RHABDOMYOSARCOMA AT RED CROSS WAR MEMORIAL CHILDREN’S HOSPITAL 1990-2010. 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.
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?
Demographics n = 115 biopsy proven rhabdomyosarcomas (RMS) on institutional registry 1990-2010. 40 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
n = 75 Age and gender 34 female (age 0-14.3 yrs; median 2.68 yrs) 41 male (age 0-14.25 yrs; median 5.39 yrs) Ethnicity 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 1 Group 1 Group 2 Group 3 Stage 2 5 20 7 2 11 Stage 3 37 Stage 4 13 10 1 Orbit 4 Orbit 2 Head and neck 3 Head and neck (non-PM) (non-PM) 10 6 Pelvis (non- 4 Pelvis (non- bladder / non- bladder, non- prostate) including prostate) including 1 Vaginal 3 Vaginal
IRS Group and Stage Stage 1 Stage 2 Stage 3 Stage 4 Group 1 7 - - - Group 2 2 - 2 - Group 3 11 5 35 - Group 4 - - - 13 3 Pulmonary 6 BM 4 Other
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
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. 2003 – 2005… [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
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
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
Outcomes 4 other/secondary malignancies • Metastatic adenocarcinoma of the rectum (10 years off treatment) [ERMS left proximal thigh stage 3, group 3 1993 ] Rx 6811 (CPM TOTAL 2.8g [350mg/kg]) Abdominal relapse. Surgery + Rx 8941 + 12Gy 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 3 1995 ] Rx 6811 XRT? • Osteogenic sarcoma of rib (7.5 years off treatment) [ARMS of right hemi-diaphragm stage 3, group 3 1995 ] 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 3 1996 ] Rx 6811 Cancer predisposition? (5.3% vs. 3.2% Neglia et al. J Nat Can Inst 2001;93(8):618)
RMS at RCHH 1990-2010 Overall Survival by Group Chi-square = 4.374965 df = 3 p = 0.22374 Complete Censored 1.0 0.9 Cumulative Proportion Surviving 0.8 0.7 0.6 0.5 0.4 0.3 Group 1 = 86% (n=7) Group 2 = 67% (n=4) 0.2 Group 3 = 62% (n=51) 0.1 Group 4 = 42% (n=13) 0.0 0 50 100 150 200 250 Time in months
RMS at RCCH 1990-2010 Overall Survival by Stage Chi-square = 6.426913 df = 3 p = 0.09261 Complete Censored 1.0 0.9 Cumulative Proportion Surviving 0.8 0.7 0.6 0.5 0.4 0.3 Stage 1 = 80% (n=20) 0.2 Stage 2 = 80% (n=5) Stage 3 = 51% (n=30) 0.1 Stage 4 = 42% (n=13) 0.0 0 50 100 150 200 250 Time in months
RMS at RCCH 1990-2010 Overall Survival by Cohort Log-Rank Test p = 0.71939 Complete Censored 1.0 0.9 Cumulative Proportion Surviving 1990-2004 60% (n=46) 0.8 2005-2010 63% (n=29) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 50 100 150 200 250 Time in months
RMS at RCCH 1990-2010 Overall Survival by Histology Log-Rank Test p = 0.42222 Complete Censored 1.0 0.9 Cumulative Proportion Surviving 0.8 Embryonal 60% (n=52) 0.7 Alveolar 55% (n=18) 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 250 Time in months
RMS at RCCH 1990-2010 Overall Survival = 61% Complete Censored 1.0 0.9 0.8 Cumulative Proportion Surviving 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 -50 0 50 100 150 200 250 Survival Time in months
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% • 2003-2005 OS 59.5% • 2005-2010 OS 64.2%
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 2001 23(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!
Questions…? Is VAC/VDC as good (or better than) IVA/VDC for: • our group 3 stage 3 para-meningeal and extremity tumours, and Protocols Total patients treated PM patients Survivors Rx 6033 4 2 2 (100%) (Stage 3 and 4 / All unfavourable histology) VAC/VDC X 51/52 Rx 6054 12 7 3 (42%) (Group 3 PM Stage 3, Extremity Stage 3; All Group 4; All UH [ARMS/UDS]) 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.
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 15 15 4 (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 7 4 2 (50%) (Group 3 PM Stage 3, Extremity All stage 3 patients Stage 3; All Group 4; All UH [ARMS/UDS]) Still does not answer the question about patients who IVA/VDC X 51/52 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.
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.
Thanks Felicity Douglas Research assistant /nurse for data collection Alan Davidson Clinical head of unit
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