Kate Wheeler

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia : the MRC UKALL X experience

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event‐free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT).

Medical cost of curing childhood acute lymphoblastic leukaemia

Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure. In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups. These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.

The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy)

Historically, the 5‐year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post‐operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5‐year OS to 73%. We report outcomes of this strategy in UK.

Reply to Comment on: The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy, and Response-Directed High-Dose Myeloablative Chemotherapy or

To the Editor: We thank Massimino and colleagues [1] for their comments on our paper.[2] Our study was a retrospective audit of survival, toxicity, and deliverability of this regimen in 14 UK centers. It was not our intention to criticize the Milan group’s work.[3] However, it is essential to monitor outcomes when introducing new treatments, especially when these are of high intensity and in high-risk patients. Single-site studies may be influenced by local in-house practice not described in detail in publications. Case selection may also be an issue. Milan is a national referral center, but the UK patients were treated in their local specialist centers. Potentially, patients with more neurological damage who might not have been able to travel to a supraregional center may have been treated on this regimen in the UK. The concerning toxicities seen in our retrospective audit highlight the importance of prospective audit and monitoring of any new treatments that are introduced. Given the rarity of the disease, this needs to take place at a national level, not at an institutional level. Large-scale phase III clinical trials are the gold standard to evaluate promising results from early phase trials. For example, in adult lymphoma, the Southwest Oncology Group (SWOG) trial showed that standard cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin R ©), prednisolone (CHOP) was actually better than three more complex regimens reported by single institutions to improve cure rates from 30% to 60%.[4] In our series of metastatic medulloblastoma patients treated with the “Milan” regimen, we did not encounter any severe neurotoxicity unlike the series of patients treated for Supratentorial primitive neuroectodermal tumor (sPNETs) in theUK.[5,6] This important issue was included in the discussion of our findings and we described neurotoxicity as rare and not unexpected in our paper. This rarity is also noted in the papers referenced by the authors of the letter.[7–9] The Milan group reference the conclusions of the international workshop[10] convened after clinically significant toxicity became so prominent that it could not be ignored. This workshop was convened after our paper was submitted and aimed at defining possible underlying reasons. However, UK audits of sPNET treated with the same therapy strategy described frequent, clinically devastating global neurotoxicity.[5,6] The combined use of high-dose chemotherapy with radiotherapy seems to have revealed this vulnerability.[6] In conclusion, the introduction of intensified chemoradiotherapy in childhood brain tumors requires an active program of clinical trials. If these are not available, there needs to be an audit of outcomes of national interim guidance shared internationally to learn from the larger number of patients treated. This would highlight the importance of first careful guideline development, second the need for compliance with detailed clinical protocols, and finally prospectively monitored toxicity and outcomes. Adequate funding and resources for such an audit are essential when implementing any regimen across multiple centers at a national level.

Hepatoblastoma in a mosaic trisomy 18 child with hemihypertrophy

To date, there are 12 reported cases of hepatoblastoma in trisomy 18 patients, three of whom had a mosaic chromosome pattern. We report on an 18-month-old child who had hemihypertrophy and developmental delay, was found to have hepatoblastoma on surveillance ultrasound scan, and was subsequently diagnosed with mosaic trisomy 18 on array comparative genomic hybridisation from a peripheral blood sample and molecular cytogenetic analysis of the tumour specimen. Although hemihypertrophy has been associated with mosaic trisomies, there are only a couple of published case reports of hemihypertrophy or asymmetry in mosaic trisomy 18 patients and none in the reported cases of hepatoblastoma in a mosaic trisomy 18 setting. We have reviewed the published case reports of hepatoblastoma in trisomy 18 patients and found that they seem to tolerate the intensive treatment very well if there are no significant comorbidities.

An unusual mandibular mass in a child

A 2-year-old boy was referred to the oral and maxillofacial department with a 1-week history of swelling affecting the right mandible (Figure 1). Although this had been noted by his parents and the nurse at his nursery, he had remained asymptomatic and systemically well. There was no history of trauma or dental pain. He had been born at 36 weeks via Cesarean section, and his medical and surgical history was positive only for an uneventful left inguinal hernia repair at 3 months of age. He was meeting all of his developmental milestones, and his childhood immunizations were up to date. On clinical examination there was mild extraoral swelling noted around the right angle and body of the mandible. Intraorally, his dentition was within normal limits, with evidence of good oral hygiene. A 3 3 cm firm swelling was noted in the right retromolar region. Systemic examination was unremarkable. Magnetic resonance imaging (MRI) was arranged, and a review appointment made. However, over the course of the following week, there was rapid growth of the mass, which was now associated with pain, particularly when eating, resulting in an emergency hospital admission. Routine hematology and biochemistry results at this time demonstrated a normal full blood count, but elevated C-reactive protein (CRP) of 15 mg/L (normal 0-8 mg/L), and lactate dehydrogenase (LDH) of 408 IU/L (normal 90-235 IU/L). An ultrasound scan of the right mandibular region showed a 3 1.8 2.5 cm solid mass overlying the right mandible with some deep extension. It did not appear overtly vascular. A radiograph of the mandible was markedly abnormal, with bony destruction, and “sunray spiculation” suggesting a degree of osteogenesis.