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Discussion of Abstracts

Discussion of Abstracts .

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Discussion of Abstracts

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  1. Discussion of Abstracts 3500 – German CAO/ARO/AIO-04: Preop CRT & post-op chemo with 5FU +/- oxaliplatin in locally advanced rectal cancer3501 – PETACC-6: Preop CRT & post-op chemo with capecitabine+/- oxaliplatin in locally advanced rectal cancer: DFS at interim analysis3502 – ADORE: Adjuvant chemo with FOLFOX vs FL for rectal cancer patients with post-op yp stage 2 or 3 after pre-op CRT: updated results of 3-year DFS from a randomized phase II study

  2. Disclosures • I have no relevant conflicts of interest to disclose

  3. What Critical Questions are Addressed by These Three Studies? • Does oxaliplatin have benefit as a radiation sensitizer beyond fluoropyrimidines in the neoadjuvant rectal setting? My Interpretation… NO

  4. What Critical Questions are Addressed by These Three Studies? • Does oxaliplatin added to fluoropyrimidine-based adjuvant therapy provide additional benefit in decreasing recurrence in patients with rectal cancer? My Interpretation… YES

  5. Stage II&III Rectal Cancer Treated with Pre-op Fluoropyrimidines+ RT +/- Oxaliplatin * Unplanned exploratory analysis

  6. My Interpretation… • The weight of evidence supports a lack of benefit for the addition of oxaliplatin to fluoropyrimidine-sensitized RT in the neoadjuvant rectal setting and is not recommended for use in clinical practice

  7. What do We Know About Adjuvant Fluoropyrimidine Therapy in Patients with Rectal Cancer? • Cochrane systematic review and meta-analysis of post-op adjuvant chemotherapy (2012) • Pre-neoadjuvant rectal era – 9,785 patients from 21 randomized trials conducted between 1983 - 2011 • Reduction in risk of recurrence & death with adjuvant chemotherapy of 25% & 17%, respectively

  8. What About Rectal Adjuvant Therapy in the “Neoadjuvant Era”? • Only one published rectal study comparing adjuvant fluoropyrimidine therapy to no adjuvant therapy in the “neoadjuvant era” (EORTC 22921*) • Failed to show a benefit for adjuvant therapy • Suffers from substantial patient drop-out & dose reductions in the experimental arm • Cannot be interpreted as definitive evidence of a lack of benefit for adjuvant rectal therapy • The totality of evidence strongly supports the benefit of adjuvant therapy in patients with rectal cancer *Bosset et al Lancet Oncology 2014

  9. Is Oxaliplatin Beneficial when Added to Adjuvant Fluoropyrimidine-based Therapy in Patients with Rectal Cancer?What do we already know? • Oxaliplatin clearly adds benefit when added to fluoropyrimidine-based therapy in patients with: • locally advanced colon cancer • MOSAIC • NSABP C-07 • metastatic colon and rectal cancers • TCGA supports rectal and colon cancers having very similar genetic underpinnings

  10. DFS Plots

  11. DFS Summary

  12. How do We Explain the Different Outcomes? • AIO-04 & ADORE • ADORE randomized AFTER surgery and excluded pCR and Stage 1 • Arms reasonably balanced for drop-out, therapy completion & dose-intensity • PETACC-6 • Substantial imbalances between the arms in both drop-out & intended therapy rates & cape dose • 38% did not receive adjuvant CAPOX vs 23% who did not receive adjuvant single agent cape • Only 53% vs 68% of eligible pts received all intended adjuvant cycles in the CAPOX vs cape arms • 54% vs 36% received <90% of cape in the CAPOX vs cape arms

  13. What do I Conclude? • Oxaliplatin adds benefit to fluoropyrimidine-based adjuvant rectal therapy for highly selected patients. • Supported by extrapolation from colon adjuvant data • Supported by the genetic similarities reported by TCGA • There is no indication for the use of oxaliplatin as a component of neoadjuvant combined modality chemoradiationtherapy in patients with rectal cancer

  14. What is the Future of Rectal Cancer Therapeutics? • Future trials should focus on : • Developing more effective & less toxic agents that can be targeted to patients most likely to derive benefit through the parallel development of companion predictive diagnostics • Altering our therapeutic algorithm to allow a greater proportion of patients to derive benefit from available & yet to be discovered systemic therapies

  15. Total Neoadjuvant Therapy (TNT) Surgery ChemoRT Chemotherapy Novel Targeted Therapies For High-risk Patients Novel Radiosensitization Strategies Courtesy of Thom George, PI

  16. Thank you…

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