Management of Ca Oropharynx

By-Dr.Satyajeet RathGuided by-Prof.Kamal Sahni

19-07-2016

TNM Staging – T Staging

N Staging

Stage & Grade

M StagingM X :Distant metastasis cant be assessedM 0 : No distant metastasisM 1 : Distant metastasis

Histoloical GradeG X : Grade cant be assessedG 1 : Well differentiatedG 2 : Moderately differentiatedG 3 : Poorly differentiatedG 4 : Undiferentiated

Management Goals

• Maximizing the chance of cancer cure while minimizing the functional impairment and treatment related toxicities

• Locally confined disease (stage I and stage II tumors) are considered as early stage

• Locoregionally advanced disease - stages III and IV (nonmetastatic) disease

Early stage

• For all subsites, early-stage tumors are usually well controlled with a single local modality, either radiotherapy or surgery.

• Selection of local modality should be based on the primary tumor size, extent of local spread, and subsite involved.

• Generally, small tumors of the tonsil can be well managed surgically, whereas the morbidity of surgery on the soft palate and base of tongue tumours favours radiotherapy

Locally Advanced

• For loco-regionally advanced disease • Two appropriate treatment strategies are used: • (a) either Sx followed by RT±CT based on pathologic risk

factors • (b) radiotherapy usually given with chemotherapy,

concurrently

Treatment Modalities

• Surgery• Role of Radiotherapy• Role of chemotherapy

Surgical Approaches

Base of Tongue• Limited role due to high morbidity and functional disability

associated with the surgical procedures

Tonsil cancer• Wide local Excision –small (<1 cm ),early stage, confined to

anterior pillar• Radical Tonsillectomy–larger tumor with extension to tongue,

mandible or soft tissue. It include resection of• Tonsil with tonsillar pillar & fossa• Portion of soft palate• Tongue• Lateral/Total pharyngectomy as needed• Mandible

• But, in general apart from small tonsillar lesion surgery is generally not done now a days and chemo-radiotherapy is preferred.

Soft Palate• Rarely recommended because

• Significant reflux into nasopharynx post surgery and functional compromise

• Midline location– B/L neck involvement is common

• In general, radiotherapy alone or along with concurrent chemotherapy is preferred.

Surgical Margins

• UK Royal college of pathologist guidelines: Datasets for histopathology

reports on head and neck carcinomas and salivary neoplasms (2nd edition).

• Clear margin: histological clearance >5mm• Close margins: 1-5mm• Positive margin: <1mm

*Langendijk JA, Ferlito A, Takes RP, Rodrigo JP, Suarez C, Strojan P et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. Oral Oncol 2010;46:577–585.

Neck dissections

2001 Classification of neck dissection• Radical Neck Dissection (RND)• Modified RND• Selective ND (SND)

• Supraomohyoid SND (I - III/IV)• Lateral SND (II - IV)• Posterolateral SND (II - V)• Anterior SND (VI)

• Extended ND• Other Nodal groups apart from Level I-VI

Proposed by American HN Society

Selective neck dissection Modified RND type 1,2,3.

Role of Radiotherapy

• RT alone• Pre-op RT vs Post-op RT• Post-op RT vs Post op CRT

RT alone

• 2 arms • CHART, where a dose of 54 Gy was given in 36 fractions over 12 days• Conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks• 918 patients• 26% oropharynx patients• Acute radiation mucositis was more severe with CHART, occurred earlier but

settled sooner

• Life table analyses of loco-regional control, primary tumour control, nodal control, disease-free interval, freedom from metastasis and survival showed no evidence of differences between the two arms

Fu et al IJROBP 32:577–588 ;2000

(60%)

Fu et al IJROBP 32:577–588, 2000

•1113 patients entered , 1073 patients randomised

Higher grade – III toxicities in all 3 arms

• Median follow up – 23 mnths• Primary end point – 2 yr LRC• 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

2013 , JJ Bietler , IJROBP

• When censored at 5 yrs • Only HFX showed significant improvement in 5-yr LRC ( p - 0.05)• HFX improved overall survival (P - 0.05)• DFS was improved for all 3 arms (non-significant)

• 350 patients• 66% oropharynx patients• 2 arms• single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days• ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days• median potential follow-up time was 53 months

• No differences in DFS, disease-specific survival and loco-regional control• Conclusion : ART does not produce improvements in loco-regional control

when the total dose is reduced.

Accelerated RT Convemtional RT

P value

DFS 41% 35% 0.323

Disease specific Survival Rate

46% 40% 0.398

LRC 52% 47% 0.300

• To find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in scc

• 1485 patients • 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 to all tumour sites except well-differentiated T1 glottic tumours, which were treated with 62 Gy)

• 29% pharynx patients• Primary end point was LRC

• Benefit of shortening of treatment time was seen for primary tumour control (76 vs 64% for six and five fractions, p=0·0001), but was non-significant for neck-node control

• No improvement in overall survival

6 # 5 # P Value

LRC 70% 60% 0.0005

DFS 73% 66% 0.01

Acute Reactions 53% 33% 0.0001

• 15 Randomized Trials of Varied Fractionation (1970-1998)

• 6515 patients

• Mostly Oropharynx(44%) and Larynx(34%) patients

• Follow up varied from 4 to 10 years

• Median follow up – 6 years

• 74% stage III & IV disease

• IPD Meta-analysis

Bourhis J, et al . Lancet 2006;368(9538):843-854

Survival curves by treatment arm for all trials and for the three groups of trials 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

HFX

Acc. Fractionation without Total dose reduction

Acc. Fractionation with Total dose reduction

All three groups

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.

HFX

Acc. Fractionation without Total dose reduction

Acc. Fractionation with Total dose reduction

All three groups

• Primary endpoint was OS

• Overall, 8% reduction in risk of death• Survival benefit at 2 years – 3.3% , at 5 yrs – 3.4 %

Overall Hyper fractionation

Accelerated fractionation with same total dose

Accelerated fractionation with total dose reduction

OS Benefit 3.4% 8.2% 2% 1.7%

LRC Benefit

6.4% 9.4% 7.3% 2.3%

• 2 armed study – • Accelerated regimen of six fractions of radiotherapy per week (n=458) • Conventional radiotherapy regimen of five fractions per week (n=450)• Total dose of 66–70 Gy in 33–35 fractions.• 52% pharynx patients• Primary end point - LRC

•No significant differences in acute & late radiation side-effects

6#/week 5#/week P value

5-yr LRC

42% 30% 0.004

DFS 50% 40% 0.03

OS 35% 28% 0.07

Cochrane database syst review, Dec 2010

• 30 trials involving 6535 participants• Pooling trials of any altered fractionation radiotherapy compared to a

conventional schedule showed a statistically significant reduction in total mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98)

• Statistically significant difference in favour of the altered fractionation was shown for the outcome of locoregional control (HR 0.79, 95% CI 0.70 to 0.89)

• No statistically significant difference was shown for disease free survival.• No statistically significant difference was shown for any other comparison.

Summary of evidence for RT alone• HFX improved LRC & OS (EORTC 22791, RTOG 9003, MARCH Meta-analysis)

• Pure acceleration (6#/week) without any dose reduction • improved LRC by 10-12% and the advantage is mainly significant at

T-site & not N-site • Improved DFS

(DAHANCA-10% & IAEA-12%)

• Acceleration with total dose reduction & CHART doesn’t confer any benefit.

(CHART, T-TROG)

Pre-op RT vs Post-op RT

Pre-op vs. post-op RTRTOG 73–03 (Kramer et al. 1987)• patient - 354• 23% oropharynx patients• Patients with advanced H&N cancer

randomized to • 50 Gy pre-op vs 60 Gy Post-op• Post-op RT improved LRC• Trend towards improvement in OS• Complications not different• Established that post-op RT is better

than pre-op RT

                                                  * Kramer S et al Head Neck Surg 1987;10:19-30

Pre-op RT

Post-op RT

P Value

LRC 48% 65% 0.04

OS 33% 38% 0.10

Post-op CT-RT

EORTC 22931

Bernier J et al N Engl J Med 2004;350:1945-1952

• 334 patients• 101 pts(34%) oropharynx • Primary end point – PFS• 2 arms :• radiotherapy alone (66 Gy over a period of 61⁄2 weeks)• same radiotherapy regimen combined with cisplatin 100 mg/m2 on days

1, 22, and 43 of the radiotherapy regimen• Median follow-up of 60 months

CT-RT RT alone P value

PFS 47% 36% 0.04

OS 54% 40% 0.02

LRF 31% 18 0.007

Acute Effects 41% 21% 0.001

RTOG 9501

Cooper JS et al N Engl J Med 2004;350:1937-1944.

• 459 patients• Oropharynx - 78(37%) in RT arm vs 99(48%) in CRT arm• Median follow-up of 45.9 months• Radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6

weeks)• RT plus concurrent cisplatin(100 mg per square meter of body-surface area intravenously on days 1, 22, and 43).• Primary end point – Local and regional tumour control• Oropharynx - 78(37%) in RT arm vs 99(48%) in CRT arm

CT-RT RT alone

P value

2 –yr LRC

82% 72% 0.01

Acute Effects

77% 34% P<0.001

•No significant difference in OS & DFS

Head & Neck,2005

In summary, these two most recent trials, support the use of postoperative CRT for patients with high risk for recurrence, i.e, margin & ECE+ve

Head & Neck,2005

So, on the basis of these trials indications of RT & CT-RT are as follows :-

Absolute Indications of Post op CT-RT : • Margin +ve• ECE +ve

Soft Indications for CT-RT: • LVI +ve• PNI +ve• Close margins• pT3 or more• p N2a or more• Bulky nodal disease• Lower neck LN

Role of Chemotherapy

• Addition of chemotherapy• NACT• CTRT definitive• CTRT adjuvant

NACT

Vermorken JB et al N Engl J Med 2007;357(17):1695-1704

• 358 patients ( 46% oropharynx)• Unresectable stage III–IV head and neck cancer • TPF (docetaxel/cisplatin/5-FU) vs. • PF (cisplatin/5-FU) induction chemotherapy followed by RT alone, • Primary end point - PFS

Vermorken JB et al N Engl J Med 2007;357(17):1695-1704

TPF PF P value

PFS 11 mnths 8.2 mnths 0.007

OS 18.8 mnths 14.5 mnths 0.02

• 501 patients ( 52% oropharynx)

• Unresectable stage III–IV head and neck cancer• TPF (docetaxel/cisplatin/5-FU) vs. • PF (cisplatin/5-FU) induction chemotherapy followed by RT alone

• Primary end point - OS

Posner et al N Engl J Med 2007

Posner et al N Engl J Med 2007

TPF PF P value

3-yr OS 62% 48% 0.006

Median Survival 71 mnths 30 mnths 0.004

LRC 70% 62% 0.04

CTRT

Is Concurrent CTRT better than RT alone ?

• 226 patients with advanced oropharyngeal Ca

• Primary end point - OS

Gortec 94-01, JNCI, Vol. 91, No. 24, December 15, 1999

Results

Conclusion : Significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

Combined modality

Radiation alone

P value

3 yr OS 51 % 31 % 0.02

3 yr DFS 42 % 20 % 0.04

LRC 66 % 42 %

Combined modality

Radiation alone

P value

5 yr OS 22 % 16 % 0.05

5 yr DFS 27 %

15 % 0.01

LRC 48 %

25 % 0.002

F Denis, Final report of GORTEC 94-01,2004G Calais, Gortec 94-01, December 15, 1999

An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemo-RT in Patients With Unresectable Squamous Cell Head and Neck Cancer.

• 295 pts• 59% oropharynx patients

• Arm A (the control)- (70 Gy at 2 Gy/d)• Arm B, same RT with concurrent bolus cisplatin 100 mg /m2, given on days

1, 22,and 43.• Arm C, a split course of single daily fractionated radiation and 3 cycles of

concurrent infusional fluorouracil and bolus cisplatin chemotherapy. 30 Gy with 1st cycle and 30 – 40 Gy with 3rd cycle.

• Primary end point - OS

J Clin Oncol 21:92-98. 2003David J. Adelstein

• Median f/u 41 mths

• 3yrs projected OS arm A – 23 %, B – 37 %(p=0.014) and C – 27 %(non-significant)

• Grd 3 or higher Toxicity A-52% , B-89%(p<0.0001) and C- 77%(p<0.001)

• Trial was closed prematurely, didn’t meet target accrual of 362

• Conclusion: The addition of concurrent high-dose, single agent cisplatin to conventional single daily fractionated radiation significantly improves survival.

• This trial established the role of Chemo-RT in HNSCC.

Which one is better?NACT or CTRT

MACH NC Meta-anaalysis Pignon, Lancet 2000; 355: 949–55

• Over 70 randomized trials• 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 radiotherapy was compared with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders.

Effect of Chemotherapy on survival

• The first meta-analysis included 63 trials.

• Trials were divided according to timing of chemotherapy: Adjuvant, neoadjuvant, and concomitant or alternating with radiotherapy.

Conclusion

• The addition of chemotherapy to locoregional treatment- the most important result was a small, but statistically significant, overall benefit in survival with chemotherapy (the absolute benefit at 2 and 5 years was 4%).

• No significant benefit of adjuvant or neoadjuvant chemotherapy but a significant benefit of concomitant chemotherapy (absolute benefit at 2 and 5 years of 8%)

MACH-NC: Update• Update to the meta-analysis by adding the data from the randomized trials

performed between 1994 and 2000.

• Added 24 new trials, most of them on concomittant chemotherapy

• 87 trials, 16665 pts

• median f/u 5.5 yrs

• An absolute benefit for chemotherapy of 4.4% at 5 yr.

• For concomitant CTRT group the absolute survival benefit at 5 yr is 8 %

IJROBP, Vol. 69, No. 2, Supplement, pp. S112–S114, 2007

MACH-NC 2009 Update

The meta-analysis included 87 randomised trials (16,485 patients) comparing loco-regional treatment versus the same loco-regional

treatment + chemotherapy.

• 87 randomised control trials from period of 1965 to 2000• 16,192 patients were analysed in a median follow up of 5.6 yrs• Evidence of improvement in overall survival• Absolute benefit 4.5% at 5 yrs• Benefit more in concurrent CTRT, with HR -0.81(p<0.0001) &

absolute benefit of 6.5%• Benefit decreases with increasing age• Absolute benefits - oral cavity-8.9%• oropharynx-8.1%• larynx-5.4%• hypopharynx-4%

MACH-NC (2011 update)

MACH- NC-Conclusions

• Addition of CT - Absolute benefit in survival-5% in 5 yrs.• Induction/adjuvant - 2% survival benefit• Concurrent CTRT 8% - 5yr survival benefit• 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 CT. Disappears by

around age of 70

Is NACT → CTRT better than CTRT?

• Locally advanced SCCHN• Induction TPF→CRT vs CRT• Three cycles of TPF followed by concurrent chemo-radiotherapy with either

docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin

• 145 PTS• Stage III-IV (55% Oropharynx) • Median follow-up : 49 mnths• Primary end point - OS

Lancet Oncol 2013; 14: 257–64

• No significant difference noted between those patients treated with induction chemotherapy followed by chemo-radiotherapy and those who received chemo-radiotherapy alone

TPF→CRT

CRT P value

OS 67% 83% 0.47

PFS 73% 83% 0.22

• 285 patients ( 58% oropharynx)• Treatment-naive patients with nonmetastatic N2 or N3 SCCHN• CRT Vs 2#TPF NACT → CRT• CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus

radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of NACT (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT regimen(NACT → CRT arm)

• Primary end point - overall survival OS

• Minimum follow-up of 30 months

• No statistically significant differences in OS or DFS.

• NACT did not translate into improved OS compared with CRT alone

• NACT didn’t improve OS when added to CRT

• 1022 patients with locally advanced HNSCC• 52% of the patients had oropharyngeal• Additional induction TPF before CT-RT didn’t improve OS (p = 0.92)• No statistically significant benefit of PFS (p = 0.32)

Radiotherapy and Oncology 118 (2016) 238–243

Treatment Intensification

• So, CTRT is better that RT alone

• Is CTRT better than hyperfractionated RT for locally advanced head neck cancers ?

• 122 patients with advanced head neck cancers• 44% Oropharynx patients (base of tongue/tonsil)

• Hyperfractionated RT 75Gy @1.25Gy BD over 6wk• Combined modality arm• RT 70 Gy @same fractionation with planned treatment interruption of 7 days after 40

Gy to manage mucosities • Chemotherapy – wk 1 and wk 6• 5 FU 600 mg/m2 /day cont. infusion for 5 days• cisplatin 12 mg/m2/day iv bolus for 5 days• 2 more cycles of adjuvant chemotherapy were given to all patients after completion of

local therapy

The New England Journal of Medicine, 1998

Results • Median follow up 41 months

• Conclusions Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

Combined modality

Hyperfractionated RT

P value

LRC 70 % 44 % 0.01

OS 55 % 34 % 0.07

• 130 patients with locally advanced head neck cancers• 37 % oropharynx pts

• Arm 1- Hfx RT 77 Gy @ 1.1 Gy/ fraction twice a day over 35 days• Arm 2 – Hfx RT + low dose daily Cisplatin • 6 mg/m2 1-2 hr before 2 nd fraction

• In case of acute high grade reactions treatment interruption of 2 wk was allowed with no dose reduction.

• Primary endpoint – OS

J Clin Oncol 18:1458-1464. © 2000

Results • Median follow up:79 months.

Combined modality

Hfx RT alone

Significance

Complete Response

75 % 48 % p = .002

2 yr OS 68 % 49 %

5 yr OS 46 % 25 % p = .0075

5 yr PFS 46 % 25 % p = .0068

Conclusion: As compared with Hfx RT alone, Hfx RT and concurrent low-dose daily CDDP offered a survival advantage, as well as improved LRPFS and DMFS.

• Locally advanced head and neck cancer • 384 patients, majority stage IV (94%) • Oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%)

• 2 arms - • Concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and

hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy)[30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU

(600 mg/m2, 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m2) on days 5 and 36]

• Hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy){14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy }

• C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions

C-HART HART P valueLRC 49.9% 37.4% 0.001

OS 28.6% 23.7% 0.023

PFS 29.3% 26.6% 0.009

• Locally advanced head and neck squamous-cell carcinoma• 840 patients (66% oropharynx pts)• 3 arms

• Conventional CT-RT(70 Gy/35# + 3 cycles concomitant carboplatin-fluorouracil)• Accelerated CT-RT(70 Gy in 6 weeks +2 cycles of 5 days concomitant carboplatin-

fluorouracil)• Very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks)

• Median follow-up was 5·2 years• Primary endpoint - PFS

•Conventional CT-RT improved PFS compared with very accelerated radiotherapy•Grade 3–4 acute mucosal toxicity

• very accelerated radiotherapy (84%) compared with • accelerated CT-RT(76%) or • conventional CT-RT(69%; p=0·0001)

•Acceleration of radiotherapy cannot compensate for the absence of chemotherapy

Biological Agents

Cetuximab• Chimeric monoclonal antibody• EGFR Inhibitor

• 424 pts, multinational study (60% oropharynx)• Locally advanced SCCHN

• Primary end point – locoregional control• RT v/s RT + Cetuximab• Cetuximab 400 mg/m2 at initial dose followed by 250 mg / m2 weekly

for rest of RT.

N Engl J Med 2006;354:567-78

• Median f/u - 54.0 mths

• With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups

Cetuximab + RT

RT alone

P value

MedianLRC

24.4 mnths

14.9 mnths

0.005

Median OS

49 mnths

29.3 mnths

0.03

• Stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab

• 891 analyzed patients, 630 were alive at analysis • Median follow-up, 3.8 years• Primary end point - PFS• Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in

• More grade 3 to 4 radiation mucositis (43.2% v 33.3%, respectively), rash, fatigue, anorexia, • But not more late toxicity

• No significant differences were found between arms A and B in• 3-year PFS (61.2% v 58.9%, respectively; P - .76)• 3-year OS (72.9% v 75.8%,P - .32)• Locoregional failure (19.9% v 25.9%, P - .97)• Distant metastasis (13.0% v 9.7%, P - .08)

• Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had

• better 3-year probability of PFS (72.8% v 49.2%,P .001) • OS (85.6% v 60.1%, P .001)

• Tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome

• Adding cetuximab to radiation-cisplatin did not improve outcome

HPV

• HPV 16 and 18 associated with squamous cell carcinoma More Common With nonsmoker Not associated with p 53 mutationUsually present with large nodal volume

HPV and survival

• 24 retrospective series were analysed.• In HNSCC, HPV positivity conferred - Better OS (HR = 0.85, 95% CI: 0.7–1.0) - Better DFS (HR = 0.62, 95%CI: 0.5–0.8)• Site specific analysis showed that for non-oropharyngeal HNSCC OS

and DFS were similar for both HPV positive and HPV negative patients.

• Stage III or IV HNSCC• 743 patients (60% oropharynx)• 2 arms• Conventional CT-RT arm• Accelerated fractionation + Concomitant boost + CT(72 Gy in 42 fractions over a 6-week period, with a concomitant boost of twice-daily

irradiation for 12 treatment days)• Concurrent Cisplatin 100 mg per square meter of body-surface area intravenously on

days 1, 22, and 43 in both arms

RTOG 0129

• Median follow-up period - 4.8 years• Primary end point – OS

• 60.1% [433 of 721]) had oropharyngeal scc• HPV status was determined in 74.6% of these patients (323 of 433)• 63.8% of patients with oropharyngeal cancer (206 of 323) were HPV+ve

HPV +ve HPV-ve P value

3 yr OS 83.6% 51.3% <0.001

PFS 74.4% 38.4% <0.001

AFC-CT CT-RT P value

3 yrs OS 59% 56% 0.183 yr PFS 57% 55.8% 0.803 yr LRC 28.2% 25.6% 0.50

Brachytherapy

Role of Brachytherapy• Historically played a role in boosting gross disease following EBRT.• Developed in the pre-IMRT, preconcurrent chemotherapy era.• Low dose rate (LDR) brachytherapy has previously been the most common

type of brachytherapy.• High dose rate (HDR) techniques are becoming much more common.• Interstitial implants selectively used in i) Accessible lesions ii) Small (preferably <3cm) tumors iii) Lesions away from bone iv) N0 nodal status v) Superficial lesions

• High rates of locoregional control have been achieved using EBRT directed at primary and bilateral neck followed by brachytherapy boost.

• Care should be taken to delineate pre-treatment tumor extent accomplished by tattoos or gold seeds.

• CTV as recommended by ESTRO – 5mm at minimum and more commonly 1 to 1.5 cm for base of tongue tumors.

• PTV is equal to CTV.• Catheters are typically placed parallel and equidistant at 1 to 1.5 cm apart.• Complication of brachytherapy for base of tongue include osteoradionecrosis

of mandible.

Brachytherapy guidelines - American Brachytherapy society (ABS)

• Recommend – EBRT doses of 45 to 60 Gy followed by an HDR boost of 3-4 GY per fraction for 6 to 10 doses.

• With locoregional control of 82 % to 94 %.• Prophylactic tracheostomy is often required.

• The ABS recommends the use of brachytherapy as a component of the treatment of head-and-neck tumors.

• No definite evidence on use of concomitant chemotherapy; risk of increased mucosal toxicity compromising treatment

• Regarding the sequencing of EBRT and brachytherapy, it may be advantageous to obtain shrinkage with EBRT before applying brachytherapy in advanced tumors.

• In case of brachytherapy boost, placement of radio-opaque markers before starting EBRT can help delineate the target volume, before any shrinkage occurs

• The dose prescription volume and dose points should be clearly specified.

General concepts based on ABS recommendations

The European Brachytherapy group (Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology)GEC-ESTRO –guidelines

• Based on consensus recommendation.

• Recommend 45 to 50 Gy EBRT followed by • 25 to 30 Gy boost for Tonsillar tumors.• 30 to 35 Gy boost to base of tongue.

• Total brachytherapy boost dose is fraction size dependent – • 21 to 30 Gy in 3-Gy fraction.• 16 to 24 Gy in 4-Gy fraction

Types of Implants

Base of tongue:interstitial volume implant

• Patients who do not have palpable LN metastasis receive elective irradiation to the neck along with EBRT to the primary site.

• Treatment is completed with an implant to the base-of-tongue, performed approximately 2-3 wks after the completion of EBRT.

External Beam Radiotherapy

• Conventional Treatment• 3-D CRT• IMRT

Radiation therapy - simulation

• Preferably CT based simulation.• Position- supine• With rigid head holder cradling the

posterior calvarium.• Shoulders should be positioned as

caudally as possible to allow adequate exposure of neck.

• Anterior and Lateral reference marks should be made on the mould

• Bite block – elevate the hard palate• Head should be immobilised with a

thermoplastic cast.• The mask should be properly fitted

and not allow the movement of the nose, chin or forehead.

• Cast is fixed to the couch top or base plate in at least 3 places.

• Image should be taken from above the calvarium to the carina.

Conventional Treatment• Delivered using a “shrinking-field” technique for the primary tumor bed and

upper neck, matched to an anterior-posterior (AP) supraclavicular field for the lower neck (LAN)

• Opposed lateral fields covering the primary tumor bed and upper neck extending to the thyroid notch are initially treated to 44 Gy in 2-Gy fractions

• Isocenter is typically placed at approximately the C1 to C2 level just anterior to the inter-vertebral space

• Off-cord boost is then created by shifting the posterior field border anteriorly to split the vertebral bodies vertically

• The final field reduction boost carries the tumor GTV plus a margin to 66 to 70 Gy

• Electron fields (commonly, 6 to 9 MeV; occasionally, 12 MeV for bulky nodal disease) are matched on the skin to abut the posterior aspect of the off-cord photon field and thereby treat the posterior neck to 50 to 54 Gy (with higher doses if positive posterior nodes are present)

Conventional Field borders• Upper margin – upto zygomatic arch• Posteriorly – tip of mastoid• Anteriorly – depending upon the clinical extension(2 cm beyond the

disease) [usually, kept 1.5-2 cm from angle of mouth]• Inferiorly – thyroid notch ( for 3-field technique), below clavicle (for

2 lateral fields) [usually kept at lower border of C-6/Cricoid]{If LAN is not to be used then to go as low as possible avoiding the humeral heads}

• Lower neck – Apposed to the upper portal and 1 cm below the clavicles

Principles & Practice of Radiation Oncology, 3rd edition, Perez & Brady (1997)Textbook of Radiation Oncology, 1st edition, Rath & Mohanti (2002)

LAN Field• Superior : Lower border of throid notch and match with upper neck lateral

fields (with a spinal cord/vocal cord block)• Inferior : inferior edge of the clavicular head• Lateral : Two thirds of the clavicle or 2 cm lateral to lymphadenopathy

(which ever more lateral)

• The treatment is generally done in 2 or 3 phases.

• In a 2 phase treatment• Phase I : 44 Gy/22 # to B/L + LAN• Phase II : 22-26 Gy to the cone down volume after off-cord

• In a 3 phase treatment• Phase I : 44 Gy/22 # to B/L + LAN• Phase II : 16 Gy to the cone down volume after off-cord• Phase III : 10 Gy to the boost volume by further conforming to the GTV

Indication for ipsilateral radiotherapy• Well lateralised Tonsillar cancer cases not involving the base of tongue

and with minimal involvement of soft palate.• The CTV can be limited to the Ipsilateral neck which limit the exposure

of the contralateral parotid, submandibular gland and pharyngeal musculature.

• Treatment to the contralateral neck – is based on the extremely low risk of occult contra-lateral neck lymph node involvement.

• Low incidence of progression seen in early stage tonsil cancer – is due to lack of invasion of soft palate and base of tongue.

• Patients with c/l cervical lymph node involvement usually seen in patients with tumor approaching or crossing midline or have extensive I/L cervical lymph node involvement.

Surgical series demonstrate – risk of contralateral cervical lymph node involvement

Study related with ipsilateral-only radiotherapy

• No c/l neck progression in patients with T1 tumors.• Only 1-2 % c/l involvement occur in T2 tumors.• C/L nodal progression in T3 tumor was 3 to 10 %.• C/L nodal progression was associated with-

• both base of tongue and soft palate involvement (13%).• T3 stage (10%)• Involvement of the midline of the soft palate (16.5%).

Radiotherapy volumes• Based on ICRU 50• 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) – GTV is expanded to include a margin for microscopic extension (not visible on clinical and imaging modalities)

• Also considering the natural avenues of spread for the particular disease and site, including lymph node, perivascular, and perineural extensions

• Planning target volume (PTV) - The PTV is defined by specifying the margins that must be added around the CTV to manage the effects of organ, tumor and patient movements, inaccuracies in beam and patient setup, and any other uncertainties

Clinical Target Volumes Delineation• CTV_HR (CTV 1) – Volume to receive the highest dose, which includes the

primary with 0.5-1 cm margin. Should be more generous if tumor borders are less well defined

• CTV_IR (CTV 2) – Volumes to receive an intermediate dose• CTV_LR (CTV 3) – Volumes to receive an elective dose for potential

subclinical disease

Dose Prescription• CTV_HR – 66-72 Gy • CTV_IR – 60-66 Gy• CTV_LR – 54-60 Gy

Practical aspects of IMRT, K S Clifford Chao

• Data pertaining to the natural course of nodal metastasis for each head-and-neck cancer subsite were reviewed

• A system was established to provide guidance for nodal target volume determination and delineation

• 126 patients (52 definitive, 74 postoperative) were treated between February 1997 and December 2000 with IMRT for head-and-neck cancer

• Median follow-up was 26 months• Patterns of nodal failure were analyzed

Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 5, pp. 1174–1184, 2002

Chao et al, IJROBP, 2002

What volumes to take for IMRT?

Chao et al, IJROBP, 2002

Tumour site

Clinical Presenatation

CTV_HR CTV_IR CTV_LR

Tonsil T 1 and T 2 N 0T 3 and T 4 N 0Any T N +

GTVpGTVpGTVp + n

- OptionalIN (adjacent ln)

IN (IB-V)IN + CN(IB-V,RPLN)IN + CN + RPLN(remaining ln)

BOT Any T N0 GTVp Optional IN + CN(IB-V,RPLN)

Soft Palate

Any T N + GTVp + n IN (adjacent ln)

IN + CN + RPLN(remaining ln)

Neck Node Contouring Guidelines

• Som’s – Radiological Classification• Robbin’s – Surgico-anatomico-pathological Classfication• Rotterdam guidelines – Nowak et al.• Brussels guidelines – Gregoire et al. 2000• Consensus guidelines – Gregoire et al., 2003, 2006, 2014

• K. Thomas Robbins, Arch Otolaryngol Head Neck Surg. 2002;128(7):751-758.

Selection & Delineation of LN Target Volumes2000

Consensus guidelines for contouring the clinically node negative neck

2003

2006

Consensus guidelines for node positive and post operative patients

Consensus guidelines for nodal contouring2014

Important considerations• Irrespective of the nodal status of the patient, i.e. node-negative or node-

positive• Holds for the post-operative situation

• Risk of microscopic extracapsular extension (ECE) was (weakly) proportional to the size of lymph node

• 20–40% for nodes smaller than 1 cm in diameter• >75% for bulky nodes more than 3 cm in diameter

• An isotropic expansion by 10–20 mm into these structures from the visible edge of the node (i.e. the nodal GTV) appears reasonable. [Modification of the previous recommendations, which arbitrarily proposed to include the full muscle in the corresponding infiltrated levels]

Specific recommendations for node-positive patients include

• Coverage of the supraclavicular fossa for patients with level IV or Vb lymphadenopathy

• Pathologic lymphadenopathy spanning adjacent levels should trigger inclusion of the full extent of both levels in the CTV

• For postoperative patients, coverage of the entire operative bed in the neck is recommended to account for potential tumor spillage

Level Ia

Level Ib

Level II & Level III

*Coverage of the retrostyloid space was recommended for all patients with pathologic level II involvement

Level II

Level III

Level IV

Level IV b (Medial supraclavicular)

Level V

Level V

Level V c(Lateral supraclavicular)

Level VI

Level VI

VI a

VI b

VI b

VI a

Level VIIa

Level VIIb

Level VIII

Level IX

Level Xa

Level Xb

Post-treatment management and surveillance

• Patients should be seen regularly for clinical evaluation.• Current guidelines –

• examination every 1 to 3 month for first year post-therapy.• every 2 to 4 month in second year post-therapy.• every 4 to 6 month in the third through fifth years.

Recurrent Locoregionally confined squamous cell carcinoma of oropharynx (SCCOP)

SCCOP: Locoregional control

Garden, et al. Patterns of disease recurrence following treatment of oropharyngeal cancer with intensity modulated radiation therapy. Int. Journal Radiation Oncology. 2013.

SCCOP: Locoregional control• MDACC• Retrospective review of 776 patients between 2000-2007

treated with IMRT with/without chemotherapy• 5-year overall survival: 84%• 5-year recurrence-free survival: 82%

• 7% recurred primary site• 4% recurred neck• 10% developed distant metastases• 8% had second primary cancers

Garden, et al. Patterns of disease recurrence following treatment of oropharyngeal cancer with intensity modulated radiation therapy. Int. J. Radiation Oncology. 2013.

Treatment Locally Recurrent SCCOP

• Surgical salvage• Reirradiation• Palliative Chemotherapy• Supportive Care

Re-treatment: Should Resi/ recc disease be treated?

Allen Ho, Head Neck. 2014 Jan;36(1):144-51.

Reirradiation• High risk of normal tissue toxicity including upto a 20% carotid

rupture rate.• 15% fatal toxicity.• Patients undergoing a second course of chemotherapy and

radiation therapy should be managed with experienced centers.• Failed phase III studies to compare systemic therapy alone or

chemotherapy and reirradiation.

Reirradiation• RTOG 9610 • 79 Pts (36% oropharynx)• 4 weekly cycles of chemoradiotherapy separated by 1 week of rest• Each cycle - 5 days of twice-daily RT 1.5 Gy per fraction separated by a

6-hour interval• 5-FU 300 mg/m2 IV bolus and Hydroxyurea 1.5 g by mouth were both

given before the second daily RT fraction

• 2-year survival: 15%• 5-year survival: 4%• Median survival 8 months• Grade 4 or higher acute toxicity: 25%• Treatment-related death: 8%

Spencer SA, Harris J, Wheeler RH, et al. Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck. 2008;30:281-288.

Reirradiation

• RTOG 9911• 105 pts (40% oropharynx)• RT at a dose of 1.5 Gy/fx bid5 days every other week X 4 cycles• Cisplatin 15 mg/m2/1 hour and Paclitaxel 20 mg/m2/1 hour each daily

X 5 every other week X 4

• 25% 2-year overall survival• Median survival 12 months• Grade 4 or worse acute toxicity: 28%• Treatment-related death: 11%

Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: Results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol. 2007;25:4800-4805.

Palliative Chemotherapy• 33% of patients have partial response to platinum-based

regimens• Median survival 4-6 months• 2-year overall survival 5-10%

Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol. 1992;10:1245-1251.

• 442 patients (34% oropharynx)• Primary endpoint: OS

Recurrent/metastatic HNSCC; no previous chemotherapy except for locally advanced

disease > 6 mos prior to study entry; no

nasopharyngeal carcinoma(N = 442)

Up to 6 cycles: cetuximab 400 mg/m2, then 250 mg/m2/wk until PD or unacceptable toxicity; carboplatin AUC 5 or cisplatin 100 mg/m2 on Day 1; 5-FU 1000 mg/m2 on Days 1-4 every 3 wks.

Cetuximab +Carboplatin or Cisplatin

+ 5-FU(n = 222)

Carboplatin or Cisplatin + 5-FU

(n = 220)

Vermorken JB, et al. N Engl J Med. 2008. 

127153

83118

6582

4757

1930

173184

220222

815

13

HR : 0.80 (95% CI: 0.64-0.99; P = .04)

Chemotherapy only (n = 220) 20Chemo + cetuximab (n = 222) 36

Surv

ival

Pro

babi

lity

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

10.1 mos7.4 mos

Pts at Risk, nCTX only

CET + CTX

Survival Time (Mos)

Cetuximab ± First-line Platinum in Recurrent or Metastatic HNSCC: OS

ORR, %

Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127. 

SPECTRUM: Cisplatin + 5-FU ± Panitumumab in Recurrent/Met HNSCC

• 657 pts

• Primary endpoint: OS

Patients with distant metastatic and/or locally

recurrent HNSCC, ECOG PS ≤ 1

(N = 657)

Stratified by previous treatment, primary tumor site, ECOG PS

Optional panitumumab maintenance q3w

Panitumumab 9 mg/kg Day 1Cisplatin 100 mg/m2 Day 15-FU 1000 mg/m2 Days 1-4

(n = 327)

Cisplatin 100 mg/m2 Day 15-FU 1000 mg/m2 Days 1-4

(n = 330)

Max six 3-wk cycles

Vermorken JB, et al. Lancet Oncol. 2013;14:697-710.

• Subgroup analysis in p16-negative patients significant: 11.7 vs 8.6 mos (P = .01)• Despite questions about p16 IHC cutoff values, hypothesized that EGFR inhibitors may be ineffective in HPV+ tumors

• Supported by lack of EGFR overexpression/amplification in HPV+ tumors

HR: 0.87 (95% CI 0.73–1.05)P = .14 

Vermorken JB, et al. Lancet Oncol. 2013;14:697-710

0      2      4      6      8     10    12    14    16    18    20    22    24    26    28    30    32Mos

100

80

60

40

20

0

Ove

rall

Surv

ival

(%)

Panitumumab    11.1 (9.8-12.2) Control            9.0 (8.1-11.2)

Median OS, months (95% CI)

Addition of Panitumumab improves survival in HPV-ve pts

Metronomic Chemotherapy

• Frequent administration

• Low doses (1/10th–1/3rd of the maximum tolerated dose [MTD]) of drugs

• Shorter intervals without interruption.

Metronomic chemotherapy in HNSCC patients

Author Year Study design Patients (n)

Protocol (n patients) Results

Patil et al. 2015 phase II 110celecoxib + methotrexate (57); cisplatinum (53)

OS 101 vs 66 days; PFS 249 vs 152 days

Pai et al. 2013 retrospective 64celecoxib + methotrexate (32); no MC (32)

2-year DFS 94.6 % vs 75.4 %

Penel et al. 2010 randomised 88cyclophosphamide (44); megestrol acetate (44)

2-month PFS 20.5 % vs 9 %; median OS 195 vs 144 days

NCCN Guidelines

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