|Year : 2015 | Volume
| Issue : 2 | Page : 391-396
Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341)
Sanjoy Chatterjee1, Charles Kelly2, Moses Arunsingh1, Chandan Chakrabarty3, Judith Mott4
1 Department of Radiation Oncology, Tata Medical Center, Kolkata, India
2 Northern Centre for Cancer Care, The Newcastle Upon Tyne Hospitals, NHS Trust, United Kingdom
3 School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, India
4 Department of Regional Medical Physics, Northern Centre for Cancer Care, The Newcastle Upon Tyne Hospitals, NHS Trust, United Kingdom
|Date of Web Publication||7-Jul-2015|
Department of Radiation Oncology, Tata Medical Center, DH Block (Newtown), Kolkata - 700 156, West Bengal
Source of Support: The authors acknowledge the funding received from the Royal College of Radiologists of UK (Short Projects Grant) and Newcastle upon Tyne Hospitals Charitable Trustees, Conflict of Interest: None
Clinical trial registration MREC No: 08/H0907/127, UKCRN ID 7341)
Objective: Technological advances have enabled clinicians to explore dose escalation strategies in various tumor sites. Intermediate and high risk oropharyngeal cancers have poor 5 year outcomes. This study aimed to assess the feasibility and dosimetric safety of 9% dose escalation in these tumors and compare the dose received by organs at risk (OAR) in escalated plans (67.2 Gy/28 fractions) versus (65 Gy/30 fractions) standard dose plans.
Materials and Methods: FDG-PET fused datasets were used to delineate gross, clinical and planning target volumes. Standard dose plans were created using two non IMRT techniques (conventional and field in field plans) whilst the patient was treated using a helical tomotherapy plan. A fourth dose escalation plan was obtained allowing comparison between the 20 plans of oropharyngeal cancer patients.
Results: It was feasible to escalate dose to the FDG-PET avid tumor within the set constraints to that of planning target volume and OAR. Comparison of the escalated dose to that of standard plans showed a statistically significant (P < 0.05) sparing of the mastication apparatus (MA) with escalated plans. Dose to the other critical and functional organs were comparable between the four plans.
Conclusion: Hypofractionated, slightly accelerated dose escalation in oropharyngeal cancers is likely to be safe and the chance of trismus is not any higher than when standard dose radiotherapy is used. Active measures to reduce dose to the MA achieves acceptable dose volume parameters even at escalated doses.
Keywords: Dose escalation, muscles of mastication, oropharynx, tomotherapy
|How to cite this article:|
Chatterjee S, Kelly C, Arunsingh M, Chakrabarty C, Mott J. Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341). J Can Res Ther 2015;11:391-6
|How to cite this URL:|
Chatterjee S, Kelly C, Arunsingh M, Chakrabarty C, Mott J. Feasibility of PET-CT based hypofractionated accelerated dose escalation in oropharyngeal cancers: Final dosimetric results of the VORTIGERN study. (Secondary endpoint of UK NCRI portfolio: MREC No: 08/H0907/127, UKCRN ID 7341). J Can Res Ther [serial online] 2015 [cited 2020 May 28];11:391-6. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/391/157311
| > Introduction|| |
Increased therapeutic index has been demonstrated in the radiation treatment of head and neck cancers with the use of intensity modulated radiotherapy.  We had earlier demonstrated that compared to forward planned conformal techniques, the use of helical tomotherapy in oropharyngeal squamous cell cancers (OPSCC) can increase the uncomplicated tumor control probability (UCP) making dose escalation a possibility.  Recent advancement in the understanding of oropharyngeal cancers have highlighted that apart from higher stage of disease, history of smoking and absence of human papilloma virus (HPV) in OPSCC prognosticates a worse outcome. 
Advancement in imaging technology has enabled radiation oncologists to identify gross tumor volume (GTV) and delineate clinical target volume (CTV) with more accuracy. Within the Vortigern study, we have demonstrated the feasibility of radiotherapy target volume definition using Fluorodeoxyglucose (FDG) based positron emission tomography (PET) and computed tomography (CT).  Such techniques have shown that PET CT based Target Volume delineation in T3 or T4 oropharyngeal cancers lead to smaller volumes when compared to CT based contouring. This has made us to hypothesise that dose escalation in oropharyngeal cancers can be safely attempted, leading to this planning study. In this report we look at the feasibility of dose escalation in oropharyngeal cancers using an accelerated hypofractionated schedule and analyse the dose received by organs at risk with escalated prescribed doses.
| > Materials and methods|| |
Of the 20 patients included in the previously reported Vortigern study,  we selected five patients with node positive oropharyngeal carcinoma. The details of the primary site, T and N stage of these patients are given in [Table 1]. Four plans were generated for each of these patients for the purposes of comparison and analysis of safe dose escalation.
All patients were immobilized using a custom made beam directional shell (BDS). Contrast enhanced CT localization scans, covering the vertex to the upper thorax, were acquired 40 seconds after 70 ml of Omnipaque™ (iohexol) injection using a Somatom Sensation Open wide bore CT scanner (Siemens, Concord, CA). Images were reconstructed with a 3 mm slice thickness and exported to Oncentra MasterPlan.
Target volume definition
Clinical target volumes (CTV) were outlined following a set in-house protocol which was similar to that described in the PARSPORT study.  A CTV (CTV1) defining the high risk area was outlined to include the entire oropharynx and involved nodal stations. All five patients had ipsilateral nodal involvement at level II, with bilateral nodal disease in one case [case 1- [Table 1]]. Given the advanced stage of the primary tumor our CTV1 included bilateral level 2 lymph node and retropharyngeal stations. The uninvolved lymph node stations (Level I-V) were included in a prophylactic CTV (CTV2). To account for the set up and random errors a 3 mm margin was added as per institutional protocol, to the CTV1 and CTV2 to get the planning target volumes (PTV1 and PTV2 respectively). Organs at risk (OAR) included spinal cord, brain stem, bilateral parotid glands, larynx and mandible. For the purposes of this study the apparatus of mastication (AOM) was outlined separately. This included bilateral temporo-mandibular joints (TMJ), bilateral medial and lateral pterygoids, and bilateral masseters and temporalis muscles [Figure 1]. A dose of 65 Gy in 30 fractions was prescribed to CTV 1 and 54 Gy in 30 fractions to CTV2. Three treatment plans were produced for each of these dose levels using three different techniques as described below.
A fourth treatment plan was produced to escalate the dose around the gross tumor volume as detected using a FDG-PET CT scan. Details of the target volume definition process using PET CT scan have been discussed by us in another report.  For the purposes of dose escalation this fourth boost target volume (BTV) was outlined inside the high risk CTV (CTV1). As discussed in our study protocol,  a tumor GTV on PET CT scan was defined by using a cut off of 40% of the maximum Standard Uptake Value (SUV) of the tumor, which was expanded to produce the BTV. BTV was contoured by adding a 1 mm geometric margin around the FDG-PET GTV in all three axes to ensure dose escalation within the high risk PTV. [Figure 2] describes the pictorial relationship between GTV, CTV1 and BTV.
|Figure 2: Representative diagram explaining the CTV delineation for dose escalation|
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- Conventional two-phase (Conv): Many centres around the world treat advanced head and neck tumors using a two-phase photon electron junctional technique. This technique has been discussed in details in another publication  by our team. Parallel opposed lateral photon fields were matched to anterior lower neck photon fields to deliver the required differential dose to the PTV. The anterior lower neck fields were split in order to shield the larynx and trachea where possible, without compromising the target volume coverage. Given the high dose required to bilateral level II areas the posterior border of the lateral photon field was moved anterior to the spinal cord after 40 Gy was delivered and a matched electron field was used to deliver the required dose to the posterior neck without exceeding spinal cord tolerance
- Field in field optimized plans (FIF): A single phase forward planned field in field technique was used to produce the second plan. In summary, the technique used anterior and posterior oblique photon beams with couch twist along with multiple segmented smaller fields to produce a horse-shoe shaped isodose, thereby avoiding high dose to the spinal cord whilst treating the PTV1. The isocentre and segmented smaller fields were adjusted such that (a) the PTV coverage was adequate (b) the doses to the OAR were within tolerance limits and (c) active effort was made to reduce the dosage to the mastication apparatus. A couch twist and floor angle combination along with simple gantry angle changes to the anterior oblique fields allowed more effective MLC shielding of the mastication apparatus and was used to ensure that there was less irradiation of the mastication structures
- Helical Tomotherapy (HT) plans: A detailed account of our treatment planning experience using HT has been reported separately.  In summary multiple assistance contours were developed by the planning physicist, called "dummy volumes" and "ring structures" to ensure adequate coverage of the PTV and improve conformity of the isodoses around the target volumes. Similarly, dose to OARs were optimized with small optimisation dummy volumes. A plan was approved for treatment when at least 95% of PTV was covered by the 95% isodose and tolerances to critical organs like the spinal cord and brain stem were respected. An attempt was made to achieve less than 30 Gy to both parotid glands. Given the paucity of reports discussing dose volume parameters for the mastication apparatus in oropharyngeal cancers, the dose to the mastication apparatus was not optimized in the standard HT plans for these oropharyngeal cancer patients. The dose volume histograms (DVH) of the mastication apparatus were recorded for comparative purposes. A field width of 2.5cm, pitch of 0.286 and modulation factor of 2.4 was used for generating treatment plans. All patients were treated using the HT plans
- A fourth plan was created for the purposes of dose escalation (DE Tomo plans) using helical tomotherapy. Escalation was planned using an accelerated and hypofractionated protocol. Based on a tumor α / β of 10 and late effects α / β of 3, doses of 67.2 Gy, 63 Gy and 56 Gy in 28 fractions was prescribed to PTV1, PTV2 and BTV. The radiobiological rationality of using this regime is discussed in details in a paper by Urbano et al.,  and allowed a 9% increase in dose escalation of the tumor as compared to the dose to the CTV1 and CTV2 equivalent to the standard regime used in our center.
IMRT acceptance criteria: All plans were generated by an experienced physicist and reviewed by oncologists based on set written IMRT protocols. [Table 2] gives the details of the plan acceptance criteria for the study.
|Table 2: Plan acceptance criteria for Vortigern study Dose specification: Targets|
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The dosimetric superiority of CTV coverage by HT plans as compared to 'Conv' and 'FIF' plans have been reported by us in a separate publication.  This report primarily explores the feasibility of dose escalation as discussed above. In order to allow clinical dose escalation it was felt appropriate that the dose received by organs at risk like the AOM, parotid glands, spinal cord and brain stem should be comparable to that received using HT plans treated to standard doses. We therefore compared the dose received by the AOM, Brain stem, spinal cord and parotid glands in DE Tomo plans to the dose received using the other three techniques. The dose to the AOM have not been compared to standard treatment plans, in any previous publications of dose escalation. We separately compared the dose difference of the individual structures in AOM as it was felt that overdose in such structures could lead to clinically unacceptable trismus.
The mean dose to the parotids, AOM, maximum dose to the spinal cord, brain stems and median dose to the PTV were compared. Test of significance was done using the Wilcoxon's signed rank test, assuming the data to be non-parametric (20 plans in 5 patients).
| > Results|| |
All plans fulfilled the criteria for PTV1 and PTV2 coverage as tabulated in [Table 2]. In the Dose escalation plans, the BTV coverage was achieved with at least 95% of the BTV covered by at least 63.84 Gy (95% of the prescribed 67.2 Gy). [Figure 3]a shows the dose distribution when treatment was planned to a prescription of 65 Gy in 30 fractions using Conv, FIF and HT plans. [Figure 3]b shows the dose distribution using the escalated dose. It is worth noting that the escalated dose (67.2 Gy) was prescribed to the BTV but 63 Gy was prescribed to the CTV1, hence the colour wash is normalized to 63 Gy in [Figure 3]b.
|Figure 3: (a) Comparison of dose distribution of the three treatment plans with dose wash normalized to 65Gy in 30 fractions, (b) Dose distribution of dose escalated plan (Normalized to 63Gy)|
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[Table 3] compares the dose received by the brain stem, spinal cord and parotid glands. As expected the dose received to these OARs using helical tomotherapy plans (both HT and DE) were lesser compared to that using forward planned techniques. Reassuringly, the DE plans were not achieved at the expense of increased dose to the parotids, brain stem or spinal cord.
|Table 3: Dose escalation plan compared to HT, Conv and FIF for spinal cord and brain stem doses|
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The plans were then compared with respect to the dose received by AOM. [Table 4] shows the comparison of the Maximum and Mean dose received by these structures using the 4 planning techniques. The maximum dose received by the AOM were comparable between techniques. DE plans produced a statistically significant minimum dose compared to the other three plans for all structures included in the AOM apart from that received by left pterygoids in FIF plans, left masseter in Conv and FIF plans and left temporalis in Conv plans. When we compared the mean dose received by these muscles, there was lower dose received by all the AOMs in DE plans as compared to Conv and FIF plans. There was no statistically significant dose difference in the AOM doses between HT and DE plans.
|Table 4: Comparison of maximum and mean dose to apparatus of mastication between the four techniques|
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| > Discussion|| |
HPV negative oropharyngeal cancers, smokers and locally advanced tumors have poorer clinical outcomes compared to those of earlier stage, HPV positive cancers in non-smokers.  This has necessitated the search for more intensive regimes to treat such tumors. Our study tried to investigate the feasibility of escalating radiation dose using a fractionated accelerated schedule, as used by Urbano et al.,  for cancers involving the Larynx and hypopharynx. In that study the investigators contoured the entire larynx as a target for dose escalation and simultaneous integrated boost was used to achieve a dose of 67.2Gy in 28 fractions. The authors concluded that not only is it feasible and safe but longer follow-up pointed towards better local control of disease.  The concept is now being investigated in a randomized phase 3 study.
In oropharyngeal cancers, the anatomical boundary of the tumor is less well defined and functional organs like the parotid glands are in closer proximity to the boost target volume. The aim of this study was to investigate a feasible method that would be effective in escalating the dose whilst maintaining that there is no compromise in the dose to the functional and critical organs at risk. In an earlier publication,  we had described as to how the use of metabolic imaging with PET-CT could help us define our target volume for dose escalation with more confidence. We showed that FDG PET-CT based target volume delineation in advanced oropharyngeal cancers could enable clinicians to identify smaller treatment volumes compared to the standard CT scan based target volumes. Similarly, in another publication by our team,  we have proven that the use of helical tomotherapy improved conformity indices compared to 3DCRT or FIF techniques. Hence further comparison has not been reported in this study. In this report we have identified a strategy by which the FDG PET-CT directed smaller tumor volumes could be treated to a higher dose without any compromise to the dose received by the parotid glands, spinal cord and brain stem.
It is important to note that the AOM is in close proximity to the oropharynx, making it extremely important for us to ensure that dose received by the AOM was not higher compared to the standard HT treatment plans. Given that the standard practice in the UK and our centre, was not to optimize AOM dose for routine treatment of oropharyngeal cancers, all 5 of our patients were treated with un-optimized AOM dose using standard HT plans. In an earlier report Teguh et al.,  had reported a steep rise in the probability of trismus in patients receiving a dose of more than 40 Gy to the muscles of mastication. During dose escalation, we therefore actively optimized dose to the OAM to ensure the clinical feasibility of such escalation. Such optimized DE plans were comparable to the HT plans ensuring the safety of use of such plans in clinical practice.
This report is one of the first planning safety study detailing the dose escalation of oropharyngeal cancers. In a recent planning study authors have showed feasibility of using Volumetric arc therapy in dose escalation of oropharyngeal cancers.  Two other groups who reported clinical data on escalating dose in head and neck cancers, , have shown clinical feasibility and early results point towards a favourable control of disease with escalated dose. These studies have not reported data on dose received by the AOM and therefore the comparison of such plans to standard treatment plans were not possible. Our study used helical tomotherapy and has clearly shown the feasibility of the escalation with no likely extra normal tissue toxicity.
This dosimetric study proves the feasibility of FDG PET-CT based dose escalation in oropharyngeal cancers. Randomized clinical studies now need to be performed to prove the clinical safety and effectiveness of using such treatment in selected intermediate and poor prognosis oropharyngeal cancers.
| > References|| |
Chatterjee S, Willis N, Locks SM, Mott JH, Kelly CG. Dosimetric and radiobiological comparison of helical tomotherapy, forward-planned intensity-modulated radiotherapy and two-phase conformal plans for radical radiotherapy treatment of head and neck squamous cell carcinomas. Br J Radiol 2011;84:1083-90.
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al
. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35.
Chatterjee S, Frew J, Mott J, McCallum H, Stevenson P, Maxwell R, et al
. Variation in radiotherapy target volume definition, dose to organs at risk and clinical target volumes using anatomic (computed tomography) versus combined anatomic and molecular imaging (positron emission tomography/computed tomography): Intensity-modulated radiotherapy delivered using a tomotherapy Hi Art machine: Final results of the VortigERN study. Clin Oncol (R Coll Radiol) 2012;24:e173-9.
Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al
. PARSPORT trial management group. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomized controlled trial. Lancet Oncol 2011;12:127-36.
Chatterjee S, Mott JH, Smyth G, Dickson S, Dobrowsky W, Kelly CG. Clinical challenges in the implementation of a tomotherapy service for head and neck cancer patients in a regional UK radiotherapy centre. Br J Radiol 2011;84:358-66.
Guerrero Urbano T, Clark CH, Hansen VN, Adams EJ, A′Hern R, Miles EA, et al
. A phase I study of dose-escalated chemoradiation with accelerated intensity modulated radiotherapy in locally advanced head and neck cancer. Radiother Oncol 2007;85:36-41.
Miah AB, Bhide SA, Guerrero-Urbano MT, Clark C, Bidmead AM, St Rose S, et al
. Dose-escalated intensity-modulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2012;82:539-47.
Teguh DN, Levendag PC, Voet P, van der Est H, Noever I, de Kruijf W, et al
. Trismus in patients with oropharyngeal cancer: Relationship with dose in structures of mastication apparatus. Head Neck 2008;30:622-30.
Teoh M, Beveridge S, Wood K, Whitaker S, Adams E, Rickard D, et al
. Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for ¹ 8
F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study. Med Dosim 2013 Spring; 38:18-24.
Lauve A, Morris M, Schmidt-Ullrich R, Wu Q, Mohan R, Abayomi O, et al
. Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas: II--clinical results. Int J Radiat Oncol Biol Phys 2004;60:374-87.
Leclerc M, Maingon P, Hamoir M, Dalban C, Calais G, Nuyts S, et al
. A dose escalation study with intensity modulated radiation therapy (IMRT) in T2N0, T2N1, T3N0 squamous cell carcinomas (SCC) of the oropharynx, larynx and hypopharynx using a simultaneous integrated boost (SIB) approach. Radiother Oncol 2013;106:333-40.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]