Neoplasie del laringe Diagnosi e trattamento Venerdì 22 maggio 2015 Alessandria Trattamenti non chirurgici: Preservazione d organo, malattia localmente avanzata Marco C Merlano A.O. S.Croce e Carle, Ospedale d Insegnamento
Induction chemotherapy (neo-adjuvant chemotherapy) Any chemotherapy regimen, with proven activity, given BEFORE definitive loco-regional treatment (radiation, surgery or both). Being part of a radical treatment, the final target of induction chemotherapy is: To improve overall survival compared to the current standard treatment(s) OR To achieve the same results of the standard treatment but with lesser toxicity OR To achieve the same results of the standard treatment with the same toxicity but at a lower economical cost
Induction chemotherapy Early trials This kind of trials are those considered in the MACH-CN meta-analysis! Second Generation trials
Why ICT is so attractive? 1. Good activity 2. Easy to delivery (and physicians are familiar with toxicities!) 3. Marginal but Significant improvement in OS observed in the meta-analysis (only with Cisplatin and 5FU) 4. Perception of a possible conversion from unresectable to resectable tumors or reduced RT volume
1 Activity of Induction chemotherapy (ICT) (in randomized trials, ICT arm, P+F only) Author (year) n. of patients subsites O.R.R. after ICT (CR+PR) CT regimen (n. of courses) Domenge C (2000) 157 Oropharynx* Forastiere A** (2003) Lefebvre J-L** (1996) Vermorken*** (2007) Posner (2007) 168 Larynx 97 Hypopharynx larynx 181 All sites 246 All sites 56% (20 + 36) 85% (21 + 64) 86% (54 + 32) 54% (6.6 + 47) 64% (15 + 49) Cddp + 5FU (x 3) Cddp + 5FU (x 3) Cddp + 5FU (x 3) Cddp + 5FU (x 3) Cddp + 5FU (x 3) * accrual between 1986 and 1992, previous to HPV era ** organ preservation *** unresectable only resectable, unresectable and organ preservation evaluation after the initial two courses
2 TOXICITY (CRT) Cumulative analysis (clinical trials only) 1989-1999 All pts 394 Cause of death # % Treatment 30 7.6 Disease 88 22.3 Comorbidities 41 10.4 Second primary 18 4.6 Unknown 20 5.1 Overall 196 50.0% Treatment related death # % 1997-2008 All pts 291 Cumulative analysis (clinical practice only) Cause of toxic death 1 # % Bleeding 1 0.3 Sepsis 2 1.0 Pneumonia 7 2.4 Sudden Death 4 2.4 Overall 14 4.8 1) Any death occurring within 1 month from treatment end, not related to disease progression Early ( 6 months) 18 4.6 Merlano MC, Oral Oncol 2012 Late (> 6 months) 12 3.0 Argiris A, Clin Cancer Res 2004
3 EFFICACY OF ICT (from MACC-HN 2000 analysis) Drug(s) makes the difference Table from E.E.Vokes 2010, modified
4 Surgical extension cannot be reduced on The basis of Chemotherapy response the extent of the primary tumor before CT was conducted by tattoo, photography Or both 32.5% of the frozen sections (initial tumor Extension) were involved with tumor and Necessitated further resection:
TAKE HOME MESSAGE The benefit of ICT depends on the drug(s) used The benefit of ICT may be improved by new drug combinations There is no evidence that ICT may reduce the extent of surgery. The same is for radiation volume. This choice might jeopardize results.
Locally advanced, unresectable HNC Vermorken TAX 323 Locally advanced, unresectable Locally advance, resectable but surgery refused Organ preservation Posner TAX 324
TAX 323 and 324: differences and cautions REGIMEN DOSES (mg/m 2 ) Antibiotic Profilax. G III/IV Neutrop. Febrile neutropenia Population Def. Treat. TAX 323 TPF PF T = 75 P = 75 F = 750 P = 100 F = 1000 yes 76.9% 5.2% no 52.5% 2.8% Unresectable RT TAX 324 TPF PF T = 75 P = 100 F = 1000 P = 100 F = 1000 yes 83%* 12%** no 56%* 7%** Resectable Unresctable Organ preservation Weekly Carbo + RT * = p < 0.001; ** = p = 0.04; for 5 days; for 4 days
TAKE HOME MESSAGE THE TRIPLET TAXANES CISPLATIN 5-FLUOROURACIL IS SUPERIOR TO P-F THE TRIPLET INCREASES THE RISK OF SEVERE EMATHOLOGICAL TOXICITY ANTIBIOTIC PROFILAXYS IS HIGHLY RECOMMENDED TAX 323 AND 324 HAVE BEEN DESIGNED TO COMPARE TWO REGIMENS OF ICT. THEY CANNOT ANSWER THE QUESTION WHETHER ICT MAY REPLACE CRT AS THE GOLDEN STANDARD FOR UNRESECTABLE LA-HNC
The today most interesting question Can the administration of induction chemotherapy prior to concomitant chemoradiotherapy further improve the results of either approach alone? 1 Third generation trials 1 ) Vokes EE, The Oncologist, 2010
TPF high dose and same pts population as in TAX 324
Arm A: TPF x 3 Arm B: PF x 3 Arm C: Standard CRT standard CRT standard CRT TPF low dose and same pts population as in TAX 323
Prior ICT impacts on the following CRT Regimen 3 CT courses < 3 CT courses TPF CRT 72.3% 27.7% PF CRT 75.0% 25.0% CRT 82.1% 17.9% Tremplin trial Regimen 3 CT courses < 3 CT courses TPF CRT 42% 58%
Cumulative conclusions, 3 TPF trials 1. All the trials failed to show any advantage by the addition of ICT to CRT 2. All the trials showed increase in toxicity compared to CRT alone 3. The worst toxic profile was observed with high dose TPF 4. ICT may negatively interfere with following standard CRT (as already observed in the Tremplin study) CRT REMAINS THE GOLD STANDARD AND THE REFERRAL REGIMEN FOR FUTURE RANDOMIZED TRIALS
ORGAN PRESERVATION EORTC 24954 RTOG 91-11
STUDIES DESIGN EORTC 24954 ARM A ARM B ALTERNATING CRT: CF x 4 + RADIOTHERAPY (60 Gy) PF x 2 RP PF x 2 RADIOTHERAPY (70 Gy) < RP SURGERY + RT ARM A PF x 3 RP RADIOTHERAPY (70 Gy) < RP SURGERY + RT RTOG 91-11 ARM B CONCURRENT CRT: C x 3 + RADIOTHERAPY (70 Gy) ARM C RT (70 Gy)
EORTC 24954 RTOG 91-11
Overall survival (RTOG 91-11) HR = 1.25 C.I. = 0.98 1.61 P = 0.08
Effects EORTC 24954 1 RTOG 91-11 2 Alternating Sequential Sequential Concurrent CT / RT CT RT CT RT CT - RT Mucositis % G 2 35 P < 0.001 41 G 3-4 21 32 24 3 43 3 Late toxicities % 35 (fib.) 41 (fib.) 24 3 30 3 P < 0.029 1) Lefebvre J-L et al: J. Natl Cancer Inst 2009;101:142-52 2) Forastiere AA et al: N Engl J Med 2003;349:2091-8; updated ASCO 2006 3) Data at two years
Induction what? JNCI 2009 Docetaxel 75 Cisplatin 75 5 FU 750 vs Cisplatin 100 5 FU 1000 RADIOTHERAPY 70 Gy
The main objective was the preservation of the larynx. Only the laryngectomy has been regarded as a failure, regardless whether the larynx was functioning or not Neither toxicity nor acute or late, nor survival or disease-free interval differ significantly between the two arms
1. ICT, Alternating CRT and Concurrent CRT are all acceptable approach to organ preservation. 2. ICT should be regarded as the best standard because of a better survival profile than concurrent CRT and a more easy delivery compared to alternating CRT. 3. There is evidence that TPF (European regimen) should be considered standard in organ preservation. CONCLUSIONS Locally Advanced HNC 1. Concurrent CRT offers a larger benefit than ICT followed by definitive locoregional treatment. 2. ICT followed by loco-regional treatment offers a larger benefit than locoregional treatment alone. 3. TPF is the referral regimen for ICT. The European scheduling should be preferred due to a better toxicity profile. 4. TPF is an aggressive regimen and deserves adequate supportive care. Organ preservation