Lessons from treatment of pediatric sarcomas at difficult sites. Dr. Andrea Ferrari Pediatric Oncology Unit Istituto Nazionale Tumori, Milan, Italy
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1 Lessons from treatment of pediatric sarcomas at difficult sites Dr. ndrea Ferrari Pediatric Oncology Unit stituto Nazionale Tumori, Milan, taly
2 Disclosure slide have no potential conflicts of interest to disclose
3 Lymphoma Head-neck tumors 0 to 18 years > 18 years Neuroblastoma Peripheral nerve tumors Retinoblastoma Bone Tumors Soft tissue sarcomas Extracranial GCT Nasopharyngeal carcinoma Malignant melanoma Skin carcinoma Salivary glands carcinoma Other Carcinomas Others period)
4 Data from German Childhood Cancer Registry (GCCR) Soft tissue sarcomas
5 solid tumors solid tumors leukemia RMS STS tumori SNC EW RMS typical embryonal tumor of childhood, composed by cells resembling normal fetal skeletal muscle high grade of malignancy, local invasiveness and a marked propensity to metastasize all RMS patients should be assumed to have micrometastatic disease at diagnosis, so systemic therapy is definitely recommended for all patients (generally) good response to chemotherapy (90% response rate) and radiotherapy
6 Head-neck region 40% parameningeal region 20% orbit 10% other 10% Trunk - 10% Other - 10% Genito-urinary region - 20% bladder-prostate 12% paratesticular 6% vagina 2% RMS site of origin Overall survival by site 5 year OS Paratesticular - vagina 90-95% Orbit 85-90% Bladder Prostate 75-80% Parameningeal 60-70% Other 60-65% Extremity 55% Extremity - 20% Relative incidence of the different tumor sites
7
8 Parameningeal rhabdomyosarcoma arises in: (1) middle ear or mastoid, (2) nasopharynx or nasal cavity (3) parapharyngeal space (4) paranasal sinuses (maxillary, ethmoid, sphenoid) (5) pterygopalatine and infratemporal fossa region signs/symptoms can vary, depending on the site and extent of the disease: nasal or sinus obstruction, swelling, pain, mucopurulent or bleeding discharge rapid growth, cranial nerve palsy, skull base bone erosion, intracranial tumor extension
9 Treatment Dilemmas High-risk patients need for intensive chemotherapy / new drugs ery limited role for surgery difficult accessibility parameningeal sites / risk of mutilation External beam radiation therapy (EBRT) high-doses, wide fields, young children / serious sequelae
10 EpSSG RMS 2005 RSK GROUP HST RS N STE SZE & GE % EFS-OS fav N0 any fav 6% 90-95% B fav N0 any unfav 6% 78% - 90% C fav - N0 fav any 18% 72% - 88% D fav - N0 unfav fav 9% 80% - 85% E fav - N0 unfav unfav 27% 55% - 60% F fav - N1 any any 8% 50% - 60% + or ± RXT + RXT 1 random 2 random stop-therapy G unfav -- N0 any any 20% 50% - 60% H unfav -- N0 any any 6% 40% - 50% Do + RXT Do + RXT + NR-oral CTX maintenance NR-oral CTX
11 surgery R Do Do Do Do radiotherapy R stop therapy 6-months maintenance therapy NR+oral CYC The anthracycline question Might RMS patients benefit from a greater doxorubicin dose intensity in the initial period of their treatment? The maintenance treatment question after completing the conventional chemotherapy, give regular and frequent low doses of drugs (metronomic therapy), with a view to obtaining an anti-angiogenic effect
12 Weeks R E S Do B Do Do B Do Do B Do Do B Do B B (B) S U R G E R Y (B) * B Radiation Therapy * NORELBNE/oral CYCLO + Bevacizumab NORELBNE/oral CYCLO Evaluation Evaluation Evaluation
13 phase window study, which tests the new agent (or new combination) in newly diagnosed patients with stage
14
15 This topotecan/cyclophosphamide experience reiterated the findings of various early studies conducted by cooperative groups, when different drugs (i.e. doxorubicin, carboplatin and cisplatin, etoposide, melphalan) were combined with standard chemotherapy and tested in randomized trials and revealed no clear-cut advantage over the standard combinations C RS- study R C + DOXO-CDDP C + DOXO-CDDP-ETO C C RS- study R C + C + E M1 C + CR-LPM f it is true that classic phase trials on recurrent patients may underestimate the effectiveness of new agents, on the other hand it is evident that most (or all) drugs proven to be active in up-front window failed to improve results in phase studies randomized with standard regimens. possible consideration could be that the spectrum of tumor cells killed by the new agent overlaps the spectrum of tumor cells killed by the standard therapy. n other words, it may be possible that any antitumor activity observed in previously-treated relapsing patients is potentially more significant than that assessed in window studies, because in the former case the real target that has to be destroyed by the new drug to improve outcome is the recurrent, treatment-resistant tumor cells.
16 CR-RNOTECN
17 dose-compression, i.e. full-dose chemotherapy administered with a shorter interval between doses, e.g. 1-2 weeks instead of the usual 3 weeks, thereby increasing the dose density
18 RST08P1 RST0431 backbone + MC-12 (GF-1R inhibitors ) RST0431 backbone + temozolomide RST0431 backbone + MC-12 + temozolomide
19
20
21
22 Use of radiotherapy RSG 93% CG 76% CWS 70% SOP MMT 37%
23 EFS Use of radiotherapy RSG 93% CG 76% CWS 70% SOP MMT 37%
24 OS Use of radiotherapy RSG 93% CG 76% CWS 70% SOP MMT 37%
25 Survivors who had not received RT RSG 6% CG 7% CWS 20% SOP MMT 41%
26
27
28 The MORE Concept blatio MOulage technique Brachytherapy Reconstruction in 1 week Courtesy JHM Merks
29 blatio Macroscopically complete resection day 1 (microscopic residual) Sparing normal tissue dequate exposure brachytherapy RMS in left pterygoid fossa MOulage placement nsert brachytherapy mould(s) (flexible catheters) Brachytherapy (day 3-6) fterloading ridium Gy to CT - 5 mm from surface of the mould Reconstruction, day 7 Remove moulage Surgical reconstruction (free vascularised/microanastomosis or Transpositional muscle flap)
30 blatio RMS right parapharyngeal space MOulage placement Reconstruction, day 7
31
32 lthough chemotherapy and radiation constitute the treatment of choice in most cases, surgery may have a role as salvage therapy and in cases that fail to respond to chemoradiation
33 No. Patients ~ 10,000 patients # M+ patients CWS 1,578 CWS CWS-96 CWS 2002-P CWS 2007-HR EOP-STSC 825 RMS79 RMS88 RMS MMT 91 # RMS4.99 # MMT 98 # EpSSG RMS 2005 SOP-MMT 1,828 RMS 75 MMT 84 MMT 89 MMT RST 0431 # COG RS RS RS RS RS RST
34
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