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 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

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

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

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

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

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

RCTs of Concurrent CRT DFS 27-61%, OS 30-50%

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 Survival benefit mainly due to improvement in locoregional control and only marginal effect on distant metastasis. Blanchard P et al. radiotherapy and Oncology2011

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 Chemotherapy …. Radiosensitizer ….Early control of micrometastatic disease

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 Response rates 50-75% Complete response rate 10-15%

Neoadjuvant Chemotherapy Study N Treatment Primary End point (Larynx Preservation) OS VA Study Group 332 Surgery  RT Cis + 5FU X 3  RT + Surgery 64% at 2 yrs 68% P= NS EORTC 24891 202 Cisplatin + 5-FU x 2-3 cycles  RT or Surgery  RT 35% at 5 yrs 35% 30% P=NS RTOG 91-11 525 RT alone (70 Gy) Cis + 5-FU 1000/m2 X 2 CR/PR  Cis/5FU X 1 RT NR  Surgery  RT Cis X 3 + RT 70% (65.7%) 75% (70.5%) 88% (83.6%) 56% (53.5%) 55% (59.2%) 54% (54.6%) RTOG 91-1 Endpoint results 2 yr(5-yr)- Distant mets less with CRT* & I+RT than RT alone (p=0.06)* VA Study Group- Distant mets less (0.016) and local recurrences (0.0005) more with CRT than RT. Changed the treatment paradigm 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

Conclusions A larynx preserving approach can be offered to patients without compromising their survival Surgery can be an option in the salvage setting Patients with comorbidities and no access to adequate speech and swallowing rehab

TPF vs PF Study N Treatment Regimen TPF PF TAX 324 501 Docetaxel 75 mg/m2 D1 Cisplatin 100 mg/m2 Cisplatin 100 mg/m2 D1 5-FU 1000 mg/m2 D1- 5 5-FU 1000 mg/m2 D1-4 Q 3 wks x 3 ->CRT ->Sx Q 3 wks x 3 ->CRT-> Sx EORTC 24971/ TAX 323 358 Docetaxel 75 mg/m2 D1 Cisplatin 100 mg/m2 Cisplatin 75 mg/m2 D1 5-FU 1000 mg/m2 D1-5 5-FU 750 mg/m2 D1-5 Q 3 wks x 4 -> RT Q 3 wks x 4 -> RT TAX 324 -> CRT included carboplatin AUC 1.5 wkly x 7 and RT 70-74 Gy ->>>> surgery in N2+PR, N3, residual disease EORTC-> RT included convention dose 66-70 Gy or acc/ hyperfractionated dose of 70-74 Gy. Vermorken JB et al. NEJM 2007; 357:1695-704 Posner MR et al. NEJM 2007; 357:1705-15

TPF vs. PF Results Outcome TAX 324 TPF PF p EORTC 24971 TPF PF p RR 72 64 0.07 72 59 0.006 OS (m) 71 30 0.006 18.8 14.5 0.02 3-yr OS % 62 48 0.002 37 26 PFS (m) 36 13 11 8.2 0.007 2-yr PFS % 53 42 0.01 25 20 Such a difference in responses- 1)Tax 324 resectable+ unresectable LAHNC….. EORTC trial had only unresectable disease. 2) Ind chemo CRT better than RT alone In EORTC –subgp analysis showed a survival benefit across all subgps but this was not statistically significant. Vermorken JB et al. NEJM 2007; 357:1695-704 Posner MR et al. NEJM 2007; 357:1705-15

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. TPF is the regimen of choice for induction chemotherapy

Radiation Conventional Fractionation Altered 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 Accelerated fractionation attempts to reduce tumor repopulation as a prominent cause of RT failure by decreasing the total time over which the radiation is administered////// IMRT much improved xerostomia

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

RTOG 0129 N = 721 with LRAHNC Randomized to No difference in OS 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 Toxicity – increased acute toxicity – skin and mucus membranes// 27% patients in both arms PEG dependent

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%

Cisplatin dose and frequency 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 Stage IV 89% and oropharynx 44% Medina JA. Radiotherapy and Oncology 2006

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%

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

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 EGFR testing not required for enrollment Bonner JA et al. NEJM 2006;354:567-78

Study End Points Outcome Cetuximab +RT RT P value LR control (m) 24.4 14.9 0.005 OS (m) 49 29.3 0.03 PFS (m) 17.1 12.4 0.006 PFS % (3 yr) 42 31 0.04 LRC % (3 yr) 47 34 <0.01 OS % (3 yr) 55 45 0.05 Check subdivision of responses in each type of HNC- Study not designed to analyse subgroup analysis i.e poor PS/ elderly. Distant mets were similar in 2 gps at 2 yrs. No difference in RT dose. Bonner JA et al. NEJM 2006;354:567-78 Bonner et al. Lancet Oncology 2010;11:21-28

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

Adverse Events Grade > 3 AE C + RT RT P value Infusion Reaction 3 0.01 Acneiform Rash 17 1 0.001 Mucositis 56 52 0.44 Dermatitis 23 18 0.27 Weight Loss 11 7 0.12 Dysphagia 26 30 0.45 Xerostomia 5 0.32 One third patients had stage III disease and they better prognosis a such. No head to head comparison of CRT vs cetuxRT. Is CRT+targeted therapy better than CRT alone. Bonner JA et al. NEJM 2006;354:567-78

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

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

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

Local failure was more in the cetuximab arm 21% versus 13% Surgical salvage was feasible in cetuximab arm 42% received 3 cycles of cisplatin 71% received 7 treatments of cetuximab

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

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.

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 2, 1.8, and 1.6 Gy/fraction to PTV1, PTV2, PTV3, respectively for 35 fractions to a total dose of 70 Gy.

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

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

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

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