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Head and Neck Cancer

Head and Neck Cancer. December 6,2016 Uzma Athar, MD. Management of LAHNC Induction when and what Weekly cisplatin vs three weekly cisplatin Cetuximab vs cisplatin Radiation dose and fractionation. Case.

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Head and Neck Cancer

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  1. Head and Neck Cancer December 6,2016 Uzma Athar, MD

  2. Management of LAHNC • Induction when and what • Weekly cisplatin vs three weekly cisplatin • Cetuximab vs cisplatin • Radiation dose and fractionation

  3. Case • Mr C is a 53 y/o caucasian male with h/o papillary thyroid carcinoma s/p total thyroidectomy and radioactive iodine ablation 20 years ago, who presented with throat discomfort and a 15 lb weight loss. Initially seen by endocrinology who noticed a palpable right level two lymph node ~ 3 cm in size on examination • He had chronic mild dysphagia, hoarseness and chronic aspiration since thyroid surgery • Smoking 1.5 ppd for 30 yrs; presently smokes half ppd • Previous heavy alcohol use but none in over 10 yrs • H/O recurrent pneumonias

  4. FNAC of the right submandibular lymph node showed moderately differentiated SC • Direct Laryngoscopy – • An area of ulceration on the posterior right aryepiglottic fold and extending to involve the laryngeal epiglottis • True vocal cords and pyriform sinus were without lesion • Fullness of the BOT was noted without any discrete mass • Rigid esophagoscopy was normal to 36 cm from the incisors

  5. Biopsy • Squamous cell carcinoma, well differentiated of right supraglottic region • Lymphoid hyperplasia of right base of tongue • Dysplasia, moderate, of left base of tongue

  6. CT Neck • A large matted lymph node in the right level II, measuring 2.0 x 3.0 cm • Prominent soft tissue suspicious for a primary tumor in the left side base of the epiglottis and bilateral lingual tonsils. • PET Scan • Right-sided cervical node level 2 with SUV max 14.9 • Left soft tissue mass in the epiglottis/vallecula with SUV max 7.3 • Bilateral piriform sinuses with SUV max 6.5 • Right aryepiglottic fold with SUV max 15.2

  7. Final Stage - IVA (T3N2cM0) • Other Studies • Dental Evaluation • Speech/Swallowing evaluation

  8. Treatment Options Definitive Concurrent Chemotherapy Chemoradiotherapy Radiotherapy Adjuvant Chemoradiotherapy Surgery Chemotherapy Radiotherapy Induction Chemotherapy Chemotherapy Chemotherapy Definitive concurrent CRT Radiotherapy Induction Chemotherapy Chemotherapy Radiotherapy or Surgery

  9. RCTs of Concurrent CRT

  10. Concurrent Chemoradiation (CRT) • MACH-NC • 87 randomized trials between 1965 and 2000 comparing locoregional treatment and chemotherapy with locoregional treatment alone • Earlier analysis showed survival benefit with chemotherapy was 8% at 5 years Blanchard P et al. radiotherapy and Oncology2011

  11. Benefit of adding chemotherapy is consistent in all tumor locations • Oral cavity 8.9% • Oropharynx 8.1% • Larynx 5.4% • Hypopharynx 4% • Chemotherapy benefit was higher for concomitant administration for all tumor locations

  12. Neoadjuvant/ Induction Chemotherapy • Organ preservation • Decrease tumor Volume • Response is predictive of subsequent response to RT • Eliminate clinically occult micrometastatic disease • Response is transient and should be followed by definitive treatment • Surgery &/ RT

  13. Neoadjuvant Chemotherapy VA laryngeal Ca Study. NEJM 1991;324:1685-1690 Lefebvre JL et al. JNCI 1996;88:890-899; Lefebvre. Ann of Oncology 2012;23:2708 Forastiere AA et al. JCO 2013;31: 845

  14. Conclusions A larynx preserving approach can be offered to patients without compromising their survival Surgery can be an option in the salvage setting

  15. TPF vs PF Vermorken JB et al. NEJM 2007; 357:1695-704 Posner MR et al. NEJM 2007; 357:1705-15

  16. TPF vs. PF Results Vermorken JB et al. NEJM 2007; 357:1695-704 Posner MR et al. NEJM 2007; 357:1705-15

  17. TPF vs PF Conclusions As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck.

  18. Radiation • Conventional Fractionation • 70 Gy in 2 Gy fractions • Altered Fractionation • Hyper fractionated • 1.1 – 1.2 Gy/Fr twice daily (interval of 6 hrs) • 74-82 Gy (higher dose but no increase in LT toxicity) • Improved LR disease control; no survival benefit with CRT • Preferred when RT is used alone • Accelerated fractionation • 1.5 – 1.6 Gy/Fr daily with an additional 2 Gy Fr/ week • Shorter total radiation course • Total dose is same or lower than conventional RT

  19. IMRT • Focally increase the dose per fraction to the tumor itself while maintaining lower doses to normal tissue/ uninvolved areas • Costly, requires planning • Often used for boost to the primary tumor • Less side effects i.e. xerostomia

  20. RTOG 0129 • N = 721 with LRAHNC • Randomized to • 70 Gy in 35 fractions over seven weeks with cisplatin 100 mg/m2 on D1,22,43 • Accelerated boost RT (70 Gy in 42 fractions over six weeks) with cisplatin on D1 and 22 • No difference in OS • 8-year survival rate 48 % percent with both schedules (HR ratio 0.96, 95% CI 0.79-1.18) • No significant differences in PFS, LRF or rate of distant metastases

  21. GORTEC 99-02 • N = 840 with LRAHNC • Treatment Schema • 70 Gy in 7 weeks with 3 cycles of carboplatin and 5-FU • Accelerated chemoradiotherapy (70 Gy in 6 weeks with two cycles of carboplatin fluorouracil) • Very accelerated RT alone twice daily (64.8 Gy in 3.5 weeks) 3-yr PFS was 34% in accelerated CRT versus 38% in conventional CRT (p = 0.88) 3-yr PFS was 38% in CRT versus 32% in very accelerated RT alone arm (p = 0.06) Similar results were observed for overall survival Acute toxicity- Gr 3/4 mucosal toxicity 69% vs 76% vs 84%

  22. Cisplatin dose and frequency • N = 94 • Stage III/IV SCC of the oropharynx, larynx, hypopharynx and oral cavity • Treatment Regimen • Cisplatin 40 mg/m2 IV week 1-4 • RT – 1.8 GY on D1-40; 1.5 Gy boost D25-40 Total dose 72 Gy Medina JA. Radiotherapy and Oncology 2006

  23. ORR was 88% (66% CR and 22% PR) • Median OS was 27 months • Est 4-yr OS was 41% • Est 4-yr local control 59% • Toxicity • Acute toxicity- Mucositis (gr III 85%), Pharyngoesophageal (gr III 50%), dermatitis (17%) • Late Toxicity- Bone 2%, larynx 4%, esophagus 2%, skin/ subcutaneous tissue 2%

  24. Conclusion • Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with LA unresectable head neck cancer with acceptable toxicity and survival data

  25. Role of Cetuximab as first line agent • Randomized control trial comparing cetuximab and radiation with radiation alone in previously untreated patients with LASCC. • Cetuximab 400 mg/m2 250 mg/m2 weekly • 3 different regimens of RT used • Once daily 70 Gy in 35 fractions • Twice daily 70-76.8 Gy in 60-64 fractions • Concurrent boost 72 Gy in 42 fractions Bonner JA et al. NEJM 2006;354:567-78

  26. Study End Points Bonner JA et al. NEJM 2006;354:567-78 Bonner et al. Lancet Oncology 2010;11:21-28

  27. Updated 5-yr survival data • OS 45.6% in cetuximab arm versus 36.4% in RT arm (HR 0.73 and p value 0.018) Bonner et al. Lancet Oncology 2010;11:21-28

  28. Adverse Events Bonner JA et al. NEJM 2006;354:567-78

  29. Cetuximab arm with grade 2 or higher rash • OS 68.8 months versus 25.6 months (HR 0.49, p 0.002) Bonner et al. Lancet Oncology 2010;11:21-28

  30. TREMPLIN Study • Phase II study of patients with Stage III/IV larynx/ hypopharynx SCC • N = 153 • TPF X 3 cycles • CR/PR CRT with cisplatin 100 mg/m2 X 3  RT with Cetuximab weekly • NR  surgery  RT

  31. Larynx preservation at 3 months was 95% in cisplatin arm and 93% in cetuximab arm • LFP was 87% (cis) vs 82% (cetux) at 18 months • OS was 92% (cis) vs 89% (cetux) at 18 months

  32. Local failure was more in the cetuximab arm 21% versus 13% • Surgical salvage was feasible in cetuximab arm

  33. Acute Toxicity Cisplatin Cetuximab • Mucositis 43% 43% • Infield skin toxicity 24% 52% • Renal 15% • Hematologic 14% • Late Toxicity • Residual renal dysfunction 22% in cisplatin arm

  34. Conclusions • There is no evidence that one treatment was superior to the other or could imporve outcomes reported with induction chemotherapy followed by radiation alone.

  35. Case • The patient was treated with IMRT to 70 Gy in 35 fractions concurrent with chemotherapy with cisplatin weekly X 6 weeks CT Scans done at 3 months showed residual neck disease

  36. Case • Underwent salvage b/l neck dissection 4/8 positive lymph nodes • He is now 5 yrs out from neck dissection with no evidence of disease

  37. Management of LAHNC • Induction when and what • Weekly cisplatin vs three weekly cisplatin • Cetuximab vs cisplatin • Radiation dose and fractionation

  38. A Randomized Phase II Trial for Patients with p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer(NRG-HN002) (CIRB) MSKCC • RT alone versus weekly cisplatin/RT

  39. Thank you

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