NACT in oral cancer - Mukesh.pptx

NACT in oral cancer
Dr. Mukesh Kumar Sah
Head and Neck Surgery (MCh SR 3)
Tata Memorial Centre, Mumbai
1

NACT oral cancer
• SCC is the most common oral cancer
• locally advanced at presentation
• standard of care for resectable cancer is the surgery f/b
adjuvant RT+/- CT
• For unresectable cases- CRT
2

NACT in oral cancer
Role in
improving locoregional control and overall survival (OS)
mandible preservation
borderline resectable/technically unresectable tumors
in order to reduce surgical margins
increase resectability, and achieve R0 resection
Improvement in survival in unresectable tumor
3

NACT in operable oral cancer
Resectable
oral cancer
Survival
benefit
Mandible
preservation
4

NACT in resectable oral cancer
• Lictra et al, 2003
5

Licitra et al.
• A randomized, multicenter trial
• Resectable, stage T2-T4 (> 3 cm), N0-N2, M0 untreated,
squamous cell carcinoma of the oral cavity
• 1989-1999
• 195 patients
• 3# cisplatin and fluorouracil followed by surgery
(chemotherapy arm) or surgery alone (control arm).
• cisplatin 100 mg/m2 and 5-fluorouracil (5FU) 1000
mg/m2
6

Licitra et al.
• NACT f/b Surgery
• 5 year OS 55%.
• PORT 33%
• Mandible resection in 31%
• 3 death due to treatment toxicity.
• pathological complete response
(CR) had a 10-year OS of 76.2% Vs
41.3% in those without a
pathological CR (P = 0.0004)
• Surgery
• 5 year OS 55%.
• PORT 46 %
• Mandible resection in 52%
• -
7
Bossi et al., after a median follow-up of 11.5 years,
confirmed the same results. NACT failed to have an impact
on LRC, distant metastasis, and OS

Zhong et al., 2013
8

Zhong et al.
9
Methods:
• A prospective open-label phase III trial
• 256 patients- locally advanced, resectable
• Upfront surgery followed by PORT vs 2# of a docetaxel,
cisplatin, and 5FU (TPF) regimen followed by surgery
and PORT
• docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on
day 1, and fluorouracil 750 mg/m2 on days 1 to 5)

Zhong et al.
10
Results:
• The clinical response rate to induction chemotherapy
80.6%.
• only 9% having Grade 3 toxicities and none having
Grade 4 toxicity.
• Median follow-up of 30 months
• No significant difference in OS (hazard ratio [HR], 0.977;
95% CI, 0.634 to 1.507; P .918) or disease-free survival
(HR, 0.974; 95% CI, 0.654 to 1.45; P 0.897)

Zhong et al.
11
Results:
• superior OS and locoregional and distant control for the
cases that showed better response to NACT
• Improved OS (HR, 0.418; 95% CI, 0.179–0.974; P =
0.043) and DMFS (HR, 0.418; 95% CI, 0.179–0.974; P =
0.043) in patients with N2 disease who received NACT.

NACT in resectable oral cancer:
Conclusions from the 2 trials
• 2# of NACT or 3# of NACT did not Improve OS or DFS
• Lower dose of drugs confers lesser toxicity
• May reduce number of cases requiring PORT
• A favorable pathological response post-NACT predicts a
better outcome
• Better disease control in patients with higher nodal
stage
12

Mandibular Preservation surgery
13

• cT2-T4 and N0/N+, M0
• Requiring resection of the mandible for paramandibular
disease in the absence of bone erosion
• 34 patients – upfront surgery f/b adj RT/CTRT (control)
• 34 patients- two cycles of NACT (docetaxel, cisplatin,
and fluorouracil) at 3-week intervals f/b Surgery f/b adj
CTRT
• 16 of 34 patients (47%) in NACT arm underwent
mandible preservation surgery
14

• DFS and OS were similar in both the arms.
• Complications were similar in both arms
• chemotherapy-induced toxicity was observed in the
majority of patients (grade III: 14, 41.2%; grade IV: 11,
32.4%) in the NACT arm
15

NACT in resectable oral cancer: Organ
preservation
16

preservation
17
• 19 patients with resectable stages III and IV OCSCC
• 1# NACT (Cis/carboplatin+5-FU)
• Patients with a response of at least 50% underwent
concurrent CRT; those with a response of less than 50%
underwent surgery f/b adj RT
• 10 of these (53%) had a response of at least 50%
• These responders received 3#cisplatin/Carboplatin + RT
70 Gy
• only 6 of 10 (60%) were disease free after completion of
definitive CRT.

preservation
18

preservation
19
• Primary surgery f/b RT/CRT results in better OS, DSS,
and LRC than does an induction selection f/b CRT.
• In addition, IS does not chemoselect patients for organ
preservation therapy in OCSCC and results in worse
treatment-related complications compared with
surgery.

NACT in Borderline resectable(technically
unresectable) oral cancer (Patil et al.)
BM-diffuse
margins and
peritumoral
edema till zygoma
Tongue-reaching
close to hyoid
bone
Extension of tumor
of oral tongue to
the vallecula
BM-Extension to
high ITF (the level
of the sigmoid
notch)
Extensive skin
infiltration
impacting doubtful
negative margin
20

unresectable) oral cancer
21
Upfront
surgery
• Margin
compromise
• Functional
disability
Radical
RT/CRT
• Inferior
survival
NACT
• R0
achievement
• Acceptable
functional
outcome

22

23
721
NACT
411
(unsatisfactory
response)
170
167 CTRT/3 RT
241
Palliative
310 (43%)
Surgery f/b adj
CTRT
3 drugs groups
resectibility
66.2%
2drugs 40.3%
2 or 3 drugs
(taxane + platinum
± 5FU)

24
LRC at 24 months
(overall cohort)
20.6 %
Nonsurgical 15 %
Surgery 32 %
P=0.0001

25
Overall
survival
Nonsurgical
8.16 months
Surgery
19.6 months
P=0.0001

26

27
Overall survival
Nonsurgical 8.8
months
Surgery+adj t/t
16.9 months
P=0.0001
80 patients 2 drugs
NACT(pacli/Carbo)
2-3#
Nonsurgical
treatment 65
cases
19(23.8%)
resectable
4 cases not operated due
to logistic issue

NACT in borderline resectable oral
cancer
28

NACT in technically unresectable oral
cancer
29
Courtesy of authors: From ASCO 2022 presentation

30

31

32

33

Summary:
• Use of induction chemotherapy in technically
unresectable cancer is safe and feasible
• Borderline resectable patients may benefit by getting
opportunity for non-morbid surgery with R0 resection
which translates in better survival
• 3 drugs(DCF) regimen has better survival outcomes
compared to 2 drugs(DC); but at the cost of increased
toxicity
• Can be considered as standard of care now
34

NACT in unresectable oral cancer
• Studies have shown variable OS and DFS in unresectable
LAHNSCC, by the use of NACT
• Studies dedicated to OSCC for the same, could not be
found
• TPF regimen has shown better results compared to PF
35

36

37
previously untreated, advanced nonmetastatic (stages
III and IV) SCC of head and neck
Initial chemotherapy (4# cisplatin and 5-FU) followed by loco-regional
treatment (group A, n = 118)
or loco-regional treatment alone (group B, n = 119)
To see the role of NACT in improving survival of patients with advanced
disease
Oral cavity
Gr A 18 cases(15.3%); Gr B 19 cases(16%)

38
Parameters Group A (NACT) Group B P
value
Operable-underwent Sx f/b adj RT 34(28.8%) 32(26.9%)
Free of disease after treatment completion 71(60%) 67(56%)
Distance metastasis at 2 years and 3 years in
inoperable cases
15%, 24% 36%, 42% 0.01
Complete remission in inoperable cases 44% 30% 0.037
DFS in inoperable case at 2 and 3 years 49%, 34% 28%, 26% 0.06
OS in inoperable case at 2 and 3 years 30%, 24% 19%, 10% 0.04
OS in inoperable case at 5 and 10 years
(further f/u by same group in same study)
21%, 16% 8%, 6% 0.04

• For operable patients, the only benefit seen was in
incidence of distant metastases.
• Improved local control, decreased incidence of distant
metastases, and improved complete remission rate and
overall survival was seen in inoperable cases.
39

40

• Platinum-based chemoradiation (CCRT) is the standard
treatment for LAHNSCC.
• Cetuximab/RT (CET/RT) is an alternative treatment
option to CCRT.
• Aim: to study the efficacy of induction chemotherapy
(IC) followed by chemoradiation compared to
chemoradiation alone.
41

42
concomitant treatment alone [CCRT
(Arm A1) or
CET/RT (Arm A2)], or three cycles of
induction docetaxel/cisplatin/5
fluorouracil (TPF) followed by CCRT
(Arm B1) or followed by
CET/RT (Arm B2)
comparison of IC versus no-IC (Arms
B1+B2 versus A1+A2) in terms of OS,
PFS and LRC

43
Oral cavity cases
Concomitant
(arms A1+A2) 44
(21.5%) Vs IC-
>concomitant
(arms B1+B2) 38
(23.5)

44
At median f/u of 44 months

• Locoregional failure and distance metastases
45
At median f/u of 44 months

46

• OS was significantly higher in the IC arm
• Complete Responses, Progression Free Survival and the
Loco-regional Control were also significantly higher in
the IC arm.
• Compliance to concomitant treatments was not affected
by induction TPF.
• It should be regarded as an option for poor prognosis
patients
47

48

49
Comparison of TPF with PF as
induction chemotherapy f/b
RT to both groups in patients
with locoregionally
advanced, unresectable
disease
TPF(N=177) -docetaxel 75
mg/sq. m, cisplatin 75
mg/sq. m, and
fluorouracil 750 mg/sq.
PF (N=181)- cisplatin
100 mg/sq. m, and
fluorouracil 1000
mg/sq.
Oral cavity
TPF 31(17.5%)
PF 32(17.7%)

50

51

52

53

• The addition of docetaxel to PF induction chemotherapy
in patients with unresectable squamous-cell carcinoma
of the head and neck improved survival and was better
tolerated than the classic PF regimen
54

55

56
Comparison of TPF with PF as
induction chemotherapy f/b
Carboplatin+RT to both
groups in patients with
locoregionally advanced,
disease
3#TPF(N=255) -docetaxel
75 mg/sq. m, cisplatin
100 mg/sq. m, and
fluorouracil 1000mg/sq.
3#PF (N=246)- cisplatin
100 mg/sq. m, and
fluorouracil 1000
mg/sq.
Oral cavity
TPF 33(13%)
PF 38(15%)

• Median survival 71 months in
the TPF group and 30 months in
the PF group (P=0.006).
• Estimated 3-year survival 62%
in the TPF group and 48% in the
PF group (P=0.002).
• The median PFS was 36 months
in the TPF group and 13 months
in the PF group.
• Estimates of PFS at 2 years were
53% in the TPF group and 42%
in the PF group (P=0.01).
57

• Grade 3 or 4 neutropenia
occurred in 83% of patients in
the TPF group and in 56% of
patients in the PF group
(P<0.001)
• Grade 3 or 4 thrombocytopenia
was more frequent in the PF
group than in the TPF group
(11% vs. 4%, P=0.005).
• Patients in the TPF group had
fewer treatment delays than
did those in the PF group (29%
vs. 65%, P<0.001)
58

• The TPF group has a consistent trend toward improved
survival, regardless of the primary site of disease,
reason for therapy, nodal status, primary tumor stage,
and surgical curability.
59

60

• Trials including patients with non-metastatic carcinoma
randomized between 1965 and 2016
• comparing curative loco-regional treatment (LRT) to LRT
+ CT
• Comparing NACT+RT/CRT with RT/CRT, with RT/CRT+adj
CT
61

• Effect on OS and the timing of CT was significant (p <
0.0001), the benefit being limited to concomitant CT
(HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute
benefit of 6.5% (3.6%)).
• OS was not increased by the addition of induction (HR =
0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]).
62

63

64

65

• Concomitant chemoradiotherapy is the mainstay of
treatment for locally advanced HNSCC. 5(10)-year
absolute benefit of 6.5% (3.6%)).
• OS was not increased by the addition of induction (HR =
0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]).
66

67

68
3#NACT (TPF) f/b CRT
(Carboplatin/Docetaxel +
RT)
cisplatin-based
concurrent
chemoradiotherapy alone
NACT f/b CRT CRT alone P value
Death after f/u of 49 months 20 21
3 year OS 73% 78% 0.77
Febrile neutropenia 16 1
(2004-2008)
145 patients
1:1
Terminated early due to
slow recruitment

69

70
2#NACT (TPF) f/b CRT
(Same regimen as CRT
alone)
(CRT arm; docetaxel,
fluorouracil, and
hydroxyurea plus
radiotherapy alone)
NACT f/b CRT CRT alone P value
Overall response rate after CRT 79% 74% 0.45
Mortality rate 39(28%) 42(31%) 0.69
Serious adverse effects 47% 28% 0.02
OS was similar in both arms (HR, 0.91; 95% CI, 0.59–1.41)
N2 or N3 SCC
122:130
30 months f/u

Summary:
Mixed outcomes have been seen for application of
NACT in inoperable cancer. Role of NACT before
standard CRT is not established.
Studies including only oral cancer in such scenario is
lacking
3 drugs (TPF) has survival and control benefits over 2
drugs(PF) with comparable adverse effects
71

References
• Goel, Alok; Singla, Anshul1; Prabhash, Kumar2,3,. Neoadjuvant chemotherapy in oral cancer:
Current status and future possibilities. Cancer Research, Statistics, and Treatment 3(1):p 51-59,
Jan–Mar 2020. | DOI: 10.4103/CRST.CRST_79_19
• Patil VM, Prabhash K, Noronha V, Joshi A, Muddu V, Dhumal S, et al Neoadjuvant chemotherapy
followed by surgery in very locally advanced technically unresectable oral cavity cancers Oral
Oncol. 2014;50:1000–4
• Rudresha AH, Chaudhuri T, Lakshmaiah KC, Babu KG, Dasappa L, Jacob LA, Suresh Babu MC, Lokesh
KN, Rajeev LK. Induction Chemotherapy in Technically Unresectable Locally Advanced T4a Oral
Cavity Squamous Cell Cancers: Experience from a Regional Cancer Center of South India. Indian J
Med Paediatr Oncol. 2017 Oct-Dec;38(4):490-494. doi: 10.4103/ijmpo.ijmpo_185_16. PMID:
29333018; PMCID: PMC5759070.
• Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in
head and neck cancer. N Engl J Med. 2007;357(17):1705-1715. doi:10.1056/NEJMoa070956
• Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in
unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695-1704.
doi:10.1056/NEJMoa071028
72

References
• Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, Brockstein BE, Agulnik MB,
Mittal BB, Yunus F, Samant S, Raez LE, Mehra R, Kumar P, Ondrey F, Marchand P, Braegas B, Seiwert
TY, Villaflor VM, Haraf DJ, Vokes EE. Phase III randomized trial of induction chemotherapy in
patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014 Sep
1;32(25):2735-43. doi: 10.1200/JCO.2013.54.6309. Epub 2014 Jul 21. PMID: 25049329; PMCID:
PMC4876357.
• Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus
concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann
Oncol. 2017;28(9):2206-2212. doi:10.1093/annonc/mdx299
• Lacas B, Carmel A, Landais C, et al. Meta-analysis of chemotherapy in head and neck cancer
(MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC
Group. Radiother Oncol. 2021;156:281-293. doi:10.1016/j.radonc.2021.01.013
• Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent
chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone
in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol.
2013;14(3):257-264. doi:10.1016/S1470-2045(13)70011-1
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