RHABDOMYOSARCOMA AT RED CROSS WAR MEMORIAL CHILDREN S HOSPITAL

Transcription

1 RHABDOMYOSARCOMA AT RED CROSS WAR MEMORIAL CHILDREN S HOSPITAL Protocol Revision and Outcome Marc Hendricks 1, Alan Davidson 1, Ann van Eyssen 1, Komala Pillay 2, Alp Numanoglu 3, Alastair Millar 3, Farieda Desai 1, Paddy Hartley 1, Cyril Karabus 1. Haematology Oncology service, Red Cross War Memorial Children s Hospital, Cape Town, South Africa.

2 Questions? 1. Has protocol revision impacted positively on survival? 2. Is the continued use of doxorubicin justified considering its potential for long term cardiotoxicity given the evidence to suggest no survival benefit? 3. What is the best treatment for patients with irresectable stage 3 para-meningeal tumours? 4. Did increased intensity make a difference for alveolar tumours?

3 Demographics n = 115 biopsy proven rhabdomyosarcomas (RMS) on institutional registry exclusions: 3 absconded 5 missing or incomplete records 32 came for diagnosis or a component of their therapy but were primarily treated at other centres (primarily PE or EL). n = 75 evaluable patients

4 n = 75 Age and gender Ethnicity 34 female (age yrs; median 2.68 yrs) 41 male (age yrs; median 5.39 yrs) 9 Caucasian, 38 Black, 28 Mixed ancestry 57 embryonal histology (ERMS) 4 spindle cell variants (favourable) 1 anaplastic variant (unfavourable) 18 alveolar histology (ARMS) Stage 1 20 Stage 2 5 Stage 3 37 Stage 4 13 Stage 1 Group 1 Group 2 Group Orbit 4 Orbit 10 6 Pelvis (nonbladder / nonprostate) including 1 Vaginal 2 Head and neck (non-pm) 3 Head and neck (non-pm) 4 Pelvis (nonbladder, nonprostate) including 3 Vaginal

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6 IRS Group and Stage Stage 1 Stage 2 Stage 3 Stage 4 Group Group Group Group Pulmonary 6 BM 4 Other

7 Site Site Number Orbit 5 Head and neck (non-pm) 15 Merks JH et al Ann Oncol 2014;25(1):231-6 Para-meningeal 17 Abdominal 5 Extremity 9 Vagina 6 Bladder 6 Pelvis (non-bladder, non-prostate) 11 No primary found 1

8 Protocols over time Before 2003 [n=42] SIOP MMT 89 Rx 6811 (Stage 1) - VA X 12/52 (Stage 2 ) - Weekly vincristine 12/52 and VAC/VDC 6 weekly X 24/52 (Stage 3 or 4) - As above but to 51/52 Rx 6911 VA X 54/52 Rx 6961 Adaptation of Rx 6811 similar to stage 3 and 4 plus IE/VDC Rx 8941 (Based on POG #8850 /CCSG #7881 (IE/VDC) Relapse protocol [n=5] Rx 6031 (Stage 1 FH) VA X 21/52 Rx 6032 No patients. Rx 6033 (Stage 3 and 4 / All unfavourable histology) VAC/VDC X 51/52 After 2005 [n=28] Rx 6051 (Group 1 /2 Orbit/Eyelid; Group 1 Para-testicular, FH only) VA 21/52 Rx 6052 (Group 1 /2 Head and neck (non-pm)/ Genitourinary / Extremity; Group 2 Para-testicular, FH only) VAC 30/52 Rx 6053 (All Group 3 excluding PM Stage 3 and Extremity Stage 3, FH only) VAC/VDC 51/52 Rx 6054 (Group 3 PM Stage 3, Extremity Stage 3; All Group 4; All UH [ARMS/UDS] IVA/VDC X 51/52

9 Results Toxicity (Non-consecutive) Days of neutropaenia (0-99 days; median 6 days) (Non-consecutive) Days of antibiotics (0-95 days); median 7 days) No patients with cardiomyopathy. Relapses (28) 14 on treatment 10 off treatment, <12 months 4 off treatment, > 12 months Salvaged relapses 1 Stage 1 disease 1 Stage 2 disease

10 Outcomes 39 long term survivors 29 died of disease 2 deaths from infection (low) 1 septic shock following final course of chemotherapy, not neutropaenic [PM stage 4, group 4 ARMS] 1 septic shock and DIC following week 10 chemotherapy, not neutropaenic [Extremity stage 3, group 3 ERMS] 1 lost

11 Outcomes 4 other/secondary malignancies Metastatic adenocarcinoma of the rectum (10 years off treatment) [ERMS left proximal thigh stage 3, group ] Rx 6811 (CPM TOTAL 2.8g [350mg/kg]) Abdominal relapse. Surgery + Rx Gy XRT. (IFM TOTAL 30g [54g/m 2 ]) Alkylator related + XRT? Mesenchymal chondrosarcoma in left buttock and hemi-pelvis (12 years off treatment) [ERMS of left psoas muscle stage 3, group ] Rx 6811 XRT? Osteogenic sarcoma of rib (7.5 years off treatment) [ARMS of right hemi-diaphragm stage 3, group ] Rx 6811 (CPM TOTAL 2.8g [350mg/kg]) Chest wall relapse. Surgery + Rx 8941 (IFM TOTAL 15g [36g/m 2 ]) Alkylator related + XRT? Brain tumour (frontal) (4.5 years off treatment) [ERMS left labia stage 1, group ] Rx 6811 Cancer predisposition? (5.3% vs. 3.2% Neglia et al. J Nat Can Inst 2001;93(8):618)

12 RMS at RCHH Overall Survival by Group Chi-square = df = 3 p = Complete Censored Cumulative Proportion Surviving Group 1 = 86% (n=7) Group 2 = 67% (n=4) Group 3 = 62% (n=51) Group 4 = 42% (n=13) Time in months

13 RMS at RCCH Overall Survival by Stage Chi-square = df = 3 p = Complete Censored Cumulative Proportion Surviving Stage 1 = 80% (n=20) Stage 2 = 80% (n=5) Stage 3 = 51% (n=30) Stage 4 = 42% (n=13) Time in months

14 RMS at RCCH Overall Survival by Cohort Log-Rank Test p = Complete Censored 1.0 Cumulative Proportion Surviving % (n=46) % (n=29) Time in months

15 RMS at RCCH Overall Survival by Histology Log-Rank Test p = Complete Censored Cumulative Proportion Surviving Time in months Embryonal 60% (n=52) Alveolar 55% (n=18)

16 1.0 RMS at RCCH Overall Survival = 61% Complete Censored 0.9 Cumulative Proportion Surviving Survival Time in months

17 Conclusion Proportionately larger numbers of tumours at adverse sites. Deaths from infection were low (2/75). Salvage rate post relapse was dismal (2/28). Higher than expected rate of secondary / other malignancy (4/75) albeit that this occurred in the earlier cohort of patients. Trend to suggest that protocol revision / standardisation has positively impacted survival over time: pre-2003 OS 54.1% OS 59.5% OS 64.2%

18 Questions? Given that the evidence suggests that there is no survival benefit using adriamycin, should we omit anthracyclines considering we do not have any evidence to support that and considering the absence of cardiomyopathy in our cohort suggesting there is no increased toxicity with its use? Evidence? (JPHO (4):215 Raney B, Anderson JR, Barr FG et al) Adriamycin IRSG I III VAC-A + XRT no significant benefit over VAC + XRT (all p < 0.17) e.g. IRSG III all non-arms G II randomised VAC + XRT +/- Adria. No benefit from adriamycin even when results from IRSG II were added in. Should we be changing? IRSG V ( 97-01) 3 protocols according to risk of recurrence Low risk 3 yr FFS 88% VA or VAC + XRT Intermediate risk 55-76% VAC +/- XRT +/- TopoT High risk <33% VAC + XRT +/- TopoT or IrinoT NO ANTHRCYCLINES!

19 Questions? Is VAC/VDC as good (or better than) IVA/VDC for: our group 3 stage 3 para-meningeal and extremity tumours, and Rx 6033 Protocols Total patients treated PM patients Survivors (Stage 3 and 4 / All unfavourable histology) VAC/VDC X 51/ (100%) Rx 6054 (Group 3 PM Stage 3, Extremity Stage 3; All Group 4; All UH [ARMS/UDS]) (42%) IVA/VDC X 51/52 our unfavourable histology (ARMS) patients with good risk anatomical disease (orbit)? cannot be answered by this cohort: only 1 patient treated on Rx6033 (ADF) and none on Rx6054.

20 Questions? Did IVA/VDC (Rx 6054) make a difference for alveolar tumours when compared to historical protocols? Protocols Total patients treated Alveolar patients Survivors All other protocols (28.5%) ADF: Stage 1 3 (1 SM) Stage 4 1 Dead: Stage 1 2 Stage 2 2 Stage 3 2 Stage 4 3 (2 relapse, 1 infection) Lost 1 Rx 6054 (Group 3 PM Stage 3, Extremity Stage 3; All Group 4; All UH [ARMS/UDS]) IVA/VDC X 51/ (50%) All stage 3 patients Still does not answer the question about patients who are ARMS but good risk by anatomical site. Patients in historical cohort pre-2005 protocol provision were certainly doing no better. Perhaps we should retain IVA/VDC for ARMS but revert Rx 6053 for para-meningeal stage 3 group 3 patients.

21 Recommendations 1. Even in the absence of cardiomyopathy in this cohort, we still believe there is a place to limit the risk of anthracycline-related cardiotoxicity by further reducing the cumulative dose of doxorubicin to 300mg/m 2 (currently 360mg/m 2 on Rx6053 and Rx6054). 2. Treat all group 3, stage 3 (including para-meningeal and extremity) patients with VDC/VAC. 3. Treat all unfavourable histology (ARMS and UDS) and all metastatic (stage 4, group 4) patients with IVA/VDC.

22 Thanks Felicity Douglas Alan Davidson Research assistant /nurse for data collection Clinical head of unit