Toxicity
In total, 181 cycles (range 2-10) were administered, and 173 were
evaluable for toxicity (105 IrIVA and 68 IrVAC cycles). The treatment
was stopped in two patients after 2 and 7 cycles due to tumor
progression, and in another two after 3 and 5 cycles due to the
clinician’s or parents’ decision. Another patient was given high-dose
chemotherapy.
No toxic deaths occurred. As expected, the most significant toxicity was
myelosuppression. Grade 4 neutropenia was observed in 108 cycles
(62.4%) and was more frequent in patients receiving IrVAC (72% of
cycles) than in those given IrIVA (56.1%). Grade 3 anemia was evident
in 40 cycles (23.1%), with 14 patients requiring blood transfusions (no
grade 4 anemia was reported). Thrombocytopenia was less severe, with
grade 4 toxicity observed in only 7 cycles (4.0%), and 4 patients
receiving platelet transfusions (Table1S-2S-3S). There were 33 episodes
of fever during neutropenia (20.2% of cycles) in 13 patients, and blood
cultures were positive in 4 cases, but without any signs of septic
shock. One patient had an episode of typhlitis, and one had surgery for
appendicitis.
Six patients experienced 19 episodes of grade 3 non-hematological
toxicity (Table 2); no grade 4 episodes were recorded.. Diarrhea
occurred in 14 cycles, with 3 episodes of grade 3 diarrhea in two
patients, one of them experienced two episodes during febrile
neutropenia (in one case a stool test was positive for Clostridium
difficilis ). The dose of irinotecan was not reduced in any subsequent
cycles because the patients recovered rapidly. No meaningful difference
in toxicity emerged between patients given IrIVA or IrVAC.
Constipation and peripheral neuropathy prompted a reduction in the dose
of vincristine in 15 cycles. The irinotecan cycles were delayed for more
than one week in 7 cycles, and not administered due to fever and
neutropenia in 2 cycles. The dose of irinotecan was never reduced.
Ifosfamide was replaced with cyclophosphamide in a child suffering from
seizures. Actinomycin was withdrawn during radiotherapy in 7 cycles.
The median interval between cycles was 23 days (range 19-51), with 151
out of 181 cycles (83.4%) administered on time or without any
significant delay (<1 week). Considering the patients who
completed the whole chemotherapy treatment (i.e., excluding the 4
patients that prematurely concluded the treatment), the median interval
between the first and ninth cycles was 195 days (range 170-231). On
comparing this outcome with the 40 patients enrolled in the MTS2008
protocol, we found that precisely the same median time - 195 days (range
169-270) – was taken to complete 9 cycles of chemotherapy.
Nine patients had a delay of more than 30 days, mainly due to local
therapies.