Management of carcinoma
By- Dr. Isha Jaiswal
Moderator- Dr. Shantanu Sapru
Date: 10th December 2014
Topics to be covered:
• Pre-treatment evaluation
• Treatment overview
• Evidence based treatment
• NCCN guidelines
Evaluation of patients with suspected
Clinical Exanimation of head & neck
Fiber optic laryngopharyngoscopy & biopsy of primary tumor
Contrast enhanced CT scan face and neck
Contrast enhanced MRI face & neck
Chest X Ray
Fiber-optic direct laryngoscopy
• used routinely to complement the laryngeal mirror examination.
• assessment of extent of primary tumor & mobility of vocal cords.
• critical in assessing the superficial spread of neoplasm
• superior to any imaging modality in detecting mucosal spread
• can be attached to a photographic device
• biopsy of the tumor is done for histopathological confirmation.
Typical findings of hypopharyngeal cancer on endoscopy:
pooling of the saliva in the pyriform fossa.
oedema of the arytenoids.
fixation of the cricoarytenoid joint,
or true vocal cords or both.
CECT Scan Face & Neck
• Timing: should be done before biopsy of to avoid post biopsy oedema.
• Advantages: aids in staging by detection of:
invasion into larynx.
extra laryngeal/extra pharyngeal spread.
paraglottic space spread.
spread to retropharyngeal space.
clinically occult metastatic lymphadenopathy.
Failure to detect small superficial tumours & early laryngeal cartilage involvement.
Underestimating ulcerative and infiltrative lesions
overestimating tumor extent due to inflammation/ oedema & distortion of adjacent normal
MRI Face & Neck
• Compared to CECT shows better soft tissue contrast & less artifact from
• An important adjunct study in three situations:
• Disadvantages :
Determining cartilage invasion :shown by increase T2 signal & post contrast
Determining extent of extralaryngeal/paraglottic space involvement
Determining oesophageal involvement shown by increased T2 signal, wall thickening
and effaced fat planes
overestimating tumour extent :inflammation/ oedema /distortion
In detection of unknown /small primary tumor
In evaluating clinically occult nodal involvement
In follow up to differentiate between treatment sequelae & tumor
Role Of 18FDG PET-CT
Impact Of FDG-PET On Staging &Management of H&N
A multicenter study of 233 H&N SCC patients (including
46 hypopharyngeal cancer)
TNM staging and therapeutic decisions were first
determined based on conventional workup & then FDG-
PET data was used to restage the patients & reanalyse their
PET and conventional workup revealed discordant
TNM staging in 100 patients (43%).
PET was deemed significantly more accurate than
conventional staging & improved the staging in 20%
Incorporation of PET data ultimately impacted
management in 32 patients (13.7%).
*Lonneux M, Hamoir M, Reychler H, et al. Positron emission tomography with [18F]fluorodeoxyglucose improves staging and patient
management in patients with head and neck squamous cell carcinoma: a multicenter prospective study. J Clin Oncol 2010;28:1190–1195.
FDG-PET is a reliable imaging procedure in the detection of clinically
occult primary tumor/node and recurrent/residual carcinomas localized in
the head and neck.
it cannot as yet replace other diagnostic procedures in pretreatment planning
but does contribute valuable complementary diagnostic information.
TNM STAGING- AJCC 7TH edition (2010)*
T1: Tumour limited to one subsite of hypopharynx and ≤ 2 cm in greatest
T2: Tumour invades more than one subsite or adjacent site or measures >2cm
but ≤ 4 cm without fixation of hemilarynx.
T3: Tumours > 4 cm or with fixation of hemilarynx or extension into esophagus
T4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland,
central compartment of soft tissue.
T4b: Tumor invades prevertebral fascia, encases the carotid artery or involves
*Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging handbook, 7th ed. New York: Springer, 2010.*
TNM STAGING- AJCC 7TH edition (2010)*
• N0: No regional LN
• N1: Single ipsilateral LN ≤ 3cm
• N2a: Single ipsilateral LN 3-6cm
b: Multiple ipsilateral LNs ≤ 6cm
c: Bilateral or contralateral LNs ≤ 6cm
• N3: Any LN more than 6cm
• M stage:
• Mx- cannot be assessed,
• M0- no distant metastasis,
• M1- distant metastasis
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1, T2
Stage IV A T1,T2,T3
Stage IV B Any T
Stage IV C Any T Any N M1
General Treatment Recommendations Based On
Hypopharynx Tumor Stage*
*Perez & Brady's Principles and Practice of RadiationOncology
• – Surgery or RT
Choice depends on
• – Tumor: site, extension
• – Patient: preference, comorbidities
• – Expertise of the multidisciplinary team, available resources
Equally effective: however no randomised trials for surgery vs. RT.
Each modality can salvage the other if local recurrence.
EARLY STAGE (I-II)(T1-T2, N0)
T1-2, N1-3 / T3-4, N0-N+
• Radiotherapy with altered fractionation schedules
• Radiotherapy with chemotherapy
• Radiotherapy with biological therapy
• Neoadjuvant chemotherapy f/b surgery
• Surgery f/b RT/CT-RT
Choice depends on
• Tumor: site, extension
• Patient: preference, comorbidities
• Expertise of the multidisciplinary team, available resources
Benefits of RT over surgery
• Probability of functional morbidity or cosmetic defects is reduced.
• Risk of a major postoperative complication is avoided
• Elective neck RT can be included with little added morbidity.
• Surgical salvage of RT failure is supposed to have better outcome than the RT salvage
of a surgical failure.
Indications for primary radiotherapy
• small sized tumor
• larynx/voice preservation
• those who refuse surgery
CAUSE-SPECIFIC AND OVERALL SURVIVAL FOR
CARCINOMA OF THE PYRIFORM SINUS TREATED WITH
As stage increases 5 years
survival with RT alone
Radiation treatment intensification
2. Addition of chemotherapy
1. Altered fractionation RT
4. Addition of biological
therapy to RT
*2Horiot JC. Controlled clinical trials of hyperfractionated and accelerated radiotherapy in otorhinolaryngologic cancers [in
French].Bull Acad Natl Med 1998;182(6)
*#Cummings B, O’Sullivan B, Keane T. 5-year results of a 4 week/twice daily radiation schedule: the Toronto Trial. Radiother Oncol2000
TRIALS OF HYPERFRACTIONATION
TRIALS OF PURE ACCELERATED FRACTIONATION
*!Jackson et al. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer.Radiother Oncol 1997
*2Skladowski Ket al. 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer—. Radiother Oncol 2000;55
*3Overgaard J,. The DAHANCA 6 and 7 trial: a study of 5 versus 6 fractions per week of conventional radiotherapy of (SCC) of the head and neck. Radiother Onco
*4Hliniak AZ.. Radiother Oncol 2000;56:S5.
Aim: to find whether shortening of treatment time by use of six instead of five radiotherapy
fractions per week improves the tumour response in squamous-cell carcinoma.
randomised trial between January, 1992, and December, 1999,
1485 patients treated with primary radiotherapy alone,
1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at
the same total dose and fraction number (66-68 Gy in 33-34 fractions)
TWO SUBPROTOCOLS: DAHANCA 6, which
included all glottic carcinomas, and DAHANCA 7,
included tumours of the supraglottic larynx,pharynx,
The only difference in the two subprotocols was that
DAHANCA 6 dealt only with the fractionation effect,
whereas the DAHANCA 7 also included treatment with
the hypoxic radiosensitiser nimorazole.
More than 97% of the patients received the planned
Median overall treatment times were 39 days (six-
fraction group) and 46 days (five-fraction group).
Primary locoregional tumour control as
function of number of fractions per week
Overall 5-year locoregional control rates were
70% and 60% for the six-fraction and five-
fraction groups, respectively (p=0.0005).
primary tumour control (76 vs 64% for six and five
fractions, p=0.0001), but was non-significant for neck-
Disease specific survival Overall survival
Disease-specific survival improved (73 vs 66%) for six and five fractions
but not overall survival
Early and late radiation-related morbidity
Acute morbidity was significantly more frequent with six than
with five fractions, but was transient.
Accelerated radiotherapy applied to squamous-
cell carcinoma of the head and neck yields better
locoregional control than does a conventional
schedule with identical dose and fractionation.
*1 Dische, et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;
*2 Poulsen, et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV SCCHN: aTTROG Radiother Oncol 2001;
*3 Bourhis, et al. Preliminary results of the GORTEC 96–01 randomized trial, comparing very accelerated radiotherapy versus concomitant
radio-chemotherapy for locally inoperable HNSCC. Int J Radiat Oncol Biol Phys 2001;
• Patients with stage III or IV SCC
(n=1076) were randomized to 4
(1) Standard fractionation
70 Gy/35 daily fractions/7 weeks
(2) Hyper fractionation
81.6 Gy/68 twice-daily fractions/7 weeks
(3) Accelerated fractionation with split
67.2Gy(1.6bid)/42 fractions/6 weeks
with a 2-week rest after 38.4 Gy
(4) Accelerated fractionation with concomitant boost
72 Gy/42 fractions/6 weeks.(1.8Gy/f with 1.5 Gy /f boost on last 12 fractions)
RTO 90-03 Results: at 2years
• significant improvement in 2 yr locoregional control
for the hyper fractionation and concomitant boost arms
• trend toward improved disease-free survival (p = 0.067
and p = 0.054 respectively for the hyper fractionation
and concomitant boost arms
• OS: difference in overall survival was not significant.
• altered fractionation regimens were associated with
higher incidence of grade 3 or worse acute mucosal
toxicity, but no significant difference in overall toxicity
at 2 years following completion of treatment.
EORTC trial 24891 compared PF (cisplatin and 5-FU) induction chemotherapy followed
by radiation therapy (RT) versus total laryngectomy, radical neck dissection, and
postoperative RT in patients with hypopharyngeal cancer
Role of NACT for larynx preservation
NACT-RT Vs Surgery-RT
• Treatment failures occurred at approximately
the same frequencies in both arms.
• Fewer failures at distant sites in the induction-
• The median duration of survival was 25
months in the immediate-surgery arm and 44
months in the induction-chemotherapy arm
• The 3- and 5-year estimates of retaining a
functional larynx in patients treated in the
induction chemotherapy arm were 42% and
CONCLUSION OF EORTC 24891
Choice of chemotherapy regimen:
2 drug vs.3 drug regimen
29%pts of ca hypopharynx
compare TPF with PF as induction
chemotherapy in patients with
Primary end point :PFS
358 patients underwent
randomization, with 177 assigned to
the TPF group and 181 to the PF
ARM A (N=177) ARM B(N=181) TOTAL P value
CONCLUSION OF TAX 323
At a median follow-up of 32.5 months, the median PFS was 11.0 months in the TPF group and 8.2
months in the PF group .
There were more grade 3 or 4
events of leukopenia and
neutropenia in the TPF group and
more grade 3 or 4 events of
vomiting, stomatitis, and hearing
loss in the PF group.
15% patients of ca
chemotherapy with docetaxel
plus cisplatin and fluorouracil
(TPF) with cisplatin and
fluorouracil (PF), followed by
treatment of SCCH& N
Results of TAX 324
more patients survived in the TPF group than in the PF group
estimates of overall survival at 3 years were 62% in theTPF group and 48% in the PF
median overall survival was 71 months and 30 months, respectively (P = 0.006).
better locoregional control in the TPF group than in the PF group (P = 0.04)
incidence of distant metastases in the two groups did not differ significantly (P = 0.14)
Rates of neutropenia and febrile neutropenia were higher in the TPF group;
chemotherapy was more frequently delayed because of hematologic adverse events in the
An Intergroup Phase III Comparison of Standard Radiation Therapy and Two
Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable
Squamous Cell Head and Neck Cancer.
J Clin David J. Adelstein Oncol 21:92-98. 20032003
CTRT VS RT ALONE
which one is better in unresectable HNSCC?
CTRT of 2 Gy/d, was split between the first CT
course (30 Gy) & third CT course (30 to 40 Gy).
A total dose of 60 to 70 Gy was given
The radiation therapy break was planned to
allow for the possibility of surgical resection in
those patients rendered resectable after the first
two courses of chemotherapy and the first
30 Gy of radiation.
Patients who had achieved a complete response
after this induction or who remained
unresectable proceeded, without surgery, to
Forastiere et al
•RT Vs. CTRT Vs. NACT-RT
which one is better?
J Clin Oncol. 2013 Mar 1;31(7):845-52. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 2
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Vol 24, No 18S (June
20 Supplement), 2006: 5517
Radiotherapy Alone Vs. Concurrent
CTRT Vs. Sequential NACT-RT
J Clin Oncol. 2013 Mar 1;31(7):845-52. doi:
10.1200/JCO.2012.43.6097. Epub 2012 Nov 2
Loco regional control Overall survival
No Published Phase 3 Trial Study Have Tested
Induction Chemotherapy f/b chemoradiotherapy
Vs Upfront Chemoradiotherapy
Lancet Oncol. 2012 Feb;13(2):145-53. doi: 10.1016/S1470-2045(11)70346-1. Epub 2012 Jan 18
aimed to assess the efficacy and safety of a combination of approaches.
STAGE III/IV, M0
RT – 70Gy/6w
1st 40Gy 2Gy/#/d, 5#/w
Next 30Gy (off the spinal cord)
CT – 2 cycles of 5days each, 4w
+ 5FU 600mg/sqm/d
RT – 70Gy/35#/7w at 2Gy/#,
CT – 3 cycles of 4days each, 3w
+ 5FU 600mg/sqm/d
RT – 64.8Gy/3.5w
Accelerated RT with
. Median follow-up was 5·2 years
Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional
chemoradiotherapy or very accelerated radiotherapy
conventional chemoradiotherapy improved PFS compared with very accelerated chemoradiotherapy,
34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very
More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal
toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205
[76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001).
(60%) of patients in the conventional chemoradiotherapy group, (64%) of patients in the
accelerated radiotherapy-chemotherapy group, and (70%) of patients in the very accelerated
radiotherapy group were intubated with feeding tubes during treatment (p=0·045).
Results of GORTEC 9902
CONCLUSION OF GORTEC 9902
1. Chemotherapy has a substantial treatment effect given concomitantly with
• 2. Acceleration of radiotherapy cannot compensate for the absence of
• 3. Acceleration of radiotherapy is probably not beneficial in concomitant chemo-
2000Lancet. 2000 Mar 18;355(9208):949-55
2007Radiother Oncol. 2007 Oct;85(1):156-70. Epub 2007 May 4.
2009Radiother Oncol. 2009 Jul;92(1):4-14. doi: 10.1016/j.radonc.2009.04.014. Epub 2009 May 14
2011Radiother Oncol. 2011 Jul;100(1):33-40. doi: 10.1016/j.radonc.2011.05.036. Epub 2011 Jun 16
platinum based regimen more effective.
no significant difference efficacy between mono and multi drug platinum regimens
• LEVEL 1 EVIDENCE OF ADDITION OF CT IN TERMS OF OVER ALL SURVIVAL.
• ADDITION OF CT-ABSOLUTE BENEFIT IN SURVIVAL-5%IN 5 YRS.
• INDUCTION/ADJUVANT-2% SUVIVAL BENEFIT
• CONCURRENT CTRT 8% 5YR SURVIVAL BENEFIT
• BENEFIT MORE IN CONCURRENT CTRT
• BENEFIT DECREASES WITH INCREASING AGE.
• ABSOLUTE BENEFITS-oral cavity 8.9%
The Lancet, Volume 368, Issue 9538, Pages 843 - 854, 2 September 2006
15 Randomized Trials of Varied Fractionation (1970-1998)
Tumours sites: mostly oropharynx and larynx
74% patients had stage III—IV disease
total dose reduction
Overall survival was
the main endpoint
median follow up:6 yr
benefit Conventional vs Altered Hyper fractionation vs
Loco regional control
6.4 %times higher
benefit was higher with hyper
( OS 8% at 5 years) than with
(2% with accelerated
fractionation without total dose
reduction and 1·7% with total
dose reduction at 5 years, p=0·02)
Survival benefit absolute benefit of 3·4% at
5 years with altered
RESULTS OF MARCH META-ANALYSIS:
There was a significant survival benefit in altered
fractionation.(3.4%at 5 years)
There was a benefit on locoregional control in favour of altered
fractionation versus conventional radiotherapy (6·4% at 5 years;
The benefit was significantly higher in the youngest patients
Altered fractionated radiotherapy improves survival in patients with
head and neck squamous cell carcinoma. Comparison of the different
types of altered radiotherapy suggests that hyperfractionation has the
Role of biological therapy
•Cetuximab with RT
• Bonner et al-
• 424 patients
• Locally advanced SCCHN
• 15% pt : Ca hypopharynx
Bonner et al,
Drawback: in control arm
RT alone given (not a
standard treatment for
stage III and IV HNSCC)
demonstrated effect of
cetuximab was pronounced in
concomitant boost radiation,
KPS 90-100 ,
EGFR expression ≤ 50%,
Surgical options in operable Ca hypopharynx
Voice preservation surgery
in early hypopharynx cancer
Radical Laryngectomy in
• T1 and T2 Tumors: voice
voice conservation approaches possible
vocal fold fixation,
deep pyriform sinus invasion,
extension beyond the larynx
• T3 / T4 Tumors
pt. with bulky destructive tumor that
severely compromise airway or destroy
cartilage, bone, soft tissue undergo
immediate laryngopharyngectomy and post
operation indication parts removed contraindication
upper 1/3-1/2 of
preserves one or
both arytenoids &
vocal fold fixation
deep pyriform sinus invasion
extension beyond the larynx
fixed neck nodes
base of tongue
same as SGL with
removal of i/l bot
operation indications removes contraindication
used for small
false vocal cord
tvc are preserved
vocal cord paralysis,
pyriform apex invasion,
poor pulmonary reserve
removes hyoid, thyroid,
epiglottis strap muscle.
Patient left with a
for more advanced
plus removal of varying
amount of pharyngeal
Advances in surgery
• In recent years, advancements in organ preservation surgery have
included the use of
• Transoral laser microsurgery
• Transoral robotic surgery.
avoiding tracheostomy and the use of feeding tubes
Transoral Laser Surgery: Inclusion Criteria *
Complete endoscopic visualization of the growth
Tumor extension to the contralateral VC < 3mm
Absence of arytenoid involvement (except vocal process)
Subglottic extension < 5mm
Supraglottic extension no further than lateral extension of ventricle
Mobile vocal folds
No cartilage involvement
*Motamed M, et. al. Salvage conservation laryngeal surgery after irradiation failure
for early laryngeal cancer. Laryngoscope 2006; 116:451-455
Preoperative RT Vs postoperative RT:
Phase III study of preoperative radiation therapy (50.0 Gy) versus
postoperative radiation therapy (60.0 Gy) for supraglottic larynx and
duration of follow-up was 9-15 years,
Loco-regional control& absolute survival was estimated & compared
Operable stage T2-T4 /N±
Postoperative stage III or
Arm 2:Post-op RT 60 Gy.
Arm 1: Pre-op RT 50 Gy
Long-term Follow-up Of RTOG Study 73-03
*(Tupchong L et al. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8.)
outcome preopRT postopRT
LRC 58% 70%
LRF within 2 years 59% 58%
LRF after 2years 27% 8%
Overall survival similar
• Post op RT is better than preop RT for LRC
Indications for post operative radiotherapy
Large primary - T4 or T3 with soft tissue
Close or positive margins of excision
Deep infiltrative tumour
High grade tumour
Lympho-vascular and perineural invasion
Bulky nodal disease N2 / N3
Extra nodal extension
Multiple level involvement
Is PO CTRT better than PORT alone?
100 mg/m2 d 1, 22, 43
Cooper et al, 2004; Bernier et al, 2004.
EORTC (66 Gy over 6 ½ wks)
RTOG (60–66 Gy over 6-6 ½ wks)