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1. Carcinoma Larynx - Management Dr. Animesh Agrawal

2. 2. Stage Grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1-3
N1 M0 Stage IVA T4a N0-1 M0 T1-4a N2 M0 Stage IVB T4b any N M0 any T N3 M0 Stage IVC
any T any N M1 Early stage Advance d stage
3. 3. Management Surgery Radiotherapy Chemotherapy
4. 4. Treatment goals Primary goal • Cure / Local control Secondary goal • Organ Preservation.
5. 5. EARLY STAGE (I-II)(T1-T2, N0) • Single Modality - Surgery or RT • Choice depends on - Tumor
factors - Patient factors - Physician factors • Equally effective: No randomised trials for surgery vs.
RT. • Each modality can salvage the other in case of local failure.
6. 6. ADVANCED STAGE:(III/IV) T1-2, N1-3 / T3-4, N0-N+ Multi Modality: • Pre-op RT f/b Surgery
• Surgery f/b Post-op RT/CT-RT • Neoadjuvant chemotherapy f/b surgery • Neoadjuvant
chemotherapy f/b RT • Radiotherapy with concurrent chemotherapy • Radiotherapy with biological
therapy
7. 7. Surgical treatment - approaches • Supraglottic laryngectomy • Extended supra glottic laryngectomy
• Cordectomy • Vertical partial laryngectomy • Supracricoid partial laryngectomy • Total
laryngectomy Supraglottic larynx Glottic Larynx
8. 8. Surgery Indication Parts removed Supraglottic (horizontal partial) laryngectomy (SGL) • Voice
preservation surgery for early supraglottic lesion. • Removes epiglottis, AE folds, false cords, upper
1/3-1/2 of thyroid cartilage. • Hyoid bone may be removed if epiglottic space involvement. Extended
Supraglottic Laryngectomy (Extended SGL) • Supraglottic lesion with < 1 cm base of tongue invasion
• Same as SGL with removal of Ipsilateral BOT up to circumvallate papillae Surgery for Sugraglottic
lesions (contd: for Glottic lesions)
9. 9. Surgery Indication Parts removed Cordectomy • Small lesion or early T1a lesion of middle 1/3rd of
vocal cord • Involved vocal cord Vertical partial laryngectomy • Lesion of mobile cord extending to
anterior commissure, i/l vocal process and anterio-superior portion of arytenoid. • Subglottic extension
< 5 mm. • Fixed VC lesion not crossing the midline. • Not involving more than anterior third of
opposite cord. • Removes adjacent thyroid cartilage. • Removal one TVC and up to 1/3 or 5mm of
other TVC Supracricoid partial laryngectomy (SCL) • Selected T2 and T3 glottis disease • Involving
b/l post commissure only • Lesion on mobile cord extending to ant. commissure • Cord fixation in an
otherwise T2 lesion • Both true and false cords + entire thyroid cartilage • May remove the arytenoids
Total Laryngectomy • Lesions with transglottic or extensive (>1cm) subglottic extension • Salvage for
RT failure • Total laryngectomy + removal of varying amount of pharyngeal wall
10. 10. Combined modality treatment • Pre-op RT f/b Surgery • Surgery f/b Post-op RT/CT-RT •
Neoadjuvant chemotherapy f/b surgery • Neoadjuvant chemotherapy f/b RT • Radiotherapy with
chemotherapy • Radiotherapy with biological therapy
11. 11. Pre-op RT followed by Surgery • Indications • Patients with fixed neck nodes. • Emergency
tracheostomy through tumor. • Direct extension of tumor involving skin. Perez & Brady's Principles
and Practice of Radiation Oncology, chapter 47, p857
12. 12. Surgery followed by Post-op RT Indications • Lymphovascular &/or Perineural invasion •
Multiple positive neck nodes • Close or positive margins • Extracapsular extension • Significant
subglottic extension (1cm or more) • Cartilage invasion • Endothelial-lined space invasion • Soft
tissue extension • Control of subclinical disease in opposite neck. Amdur RJ, Parson JT, Mandenhall
WM et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of
treatment results and complications. Int J Radiat Oncol Biol Physics 1989;16(1):25-36.
13. 13. • 354 patients with advanced H&N cancer randomized to 50 Gy pre-op vs Post-op 60 Gy, 320
analyzed. • At a median FU 60 months with a primary end point of Locoregional control, post-op RT
improved LRC at 4 years (48% vs 65%, p = 0.04) • For primaries of the supraglottic larynx (26%
patients): • LRC at 4 years 53% vs 77% • OS at 4 years 41% vs 47% • Complications not different •
 PORT was shown to result in superior locoregional control (70% vs. 58%) when compared to
preoperative radiotherapy but did not affect survival. Preoperative RT Vs postoperative RT: RTOG
73-03 (1987) Kramer et al. Head Neck Surg, 1987.
14. 14. Preoperative RT Vs postoperative RT: RTOG 73-03 long term update (1991) • The loco-regional
control rates were significantly better for the PORT patients (70%) than for the Pre-Op RT patients
(58%), p = 0.04. • Loco-regional failures constituted 59% of all failures within 2 years in the PRE-OP
RT patient versus 55% for POST-OP RT. Beyond 2 years it was 27% versus 8%. RTOG 73-03
Conclusion: • Post op RT is the better approach for management of resectable disease. Tupchong et al.
IJROBP 1991
15. 15. Post-op RT alone Vs Post-op CTRT
16. 16. Post-operative Chemoradiation • In 2004, two major trials were reported (RTOG 95-01, Cooper
and EORTC 22931, Bernier) which evaluated post operative CCRT against RT alone. • Both found a
better PFS in their CCRT arms; a combined analysis was also done (Bernier, 2005). • Conclusion:
Patients with resected head and neck cancer with positive margins or extranodal extension should be
assigned to combined chemoradiation approach using concurrent cisplatin. 1. Bernier et al. NEJM,
2004 2. Cooper et al. NEJM, 2004 3. Bernier et al. Head Neck, 2005
17. 17. EORTC 22931 (Bernier et al) RTOG 9501 (Cooper et al) N = 334 (167 to each arm, n = 75/334) N
= 459 (231 RT, 228 CTRT, n = 86/416) RT: 66 Gy/33# RT: 60 Gy/30# Chemotherapy: CDDP
100mg/m2 on days 1, 22, 43 of RT 74% patients received all 3 cycles 61% received all 3 cycles
Median FU: 60 months Median FU: 45.9 months HR for progression: 0.75 (95% CI 0.56 – 0.99, p =
0.04) HR for recurrence/death: 0.78 (95% CI 0.61 – 0.99, p = 0.04) OS: Significant benefit HR 0.7, p
= 0.02 (95% CI 0.52 – 0.95) OS: Non significant benefit HR 0.84, p = 0.19 (95% CI 0.65 – 1.09)
Combined analysis: Inclusion criteria
18. 18. On the basis of these trials, indications of CT-RT Absolute Indications • Margin +ve • ECE +ve
(in Node +ve) Relative Indications • LVE/PNI • Close margins • pT3 or more (Stage III or beyond) •
pN2a or more (Stage IV or beyond) • Bulky nodal disease • Lower neck LN • The latter are generally
taken as indications for RT alone.
19. 19. Morbidity of Laryngectomy • Loss of natural voice • Altered deglutition • Permanent stoma •
Pharyngocutaneous fistula (upto 30%) • Stomal stenosis (25% - 40%) • Aspiration (with partial
laryngectomy, upto 40%) 1. Benito et al. Head Neck, 2011 2. Agrawal et al. Otolaryngol Clin North
Am, 2008 3. Wax et al. Otolaryngol Head Neck Surg, 1995 4. Cousins et al. J Laryngol Otol, 1987
20. 20. Radiotherapy approaches • Definitive (Larynx Preservation) • As a part of Combined modality
treatment • Alone • With Concomittant chemotherapy • NACT f.b. RT • The biggest advantage with
Radiotherapy as definitive management is organ preservation.
21. 21. Larynx Preservation • Retrospective reviews: Posner (2009) • Randomized Trials: VA trial (1991),
RTOG 91-11 (2003), GORTEC 2000-01 (2009), EORTC 24954 (2009), TREMPLIN (2013) • Meta-
Analysis: MACH-NC (2000, 2006, 2009; subsite analysis 2011) Several studies have shown the
effectiveness of Radiotherapy in definitive management for disease that would otherwise need
surgical resection. They also studies with the question of the optimal chemotherapy regimen and
approach.
22. 22. VA trial: Induction Chemotherapy and RT vs Surgery and adjuvant RT (1991) The Department of
Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324:1685-1690 • 332 patients
with locally advanced (Stage III 188, IV 144) glottic (124) and supraglottic (208) cancer were
randomized into 2 arms: Induction Chemotherapy 2 cycles PF followed by response assessment At
least PR 3rd cycle IC then RT < PR Surgery + PORT Surgery + Post op Radiotherapy versus n = 166
n = 166 117/166 85%* • 64% patients had biopsy confirmed CR after 3 cycles of PF. • *14 patients in
the Induction arm were taken up for RT after C2 NACT because of toxicity or refusal for further
chemotherapy.
23. 23. Results At a median follow up of 33 months: • Larynx preservation: 107/166 patients (64%) • No
difference in OS at 2 years (68% each) • Local recurrence was higher in IC group (12% vs 2%, p =
0.001) • Distant mets (17% vs 11%, p = 0.001) and rate of 2nd primary (6% vs 2%, p = 0.048) were
 higher in the surgery group. Overall Survival (months)Disease Free Survival (months) Solid Line: IC
Dotted line: Surgery Neither OS nor DFS was significantly different. Conclusion Induction
chemotherapy followed by definitive RT is an effective means of preserving the larynx without
compromising overall survival.
24. 24. RTOG 91-11: Randomized trial evaluating Concurrent chemotherapy in Carcinoma Larynx
Forastiere et al. N Engl J Med. 2003;349(22):2091-8. Radiotherapy alone (70Gy/35#) Upfront
chemoradioation (50-70 Gy) Cisplatin [100 mg/m2] days 1,22 and 43 Induction Chemotherapy (PF, 2
cycles) Cisplatin (100 mg/m2) d1 5-FU (1000 mg/m2/day) d1-d5 At least PR 3rd cycle IC then RT <
PR Surgery + PORT n = 173 n = 172 n = 173 • 547 patients with locally advanced (Stage III 337, IV
181) glottic (162) and supraglottic (356) cancer randomized into 3 arms. Exclusion criteria: T1 or
large volume T4 • Primary end point was larynx preservation, secondary end points were OS, DFS,
Laryngectomy Free Survival (LFS), Locoregional control (LRC).
25. 25. Results Induction (n=173) Concurrent (n=172) Radiation (n=173) Laryngeal preservation (2 yrs)
75% 88% 70% LFS (2 yrs) 59% 66% 53% LFS (5 yrs) 43% 45% 38% OS (2 yrs) 76% 74% 75% LRC
(2 years) 61% 78% 56% Distant failures (5-year) 15% 12% 22% Median FU 3.8 years • Concurrent
Chemoradiotherapy gave higher rates of larynx preservation than Induction (p = 0.005) and RT alone
(p < 0.001), and better LFS and LRC than RT alone (p = 0.01, p < 0.001 respectively). Other
comparisons, including OS, were non significant.
26. 26. Laryngeal preservation Locoregional Control • Treatment failures were significantly fewer in the
CRT [35] arm (p = 0.004 for induction arm [61], p < 0.001 for RT alone[72]). • Overall, patients who
received chemotherapy had a better DFS than those who didn’t (p = 0.02). Conclusion Concurrent
chemoradiotherapy should be standard of care when attempting laryngeal preservation in locally
advanced disease.
27. 27. RTOG 91-11 Long term results (2013) • At a median follow up of 10.8 years, the advantage of
CCRT over IC and RT alone was maintained. • However this was for end points other than DFS and
OS.
28. 28. LFS OS LRC Laryngeal preservation • The authors concluded that similar LFS is afforded by both
chemotherapy based approaches (better than RT alone). • The impact on OS and DFS still remains a
subject of investigation.
29. 29. EORTC 24954: Sequential vs Alternating Chemotherapy & RT (2009) • 450 patients with
carcinoma larynx (218) and hypopharynx (231) and predominantly Stage III (39%) or IV (58%)
disease randomized to: Lefebvre et al. J Natl Cancer Inst. 2009;101(3):142–152. Alternating arm (n =
226) 4 cycles PF, Weeks 1,4,7 and 10 Alternated with 3 courses of RT (20Gy/10# each) Sequential
Arm (n = 224) 2 cycles PF followed by response assessment At least PR 2 more cycles of induction
PF < PR Surgery + PORT EBRT 70Gy/35# versus Primary end point: • Survival with a functional
larynx Secondary end points: • DFS • OS • Larynx preservation • QoL • At a median FU of 6.5 years,
no difference in OS, PFS, or survival with a functional larynx. Toxicity was also similar.
30. 30. Choice of induction chemotherapy: TPF vs PF
31. 31. GORTEC 2000-01: Larynx preservation with TPF or PF • 213 patients with larynx (98) or
hypopharynx (115) cancers with T2-T4, N0-N3 disease randomized to: 3 Cycles Induction
Chemotherapy followed by response assessment At least PR RT (optional 4th IC) < PR Surgery +
PORT TPF PF n = 110 n = 103 N = 213 • Primary end point: 3 year-laryngeal preservation rate •
Secondary end points: • Overall survival • Response rate to ICT • DFS • Acute and late toxicity rates
Pointreau et al. J Natl Cancer Inst. 2009;101(7):498-506.
32. 32. • The overall response rate after induction chemotherapy was 80.0% (41.8% complete response
and 38.2% partial response) in the TPF group and 59.2% (30.1% complete response and 29.1% partial
response) in the PF group (difference = 20.8%; P = .002). RT: 84/106 RT: 57/100
33. 33. Median FU of 36 months: • 3-year LPR 70.3% in TPF arm and 57.5% in PF arm. (p = 0.03). • 3
year OS was the same in both arms (60%). • 3 year DFS was better with TPF but failed to reach
statistical significance (58% vs 44%, p = 0.11). DFS Larynx preservation Overall Survival
34. 34. GORTEC 2000-01: Larynx preservation with TPF or PF Long term update (2016) Janoray et al. J
Natl Cancer Inst. 2016;108(4). Median FU 105 months 5 years 10 years TPF PF TPF PF Larynx
Preservation 74% 58.1% 70.3% 46.5% LDFFS 67.2% 46.5% 63.7% 37.2% OS 50.9% 41.9% 30.2%
23.5% DFS 42.4% 31.4% 25% 18.7% LRC 46.6% 36.3% 27.9% 20.8% • Differences observed in
Larynx Preservation and Larynx dysfunction free survival (LDFFS) were statistically significant. •
The authors noted that the study was underpowered to detect a difference in OS, DFS and LRC.
Conclusion: The TPF regimen was superior to the PF regimen in terms of organ preservation and
preservation of functionality of the larynx. Therefore when NACT → RT is given, TPF should be the
preferred regimen.
35. 35. Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324
• A retrospective subgroup analysis of TAX 324 • 166 patients (90 TPF, 76 PF) with carcinoma larynx
(89) and hypopharynx (77). However, only 123/166 had resectable disease (67 TPF, 56 PF). Posner et
al. Ann Oncol. 2009;20(5):921-7. • LFS was significantly improved with TPF compared with PF (HR:
0.59; 95% CI 0.37–0.95; p = 0.030)
36. 36. 2013: TREMPLIN Induction chemotherapy followed by either chemoradiotherapy or
Bioradiotherapy 3 Cycles Induction Chemotherapy followed by response assessment CDDP
Cetuximab EBRT 70Gy/35# N = 153 > PR n = 116 • Stage III (65) and IV (38) patients of carcinoma
hypopharynx (69) and larynx (47) were randomized for a Phase II study. n = 60 n = 56 Primary end
point • LP rate at 3 months post-treatment (95% vs 93%, NS) Secondary end points • Larynx function
preservation (LFP) at 18 months (87% vs 82%, NS) • Overall Survival (92% vs 89%, NS) • Tolerance
and compliance with treatment Median FU 36 months Conclusion: Bioradiotherapy can be considered
as a substitute for Cisplatin based CCRT.
37. 37. MACH NC Meta-analysis • 1st publication1 (2000): Over 70 trials that randomized >10,000
patients. • Update #12 (2007): 87 trials, 16665 patients, median f/u 5.5 years. • Update #23 (2009): 93
trials, 17,346 patients, median f/5 5.6 years. • Three comparisons 1. The effect of chemotherapy: LR
treatment was compared with LR treatment plus chemotherapy. 2. The timing of chemotherapy:
NACT plus radiotherapy was compared with concomitant or alternating Radio-Chemotherapy with the
same drugs. 3. Larynx preservation with neoadjuvant chemotherapy: Radical surgery plus RT was
compared with NACT + RT in responders or radical surgery and radiotherapy in non-responders. 1.
Pignon et al, Lancet 2000; 355: 949–55 2. Pignon et al. Int J Radiat Oncol Biol Phys. 2007;69(2
Suppl):S112-4. 3. Pignon et al. Radiother Oncol. 2009;92(1):4-14.
38. 38. • 87 randomised control trials from period of 1965 to 2000 • 16,485 patients were analysed with a
median follow up 5.6 years • Absolute benefits - Oral cavity: 8.9% - Oropharynx: 8.1% - Larynx:5.4%
- Hypopharynx: 4% Larynx • 3216 patients with laryngeal cancer and 61 comparisons included. • The
HR of death associated with chemotherapy was 0.87 (95% CI: 0.80–0.96), corresponding to an
absolute 5-year OS benefit of 4.5% (95% CI: 0.8–8.2), increasing from 42.5% to 47.0%. • Apart from
chemotherapy timing, no analysed subset or subgroup characteristic had a significant interaction with
chemotherapy benefit. MACH-NC: Analysis by subsite (2011) Blanchard et al. Radiother Oncol. 2011
Jul;100(1):33-40.
39. 39. MACH- NC-Conclusions • Addition of CT - Absolute survival benefit of 5% at 5 yrs. -
Induction/adjuvant: 2% - Concurrent: 8% • Platinum based regimen more effective. • No significant
difference in efficacy between mono and multiple drug platinum regimens • Small reduction in distant
metastasis found in population of patients with CTRT. • Inverse relation between age and impact of
chemotherapy that disappears by around age of 70.
40. 40. Chemotherapy: Summary • Addition of chemotherapy to definitive radiotherapy is an effective
means of laryngeal preservation without compromising survivals. • The benefit is more with
concurrent than with Neoadjuvant chemotherapy. • While the MACH-NC analyses suggest a survival
advantage, individual head-to-head trials have failed to show this benefit.
41. 41. Altered Fractionation Evidence • Retrospective reviews: Lee (1997), Garden (2003) • Randomized
Trials: RTOG 90-03 (2000), Overgaard (2003), Yamazaki (2006), RTOG 95-12 (2014) • Meta-
Analysis: MARCH (2006)
42. 42. Lee et al (1997): Influence of fraction size, total dose, and overall time on local control of T1–T2
glottic carcinoma Quynh-Thu X. Le, Karen K. Fu, Steward Kroll, et al. International Journal of
Radiation Oncology*Biology*Physics, Volume 39, Issue 1, 1 August 1997, Pages 115-126 •
Retrospectively reviewed 398 patients (315 T1 and 83 T2 Glottic Cancers) treated with RT alone. •
The fraction sizes were: • For T1 lesions, within the dose and time range evaluated, there was no
apparent relationship between fraction size, overall time, total dose, and local control on multivariate
analysis.  Improved local control for T2 lesion as compare to T1 lesion (85% vs 70%).  100% for
fraction size ≥2.25 Gy vs. 44% for fraction size <1.8 Gy. (p = 0.003),  78% for total dose >65 Gy vs.
60% for total dose ≤65 Gy. (p 0.01)  58% for lesions with sub glottic extension vs. 77% for those
without (p 0.04). <1.8 Gy in 146 1.8-1.99 Gy in 128 2.0-2.24 Gy in 62 ≥2.25 Gy in 62
43. 43. Garden et al (2003): Results of Radiotherapy for T2N0 Glottic carcinoma. Does the “2” stand for
twice daily treatment? • Reviewed 230 patients of T2 glottic cancer treated with RT alone • 3 different
fractionation schedules • Conventional: ≤2 Gy/fraction; Once daily treatment (89 pts.) • Accelerated:
>2Gy/fraction; Once daily treatment (57 pts.) • Hyperfractionation : 1.1-1.2 Gy/fraction; Twice daily
treatment. (83 pts.) • 5-year local control • Twice daily fractionation: 79% • Once daily fractionation:
68% • Once daily with doses > 2 Gy: 82%. • Subglottic extension: 63%; No subglottic extension: 81%
Garden AS et al. Int. J Radiation Oncology Biol Phys, vol 55, No. 2, pp 322-328,2003.
44. 44. RTOG 90-03 (2000): Phase III Study of Altered fractionation vs Standard Fractionation • Patients
with stage III or IV SCC (n=1076) were randomized to 4 arms with 2 year LRC being the primary end
point. • 173/1076 (16%) patients of Supraglottic larynx • Median follow up – 23 months • HFX
(p=0.045) & AFX-C (p=0.05) improved LRC • Trend towards improvement in DFS for both HFX &
AFX-C • No significant difference in OS Int J Radiat Oncol Biol Phys, 2000 Aug 1;48(1):7-16.
45. 45. RTO 90-03 Results TOXICITY: 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. 2 yr LRC 2 year DFS 2 yr OS Standard Fractionation
46% 31.7% 46.1% Split course Accelerated 47.5% 33.2% 46.2% Concomitant Boost 54.5% (p = 0.05)
39.3% (p = 0.054) 50.9% Hyperfractionated 54.4% (p = 0.045) 37.6% ([p = 0.067) 46.1% Updated
results: 2014 (Beitler et al, IJROBP 2014) • When censored at 5 yrs for LRC, • Only HFX showed
significant improvement ( p - 0.05) • HFX improved overall survival (HR 0.81, P=.05) • DFS was
improved for all 3 arms (non-significant)
46. 46. • To assess if shortening the OTT by pure acceleration (6#/wk) improves the tumour response
compared to standard fractionation • 1476 patients of glottic (690), supraglottic (218) and other sites
(568) with 29%, 25%, 21% and 25% Stage I, II, III and IV disease. • Comprising two subprotocols:
DAHANCA 6, which included all glottic carcinomas, and DAHANCA 7, which included the rest. •
Primary end point: LRC • Secondary end points: - Local T site and regional N site control - Voice
preservation - Disease-specific survival - Overall survival - Treatment morbidity DAHANCA 6 & 7
(2003): Five vs Six fractions a week in Head and Neck Cancer Overgaard et al. Lancet. 2003 Sep
20;362(9388):933-40.
47. 47. 5-year LRC: 70% vs 60% for 6# vs 5#, p=0.0005 Primary tumour control: 76 vs 64% for 6# vs 5#,
p=0.0001 Disease-specific Survival: 73 vs 66% for 6# vs 5#, p = 0.01 OS was similar; HR 0.98 (95%
CI 0.8 – 1.21, p = 0.78
48. 48. Yamazaki et al (2006): Randomized trial in T1N0M0 glottic Carcinoma Int J Radiat Oncol Biol
Phys. 2006;64(1):77-82 ARM Tumor <2/3 of glottis (minimal disease) Tumor >2/3 of glottis (>
minimal disease) A1 (n=31) 60 Gy/30#/6 wks A2 (n=57) 66 Gy/33#/6.5 wks B1 (n=31) 56.25
Gy/25#/5 wks B2 (n=61) 63 Gy/28#/5.6 wks N = 180 Results • The 5-year local control rate for the
entire group was 86% • 76% for Arm A vs 92% for Arm B (p = 0.004) • Treatment toxicity was not
significantly different between the two arms.
49. 49. Conclusion • The 2.25-Gy/fraction scheme with a shorter overall treatment time is superior to 2
Gy/fraction for local control of Stage T1 glottic carcinoma. • No difference was found between the
two arms in terms of OS (87% for Arm A, 88% for Arm B) or cause specific survival (98% for Arm A
and 100% for Arm B). Yamazaki et al. Int J Radiat Oncol Biol Phys. 2006;64(1):77-82
50. 50. RTOG 95-12 (Trotti, 2014): Randomized trial in T2 Glottic Carcinoma Int J Radiat Oncol Biol
Phys. 2014;89(5):958-63. • 250 patients, randomized into • Standard Fractionation Arm (SFX) 70Gy /
35# (2Gy/#, once daily, 5 days/wk, 7 wks) • Hyperfractionation Arm (HFX) 79.2Gy / 66# (1.2Gy/#,
twice a day, 5 days/wk, 6.5 weeks) Results • Similar Grade 1 and 2 acute toxicities in both arms •
Higher acute grade 3 toxicity with HFX than with SFX (33.3% vs 22.7%; p=0.084), but no difference
in late grade 3 toxicity at 5 years (8.5% in both arms). • Primary end point: Local control at 5 years
was 70% vs 78%, p = 0.14. • Locoregional control was 67% vs 73% (HR 0.77, p = 0.26).
51. 51. Conclusion • The 5-year local control was modestly higher with HFX compared to SFX for T2
glottic carcinoma, but the difference was not statistically significant. 5 year local control Trotti et al.
Int J Radiat Oncol Biol Phys. 2014;89(5):958-63.
52. 52. • 15 Randomized Trials of Varied Fractionation with 6515 patients (1970-1998) • Mostly
Oropharynx (44%) and Larynx (34%) patients • Follow up from 4 to 10 years, median 6 years • 74%
stage III & IV disease Overall Hyper- fractionation Accelerated fractionation, same total dose
Accelerated fractionation, total dose reduced OS Benefit 3.4% 8.2% 2% 1.7% LRC Benefit 6.4%
9.4% 7.3% 2.3% • Overall, 8% reduction in risk of death • Survival benefit at 2 years – 3.3% , at 5 yrs
– 3.4 % MARCH Meta-analysis (2006): Hyperfractionated or accelerated radiotherapy
53. 53. Survival curves by treatment arm for all trials and according to the type of altered fractionated
radiotherapy (A) Hyperfractionation. (B) Accelerated fractionation without total dose reduction. (C)
Accelerated fractionation with total dose reduction. (D) All three groups together. The slopes of the
broken lines from year 6 to year +7 are based on the overall death rates in the seventh and subsequent
years Hyperfractionation Accelerated RT without dose reduction Accelerated RT with dose reduction
A, B and C combined
54. 54. Locoregional control curve by treatment arm according to the type of radiotherapy(A)
Hyperfractionation. (B) Accelerated fractionation without total dose reduction. (C) Accelerated
fractionation with total dose reduction. (D) All three groups together. Hyperfractionation Accelerated
RT without dose reduction Accelerated RT with dose reduction A, B and C combined
55. 55. Altered Fractionation: Summary • In early Glottic Carcinoma, reducing the overall treatment time
(OTT) provides good disease control and hypofractionated RT can be considered for this purpose.
(Yamazaki, DAHANCA 6&7) • In locally advanced disease, conventional fractionation is still the
norm though there is benefit from reduction in OTT by acceleration or hypofractionation (MARCH
meta-analysis). • Hyperfractionation is a valid option, but its adoption in a resource strained setting is
difficult. (RTOG 90-03, MARCH)
56. 56. Other major studies Induction Chemotherapy • TAX 323 (2007) and 324 (2007, upd 2011),
PARADIGM (2013), DeCIDE (2014) Concurrent chemo/biological therapy • Jeremic et al (1997),
Wendt et al (1998), Adelstein et al (2000 and 2003) • Bonner et al (2006, upd 2010), RTOG 0522
(2014) Altered fractionation • Brizel et al (1998), Jeremic et al (2000), RTOG 0129 (2014)
57. 57. Other major trials: Concurrent chemo/biological therapy Jeremic et al (1997) n = 28/159 CTRT
(low dose daily Cisplatin or carboplatin) vs RT alone CTRT: better than RT alone Wendt et al (1998)
n = 97/270 CTRT (PF) vs RT alone (split course RT with 2 breaks) CTRT: better than RT alone
Adelstein et al (2000) n = 52/118 CTRT (PF) vs RT alone (RT given: SFX upto 72 Gy) CTRT: better
local control, but not OS Adelstein et al (2003) n = 75/271 CTRT (SFX and Split course) vs RT alone
(SFX only): 3 Arm study CTRT-SFX superior to both other arms Bonner et al (2006, 2010) n =
163/424 RT + Cetuximab vs RT alone Bioradiotherapy is superior to RT alone. RTOG 0522 (2014) n
= 266/891 Cisplatin with AFX-RT with or without Cetuximab No benefit from addition of Cetuximab
58. 58. Other major trials: Altered Fractionation Brizel et al (1998) n = 18/116 Accelerated
hyperfractionation (A- HFX) vs CCRT in SFX SFX-CCRT is more efficacious, and not more toxic.
Jeremic et al (2000) HFX-RT with or without daily concurrent low dose cisplatin Concurrent CDDP
gave significant OS benefit. RTOG 0129 (2014) Concurrent CDDP: AFX-C vs SFX AFX doesn’t
improve outcome if concurrent Chemo is given. Other major trials: Induction Chemotherapy TAX 323
(2007) n = 130/321 TPF vs PF as NACT, followed by RT alone TPF gave better OS and DFS TAX
324 (2007) n = 166/501 TPF vs PF as NACT, followed by CCRT (carboplatin) TPF gave better OS
 than PF. PARADIGM (2013) n = 39/145 NACT followed by CCRT vs upfront CCRT IC doesn’t
improve survival. DeCIDE (2014) n = 37/273 NACT followed by CCRT vs upfront CCRT No
difference in OS
59. 59. Site & Stage 5 Yr. LRC OS Cause Specific Survival Early stage Glottic cancer Stage I : 85-95%
Stage II:70- 80% 75-90% 90-100% Early stage Supraglottic cancer Stage I :100% Stage II:85% 60-
65% 90-100% Results of Definitive Radiation Therapy Mendenhall et al. Cancer, 2004 Hinerman et
al. Head Neck, 2002 • Early stage disease Site & Stage 5 Yr. LRC OS 5 Yr DFS Advanced stage
larynx cancer 35-75% 25-55% 25-45% • Advanced disease Fu et al. 2000; Forastiere et al. 2003;
Bonner et al. 2006; Adelstein et al.2003; Brizel et al.1998).
60. 60. Summary • Radiotherapy is an effective means of larynx preservation without compromising
survivals. • Addition of chemotherapy provides better results for larynx preservation than RT alone
(concurrent > NACT). However the impact on survival is still unclear. • Specifically for early glottic
cancers, hypofractionated RT can provide better outcomes.
61. 61. Radiation Therapy • Pre treatment prophylaxis • Technique • Dose & fractionation • Post treatment
follow up • Side effects
62. 62. Pre-treatment Prophylaxis • Dental prophylaxis: • Extraction • Scaling • Repair of sharp edged
teeth • Application of fluoride gel 64
63. 63. RTP Technique • CT-based planning is recommended • Laryngeal primaries typically treated with
lower energy beams, Co- 60 or Linear Accelerator (4 MV – 6 MV photons). • Position: supine with
rigid head holder cradling the posterior calvarium. • Shoulders should be positioned as caudally as
possible to allow adequate exposure of neck. • Head should be immobilised with a thermoplastic cast.
• Anterior and Lateral reference marks should be made on the mould • Bite block may be used to
elevate the hard palate • Image should be taken from above the calvarium to the carina.
64. 64. Radiation therapy - simulation Head Rest - Timo Thermoplastic Mask Shoulder Retractor
Especially when LAN fields not to be used, to maximize coverage with lateral fields.
65. 65. Conventional radiotherapy
66. 66. Radiotherapy for early glottic cancer (Tis/T1/T2;N0)
67. 67. Conventional: 2 Field Technique • Typically delivered by small portals covering only the primary
lesion; cervical node are electively not treated. • 5×5 or 6x6 cm opposed lateral fields •
Wedges/compensators for tissue deficit due to neck anatomy may be required. • Bolus may be needed
for anterior commissure tumors and over the tracheostoma (if present)  Randomized study
comparing 5×5 cm to 6×6 cm fields showed that 5 × 5 cm is associated with less arytenoid edema
with identical year recurrence free survivals.1 1. Chatani et al. Strahlenther Onkol, 1996
68. 68. Superior border: Top of the thyroid notch Inferior border: bottom of the cricoid cartilage Anterior
border:1 cm flush of skin at the level of thyroid cartilage Posterior border: Ant. edge of vertebral
bodies Fields For Tis/T1 Glottis Carcinoma For T1N0, use a 5 × 5-cm field
69. 69. RT Fields For T2 Glottic Cancer : depend on degree of Supraglottic /subglottic extension • Field
size increased to 6×6 cm opposed lateral fields • Larger fields covering level II-III L.N (2-7% risk of
nodal involvement) Superior border: adjusted according to the lesion. • Early lesion: middle of the
thyroid notch • Larger lesions: top of the thyroid notch Inferior border : • No subglottic extension:
Bottom of the cricoid cartilage • Subglottic extension: Border lowered up to 1 tracheal ring Anterior
border: • 1 cm flush of skin at the level of thyroid cartilage Posterior border: • Ant. 2/3 of V.C: ant.
edge of vertebral bodies • Posterior 1/3 V.C involved: at middle of vertebral bodies
70. 70. Glottic larynx traditional field design. Lateral portal showing a field used to treat a T1 glottic
carcinoma • Wedges can be removed to add hotspot in anterior region with an anterior bolus. • For
anteriorly placed tumours without involvement of the posterior vocal cord, posterior border can be
moved anteriorly by 0.5 cm after a dose sufficient for subclinical disease (approximately 50 Gy for
standard fractionation) is achieved. - To reduce arytenoid edema
71. 71. Technique for early glottis carcinoma: 3 field technique • ~90 - 95% dose is delivered through
opposed lateral wedged fields weighted to the side of the lesion • Remaining dose is delivered by an
 anterior field shifted 0.5 cm toward the side of the lesion • In such cases, dose is usually specified at
the 95% normalized isodose line. Normalized isodose distribution for three-field technique for
treatment of a tumor involving the anterior two-thirds of one true vocal cord. The dose is specified at
the 95% isodose line.
72. 72. T1 Glottic Cancer • Conventional Fractionation: 66 Gy in 33# @ 2 Gy/# • Hypofractionation1:
2.25Gy/# ; - 63 Gy/28 fr/5.6 wk - 56.25Gy for Cis • Smaller daily fractions should not be used as
studies have suggested that they are associated with reduced local control rates.2,3 Dose and
Schedules 1. Yamazaki et al. IJROBP 2006 2. Mendenhall et al, Cancer 2004 3. Mendenhall et al,
IJROBP 1988
73. 73. • Conventional Fractionation 70 Gy/ 35#/7 weeks @ 2 Gy/# If level II-III nodes included 54 Gy to
larger field with smaller field covering larynx only upto 70 Gy • Hypofractionation 65.25Gy/29#
@2.25Gy/# • Hyperfractionated 79.2 Gy/ 66 #/6.5 weeks @ 1.2Gy/# bid) - May provide better sidease
control - No prospective evidence-based data 1. Garden et al, IJROBP 2003 2. Yamazaki et al,
IJROBP 2006 3. RTOG 95-12, IJROBP 2014 Dose and Schedules T2 Glottic Cancer
74. 74. Radiotherapy for early supraglottic cancer
75. 75. General Principles • 20-50% of T1-T2 Supraglottic cancer have +L.N so objective is to cover both
the primary and clinical/subclinical disease in the Levels II and III cervical nodal beds. • Shrinking
field technique with off cord + GTV boost (2 or 3 phases) • For extensive supraglottic disease 3 Field
technique used - 2 lateral field + matched LAN field to cover the low anterior nodes (i.e. levels I - IV)
• Gross nodal disease in the post neck to be bossted with 6–9 MeV electrons after off cord done at
45Gy.
76. 76. Low anterior neck field • Superiorly: Match with the inferior borders lateral field • Laterally: at
junction of medial 2/3rd and lateral 1/3rd of clavicle • Inferiorly: 1cm below clavicle
77. 77. Initial treatment portals: Lateral opposed fields Off spinal cord lateral fields Post. neck boosted
with matched electron-beam Final boost fields to the tumor with a margin. SCF field matched to the
upper neck (lateral) fields
78. 78. Radiation therapy for locally advanced laryngeal cancer
79. 79. Dose and Schedules Standard fractionation: - 70 Gy in 35 fractions over 7 weeks to gross disease -
50 Gy to subclinical disease. Altered fractionation: - Hyper fractionated:76.8 Gy/1.2Gy/# -
Concomitant boost :72 Gy/42 fractions/6weeks 54 Gy/30#/6weeks @ 1.8 Gy/#/day to larger field 1.5
Gy/#/day boost field given 6hrs later for the last 12 treatment days
80. 80. Radiotherapy for advanced larynx cancer
81. 81. Field design for locally advanced disease Anterior border: • Allowed to fall off, entire pre-
epiglottic space included Posterior border • Behind the vertebral spinous process (typically C1 or C2,
more posteriorly in presence of large nodal mass) Inferior border • If no subglottic spread: Bottom of
cricoid cartilage in the presence of subglottic extension, 2 cm below lower extent Superior border: •
2cm above the angle of mandible if N0 • 1cm above tip of mastoid if N+ • May extend upto base of
skull to cover retropharyngeal L.N
82. 82. • Conventional treatment involves a shrinking field technique; 3 field - 2 parallel opposed lateral
field encompassing the primary tumor and upper neck lymphatics - Low anterior neck field:to include
level IV L.N - Match the lateral fields to the low-neck AP field. Field design for locally advanced
disease
83. 83. Standard Fractionation - Gross disease :70 Gy/35#/7 weeks @ 2 Gy/#/day - Subclinical disease: 50
Gy@2 Gy/#/day Concomitant Boost Radiotherapy Therapy - Total dose:72.0 Gy/42 # over 6 weeks as
54 Gy in 30 # (1.8 Gy/#/day) to a relatively large field including subclinical disease - A second daily
fraction at least 6h later 18.0 Gy/12# (1.5 Gy/#) to a small “boost field” for gross disease
Hyperfractionation - 81.6 Gy in 7 weeks at 1.2 Gy b.i.d. Dose and Schedules
84. 84. 3D Conformal Radiotherapy
85. 85. Delineation • Gross tumor volumes (GTV) – includes all known primary and cervical lymph node
tumor extension based on clinical, endoscopic and imaging findings. • Clinical target volume (CTV) –
 • HRCTV: GTV is expanded to include a margin for microscopic extension forming high dose CTV. •
LRCTV: nodal regions at low risk for occult submicroscopic spread included in a low-risk CTV. •
IRCTV: optional. Includes area adjacent to GTV at high risk of having occult submicroscopic spread •
Planning target volume (PTV): CTV is expanded with 3-7 mm margin to account for organ motion &
setup error
86. 86. Determination of CTV • Based on the incidence & location of metastatic node from larynx
primary
87. 87. Chao et al. IJROBP, 2002
88. 88. CTV Determination Tumor site Clinical Stage CTV1 CTV2 CTV3 GLOTTIC T1-T2 N0 GTVp - -
T3-T4 N0 GTVp Optional I/L +C/L II-V anyT N+ GTVp+N I/L adjacent L.Ns I/L+C/L (remaining
L.N) ± RPLN SUPRA- GLOTTIC Any T N0 GTVp Optional I/L+C/L II-V Any T N+ GTVp + N I/L
adjacent L.Ns I/L+C/L (remaining L.N) ± RPLN *Practical Essentials Of IMRT; KS Clifford Chao
89. 89. Pre-op RT followed by Surgery • Indications • Patients with fixed neck nodes. • Emergency
tracheostomy through tumor. • Direct extension of tumor involving skin. • The treatment technique is
same as that of RT alone • Lower dose: 50 - 60 Gy@1.8- 2.0 Gy/# to entire target • Boost dose: 66-
70Gy to areas of unresectable disease (usually the neck) Perez & Brady's Principles and Practice of
RadiationOncology, chapter 47, p857
90. 90. Post-op RT • Conventional 2-3 field technique • Lateral fields cover tumor bed, neopharynx,
adenopathy and 1.5– 2 cm margin on preoperative extent of disease • Stoma is included in LAN field
(with a subsequent boost if indicated) • Emergent tracheostomy • Subglottic extension, • Tumor
invasion to soft tissues of neck, • Extranodal extension in level VI, • Close/+ margin, • Scar crosses
stoma
91. 91. Post-op RT: dose & fractionation • The dose for postoperative RT as a function of known residual
disease is as follows: • negative margins, 60 Gy/ 30 # • microscopically positive margins, 66 Gy /33# •
gross residual disease, 70 Gy/35# • The lower neck (including stoma) is treated with doses to 50
Gy/25#. Stoma to be boosted upto 66 Gy if indicated. • If there is subglottic extension, the dose to the
stoma is boosted with electrons usually 10 to 14 MeV electron for an additional 10 Gy/5#. • If
postoperative RT is added after supraglottic laryngectomy, the dose may be lowered to 55.8 Gy given
in 1.8-Gy fractions.
92. 92. • The most common indications for IMRT for laryngeal cancers would be patients with a node-
positive T3–T4 cancer, where the retropharyngeal nodes would be electively irradiated. • Extensive
subglottic invasion, where achieving an difficult to achieve adequate inferior margin with
conventional lateral portals. • Advantages: • Dose to the contralateral parotid gland can be reduced •
Can circumvent a difficult low match between the lateral fields and the LAN field in a patient with a
short neck and large shoulders. • Carotid sparing IMRT only in selected cases Role Of IMRT In
Laryngeal Cancer • IMRT is not recommended for T1–2, N0 glottic cancers, but may be considered
for more advanced lesions
93. 93. Fractionation schedule in IMRT Simultaneous integrated boost (SIB) • in 35#: GTV = 70Gy/35#,
CTV1 = 63Gy @ 1.8Gy/#, CTV2 = 56 Gy @ 1.6Gy/#. • In 33#: GTV = 70Gy/33# @ 2.12Gy/#,
CTV1 = 59.4 Gy @ 1.8Gy/#, CTV2 = 54Gy at 1.64Gy/#. Sequential (2 or 3 phase planning) • Initial
lower-dose phase (weeks 1–5) followed by high dose boost volume phase (weeks 6 and 7) using 2-3
separate dose plans. Concomitant Boost schedule. • Delivers dose to subclinical targets once daily for
6 weeks, and a separate boost plan as second daily treatment during last 12 treatment days.
94. 94. Dose limitations • Spinal cord maximum dose <45–50 Gy. • Brainstem maximum dose <54 Gy. •
50% of the volume of each parotid <20 Gy and mean dose <26 Gy. • Mandible maximum dose <70
Gy. • Brachial plexus dose <60 Gy. *WL: Whole Larynx, SVCI: Single Vocal Cord Irradiation
95. 95. Post-Treatment Follow-Up • Follow-up is important because early detection of recurrence results
in salvage that may include cure with voice preservation. • The majority of recurrences will occur
within the first 2 years and nearly all within 3 years (Fu et al. 2000; Forastiere et al. 2003, 2013). •
Patients are followed 1-2 monthly for the 1st year, 2-4 monthly for the 2nd year, 3-6 monthly for years
3-5 and annually thereafter.
96. 96. Work-Up at each follow up • History/physical examination • endoscopy or indirect mirror exam. •
Imaging of the neck (whenever patients develop new signs or symptoms suggestive of recurrence) •
Imaging of the thorax recommended annually. • TSH every 6–12 month if neck irradiated. • Speech,
swallow, dental, and hearing evaluations and rehabilitation as indicated. • Smoking cessation
counselling.
97. 97. Acute Effects • Hoarseness • Sore throat • Dysphagia • Odynophagia • Mucositis • Skin
pigmentation in radiation field • During RT or within 90 days of start of RT
98. 98. Late reactions • Develop/persist more than 90 days after start of RT • Laryngeal oedema • Glottic
stenosis • Xerostomia • Swallowing dysfunction • Pharyngeal stricture • Weight Loss •
hypothyroidism
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