Organ-Preservation Strategies in head and neck cancer Teresa Bonfill Abella Oncologia Mèdica Parc Taulí Sabadell. Hospital Universitari
Larynx Hypopharynx
The goal of treatment is to achieve larynx preservation with good function without compromising survival Witch is the optimal primary endpoint? - Larynx preservation rate - Larynguectomy- FS? - Survival Rate at 2, 5, 10 years? - QoL.
Summary of the Relevant Literature
Induction chemotherapy 3 randomized studies: - VA - EORTC 24891 - GETTEC larynx hypopharynx T3 larynx VALCSG. N Engl J Med 1991 Lefebvre JL et al. J Natl Cancer Inst 1996 Richard JM et al. Oral Oncol 1998 Surgery + RT Surveillance PF x 3 no response surgery + RT surveillance response RT +/- salvage surgery
Veterans Affairs Laryngeal Cancer Study Group 332 pts, laryngeal SCC stage III/IV Surgery Adjuvant RT RT: 5000cGy/25fx RT: 6600-7600cGy T1/T2 9% T3 65% T4 26% Glottis 37% IC x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w IC x 1 Poor respond Definitive RT Surgery +/- RT Residual disease Supraglottis 63% 2yr DFS OS Recur at primary Recur at regional Distant mets Surgery 75% 68% 2% 5% 17% Laryngectomyfree survival IC RT 65% 68% 12% 8% 11% 39% p value 0.12 0.98 0.001 NS 0.001 New England Journal of Medicine 1991; 324: 1685-1690 LPR: 64% (2y)
EORTC 24891 194 pts, hypopharynx SCC stage II/III/IV Surgery Adjuvant RT RT: 5000cGy/25fx RT: 7000cGy IC x 2 IC x 1 Definitive RT T2 20% T3 75% Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w Poor respond Surgery +/- RT Residual disease T4 5% Pyriform sinus 78% 5yr DFS OS Recur at local Recur at regional Distant mets Laryngectomyfree survival Aryepiglottic fold 22% Surgery 32% 35% 17% 23% 36% IC RT 25% 30% 12% 19% 25% 42% (2y) 35% (5y) p value NS NS NS NS 0.041 Journal of National Cancer Institute 1996; 8: 890-899
Induction chemotherapy Trial/ site of tumour N Therapy aproach Larynx Preservation LFS Survival Difference VALCSG (larynx) EORTC 24891 (hypopharynx) 332 S RT vs PF 1 x3 RT 202 S RT vs PFx3 RT 64%(2y) 39%(2y) No difference 40,5% (5y) 42% (2y) 35% (5y) No difference 1 CDDP 100mg/m²/ev d1 5-FU 1000mg/m²/ev d 1-5 (ic) every 3w x 3courses Induction PF + RT can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival
Chemoradiotherapy RTOG 91-11 (USA) larynx RT RT-CT concomitantly (cisplatin days 1, 22 and 43) N=547pt PF induction 1 CDDP 100mg/m²/ev d1 5-FU 1000mg/m²/ev d 1-5 (ic) every 3w x 3courses no response surgery + RT surveillance response RT +/- salvage surgery T2 12% T3 78% T4 10% Supraglottis 69% Glottis 31% Forastiere A et al. N Engl J Med 2003
Chemoradiotherapy RTOG 91-11 (USA) larynx 2yr DFS OS Intact larynx LR control LFS Distant mets A: RT 27% 56 % 70% 56% 53% 38% (5y) 22% B: CCRT 36% 54 % 88% 78% 66% 45% (5y) 12% C: IC RT 38% 55 % 75% 61% 59% 43% (5y) 15% Difficulties in p Speech/swallow : similar (2y) 15% 0.02(C v A) 0.006(B v A) NS 0.005(B v C) 0.001(B v A) 0.004(B v C) 0.001(B v A) 0.49(BvC) 0.01 (AvB) 0.03(B v A) Forastiere A et al. N Engl J Med 2003
Toxicity: - The rate of high grade toxic effects was greater in Ch-based regimens 81% (Chi->RT), 82% (Ch-RT) & 61% (XRT) - The mucosal toxicity of concurrent RT-CDDP was nearly twice as frequent as the mucosal toxicity of the other two treatments during RT - No differences in late toxicity or speech or swallowing function were demonstrated between treatment groups
GORTEC 2000-01 Induction chemotherapy Induction CT Larynx Preservation Larynx or hypopharynx tumors Resectable tumors or nodes requiring total (pharyngo[p] laryngectomy) No previous treatment TPF arm Docetaxel (75 mg/m² d1) Cisplatin (75 mg/m² d1) 5-FU (750 mg/m²/dx5) Q 3 weeks x 3 cycles PF arm Cisplatin (100 mg/m²) 5-FU (1000 mg/m²/dx5) Q 3 weeks x 3 cycles No Response to induction treatment Yes Non-responders: Total (P)laryngectomy + post-op RT Responders: RT T2 18% T3 67% T4 15% Primary Objective: larynx preservation rate Pointreau et al. ASCO 2006 Calais G, et al. ASCO 2006, abstract 5506.
GORTEC 2000-01 Induction chemotherapy
GORTEC 2000-01 Induction chemotherapy Grade 3/4 Acute Toxicities % of patients NCI/CTC Grade 3/4* TPF PF p Mucositis 4.6 7.8 0.49 Neutropenia 55.6 37.3 0.01 Febrile neutropenia 13.9 7.8 0.24 Thrombocytopenia 1.9 7.8 0.09 Deaths 3.6 2.9 0.71 *Among patients treated with RT alone, no differences were observed between the 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with permanent feeding tube. Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.
TAX 324 Induction chemotherapy Sequential therapy for locally advanced larynx and hypopharynx cancer: Subgroup analysis from TAX 324 study
TAX 324 Induction chemotherapy -Significant improvement in PFS (Hazard Ratio 0.61 (0.40-0.96) p=0.033 -Strong trend for OS (Hazard Ratio 0.67 (0.41-1.11) p =0.12 ASCO 2008
Five phase III trials (VALSG, EORTC 24891, RTOG 91-11, GORTEC 2000-01, TAX 324) STUDY LFS LPR VETERANS (L) EORTC 24891 (H) RTOG 91-11 PF (L) RTOG 91-11 QT+RT (L) GORTEC 2000-01 PF (L&H) GORTEC 2000-01 TPF (L&H) TAX 324 PF (L&H) TAX324 TPF (L&H) 39% (2y) 42% (2y) 35% (5y) 59% (2y) 43% (5y) 66% (2y) 45% (5y) 37% (3y) 53%(3y) 32% (3y) 52%(3y) 64% (2y) 75%(2y) 88%(2y) 57% (3y) 70%(3y)
TREMPLIN: French randomized phase II study of laryngeal preservation Resp. RT + cetuximab TPF x 3 RT + cisplatin N=153 Larynx/hypopharynx suitable for TL No resp. S + PORT Randomized phase II, GORTEC-GETTEC) ASCO 2009 i ASCO 2011 JCO 2013
From these studies we have learnt that: - Ch combined with RT has allowed to preserve a significant number of larynx without compromising survival - PF followed by RT and Ch-RT show similar efficacy in LFS - LCR and LPR were significantly improved with Ch-RT - Ch decreased the incidence of DM without impact in OS - TPF is better than PF in LFS & PFS - Chemoradiotherapy & Induction Chemotherapy are alternatives -TPF-based ICT followed CRT or BRT was feasible but had substantial overall toxicity None of the ch-based protocols has provided better results than surgery except in terms of larynx preservation
There is currently no good evidence base from larynx preservation trials with which to assess the functional outcomes achieved with different larynx preservation strategies
The Oncologist 2010;15 (suppl3): 25-29
Suggested approaches to management
T1, T2 TT Intent to preserve the larynx RT or larynx preservation surgery tt selection depends on: pt factors, local expertise & rehabilitation services Concurrent Ch-RT only in: Stage III, T2 N+ pts whom total LT is the only surgical option OR larynx-preservation surgery is expected to yield an unsatisfactory functional outcome OR organpreservation surgical expertise is unavailable Narrow margin excision followed by postoperative radiation therapy IS NOT an acceptable treatment approach
T3, T4 Organ preservation surgery, Ch-RT, Chi RT and Rt alone offer potential for larynx preservation without compromising survival Tt selection depends on: pt factors, local expertise and rehabilitation services Pt with tumor penentration through cartilage into soft tissues are considered poor candidates for larynxpreservation approach. LT is recommended in these cases
Factors associated with decreased larynxpreservation outcomes: Male gender Anemia (at start of treatment) Smoking Advanced T stage Clinically detectable impaired vocal cord mobility Subglottic extension Involvement of anterior commissure Large tumor volume Invasion of specific anatomic sites (determined by CT or MRI)
Recommended management approach for treatment of resectable T3-4 N0-3 laryngeal cancer JCO, Vol 31, No7 (march1), 2013:pp840-844
CONCLUSIONS Larynx-preservation therapy is intended to offer improved function and quality of life without compromising survival. All patients with T1-T2 should be treated initially with intent to preserve the larynx. Pt with T3- selected T4 should be offered a larynxpreservation treatment option. Chemoradiotherapy & Induction Chemotherapy are alternatives
CONCLUSIONS Preservation of the laryngeal structure is not considered a functional success if persistent dysphagia, aspiration, or chronic tracheostomy. Selection of treatment for laryngeal cancer should always depend on patient factors, local expertise, and appropiated support and rehabilitative services. A multidisciplinary team with specialized expertise is necessary to ensure optimal outcomes.