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Patients with large embryonal RMS localized in unfavourable sites, alveolar RMS, and N1 are included in this Group.

The different Subgroups included in this category share the same unsatisfactory prognosis and therefore the need for a more effective strategy.

This protocol will try to improve the outcome of these patients by implementing two novel strategies:

1) the intensification of initial chemotherapy adding anthracyclines to the standard IVA regimen 2) the adoption of a low dose maintenance treatment after 1st line chemotherapy.

8.4.1 Doxorubicin in RMS treatment

Doxorubicin (Doxo) is an effective drug in the treatment of RMS. However its role as part of a multidrug regimen is controversial. It is not clear whether adding Doxo to an established regimen such as VAC or IVA improves the survival of patients. This must be carefully considered as the toxicity profile of the drug may worsen the immunosuppression in the short term and cause cardiotoxicity in the long term.

An IRS phase II window in children with newly diagnosed metastatic rhabdomyosarcoma demonstrated the efficacy of IFO and Doxo with a 63% CR+PR rate at 12 weeks 19. Furthermore the preliminary results of the window study with Doxo in high risk RMS in the SFCE experience (65% CR+PR) support the value of Doxo as an efficient drug in RMS (Bergeron C, unpublished data). Doxo is also considered an important drug in the treatment of other paediatric sarcomas such as osseous Ewing’s and PNET 20. Moreover a meta-analysis of several trials demonstrated that an induction treatment including Doxo in every course was better than a schema alternating Doxo with ACT-D 21.

Doxo is also one of the most effective drugs in the treatment of soft tissue sarcoma in adult patients 22_.

Unfortunately different randomised trials performed by the IRS Group did not show a substantial difference in survival and progression free survival for patients with RMS treated with VAC or VAC plus anthracyclines. In IRS-I the addition of 5 VadrC course to VAC did not improve the results 23_{. In IRS-II a similar comparison, but with higher cumulative doses of Doxo (480 mg/m}2₎ showed no improvement 24. In IRS III further randomised comparison did not yield to different

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results. However it was noted that a more complex therapy including administration of Doxo and cisplatin appeared to have caused a significative improvement in some subgroups of patients i.e. IRS group I/II alveolar histology and special pelvic sites 17

It should be noted that in IRSG studies the treatment scheme was based on the alternating administration of VAC and VadrC, consequently the intervals between Doxo containing courses were wide, reducing the anthracycline dose-intensity.

In conclusion Doxo seems a very effective drug against RMS, however its role as part of a multi- drug regimen remains to be established.

8.4.2 The IVADo Regimen

This regimen combines the Doxo with the standard combination IVA. This allows the intensification of the chemotherapy avoiding the need to alternate courses with and without the anthracyclines as has been done up to now. This combination has been tested in a pilot study conducted by the STSC in which 29 patients with metastatic STS have been treated with the IVADo regimen (G. Bisogno et al, Cancer in press). Toxicity was mainly haematological with grade 4 neutropenia encountered in 67% of evaluable cycles and 17 patients and 8 patients receiving blood and platelets, respectively. Major toxicity occurred in two patients: VOD and seizures. Grade 3-4 organ toxicity were constipation (9.7% of cycles), mucositis (6.5%) and peripheral neuropathy (6.5%). The median interval between courses was 23 days (range 19-51). Clinical complete response after three IVADo was evident in 5 patients, PR in 17, minor PR in 2, mixed response in 2. Stable tumour was evident in 2 children with desmoplastic small round cell tumour, whereas tumour progression was evident in a patient with malignant schwannoma.

These data are also supported by preliminary data from a window study for metastatic RMS run by the SFCE group in France where no unexpected toxicities were observed in the first 7 patients enrolled.

In conclusion the IVADo regimen has proved to be active against soft tissue sarcomas but, more importantly, it is feasible because no unacceptable toxicities have been reported.

8.4.3 Maintenance treatment in RMS

Chemotherapy regimens have been progressively intensified 15 improving the survival of patients with localised disease. However patients with unfavourable characteristics, such as unfavourable site or alveolar subtype, did not show major improvements 25 and any attempt to further increase the drug dose in metastatic RMS has not significantly changed the poor prognosis of these patients 26. When complete remission has been achieved, minimal residual disease, resistant to high dose short- term treatment, remains an obstacle to major increases in cure rate.

It is, therefore, important to identify new approaches to improve the outcome for high-risk patients. Low dose continuous chemotherapy has been used with some success 27 and new hypotheses on antitumour mechanism have been advanced 28. This approach is also attractive if we consider the reduced toxicity of low dose treatment.

Although there is little experience in the treatment of soft tissue sarcoma promising results have been reported by the CWS group. They used standard chemotherapy in children with metastatic soft tissue sarcoma followed by high dose chemotherapy (thiotepa + cyclophosphamide and melphalan + etoposide) or an oral treatment with trofosfamide + idarubicine. The results in 62 patients are very promising with 3-year EFS above 50% for patients taking oral treatment (and EFS 20% after high dose). Since the comparison was not randomised a risk bias between the two groups must be taken into consideration. It seems though that oral maintenance therapy has a greater benefit for group IV patients than does high dose chemotherapy.

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The duration of treatment should also be addressed. This has been progressively decreased over years without apparently impairing the results. In IRS-I chemotherapy was administered for 2 years. In the latest North American protocols most patients received one year of treatment.

In the SIOP studies the treatment duration for the majority of patient was 27 weeks.

In Italian protocols the treatment duration has been progressively reduced from 52-78 weeks in the first study to 22-37 weeks in the second and 25 in the third one. Also in the CWS studies the treatment duration have been reduced for most patients from 35 weeks in the early studies to 25 in the latest ones.

The drug doses administered in each cycle have been increased progressively in the most modern protocols and this may have hindered the benefit of a longer treatment. Up to now no studies have been performed to establish which is the optimal duration of treatment for RMS.

In this protocol we propose to investigate the role of low dose chemotherapy in patients with RMS. On the basis of previous experience with RMS cyclophosphamide appears an interesting drug for the following reasons:

a) is active against RMS

b) has been successfully used at low dose (2.5 mg/kg/day for up to 2 years) in the initial IRS studies 23, 24_.

c) it may be easily included in the current European protocols where different drugs are used during the initial intensive treatment.

The activity of vinorelbine in the treatment of heavily pre-treated patients with soft tissue sarcoma has recently been published 29. A dose finding study has been performed by the STSC 30.

Therefore the combination of these two drugs is proposed to investigate the role of low dose chemotherapy in patients with rhabdomyosarcoma. Patients in complete remission at the end of standard treatment will be randomised to stop the therapy or to continue for 6 more months with the vinorelbine-cyclo regimen.

8.4.4 Alveolar Paratesticular tumours

Despite unfavourable pathology this very small group of patients showed a good outcome in previous European studies. In the CWS/STSC experience they represented 8% of all paratesticular RMS and the 5 year survival rate was 93% after IVA + doxorubicin chemotherapy 31. However 4 relapses occurred. Similar data come out from the SIOP experience.

According to these data patients with paratesticular alveolar RMS will be kept in the high risk group, according to the histology factor, however in consideration of the better outcome they will not be included in the randomised trial and will be treated with IVAx9 (avoiding anthracyclines). Patients with Alveolar N1 tumor will be treated according to the very high risk arm.