# Radiation Oncology/Head & Neck/Nasopharynx/Early Stage

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Nasopharyngeal Cancer - Early Stage

## Overview

* Early-stage (I-II) outcomes are good with radiation alone
* 5-year RFS is 75-95% and OS is 70-80%
* Most historical series use 2D radiation, but several reports with a short follow up show good outcomes with IMRT
* IMRT in particular has significantly better sparing of the objective (stimulated/unstimulated flow) parotid function in a randomized setting
* Dose tends to be 66-72 Gy in 2 Gy/fraction; elective sites receive 50-60 Gy using dose painting

## ChemoRT for Stage II

* Chinese Stage II Trial PMID 22056739 -- "Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial." (Chen QY JNCI 2011)
** Methods: 230/236 pts with stage II (used Chinese staging) NPC randomized to RT vs chemoRT with weekly cisplatin 30mg/m2 x 7c
*** RT: Conventional 2D RT: 68-70Gy/34-35fx to primary, 60-62Gy to node positive neck, 50Gy to node negative neck
*** Primary endpoint OS
** Results: Median f/u: 60 months
*** ChemoRT improved:
**** 5 yr OS: 95% vs 86%, HR=0.30, P =0.007
**** 5 yr PFS: 88% vs 79%, HR 0.45, P=0.017
**** 5 yr DMFS: 95% vs. 84%, HR = 0.27, P =0.007
*** No difference in LRC: 93% vs 91%, P=0.29
*** Toxicity: More acute toxicity with chemoRT:64% vs 41% P = 0.001, no difference in late toxicity
** Conclusion: ChemoRT improves survival in stage II NPC

## Radiotherapy alone

* Taiwan; 2005 (1983-1998) PMID 15936544 -- "Treatment outcomes and late complications of 849 patients with nasopharyngeal carcinoma treated with radiotherapy alone." (Yeh SA, Int J Radiat Oncol Biol Phys. 2005)
** Retrospective. 849 consecutive NPC patients (Stage I 6%, Stage IIA 3%, Stage IIB 35%, Stage III 32%, Stage IVA 19%, Stage IVB 5% by AJCC-5), WHO type I 1%, II 62%, type III 37%. RT median 70 Gy, if BT boost median 74 Gy
** Outcome: 5-year OS 59%, DFS 52%; OS by Stage: I 82%, II 72%, III 55%, IVA 42%, IVB 39%
** Toxicity: xerostomia 90%, hearing impairment 54%, tinnitus 52%, Lhermitte's sign 21%, trismus 12%, temporal necrosis 6%
* RTOG (Marcial et al) - PMID 6993442 (no abstract) — complete response to local tumor, 96% for T1, 88% for T2, 81% for T3, and 74% for T4. For N+ neck, ranged from 93% to 71%. 5-year survival overall was 40%.

## Altered fractionation

* RTOG 71-03 (1971-1979)
** Randomized. 121 patients. All Stages. Arm 1) split course RT (30/10, 3 week rest, 30/10) vs. Arm 2) 66/33 or 66/30
** 1980 PMID 6993442 -- "Split-course radiation therapy of carcinoma of the nasopharynx: results of a national collaborative clinical trial of the Radiation Therapy Oncology Group." (Marcial VA, Int J Radiat Oncol Biol Phys. 1980 Apr;6(4):409-14.)
*** 5-year outcome: LC 86% vs. 80% (NS), LRC 86% vs. 78% (NS), DFS 40% vs. 30% (NS)
*** Late toxicity: comparable, except edema worse with continuous RT (42% vs. 24%)
*** Conclusion: No difference between fractionation schedules, less social impact with split course
* Wang et al. - PMID 2720596 — Not randomized. Accelerated hyperfractionation (twice a day). Compared to similar stage patients treated with once a day XRT, and 5-year local control for T1-2 was 89% (hyperfract) vs 55%, and 77% vs 45% for T3-4.

## Treatment Technique
### Use of IMRT

* UCSF experience
** 2000 PMID 11020568 — "Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California-San Francisco experience." Sultanem K et al. Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):711-22.
*** 65-70 Gy to GTV (including + LN), 60 Gy to CTV, 50-60 Gy to the negative neck. Treated at 1.8 Gy per day to CTV and neck and 2.12-2.25 Gy/day to GTV. CTV consisted of entire nasopharynx, posterior 1/3 of nasal cavity and maxillary sinuses, retropharyngeal LN region, clivus, skull base, pterygoid fossae, parapharyngeal space, inferior sphenoid sinus.
*** 4-year local PFS was 97%, local-regional PFS 98%, and DM-free rate 66%. 4-year OS 88%
** 2002 PMID 12007936 — "Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience." Lee N et al. Int J Radiat Oncol Biol Phys. 2002 May 1;53(1):12-22.
** 2004 Dose constraints PMID 15183492
*** First group of pts treated with IMRT for the primary tumor and conventional fields for the lymph nodes. This group retrospectively reviewed to determine dose endpoints to critical normal structures. Second group of pts treated with IMRT to both primary and nodes. Based on dose endpoints defined, new plans were developed for the second group of pts and compared to the original plans.
*** Prescription dose 70 Gy at 2.12 Gy/fx (33 fx) to GTV, 59.4 Gy at 1.8 to PTV.
UCSF IMRT Dose Constraints :
| Organ Max | T1-T2 | T3-T4 | Organ Limit | T1-T2 | T3-T4 |
| Serial Organs |
| Chiasm max | 27.5 | 42.7 | Chiasm 5% | 21.5 | 36.4 |
| Spinal cord max | 38.3 | 42.2 | Spinal cord 1mL | 30.6 | 33.0 |
| Brainstem max | 50.9 | 55.3 | Brainstem 5% | 40.4 | 43.1 |
| Optic nerve | 23.7 | 41.6 | Optic nerve 5% | 22.2 | 34.4 |
| Eye | 25.0 | 32.8 | Eye 5% | 13.5 | 21.9 |
| Parallel Organs |
| Parotid mean | 26.8 | 27.8 | Parotid 50% | 25.1 | 24.6 |
| TMJ mean | 33.8 | 38.0 | TMJ 50% | 30.5 | 36.7 |
| Ear mean | 41.4 | 49.6 | Ear 50% | 38.3 | 49.8 |

### Side Effect Trials

IMRT salivary function
* Prince of Wales Hospital; 2007 (Hong Kong)(2001-2003) PMID 17971582 -- "Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients." (Kam MK, J Clin Oncol. 2007 Nov 1;25(31):4873-9.)
** Randomized. 60 patients with T1-2bN0-1 nasopharynx. Arm 1) IMRT 66 Gy (CTV=GTV + 1cm; at-risk anatomic sites; LN Levels IB-II, LN upper Level V, LN retropharyngeal; PTV=CTV+3mm), lower neck LN+ 66 Gy anterior field, LN- 54-60 Gy + intracavitary BT boostvs. Arm 2) 66 Gy 2D + intracavitary BT boost
** Outcome: observer-rated severe xerostomia IMRT 39% vs. 2D-RT 82% (SS), stimulated parotid flow (SS), unstimulated parotid flow (SS), but no difference in patient-reported feeling of xerostomia
** Conclusion: IMRT superior in preserving objective parotid function, but no difference in patient-reported benefit
** Editorial (PMID 17971579): Observer-rated scoring underestimates patient reports and has low agreement among various observers. Suspect sparing of parotid alone not sufficient. Parotid gland produces saliva without mucins (lubricants, bind water, and provide selective permeability barrier). Mucin-secreting glands (e.g. minor salivary glands, submandibular glands) produce <10% saliva but >50% mucins. May need to spare these glands as well for subjective feeling of benefit
* Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 17145528 -- "Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial." (Pow EH, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):981-91.)
** Randomized. 51 patients, Stage II (T2N0-1, AJCC 1997). Arm 1) conventional RT 68 Gy, neck 66 Gy vs. Arm 2) IMRT, GTV dose 68-72 Gy, PTV 66-68 Gy. Stimulated whole (SWS) and parotid (SPS) saliva flow evaluated, QoL SF-36, EORTC Core, EORTC QLQ-H&N35 questionnaires. Minimum F/U 1 years
** 1-year outcome: 25% whole flow (SWS) IMRT 50% vs. 2D 5% (SS), 25% parotid flow (SPS) 83% vs. 9% (SS). At 2 months, both group had xerostomia, but IMRT group improved significantly better over time. Also improvements in QoL
** Conclusion: IMRT significantly better than conventional RT for salivary function and QoL
Middle ear ventilation tube
* Hong Kong; 2002 PMID 12512893 -- "Randomized evaluation of the audiologic outcome of ventilation tube insertion for middle ear effusion in patients with nasopharyngeal carcinoma." (Ho WK, J Otolaryngol. 2002 Oct;31(5):287-93.)
** Randomized. ? patients. NPC and middle ear effusion. Arm 1) pre-RT ventilation tube insertion vs. Arm 2) observation. Audiologic assessment throughout. F/U 4 years
** Outcome: No difference in hearing changes up to 4 years
** Conclusion: Ventilation tube insertion before RT did not offer hearing benefit
Pointers
* Pre-treatment
** Nutrition consult, with consideration for G-tube
** Dental evaluation
* Set-up
** Supine, head extended
** Thermoplast mask to shoulders