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The usual radical radiotherapy treatment prescribed for head and neck squamous cell carcinoma (HNSCC) is 70 Gy (in 2 Gy per fraction equivalent) administered to the high-risk target volume (TV). This can be planned using either a forward-planned photon-electron junction technique (2P) or a single-phase (1P) forward-planned technique developed in-house. Alternatively, intensity-modulated radiotherapy (IMRT) techniques, including helical tomotherapy (HT), allow image-guided inversely planned treatments. This study was designed to compare these three planning techniques with regards to TV coverage and the dose received by organs at risk.
We compared the dose–volume histograms and conformity indices (CI) of the three planning processes in five patients with HNSCC. The tumour control probability (TCP), normal tissue complication probability (NTCP) and uncomplicated tumour control probability (UCP) were calculated for each of the 15 plans. In addition, we explored the radiobiological rationality of a dose-escalation strategy.
The CI for the high-risk clinical TV (CTV1) in the 5 patients were 0.78, 0.76, 0.82, 0.72 and 0.81 when HT was used; 0.58, 0.56, 0.47, 0.35 and 0.60 for the single-phase forward-planned technique and 0.46, 0.36, 0.29, 0.22 and 0.49 for the two-phase technique. The TCP for CTV1 with HT were 79.2%, 85.2%, 81.1%, 83.0% and 53.0%; for single-phase forward-planned technique, 76.5%, 86.9%, 73.4%, 81.8% and 31.8% and for the two-phase technique, 38.2%, 86.2%, 42.7%, 0.0% and 3.4%. Dose escalation using HT confirmed the radiobiological advantage in terms of TCP.
TCP for the single-phase plans was comparable to that of HT plans, whereas that for the two-phase technique was lower. Centres that cannot provide IMRT for the radical treatment of all patients could implement the single-phase technique as standard to attain comparable TCP. However, IMRT produced better UCP, thereby enabling the exploration of dose escalation.
Radiotherapy for head and neck squamous cell carcinoma (HNSCC) entails delivering a high radiation dose (70 Gy in 2 Gy fraction equivalent) to the high-risk area and a prophylactic dose to the cervical nodal chain at lower risk. Treating complex planned target volumes (PTV) while sparing adjoining organs at risk (OAR) can be challenging . The benefits of linear accelerator-based intensity-modulated radiotherapy (IMRT) in improving PTV conformity , and normal tissue complication probability (NTCP) by sparing OAR have been well documented. Several publications have addressed the benefits of IMRT in reducing xerostomia after radiotherapy [3-14].
The development and commercial release of the helical tomotherapy (HT) system by Mackie et al (Tomotherapy Inc., Madison, WI) introduced advanced helical IMRT delivery techniques in combination with integrated image-guidance capability [15,16], providing image-guided IMRT. Helical tomotherapy techniques have been assessed against linear accelerator-based IMRT in head and neck cancers and have been found to produce better homogeneity and normal tissue sparing [17,18]. The adoption of this new technology is limited by the additional resources required, by the need for clinicians to find extra time for outlining target volumes and by the increased physics time required for the complex planning and quality assurance needed for these inverse-planned techniques .
Conventionally, head and neck cancers have been treated with a two-phase technique requiring a junction between a lateral photon field covering the anterior part of the target volume and, during the second phase of treatment, a matched lateral electron field covering the posterior part of the target volume. Mismatch at this junction can lead to overdosage or underdosage, and to a decrease in dose homogeneity in an important area of the treatment volume, including diseased cervical nodes.
Many centres in the UK continue to treat head and neck cancers with this technique. At the Northern Centre for Cancer Care, Newcastle upon Tyne, UK, all patients requiring radical radiotherapy for HNSCC are treated using either helical tomotherapy or a field-in-field forward-planned single-phase linear accelerator-based method. This study compared the dosimetric and radiobiological aspects of three different planning techniques: a forward-planned photon-electron junction technique (2P), a single phase (1P) forward-planned technique developed in-house and HT.
Five patients who had HT treatment for HNSCC were identified. The primary site, TNM stage and dose prescribed to the different PTVs are described in Table 1. All patients were immobilised using a custom-made beam directional shell (BDS) made of polyethylene terephthalate glycol (PTEG). Contrast-enhanced CT localisation scans covering the vertex to the upper thorax were acquired using a Somatom Sensation Open widebore CT scanner (Siemens, Concord, CA) 40 s after the injection of 70 ml iohexol (Omnipaque; GE Healthcare, Waukesha, WI). Images were reconstructed with a 3-mm slice thickness and exported to Oncentra MasterPlan.
The details of our HT planning technique have been discussed in another paper published by our group . In summary, gross tumour volumes (GTVs), clinical target volumes (CTVs), PTV and OAR were outlined by a consultant clinical oncologist using a local protocol. A high-risk CTV (CTV1), comprising the gross primary tumour with adequate margin and the entire involved cervical node level was outlined first, followed by a lower-risk CTV2, which included the uninvolved cervical nodal stations. A 3-mm margin was added to the CTV to get the PTV. OAR that were routinely outlined included the spinal cord, brain stem, bilateral parotids, mandible and larynx. This planning was followed by the creation of additional “dummy volumes” by the planning physicist and dosimetrist in order to achieve an optimised HT plan. HT calculates the multileaf collimator (MLC) position every 7 degrees of rotation, providing very conformal isodose distributions [12,13,21,22]. All five patients were treated on an optimised HT plan.
For the purposes of this study, two further plans using forward-planned techniques were created for each patient, using the same PTVs.
Plan 1 was a two-phase plan designated “Conventional”. Two lateral photon fields (Field 1 and 2 in Figure 1a) were used in the first phase to treat the PTV of the primary tumour and upper neck. The lower neck treatment was planned by using a half beam anterior asymmetric field matched on to Fields 1 and 2 (Figure 1b). The lower neck (prophylactic dose) field was “split” to block the spinal cord, larynx and trachea (Figure 1c), unless such an arrangement impeded the dose received by the PTV, in which case the lateral fields were extended to cover the inferior aspect of the PTV, accepting compromise on the dose distribution. In order to achieve the dose specified for the PTVs without compromising spinal cord tolerance, the treatment was carried out in two phases, requiring a junction between a lateral photon field covering the anterior part of the target volume and a matched lateral electron field covering the posterior part of the target volume administered during phase 2 (Table 1).
This technique has been in use since 2002 at our institution, having been introduced and developed by the authors (CGK) before our department’s acquisition of IMR-capable technology. The technique has recently been modified to allow differential dose prescription to different regions of the PTV. The plan created using this technique involved multiple segmented photon fields and enabled adequate coverage of the PTV in a single phase without compromising the dose to the spinal cord or brain stem. The position of the isocentre was chosen such that it fell within the high-dose PTV. Depending on the shape of the high-dose PTV, the position of the isocentre was adjusted in the supero-inferior, lateral and anteroposterior directions. Moving the isocentre in the superior direction allowed for better, more homogeneous coverage inferiorly. The position of the isocentre was adjusted anteriorly such that there was adequate coverage of level IIB lymph nodes without beam entry through the spinal cord (Figure 2a). The lateral position was restricted such that the isocentre needed to be at least 1.8 cm from the MLC bank to account for accurate calculation using the beam information available. Four gantry angles (typically at 50°, 310°, 130° and 230°) corresponding to two anterior oblique and two posterior oblique angles were set to cover the PTV. If required, a floor twist was added to the posterior oblique fields to enable adequate dose coverage inferiorly without entering through the shoulders. The spinal cord and brain stem were fully shielded on the posterior obliques. These gantry angles were offset slightly to the right or left cervical nodal chains, according to the requirement for more dose. Figure 2b shows the field arrangements for the single-phase plan.
The forward-planned two-phase and single-phase techniques were calculated using Oncentra Masterplan (OMP) software. In OMP, we used the “Pencil Beam” algorithm with a calculation grid of 0.5 cm. The tomotherapy plans were produced using a “Fine” grid and the “Convolution/Superposition” calculation algorithm.
BIOlogical evaluation of PLANs (BIOPLAN) was conceived and developed as a PC-based software that allows the user to evaluate and compare treatment plans in terms of the biological responses of tissues—both tumour and the OAR—to irradiation. In this study, BIOPLAN was used to calculate tumour control probability (TCP) using the Poisson model and NTCP using the Lyman–Kutcher model. Dose–volume histogram (DVH) data were extracted from the treatment planning system (TPS) and pasted into a Microsoft Excel spreadsheet, which was pre-written by staff at the Regional Medical Physics Department (RMPD), in order to parse the data as required by BIOPLAN then re-export in ASCII format ready to be picked up by the BIOPLAN software. BIOPLAN contains a library of model NTCP parameters; for this study, the NTCP was calculated as described by Emami et al  and by Burman et al  (Table 2).
An estimate of the tumour clonogenic cell density is required to calculate TCP. TCP = e-sf.m, where sf is survival fraction and m is clonogenic cell number. Bentzen and Thames  estimated the number of clonogens for a large series of patients with squamous cell carcinoma of the oropharynx as being between 1.8×103 and 6.6×105 cm−3. Other investigators have reported similar values . To assist us in picking a realistic value from within this range, we used BIOPLAN to calculate a clonogenic cell density, assuming an 80% cure probability for a T1 squamous cell carcinoma. These densities were applied to each case, thereby ranking them according to their stage and grade; this provided us with the required densities for the high- and low-dose PTVs.
From the plotted TCP and NTCP (total) data, an uncomplicated tumour control probability (UCP) was calculated as a function of the prescribed dose. UCP = TCP (1 – NTCPTot). UCP values provide an objective function that denotes the biological benefit that could be provided by that particular treatment plan, depending on the TCP and NTCP values. By displacing a vertical line on the plot for TCP and NTCP values in BIOPLAN, the coordinates of the intersecting points on the curves were displayed in the adjacent text boxes, thereby enabling us to calculate an UCP value for a prescribed dose. This tool has helped to predict the outcomes of different prescribing regimes, including those postulated for dose escalation within the UK Clinical Research Network VortigERN study .
To analyse the conformity of the 95% isodose to the PTV, CIs were calculated for all plans in all five patients. CI was calculated for each of the plans using the following formula : CI = PTV (enclosed by 95% isodose)2/PTV (total volume)×volume enclosed by 95% isodose.
The 95% isodoses for the high- and low-dose PTVs are different. We calculated the CI values for the high-dose PTV (65 Gy) so that a unique value of the 95% isodose could be used.
Table 3 shows the maximum, minimum and mean dose achieved in each case using the three different planning techniques. The HT technique produced the most homogenous treatment plans with adequate PTV coverage, although the single-phase technique plans covered the PTV adequately in almost all cases. The PTV coverage and CI were better for the single-phase plans than for the two-phase technique.
Similarly, HT plans were better in sparing the parotid glands and other OAR, followed by the single-phase plans, then the two-phase plans. Table 4 shows the DVH data for the OAR. Dose to the spinal cord and brain stem was similar for the two forward-planned techniques, but the HT plans provided significantly lower doses.
The CIs for each of the plans are shown in Table 3. This confirms the superior conformity of the 95% isodose to the target for HT plans, followed by single-phase and two-phase plans. The integral dose calculated for each of the techniques is shown in Table 5. These calculations show that the single-phase plans delivered a higher integral dose than did the HT and two-phase plans.
HT plans were best in achieving adequate TCP and lowest NTCP in all cases (Tables 6 and and7).7). The single-phase plans had TCP values that were comparable with those of the HT plans. The slightly higher TCP values for Case 2 may be caused by “hot spots” above 107% within the CTV, which would have driven up the calculated TCP in marginal cases of good overall dose coverage. Conventional two-phase plans had the least TCP and the highest NTCP values.
Figure 3 shows the UCP values for Case 4, representing the therapeutic indices for the three plans. It is clear from the UCP plots that the HT plan has the highest UCP resulting from much lower NTCP values.
With the possibility of increased therapeutic index with HT treatment, we explored the TCP values that could be achieved with dose escalation. The Royal Marsden Hospital has explored the dose-escalation schedule for squamous cell carcinomas of the hypopharynx , whereas we used a similar dose-escalation protocol for oropharyngeal primaries within the VortigERN study . None of the five cases described here were re-planned to the escalated dose using HT. However, we used BIOPLAN software to calculate the UCP, TCP and NTCP values for the GTV and parotid glands when prescribing a dose of 67.2 Gy in 28 fractions to the tumour, thereby delivering a 9% increase in dose to the primary tumour based on a tumour α/β of 10 and late effects α/β of 3. Table 8 confirms the raised UCP values for HT plans using 67.2 Gy in 28 fractions and provides theoretical confirmation of the possible benefits of dose escalation.
It is clear that HT plans provide the best conformity of the three techniques. Previous studies have demonstrated the superiority of inverse-planned IMRT techniques in the treatment of head and neck tumours [31,32]. This study compares HT treatment to the conventional two-phased photon electron junction technique and a forward-planned single-phase field-in-field photon-only technique. The latter is a safe technique that is easy to implement, is within the tolerance limits of the spinal cord and could be considered for routine use for all non-inverse-planned IMRT head and neck cases. This single-phase technique has the added advantage of reliable and reproducible dosimetric verification checks, which may be difficult to achieve in a two-phased photon electron junction approach. The DVH analysis and TCP values reported here indicate that the single-phased techniques provide better conformity than do the two-phased techniques. This single-phased technique can therefore be implemented by centres that lack the resources necessary to implement inverse-planned IMRT techniques for all the head and neck cancer cases. The disadvantages of the single-phase technique include higher doses to the OAR, including the parotid glands, when compared with HT.
Comparison of the NTCP data confirms the superiority of the HT technique in reducing the NTCP and improving the UCP. The high UCP values provided by HT make dose-escalation techniques possible, and the TCP and NTCP values confirm the possibility of improved outcomes. Centres using inverse-planned IMRT techniques should explore such dose escalation within a controlled trial setting. At the Royal Marsden Hospital, a Phase 1 study for patients with hypopharyngeal cancer has been conducted, in which the PTV1 (high dose) was treated with a dose of 67.2 Gy in 28 fractions and the PTV2 (prophylactic dose) with 56 Gy in 28 fractions . In the VortigERN study, a 5-mm isotropic margin was outlined around the GTV (both primary and nodal) to create a PTV3. For dose escalation in the oropharynx, consideration needs to be given to the pharyngeal constrictor muscles, the temporo-mandibular joint and the muscles of mastication. These were outlined in the VortigERN study to evaluate the feasibility of future Phase 1 and Phase 2 clinical studies. We are exploring the doses to these extra OAR in another in-house study.
Cold spots will rapidly drive down the TCP, which cannot be rescued by hotspots at different locations in the PTV. It is interesting to note that although HT treatment might be expected to deliver a higher integral dose per plan, the single-phased technique actually seemed to have a higher integral dose. Although the concepts of higher integral dose [33,34] and second malignancies are debatable, this study highlights the fact that current forward-planned techniques may not be delivering lower integral dose than inverse-planned HT techniques in complex head and neck treatment plans.
It is worth noting that recent QUANTEC publications [35-37] have described a predictive model based on pooled data from multiple studies. The tolerances described in these papers are slightly different to those discussed by Emami et al . Although the possible limitations of QUANTEC studies have been highlighted , the new data may well be more accurate clinically. We did not base our calculations on these new values, although we understand that they could provide changed NTCP values for the DVH generated in the plans. This could well be a limitation of our study. On the other hand, we tried to keep our calculations pure and used BIOPLAN to calculate the NTCP values as described by Sanchez-Nieto and Nahum . In addition, it is worth noting that the HT plans were calculated using a different planning algorithm and grid than that used for the forward-planned techniques. This could mean that the DVH could have had some inherent differences originating from the differences in planning systems.
In conclusion, while confirming the superiority of HT plans in treating head and neck tumours, our study establishes the role of a single-phase photon-only technique in this context. This technique could be used as a standard technique for managing head and neck tumours in departments that lack the resources necessary to implement inverse-planned approaches for all patients.