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

Ind

uct

ion

ch

em

oth

era

py

Early trials

Second Generation

trials

This kind of trials are those considered in the MACH-CN meta-analysis!

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

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* 56%

(20 + 36) Cddp + 5FU

(x 3)

Forastiere A** (2003)

168 Larynx 85%°°

(21 + 64) Cddp + 5FU

(x 3)

Lefebvre J-L** (1996)

97 Hypopharynx

larynx 86%

(54 + 32) Cddp + 5FU

(x 3)

Vermorken*** (2007)

181 All sites 54%

(6.6 + 47) Cddp + 5FU

(x 3)

Posner° (2007)

246 All sites 64%

(15 + 49) 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

1

TOXICITY (CRT)

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 # %

Early (≤ 6 months)

18 4.6

Late (> 6 months) 12 3.0

Cumulative analysis (clinical trials only)

Argiris A, Clin Cancer Res 2004

1997 - 2008

All pts 291

Cause of toxic death1 # %

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

Cumulative analysis (clinical practice only)

Merlano MC, Oral Oncol 2012

2

EFFICACY OF ICT (from MACC-HN 2000 analysis)

Table from E.E.Vokes 2010, modified

Drug(s) makes the difference

3

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:

4

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.

Vermorken TAX 323

Locally advanced, unresectable HNC

• Locally advanced, unresectable • Locally advance, resectable but surgery refused • Organ preservation

Posner TAX 324

TAX 323 and 324: differences and cautions

REGIMEN DOSES

(mg/m2) Antibiotic Profilax.

G III/IV Neutrop.

Febrile neutropenia

Population Def.

Treat.

TAX 323

TPF T = 75 P = 75

F = 750° yes 76.9% 5.2%

Unresectable RT

PF P = 100 F = 1000

no 52.5% 2.8%

TAX 324

TPF T = 75

P = 100 F = 1000°°

yes 83%* 12%** Resectable

Unresctable

Organ

preservation

Weekly Carbo

+ RT PF

P = 100 F = 1000

no 56%* 7%**

* = 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

1) Vokes EE, The Oncologist, 2010

Third generation trials

TPF high dose and same pts population as in TAX 324

Arm A: TPF x 3 standard CRT Arm B: PF x 3 standard CRT Arm C: 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

RTOG 91-11

EORTC 24954

ORGAN PRESERVATION

PF x 2 ≥ RP PF x 2 RADIOTHERAPY (70 Gy) < RP SURGERY + RT

ALTERNATING CRT: CF x 4 + RADIOTHERAPY (60 Gy)

CONCURRENT CRT: C x 3 + RADIOTHERAPY (70 Gy)

STUDIES DESIGN

EORTC

24954

RTOG 91-

11

ARM A

ARM B

ARM A PF x 3 ≥ RP RADIOTHERAPY (70 Gy) < RP SURGERY + RT

ARM B

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 249541 RTOG 91-112

Alternating

CT / RT

Sequential

CT RT

Sequential

CT RT

Concurrent

CT - RT

Mucositis

% G 2

G 3-4

35

21

41

32

243

433

Late

toxicities

%

35 (fib.) 41 (fib.) 243 303

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

P < 0.001

P < 0.029

Induction… what?

Docetaxel 75 Cisplatin 75 5 FU 750

Cisplatin 100 5 FU 1000

vs

RADIOTHERAPY 70 Gy

JNCI 2009

Neither toxicity nor acute or late, nor survival or disease-free interval differ significantly between the two arms

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

CONCLUSIONS

Locally Advanced HNC

1. Concurrent CRT offers a larger benefit than ICT followed by definitive loco-

regional treatment.

2. ICT followed by loco-regional treatment offers a larger benefit than loco-

regional 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

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.