PLADO, according to the SIOPEL 1 schedule, or single-agent Cisplatin, according to the "good risk" SIOPEL 2 regime. The number of "high risk" patients in SIOPEL 2 was insufficient to draw conclusions about any advantage of the Super PLADO regime over standard PLADO, so SIOPEL 3 continues to use this treatment in the "high risk" group. SIOPEL 3 is recruiting well and new Centres are joining in. Secure funding has been acquired from the major UK cancer charity, "Cancer Research UK", with important contributions from the Swiss Cancer League and a group of families of UK children who had developed hepatoblastoma. SIOPEL 3 is coordinated and administered by Data Managers in the Leicester Office of the United Kingdom Children's Cancer Study Group (UKCCSG) and statistical input is from Dr Rudolph Maibach in Bayern, Switzerland.
Resection of hepatic lesions in children is a major undertaking and requires optimising the patient pre-operatively to achieve the best possible results. Malnutrition or infection must be treated. This is especially important in geographical areas where specific types of malnutrition or endemic infection, e.g., malaria, occur. Both can affect the patient's tolerance of a major hepatic resection. The functional status of the liver must be assessed, to determine the capacity of the remaining liver mass to sustain the child post-operatively. Liver enzymes, complete blood count, coagulation factors and serum proteins are measured pre-operatively. Adequate amounts of blood products must be available. The coagulation profile should be as close to normal as possible. Some children may benefit from a pre-operative dose of vitamin K. Occasionally an enema is administered the day before the procedure, though formal "bowel prep" is usually unnecessary. Intravenous antibiotics are given pre-operatively to cover for organisms that might cause cholangitis.
The PRETEXT scheme is helpful for "risk group" classification, but thorough knowledge of the functional anatomy of the liver, as described by Couinaud and others, is essential for safe and successful resection of liver tumors because it allows the surgeon to perform a relatively bloodless dissection by dividing the tissue along the natural lines of demarcation between segments. Using this classification, which is based upon the location of the portal pedicles and the hepatic veins, the liver has 8 segments (I-VIII). The procedure is performed under general endotracheal anaesthesia with positive pressure to prevent air embolisation from the hepatic veins or inferior vena cava during the dissection. Monitoring lines and catheters usually include two large bore peripheral lines for volume infusion, a central venous catheter and arterial line to monitor central venous pressure and systemic arterial pressure respectively, an indwelling urinary catheter to measure urinary output, a nasogastric tube for gastric decompression, and a probe for core temperature measurement (oesophageal or rectal). In the event that the vena cava is occluded during the procedure, it is vital to have enough intravenous access in the upper trunk in case rapid fluid infusion is required, and to administer any necessary products to stop bleeding. Sometimes, an intra-operative cholangiogram or ultrasound can be very helpful. Details of surgical technique are beyond the scope of this article. Excessive bleeding is by far the most common surgical complication encountered, but can usually be avoided by strict adherence to safe surgical technique. Other intra-operative complications include bile duct injury, air embolisation, injury to adjacent intra-abdominal organs, or tumor rupture with spill. Subhepatic closed suction drains are usually placed and retained for 24-48 hours. The child can usually be extubated post-operatively and would normally spend about 24 hours in the intensive care unit. Metabolic abnormalities known to occur after major hepatic resections, including hypoglycaemia, hypophosphataemia, hypoal-buminaemia, and prolonged prothrombin time should be anticipated (and monitored for) and promptly corrected. Later complications of hepatic resection include atelectasis, fever, intra-abdominal or wound infection, pneumonia, bile leak, "biloma" or biliary fistula, post-operative bleeding and liver failure. This is not "easy surgery" and referral to a tertiary or quaternary centre may be advisable.
In summary, hepatoblastoma—a rare tumor recently considered "incurable" in most cases—is now regarded as one of the success stories in paediatric oncology, with cure rates now approaching those for Wilms' tumor. Pleasingly, treatment is usually not complex, lengthy or especially expensive. For instance, the estimated chemotherapy and antibiotic costs for the 2 arms of the SIOPEL 3 trial are approximately 550 pounds sterling (Cisplatin only arm) and 1080 pounds sterling (PLADO arm), respectively (although these costs will vary from one country to another). Toxicity is mild or moderate with easily manageable complications, so that most patients are "cured at little cost." Requirements for centres treating these children include: (a) resources for the placement of secure central venous lines, the measurement of serum alphafetoprotein (AFP) levels and monitoring for the toxicities of Cisplatin, Carboplatin and Doxorubicin, (b) availability of expert liver surgery, including access to a paediatric OLT Centre and (c) the conviction that most children with hepatoblas-toma can be cured, so that protocols are followed closely. These resources are now available in many "developing countries"—one reason for the popularity of the SIOPEL studies internationally. Some centres, however, are either unaware of, or unconvinced by the results of the SIOPEL trials. It is therefore our responsibility—nurses, doctors, pharmacists and other health "professionals"—wherever we work, to bring these results to the attention of our immediate paediatric and paediatric surgical communities, either by "word of mouth" or via our national Paediatric Cancer Study Group. There are approximately 187 separate nations in the world. It appears that 150 of these countries are not taking part in clinical trials. Through various agencies, including the INCTR, we hope to increase the number of participating centres considerably over the next decade. Otherwise, children with hepatoblastoma may receive ineffective or unnecessarily toxic treatments and some of them will die needlessly. Promising collaborations are now being developing between the SIOPEL, US/Canadian, Japanese and GPOG Study Groups. In particular, new strategies for the improved management of "difficult" liver tumours—high-risk hepatoblastoma and also hepatocellular carcinoma(8) —are under discussion and pilot trials, including Phase I and II studies of newly available agents, have already started. Information on the SIOPEL trials can be obtained from Margaret Childs, SIOPEL Trials Coordinator, at the United Kingdom Childrens Cancer Study Group (UKCCSG) in Leicester, at e-mail: msc8@leicester.ac.uk or from one of the authors of this article, drjpritchard@hotmail.com Submitted by: J Pritchard, Royal Hospital for Sick Children, EDINBURGH ; and K H Mutabagani, New Jeddah Clinic, SAUDI ARABIA (References REFERENCES
|
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
