Carcinoma Larynx- Management

Dr. Animesh Agrawal

Stage Grouping

Stage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0

Stage IIIT3 N0 M0T1-3 N1 M0

Stage IVAT4a N0-1 M0T1-4a N2 M0

Stage IVBT4b any N M0any T N3 M0

Stage IVC any T any N M1

Earlystage

Advanced stage

Management

Surgery

Radiotherapy

Chemotherapy

Treatment goals

Primary goal • Cure / Local control

Secondary goal • Organ Preservation.

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.

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

Surgical treatment - approaches

• Supraglottic laryngectomy • Extended supra glottic laryngectomy• Cordectomy • Vertical partial laryngectomy • Supracricoid partial laryngectomy• Total laryngectomy

Supraglottic larynx

Glottic Larynx

Surgery Indication Parts removedSupraglottic (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 SupraglotticLaryngectomy (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)

Surgery Indication Parts removedCordectomy • 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

Supracricoidpartial 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

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

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

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.

• 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.

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

Post-op RT alone Vs Post-op CTRT

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, 20042. Cooper et al. NEJM, 20043. Bernier et al. Head Neck, 2005

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 RT74% patients received all 3 cycles 61% received all 3 cyclesMedian FU: 60 months Median FU: 45.9 monthsHR 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 benefitHR 0.7, p = 0.02 (95% CI 0.52 – 0.95)

OS: Non significant benefitHR 0.84, p = 0.19 (95% CI 0.65 – 1.09)

Combined analysis:Inclusion criteria

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.

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, 20112. Agrawal et al. Otolaryngol Clin North Am, 2008 3. Wax et al. Otolaryngol Head Neck Surg, 19954. Cousins et al. J Laryngol Otol, 1987

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.

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 definitivemanagement for disease that would otherwise need surgical resection. Theyalso studies with the question of the optimal chemotherapy regimen andapproach.

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

versusn = 166

n = 166

117/16685%*

• 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.

ResultsAt 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: ICDotted line: Surgery

Neither OS nor DFS was significantly different.

ConclusionInduction chemotherapy followed by definitive RT is an effective means of preserving the larynx without compromising overall survival.

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).

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 FU3.8 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.

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).

ConclusionConcurrent chemoradiotherapy should be standard of care when attempting laryngeal preservation in locally advanced disease.

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.

LFS

OS

LRC

Laryngealpreservation

• 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.

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 10Alternated 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

EBRT70Gy/35#

versus

Primary end point:• Survival with a

functional larynxSecondary 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.

Choice of induction chemotherapy:TPF vs PF

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 = 103N = 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.

• 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

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

GORTEC 2000-01: Larynx preservation with TPF or PFLong term update (2016)

Janoray et al. J Natl Cancer Inst. 2016;108(4).

Median FU105 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.

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)

2013: TREMPLIN Induction chemotherapy followed by either

chemoradiotherapy or Bioradiotherapy

3 Cycles Induction Chemotherapy followed by response assessment

CDDP

Cetuximab

EBRT70Gy/35#

N = 153

> PRn = 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 = 56Primary 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 FU36 months

Conclusion: Bioradiotherapy can be considered as a substitute for Cisplatin based CCRT.

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: 949–552. 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.

• 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.

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.

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.

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)

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

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.

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.

RTO 90-03 ResultsTOXICITY:

Altered fractionation regimenswere associated with higherincidence of grade 3 or worseacute mucosal toxicity, but nosignificant difference in overalltoxicity at 2 years followingcompletion of treatment.

2 yr LRC 2 year DFS 2 yr OSStandard 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)

• 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.

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

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 wksA2 (n=57) 66 Gy/33#/6.5 wksB1 (n=31) 56.25 Gy/25#/5 wksB2 (n=61) 63 Gy/28#/5.6 wksN = 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.

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

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).

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.

• 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

OSBenefit 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

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

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

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)

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)

Other major trials: Concurrent chemo/biological therapyJeremic 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 withor without Cetuximab

No benefit from addition of Cetuximab

Other major trials: Altered FractionationBrizel 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 gavesignificant OS benefit.

RTOG 0129 (2014)

Concurrent CDDP: AFX-C vs SFX AFX doesn’t improveoutcome if concurrent Chemo is given.

Other major trials: Induction ChemotherapyTAX 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

Site & Stage 5 Yr. LRC OS Cause Specific SurvivalEarly stage

Glottic cancerStage 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, 2004Hinerman et al. Head Neck, 2002

• Early stage disease

Site & Stage 5 Yr. LRC OS 5 Yr DFSAdvanced 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).

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.

Radiation Therapy

• Pre treatment prophylaxis• Technique• Dose & fractionation• Post treatment follow up • Side effects

Pre-treatment Prophylaxis

• Dental prophylaxis: • Extraction• Scaling• Repair of sharp edged teeth• Application of fluoride gel

64

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.

Radiation therapy - simulation

Head Rest - Timo Thermoplastic Mask

Shoulder Retractor

Especially when LAN fields not to be used, to maximize coverage with lateral fields.

Conventional radiotherapy

Radiotherapy for early glottic cancer(Tis/T1/T2;N0)

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

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

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

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 withoutinvolvement 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

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.

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 20062. Mendenhall et al, Cancer 20043. Mendenhall et al, IJROBP 1988

• 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

• Hypofractionation65.25Gy/29# @2.25Gy/#

• Hyperfractionated79.2 Gy/ 66 #/6.5 weeks @ 1.2Gy/# bid)- May provide better sidease control- No prospective evidence-based data

1. Garden et al, IJROBP 20032. Yamazaki et al, IJROBP 20063. RTOG 95-12, IJROBP 2014

Dose and Schedules

T2 Glottic Cancer

Radiotherapy for early supraglottic cancer

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.

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

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

Radiation therapy for locally advanced laryngeal cancer

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 field1.5 Gy/#/day boost field given 6hrs later for the last 12 treatment days

Radiotherapy for advanced larynx cancer

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

• 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

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

3D Conformal Radiotherapy

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

Determination of CTV

• Based on the incidence & location of metastatic node from larynx primary

Chao et al. IJROBP, 2002

CTV Determination

Tumor site Clinical Stage CTV1 CTV2 CTV3GLOTTIC 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

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

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

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.

• 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

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.

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

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.

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.

Acute Effects

• Hoarseness• Sore throat• Dysphagia• Odynophagia• Mucositis• Skin pigmentation in radiation field

• During RT or within 90 days of start of RT

Late reactions

• Develop/persist more than 90 days after start of RT

• Laryngeal oedema• Glottic stenosis• Xerostomia • Swallowing dysfunction• Pharyngeal stricture• Weight Loss• hypothyroidism