Dose Constraints for the Temporal Lobes During the Optimization of Intensity-modulated Radiotherapy Treatment Plans for Nasopharyngeal Carcinoma
Phase: NA
Conditions: Injury; Temporal Region
Sponsor: Jiangxi Provincial Cancer Hospital

Dose constraints for the temporal lobes during the optimization of 
intensity-modulated radiotherapy treatment plans for nasopharyngeal 
carcinoma 
 
 
Background 
Nasopharyngeal carcinoma (NPC) is common among Asians, especially in Southern China. 
Radiotherapy (RT) has been the mainstay of treatment for patients with non-disseminated NPC due 
to its anatomic location and radiosensitivity. In the management of NPC, incidental irradiation of 
the temporal lobe with consequent long-term injury is one of the most feared complications after 
radical radiotherapy, as it is can be devastating for patients and is associated with severe impairment 
of quality of life. Lee et al. reported a 3% cumulative incidence of temporal lobe injury (TLI) after 
2D-RT in a series of 4527 patients [1]. In another study, Lee et al. showed that 64 Gy irradiation (at 
conventional daily fraction of 2 Gy daily) would lead to a 5% necrotic rate in temporal lobes at 10 
years after 2D-RT in NPC patients [2]. 
   Intensity-modulated RT (IMRT) is a major breakthrough in the treatment of NPC, and it was 
capable of producing highly conformal dose distributions with steep dose gradients and complex 
isodose surfaces [3]. The design of appropriate dose constraints for the organs at risk (OAR) during 
the optimization of IMRT treatment plans can enable significantly better OAR sparing and reduce 
subsequent complications. IMRT technique can reduce the volume of high dose areas in the 
temporal lobes and thereby reduce risk of toxicities, compared with 2D-CRT [4, 5]. 
  IMRT offers detailed dosimetric parameters for temporal lobes based on dose-volume histogram 
(DVH). Some studies investigated the correlation between the incidence of TLI and IMRT 
dosimetric parameters. A retrospective study reported by Su et al. demonstrated that the 5-year 
incidence of TLI for a maximum dose of 64-68Gy or D1cc (the dose delivered to the 1 cubic 
centimeter volume, Gy) of 52-58 Gy was less than 5.0% after IMRT [6]. Similarly, a recent 
retrospective analysis of 20 patients with NPC and unilateral TLI showed that a dose of 69 Gy 
delivered to D0.5cc may be the dose tolerance of the temporal lobes after IMRT [7]. In our previous 
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study, we reported that the D1cc was the only independent predictor for radiation-induced TLI and 
estimated that the biologically equivalent tolerance doses at 2 Gy for the 5%,10% and 50% 
probabilities at 5 years to develop TLI were 62.83 Gy equivalents, 66.67Gy equivalents and 77.58 
Gy equivalent, respectively [8]. However, only a few publications have quantified the risk of TLI 
complications in terms of normal tissue complication probability (NTCP) models. 
   Recently, we apply on five NTCP models, including (1) Lyman model and (2) logit-formula 
with dose-volume histogram (DVH) reduced to generalized equivalent uniform dose (EUD), (3) 
serial reconstruction unit (RU) model, (4) Poisson-EUD model, and (5) mean dose model for TLI 
to a population of 351 NPC patients treated with IMRT. As assessed qualitatively and quantitatively, 
the Lyman-EUD model fitted the data very well. The tolerance dose (TD) for the 5% and 10% 
probabilities of TLI development were 77 Gy and 80.4 Gy for Dmax in 2-Gy fractions (α/β ratio, 3) 
in the current study (Manuscript has not been published). 
  According to the ICRU 83 report [9], overlap between the planning target volume (PTV) and the 
planning organ at risk volume (PRV) leads to a volume that is shared by two contoured volumes. A 
conflict can occur if the planning aims of the overlapping contoured volumes lack a common desired 
absorbed-dose range. To ensure that the conflict does not occur in the planning aims, at least two 
different methods can be applied. One method is based on subdivision of the volumes. Subdivision 
of the PTV of the gross target volume (PTVnx) into regions with different prescribed absorbed doses 
(PTVsv1,PTVsv2, PTVsv2 is the overlaps between PTVnx and temporal lobe) can be used in cases 
for which the PTVnx overlaps temporal lobe. When the volume of PTVsv2 is less than 0.2 cubic 
centimeter (cc), the prescribe dose for PTVsv2 is as the same as that of the PTVsv1, D1cc 63.1Gy, 
Dmax 72.9Gy for TL (32 fractions). When the volume of PTVsv2 is between 0.2 cc and 0.5cc, the 
prescribe dose for PTVsv2 is 66Gy, D1cc 63.1Gy, Dmax 72.9Gy for TL (32 fractions). When the 
volume of PTVsv2 is between 0.5 cc and 1cc, the prescribe dose for PTVsv2 is 66Gy, D1cc 65.8Gy, 
Dmax 75.2Gy for TL (32 fractions). A study by Ng et al. showed that the 5-year local failure-free 
rate dropped to 54% if more than 3cc volume within the gross primary tumor was under-dosed to 
below 66.5 Gy, compared with 90% in patients with smaller under-dosed volumes [10]. So, it is 
reasonable that prescribe dose for PTVsv2 is 66 Gy. The purpose of this prospective study is to 
evaluate the feasibility of dose constraints based on D1cc and Dmax for the temporal lobes 
following IMRT for NPC. 
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Reference 
[1] Lee AW, Law SC, Ng SH, et al. Retrospective analysis of nasopharyngeal carcinoma treated 
during 1976–1985: late complications following megavoltage irradiation. Br J Radiol 1992;65:918-
28. 
[2] Lee AW, Foo W, Chappell R, et al. Effect of time, dose, and fractionation on temporal lobe 
necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 
1998;40:35-42. 
[3] Xia P, Fu KK, Wong GW, et al. Comparison of treatment plans involving intensity-modulated 
radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000,48(2):329-37. 
[4] Kam MK, Chau RM, Suen J, Choi PH, Teo PM (2003) Intensity-modulated radiotherapy in 
nasopharyngeal carcinoma: dosimetric advantage over conventional plans and feasibility of dose 
escalation. Int J Radiat Oncol Biol Phys 2003;56:145-57. 
[5] Zhou GQ, Yu XL, Chen M, et al. Radiation-induced temporal lobe injury for nasopharyngeal 
carcinoma: a comparison of intensity-modulated radiotherapy and conventional two-dimensional 
radiotherapy. Plos One 2013;8(7):e67488. 
[6] Su SF, Huang Y, Xiao WW, et al. Clinical and dosimetric characteristics of temporal lobe injury 
following intensity modulated radiotherapy of nasopharyngeal carcinoma. Radiother Oncol 
2012;104(3):312-316. 
[7] Sun Y, Zhou GQ, Qi ZY, et al. Radiationinduced temporal lobe injury after intensity modulated 
radiotherapy in nasopharyngeal carcinoma patients: a dose-volume-outcome analysis. BMC Cancer 
2013;13:397. 
[8] Zeng L, Huang SM, Tian YM, et al. Normal Tissue Complication Probability Model for 
Radiation-induced Temporal Lobe Injury after Intensity-modulated Radiation Therapy for 
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Nasopharyngeal Carcinoma. Radiology 2015;276(1):243-9. 
[9] Hodapp N. The ICRU Report 83: prescribing, recording and reporting photon-beam intensity-
modulated radiation therapy (IMRT). Strahlenther Onkol 2012;188(1):97-99. 
[10] Ng WT, Lee MC, Chang AT, et al. The impact of dosimetric inadequacy on treatment outcome 
of nasopharyngeal carcinoma with IMRT. Oral Oncol 2014;50:506-512. 
 
 
 
Inclusion Criteria: 
- 
Newly-diagnosed and confirmed histopathologic diagnosis of nasopharyngeal squamous cell 
carcinoma, types WHO II-III, Stage I-IVA (AJCC staging, 2017, 8th edition), treated with 
intensity-modulated radiotherapy. 
- 
No head and neck surgery of the primary tumor or lymph nodes except for incisional or 
excisional biopsies. 
- 
Age between 18 years and 70 years. 
- 
Karnofsky score ≥80 
- 
WBC≥ 4,000/ul, platelets≥ 100,000/ul; serum creatinine≤ 1.6 mg/dl or 24hr. calculated 
creatinine clearance ≥ 60ml/min. 
- 
Must undergo pre-treatment evaluation of tumor extent and tumor measurement. Tumor may 
be measurable or evaluable. 
- 
Signed study-specific consent form prior to study entry. 
 
Exclusion Criteria: 
- 
Stage IVB 
- 
Evidence of distant metastases 
- 
Previous irradiation for head and neck tumor ≤ 6 months prior to study entry 
- 
Previous chemotherapy ≤ 6 months prior to study entry 
- 
Patient is on other experimental therapeutic cancer treatment 
- 
Other malignancy except non-melanoma skin cancer or a carcinoma not of head and neck origin 
and controlled at least 5 years 
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- 
Active untreated infection 
- 
Major medical or psychiatric illness, which in the investigator’s opinions, would interfere with 
either the completion of therapy and follow-up or with full and complete understanding of the 
risks and potential complications of the therapy 
- 
Pregnant women 
 
Pretreatment evaluation 
  Each patient must have completed the following studies within six weeks prior to study entry 
unless otherwise indicated. 
  Complete history and physical exam including weight and performance status. 
  Complete diagrammatic and descriptive documentation of the extent of the primary and regional 
(if any) following appropriate endoscopic procedures. 
  Complete dental and nutritional evaluation. Any required dental repairs must be made and 
prophylaxis instituted prior to radiotherapy. 
  Completion of the following laboratory studies within 14 days of study entry: CBC and platelet 
count; serum creatinine, creatinine clearance, BUN, EBV-DNA, serum pregnancy test for women. 
  Completion of the following laboratory studies within six weeks of study entry: liver function 
tests including AST, bilirubin, alkaline phosphatase. 
  Completion of the following radiologic studies within 6 weeks prior to study entry: 
    Chest CT scan 
    An MRI of head and neck with T1 contrast with gadolinium and T2 sequences is required. 
    Abdominal ultrasonography 
    Bon scan 
 
Radiotherapy 
All patients were immobilized in the supine position with a thermoplastic mask. After 
administration of intravenous contrast material, 3mm CT slices were acquired from the head to the 
level 2cm below the sternoclavicular joint. Target volumes were delineated according to the 
International Commission on Radiation Units and Measurements Reports(ICRU)50 and 62. The 
primary nasopharyngeal gross tumor volume (GTVnx) and the involved cervical lymph nodes were 
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determined from the imaging, clinical, and endoscopic finding.The enlarged retropharyngeal nodes 
were outlined, together with primary GTV, as the (GTVnx) on the IMRT plans. The first clinical 
tumor volume (CTV1) was defined as the GTVnx plus a margin of 5-10mm for potential 
microscopic spread, including the entire nasopharynx mucosa plus a 5mm submucosal volume. The 
second CTV (CTV2) was defined by adding a margin of 5-10mm to CTV1 ( when CTV2 was 
adjacent to critical organs such as brain stem and spinal cord, the margin was reduced to 3-5mm) 
and included the retropharyngeal lymphnodal regions, clivus, skull base, pterygoid fossae, 
parapharyngeal space, inferior sphenoid sinus, and posterior edge of the nasal cavity and maxillary 
sinuses. The upper neck was also included in CTV2. Elective level IB irradiation was decided by 
the attending physician. The lower neck and the supraclavicular fossae were treated with a single 
anterior split field by conventional RT. Planning target volumes(PTVs) for all gross tumor volumes 
and CTVs were generated automatically after delineation of tumor targets according to the 
immobilization and localization uncertainties. A simultaneous integrated boost method was used. 
The prescribe dose was 66-70Gy to the PTV of the GTVnx, 60Gy to the PTV of CTV1(i.e., high-
risk regions),54-56Gy to the PTV of CTV2(i.e., low-risk regions),and 64-70Gy to the PTV of the 
GTVnd for the metastatic cervical lymph nodes in 30-33 fractions. For the GTV and CTV, the target 
volumes that received more than 95% of the prescribed dose was used to reflect the target coverage. 
The dose received by each critical organ except temporal lobe was limited to tolerance according to 
the RTOG 0225 protocol. 
Dose constraints for the temporal lobes: D1cc was the only independent predictor for radiation-
induced TLI and estimated that the biologically equivalent tolerance doses at 2 Gy for the 5% and 
10% probabilities at 5 years to develop TLI were 62.83 Gy equivalents and 66.67Gy equivalents, 
respectively The tolerance dose (TD) for the 5% and 10% probabilities of TLI development were 
77 Gy and 80.4 Gy for Dmax in 2-Gy fractions (α/β ratio, 3). These D1cc and Dmax of temporal 
lobes are converted to different dose constraints based on different fractions. Subdivision of the 
PTV of the gross target volume (PTVnx) into regions with different prescribed absorbed doses 
(PTVsv1,PTVsv2, PTVsv2 is the overlaps between PTVnx and temporal lobe) can be used in cases 
for which the PTVnx overlaps temporal lobe (Figure 1). For example, when the volume of PTVsv2 
is less than 0.2 cubic centimeter (cc), the prescribe dose for PTVsv2 is as the same as that of the 
PTVsv1, D1cc 62.0Gy, Dmax 71.5Gy for TL (30 fractions), D1cc 63.1Gy, Dmax 72.9Gy for TL (32 
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fractions) and D1cc 63.7Gy, Dmax 73.6Gy for TL (33 fractions), respectively. When the volume of 
PTVsv2 is between 0.2 cc and 0.5cc, the prescribe dose for PTVsv2 is 66Gy, D1cc 63.1Gy, Dmax 
72.9Gy for TL (32 fractions), D1cc 63.7Gy, Dmax 73.6Gy for TL (33 fractions), respectively. When 
the volume of PTVsv2 is between 0.5 cc and 1cc, the prescribe dose for PTVsv2 is 66Gy, D1cc 
65.8Gy, Dmax 75.2Gy for TL (32 fractions), D1cc 66.4Gy, Dmax 75.9Gy for TL (33 fractions) , 
respectively (Table 1). If the volume of PTVsv2 is more than 1cc, dose constraints for temporal 
lobes is not protocolized, and is based on the discretion of the attending physician in individual 
cases. 
 
 
 
 
 
 
 
Figure 1. Subdivision of the PTV of the gross target volume (PTVnx) into regions with different 
prescribed absorbed doses (PTVsv1,PTVsv2, PTVsv2 is the overlaps between PTVnx and temporal 
lobe) can be used in cases for which the PTVnx overlaps temporal lobe. 
 
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Table 1. The relationship between dose constraints for the temporal lobes and the incidence of 
temporal lobe injury (TLI). 
Total dose70Gy/fractions 
Incidence of TLI 
Volume of TL D1cc 
TL Dmax 
30 
5% 
62.0 
71.5 
 
10% 
64.6 
73.7 
32 
5% 
63.1 
72.9 
 
10% 
65.8 
75.2 
33 
5% 
63.7 
73.6 
 
10% 
66.4 
75.9 
 
 
 
 
Chemotherapy 
Chemotherapy included concurrent chemotherapy, concurrent chemotherapy combined with 
induction chemotherapy and/or adjuvant chemotherapy. The regimens of induction chemotherapy 
and adjuvant chemotherapy included docetaxel and cisplatin (DP), gemcitabine and cisplatin (GP)  
and 5-Fu and cisplatin(PF). The DP protocol consisted of docetaxel 75mg/m2 IV on day 1, cisplatin 
75 mg/m2 on day1. The GP protocol consisted of gemcitabine 1.0g/m2 IV on day 1, 8, cisplatin 75 
mg/m2 on day1. The PF protocol consisted of cisplatin 80mg/m2 IV on day 1 and 5-Fu 800mg/m2d 
continuously IV on day 1-5. For patients who receive induction chemotherapy, both DP, GP and PF 
are repeated every 3 weeks for 2-3 cycles. This is followed by cisplatin 30mg/m2 IV weekly or 
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cisplatin 80mg/m2 IV on day1,22 during radiation. For patients who received adjuvant 
chemotherapy, regimens are repeated every 3 week for 3cycles. Chemotherapy is not protocolized 
and is used at the discretion of the attending physician in individual cases. 
 
Follow up 
After the completion of radiotherapy, all patients will be followed up every 1-3months during the 
first 2 years, every 6 months in years 2 to 5 and annually thereafter. During the follow-up sessions, 
disease status and treatment toxicity will be assessed by performing MRI to the head and neck region, 
chest radiograph, abdominal ultrasonograph, and physical examination. When indicated, as well as 
whole-body bone scan if required.  
 
Statistical analysis 
The sample size will be adjusted by 20% to account for patients that die within the 5 years and 
are not evaluable for the toxicity endpoint, and for ineligible or inevaluable (no data) cases. The 
total target accrual is 350 patients. The survival time is measured from Day 1 of RT completion to 
the date of the event or last follow-up visit. All analyses will be performed with SPSS software, 
version 19.0.The Kaplan-Meier method is used to calculate the overall survival (OS), local 
recurrence-free survival (LRFS) rates. Multivariate analysis will be done by using the Cox 
proportional hazard model to define independent predictors among various side effects. 
 
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