1. The more it hurts, the better it works?
Chemotherapy toxicity as a predictor of outcome from osteosarcoma: a report from the European Osteosarcoma Intergroup Jeremy Whelan University College Hospital, London
A McTiernan, RC Morgan, MR Sydes, B Uscinska, M Van Glabbeke, V Bramwell, RL Souhami, I Lewis, AH Taminiau, MA Nooij, PC Hogendoorn

2. Acknowledgements
Clinicians and staff at centres who randomised patients and collected data
Staff at MRC CTU and EORTC who worked on the three trials since 1983
Last but not least, all 1067 patients who were treated within these trials

3. I feel terrible, doc. That means it must be working, doesn’t it?
Patients commonly associate side effects of chemotherapy with efficacy
Oncologists recognise great interpatient variability in severity of toxicity
Patients are prepared to suffer toxicity for defined benefit
For example, see Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990;300:
Patients would accept severe side effects for a 1% better chance of cure, in contrast to controls, oncologists, and cancer nurses

4. Myelosuppression most strongly associated with survival
Chemotherapy-induced toxicity has been identified as an independent prognostic indicator in several cancers
Myelosuppression most strongly associated with survival
10% survival advantage in breast cancer pts with grade 2-3 neutropenia compared to those with none
Similar associations in NSCLC and gastric cancer
Cetuximab-related skin toxicity associated with greater response & survival in metastatic colorectal cancer
If associations were found in patients with osteosarcoma, this may provide a useful tool for predicting clinical outcome
Prospect of greater individualisation of treatment

5. Background to EOI trials
The EOI has completed 3 randomised controlled trials, involving over 1000 patients with localised extremity osteosarcoma
Each of the 3 studies used a “standard” treatment arm
Six 3-weekly cycles of doxorubicin 25 mg/m2 daily times 3 in combination with cisplatin 100 mg/m2 as a continuous infusion perioperatively
All three trials had a similar follow up schedule
Median (IQR) follow up overall 9.9 years ( )
BO02: 17.9 ( )
BO03: 12.7 ( )
BO06: 5.0 ( )
533 control arm patients in total provide a valuable dataset for detailed investigation of prognostic factors
Robust survival data
Mature follow up
Other research is also being conducted with this data
See poster #35060: analysis of all 1067 patients
Analysis of post-recurrence survival ASCO abstract 10505

6. Background to EOI trials
BO02/80831 ( ) 179 neoadjuvant patients
Bramwell VH et al: A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol 10: , 1992
BO03/80861 ( ) 391 patients
Souhami RL et al: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 350:911-7, 1997
BO06/80931 ( ) 497 patients
Lewis IJ et al: Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 99:112-28, 2007
EOI now a partner in the EURAMOS 1 trial
Registered 1157/1400 patients as of 1st October 2008

7. Characteristics of control arm patients
Median (IQR) age at randomisation 15 (12-19)
More younger patients in BO06: 59% aged under 16 compared to BO02 43% and BO03 46%
61% male
66% conventional osteosarcoma
More chondroblastic tumours in later studies: BO02 5%, BO03 13%, BO06 12%.
58% femur, 26% tibia

8. Treatment information
Use of limb-sparing surgery increased over time
56% in BO02 compared with 74% in both BO03 and BO06
Good histological response reported in 35% of cases
surgery performed after 3 cycles in first two trials, and after 2 cycles in BO06
But 182/533 patients missing this data
Overall, 80% completed treatment as per protocol
14% in BO02 stopped early due to toxicity, compared to 6% in BO03 and 5% in BO06

9. Statistical methods The following toxicities were considered:
Mucositis
Nausea/vomiting
Leucopenia (not collected in BO02)
Thrombocytopenia (not collected in BO02)
Infection
Cardiac toxicity
Neurological toxicity
The worst grade of each toxicity was categorised as:
Grade 0
Grade 1-2
Grade 3-4

10. Statistical methods
Separate analyses were undertaken to examine the prognostic factors for histological response, overall survival (OS) and progression-free survival (PFS)
For histological response
Logistic regression used (univariate and multivariate)
Only toxicities experienced before surgery considered
For OS & PFS standard survival analysis methods used
Univariate Cox models timed from randomisation
Multivariate Cox models timed from surgery
Toxicity over whole chemotherapy period considered
All models stratified by trial

11. Survival outcomes for control arm
Overall survival
At 5 years: 57% (52-61%)
At 10 years: 53% (49-58%)
Progression-free survival
At 5 years: 44% (40-49%)
At 10 years: 44% (39-48%)

12. Overview of toxicity rates
Mucositis increased in later trials
Grade 1-4: 50%, 61%, 73% (BO02, BO03, BO06)
Nausea / vomiting severe toxicity lower in BO06
Grade 3-4: 74%, 74%, 48%
Infection increased in later trials
Grade 1-4: 44%, 60%, 70%
Leucopenia
Grade 3-4: 75%, 81% (BO03, BO06)
Thrombocytopenia increased in BO06
Grade 3-4: 46%, 58% (BO03, BO06)
Cardiac toxicity
Grade 1-2: 12%, 6%, 11%
Neurological toxicity
Grade 1-2: 15%, 11%, 10%

13. Mucositis (OS)
Grade 1-2 HR (95% CI): 0.75 (0.57,1.00) compared to grade 0
Grade 3-4 HR: 0.38 (0.25,0.57) compared to grade 0

14. Nausea / vomiting (OS) Grade 1-2 HR: 0.60 (0.31,1.16)

15. Infection (OS) Grade 1-2 HR: 0.84 (0.62,1.14)

16. Leucopenia (OS) Grade 1-2 HR: 0.88 (0.48,1.62)

17. Thrombocytopenia (OS)
Grade 1-2 HR: 0.56 (0.37,0.84)
Grade 3-4 HR: 0.59 (0.42,0.83)

18. Cardiac toxicity (OS) Grade 1-2 HR: 0.84 (0.52,1.36)

19. Neurological toxicity (OS)
Grade 1-2 HR: 0.51 (0.31,0.85)
Grade 3-4 HR: 1.73 (0.24,12.42)

20. Multivariate model (OS)
The following toxicities and grades kept their significant association with OS in the multivariate model:
Mucositis grade 3-4 HR (95% CI): 0.51 (0.29,0.91)
Nausea / vomiting grade 1-2: 0.37 (0.16,0.85)
Thrombocytopenia grade 1-2: 0.49 (0.27,0.87)
The following other terms were also independently prognostic, all associated with better OS:
Good histological response: 0.42 (0.27,0.65)
Distal tumour site: 0.45 (0.28,0.71)
Female gender: 0.68 (0.45,1.01)

21. Histological response
No chemotherapy-related toxicity was found to be associated with the likelihood of good histological response.
Two other factors were found to be independently associated, both with a lower chance of a good response:
Age ≥ 26 odds ratio (OR) (95% CI): 0.20 (0.05,0.80)
Chondroblastic tumour type: 0.28 (0.10,0.77)

22. Limitations Patients recruited over a long time period
Some changes in practice difficult to account for in analysis
Missing data reduces certainty of results & limits number of patients included in multivariate models
Most histological response data from BO02 missing
Haematological toxicities not available for BO02
Lack of data on tumour size, surgical margins, alkaline phosphatase

23. Conclusions and implications
Chemotherapy-induced toxicity was associated with improved survival, both for OS and PFS
Non-haematological toxicity was found to be a better indicator of survival than haematological toxicity
Relationship between myelosuppression and survival possibly diminished due to aggressive chemotherapy
Relevance of nausea/vomiting in predicting outcome has probably decreased over time due to better anti-emetics
No association was found between chemotherapy-induced toxicity and histological response

24. Conclusions and implications
For now: lack of toxicity may provide early evidence of reduced tumour chemosensitivity, and predict poorer outcome in patients with osteosarcoma
Further research needed
To elucidate the underlying mechanisms which account for individual toxicity, and
To explain how these may link to tumour sensitivity
Investigate in prospective cohorts