42 03

One may decrease the dose to the masseter muscle significantly with IMRT by putting a constraint on the masseter muscle (Fig. 42.36).

Speech and Quality of Life

For technical treatment planning reasons, voice, and speech can be affected at the time of the actual treatment of cancers in the oropharynx and during the follow-up period. In a recent article by van Gogh et al. (104), the authors also concluded that deviant voice quality can also lead to limitations in social life (302,303). A robust, short, five-item questionnaire was suggested to be able to detect voice deterioration and differentiate this in a busy outward clinic from a cancer in the larynx (104,152).

Dysphagia and Quality of Life
Swallowing function may be affected adversely by surgical and nonsurgical treatment of advanced oropharyngeal cancer (281). Gastrotomy tube (G-tube) dependence 6 to12 months after surgical management varies in the literature between 6% and 39% (75,280). Rates of swallowing dysfunction after chemoradiation are less well defined; G-tube dependence varies between 13% and 64% at short-term follow-up and between 13% and 33% at long-term follow-up (94,107,185,215,216,221,265). In general, after long-term follow-up (>1 year), one third of patients were reported to be G-tube–dependent (BOT 67% vs. TF/SP 25%; p = .049). The swallowing apparatus, being the wall of the pharynx (Fig. 42.37), is composed of two layers of muscles: the external three constrictor muscles (superior, middle, and inferior constrictor [with its cricopharyngeal and thyropharyngeal part]), the circular fibers of esophagus inlet, and the internal longitudinal levator muscles (stylopharyngeus and palatopharyngeus muscles). Deglutition or swallowing is a complex act of these seven muscular structures.
A study was recently initiated in Erasmus MC to get more insight in the problem of dysphagia. First, the components of the swallowing apparatus were determined and delineated on CT. After delineation, dose-volume histograms were constructed and mean doses calculated for every muscular structure. Fifty-five patients with cancer in the oropharynx who were treated


between 2000 and 2005 in Erasmus MC were used to study the problem of dysphagia in more detail. All patients were asked to respond to validated questionnaires PSS, EORTC H&N35, and the MD Anderson Dysphagia Inventory (Fig. 42.38). Using a univariate ordered logistic regression analysis technique, it was found that the probability for having serious complaints with swallowing increases significantly with dose (Fig. 42.39), but interestingly, this was significant for the superior and middle constrictor muscles. A multivariate analysis showed that the only significant factor was BT (dose). However, given the tight enveloping nature of the deglutition musculature, it needs very sophisticated three-dimensional treatment planning to spare the constrictor muscles without compromising on the dose to the primary tumor.

Brachiterapia
The history of BT dates back to the beginning of the 20th century, when the first BT procedures were performed using Radium-226 needles. Brachytherapy (“brachy” = Greek for “short”) is a treatment modality in which the tumor is irradiated by positioning the radioactive sources very close to (mould or endocavitary techniques) or even inside the tumor volume (interstitial implant), either by permanent (seed) implant or by temporarily inserted applicators or afterloading catheters. In principle, BT is a conformal type of radiation therapy technique. In recent years, artificial radionuclides such as Cs137, Co60, I125, and Ir192 have become available. Manual afterloading of the sources into applicators or afterloading tubes replaced direct loading of sources into the patient. The French developed the so-called “Paris system” for low-dose-rate dosimetry purposes; that is, for parallel-equidistant sources, the system suggests specifying the dose of the implant as being 85% of the average dose in the basal dose points (local minima). A similar type of dose prescription is used for HDR BT (Figs. 42.40 and 42.41). Also, computer-controlled afterloading devices, supported by sophisticated treatment planning software with optimization capabilities, became available. The BOT implant consists of afterloading catheters after the percutaneous introduction of trocars in a submental or submandibular approach (Fig. 42.42) (103). For patients with disease extension toward the pharyngoepiglottic fold, lateral loops are added. The spacing between each end of the “looping” catheters running over the dorsum of the tongue is ±1 cm. As a safety precaution, when removing the implant, a temporary tracheostomy is sometimes performed in patients immediately before the implantation. A typical case for fractionated HDR TF and SP implant is depicted in Figure 42.41. In the majority of cases, two to three catheters are implanted in TF and faucial arches (Fig. 42.41, inset). A temporary nasogastric feeding tube is placed at the completion of most of our BT procedures. Lo sviluppo


of radiobiologic models enables one to predict to a certain extent the tumor control probability and normal tissue complication probability after the application of BT, much depending on factors such as fraction size, dose rate, the tumor, and the normal tissues one is dealing with. Temporary BT has been used with several dose-rate categories.
The French have published extensively on interstitial radiation therapy of TF and/or SP tumors, as well as on cancers of the BOT (32,60,69,79,86,98,139,175,201,229,235,236,249,274,327); most of these data regard LDR implants. For example, Mazeron et al. (199) report on a subset of patients with early-stage (T1, T2) tumors of the TF and/or SP, with a LC rate of approximately 85%, that is, a regional control rate of 97% for N0, and 88% N1–3 disease. Patients were typically treated by 45 Gy EBRT and a 30 Gy LDR Ir192 boost. Soft tissue ulceration occurred in 17 patients. Similar locoregional control rates were reported by Pernot et al. (235,236) (LC LDR boost TF/SP T1, T2N0 tumors 90% vs. T1, T2N1–3 86%) and Levendag et al. (175,177) (TF and/or SP tumors LRC 87% at 5 years). The series of patients in Rotterdam were treated by fractionated HDR BT (daytime regimen) or PDR (24 hours regime) (Table 42.18). Esche et al. (79) described 43 patients with carcinoma of the SP and uvula with LC rate of 92%. Overall survival was 60% at 3 years and 37% at 5 years. The cause-specific survivals were 81% and 64%, respectively. The leading cause of death was other aerodigestive cancers (these cancers occur with an actuarial rate of 3% per year posttreatment). The “BT school” of Memorial Sloan Kettering Cancer Center in New York pioneered large-volume implants in particular for cancer of the BOT, a technique initially designed by Vikram and Hilaris (307) and Vikram et al. (308). Harrison et al. (120,121,125,127) elaborated on cancer of the BOT and also related outcomes to QOL. Some of the control rates with IRT can be taken from Table 42.11 (TF/SP) and Table 42.14 (BOT). In skillful, well-trained, hands, BT remains an extremely gratifying technique for applying high doses of radiation for small-volume disease located in the midline (eg, SP tumors) with (in case of fractionated HDR) highly conformal and accelerated properties.
Finally, IRT can also be a very rewarding technique, given the high doses in small-volume disease and the rapid dose falloff in the treatment of recurrent cancers and/or in case of reirradiation (58). For the future, image-guided BT will become routine; summation of dose distributions of BT and EBRT will become mandatory (Fig. 42.43). Moreover, by the development of soft x-ray sources and afterloading machines that carry multiple sources and have multiple drives, the flexibility of intraoperative BT has increased. One of these sources that is currently being tested is yyterbium (169).

Chemotherapy Targeted Therapy, and Altered Fractionation Regimes
Concurrent CHT and altered fractionated irradiation have shown independently to improve the outcome for head and neck cancer patients. The combination maximizes the chance for preservation of organ function and has the potential to improve the results even more by integration with new biologic agents (10,36,187,206,261,264,288). Many of the hyperfractionated and/or accelerated schedules have resulted in improved locoregional control. Concomitant CHT appears to result in improved LRC and OS, in contrast to neoadjuvant CHT and maintenance CHT (22,42,217). Not infrequently, these treatment regimes increase toxicity as well. Finally, the role of intra-arterial CHT (206,213,257) as well as the benefit of induction (neoadjuvant) and adjuvant CHT remains to be determined. In their concise review on randomized trials concerning multimodality treatment approaches, Bernier and Bentzen (22) emphasized that, to maximize outcome, each of the components of a particular treatment regime needs to be optimized separately. Importantly, Benasso et al. (20) and Taylor et al. (295) conducted multivariate analyses of patients treated in chemoradiotherapy head and neck trials, and pointed out that the second most important prognostic factor is the experience of the Center.
Regarding the effects on OS and locoregional control by altered fractionation and/or concomitant CHT, in 2004 Rosenthal and Kian (261) made some recommendations for treatment selection: conventional fractionation (and dose) for T1 and favorable T2N0,1 tumors, altered fractionation for unfavorable T2 or exophytic T3N0,1 (with or without neck dissection in case of N2,3 disease), and concurrent CHT for the more advanced cancers. Meanwhile, toxicity amelioration and identification of predictive biomarkers and effective molecularly targeted therapy should be pursued (261,292). Salama et al. (264)


published on aggressive trimodality treatment for the subset of patients with recurrent and/or second primary cancers in the head and neck. They evaluated 115 patients treated with a median lifetime radiation dose of 131 Gy. The locoregional control, OS, and freedom from distant metastasis rate at 3 years were 22%, 51%, and 61%, respectively. However, of note is that 19 patients died of treatment-related toxicity, 5 of these because of carotid blow-out. Suntharalingam (292) reviewed the early trials in 2003. Recognizing the mostly nonspecific nature of the toxicities of healthy tissues consequential to combined modality therapy, he argued that the real focus should be on researching newer biologic agents, targeting cellular protein receptors. Epidermal growth factor receptor is one of these receptors critical to cellular proliferation, differentiation, and survival. As it has been shown to be widely expressed in SCC cells of the head and neck, it was suggested that anti–epidermal growth factor receptor therapy could become a powerful agent in combined modality therapy in the future.

Nonrandomized Studies
Some of the studies reviewed in this section are designed to treat advanced cancers in the head and neck in general and not focused solely on tumors in the oropharynx. As has been shown by the meta-analyses, concomitant CHT and/or altered fractionation result in improved locoregional control and OS, but also a substantial amount of toxicity has been observed (35,238). In fact, with regard to concomitant CHT, Pignon and Bourhis (238) showed at 5 years an 8% increase in OS and a hazard ratio of 2.17 for overall toxicity. Harrison (128) published the results of a phase II trial treating 82 patients with unresectable head and neck cancer using the delayed concomitant boost technique with concurrent cisplatin. The 3-year LC for oropharynx cancers was 64%. Twenty-four percent of patients required a treatment break. Two deaths due to sepsis occurred during treatment. Severe chronic toxicity occurred in three patients: one osteoradionecrosis, one frontal lobe necrosis, and one case of lung toxicity secondary to adjuvant CHT. Bieri (25) reported on delayed concomitant boost radiation in which a planned total dose of 69.6 Gy was given in 5.5 weeks; one third of the patients received concurrent cisplatin-based CHT. Among the 55 patients with oropharynx carcinoma, LRC at 3 years was 69.5%. Eighty-two percent experienced grade 3 and 4 mucositis. Patients receiving CHT had more grade 3 dysphagia (68% vs. 25%; p = .003), hospitalization (37% vs. 14%; p = .08), and a need for nasogastric tube (68% vs. 22%; p = .001). Nathu (214) published the results of induction CHT followed by RT for patients with oropharyngeal carcinomas treated at the University of Florida. Neoadjuvant CHT consisted of cisplatinum (100 mg/m2) and 5-fluorouacil (1.0 mg/m2/day × 5 days) for three cycles, and was followed by definitive RT (83% received hyperfractionated RT from 74.4 to 81.75 Gy). Outcome was compared with oropharyngeal tumors treated with a similar radiation regimen, but without CHT. Multivariate analysis showed no difference in local failure or distant failure. However, disease-specific survival and OS were improved in those who received induction CHT (58% vs. 27% and 42% vs. 17%, respectively). Because of the nonrandomized nature of the study and the lack of statistically significant improvement in parameters of tumor control, the authors cautioned against any conclusions regarding the benefit of induction chemotherapy.
A phase II study on 61 patients with advanced oropharyngeal carcinoma using induction chemotherapy followed by concurrent chemoradiation was reported by Vokes (309). Neck dissections (n = 35) were performed for N2 to N3 disease. At a median follow-up of 39 months (68 months among survivors), LRC was 70%, distant metastasis-free survival was 89%, disease-free survival was 64%, and OS was 51%. Acute toxicity was substantial, with severe or life-threatening mucositis and leukopenia during the induction phase, whereas 81% had grade 3 or 4 mucositis during the concurrent chemoradiotherapy. The authors concluded that the treatment sequence of induction chemotherapy followed by concurrent chemoradiotherapy and optional organ-preservation surgery is promising but that less toxic regimens need to be identified. Bensadoun (21) reported on 54 patients with unresectable oropharynx and hypopharynx carcinoma treated with concomitant hyperfractionated radiation (75.6 to 80.4 Gy) and three cycles of 5-FU/cisplatin in weeks 1, 4, and 7. Four percent mortality was observed from treatment related septicemia, 86% grade 3/4 mucositis but no patient required a treatment break greater than 4 days because of


mucositis. Grade 2 xerostomia was observed in 70% of the patients and grade 2 cervical fibrosis in 45% of the patients. At a median follow-up of 16 months, disease-specific survival was 72%.
There are many other examples of chemoradiotherapy regimen for oropharyngeal carcinomas with encouraging LRC rates, but with short-term follow-up and/or too small patient numbers (10,100,187). A promising approach was presented by the Memorial Sloan Kettering Cancer Center. Arruda et al. (62) studied 50 patients treated by IMRT in conjunction with concurrent CHT (86%). At 2 years, local progression-free OS and distant metastases-free survival is 98%, 98%, and 84%, respectively. Six of 42 patients remained with their percutaneous endoscopic gastrostomy until the time of analysis.
Randomized Trials
A prime example of a multinational, randomized trial of molecularly targeted therapy is the study by Bonner et al. (33) that was recently published in the New England Journal of Medicine. It compares patients with advanced cancers in the head and neck treated with high-dose RT alone (n = 213) or with RT plus weekly cetuximab, a monoclonal antibody against epidermal growth factor. The outcome of the study showed a significant improvement of locoregional control (hazard ratio locoregional progression or death 0.68; p = .005) and OS (49 months for combined therapy vs. 29.3 months for RT alone [hazard ratio for death, 0.74; p = 0.03]). It reduced mortality without increasing the common side effects of radiation. Studies for future targeted therapies combining cetuximab with chemotherapeutic agents such as Taxotere, cisplatin, and 5FU are now underway. Concurrent CHT with hyperfractionated radiation was explored by Brizel (36) in a phase III randomized trial. One hundred sixteen patients with advanced head and neck cancer were randomized to hyperfractionated radiation alone treated with 1.25 Gy twice daily 5 days per week to 75 Gy during a 6-week period versus a concurrent CHT arm consisting of 5-FU/CDDP given on weeks 1 and 6 of split-course hyperfractionated radiation. Both groups received two adjuvant courses of 5-FU/CDDP after completion of radiation. At a median follow-up of 41 months, the concurrent CHT showed improved LRC (70% vs. 44%; p = .01) and a trend toward improved 3-year OS (55% vs. 34%; p = .07) and relapse-free survival (61% vs. 41%; p = .08). However, patients in the chemoradiotherapy arm developed more acute toxicity, including the requirement for more feeding tubes (44% vs. 29%) and worse hematologic suppression. Chronic toxicity was no different, with about a 10% incidence of necrosis of the skin or bone in both arms. The trial has been criticized, not only for the added toxicity, but also because of the imbalance in the proportion of advanced neck disease (44% vs. 63%) treated in the concurrent chemoradiotherapy, which may have accounted for the difference in LRC. Jeremic (148) reported a phase III randomized study testing whether daily low-dose cisplatin improved outcome for patients undergoing hyperfractionation radiation compared with those treated with the same hyperfractionated radiation alone in locally advanced head and neck cancers (37% were oropharynx). One hundred thirty patients with stage III or IV disease were randomized to 1.1 Gy twice daily to 77 Gy per 7 weeks with or without cisplatin (6 mg/m2/day). At a median follow-up of 79 months, the investigational arm showed improved LRC (50% vs. 36% at 5 years; p = .041), progression-free survival (46% vs. 25% at 5 years; p = .0068), and OS (46% vs. 25% at 5 years; p = .0075), and fewer distant metastases (14% vs. 43% at 5 years; p = .0013). Daily concurrent CHT was well tolerated, with no increase in acute grade 3 mucositis and esophagitis. There were no increases in late skin or severe effects to bone or salivary gland. A multicenter randomized trial reported by Staar (288) tested whether the combination of hyperfractionated accelerated radiation (69.9 Gy/5 × 5.5 weeks) with carboplatin (70 mg/m2) and 5-FU (600 mg/m2/day × 5 days) on weeks 1 and 5 of RT improved outcome compared with the same radiation regimen alone. At a median follow-up of 22 months, the 1- and 2-year respective rates of LRC were 69% and 52% after chemotherapy/RT compared with 58% and 45% after RT alone (p = .14). Patients with oropharyngeal carcinomas had a trend toward improved 2-year LRC with chemoradiotherapy compared with RT alone (51% vs. 42%; p = .07).
Another German multicenter randomized trial compared hyperfractionated accelerated radiotherapy alone (77.6 Gy) with hyperfractionated accelerated radiochemotherapy (70.6 Gy) using mitomycin C and 5-FU (130). For patients treated inside the trial, no significant difference in survival was observed. A randomized phase II EORTC trial explored the feasibility of concomitant cisplatin and RT with conventional fractionation or multiple fractions per day (MFD). The MFD schedule was designed to achieve higher tumor concentrations of cisplatin at the time of irradiation by reducing the number of radiation treatment weeks from 7 to 3. No difference in acute and late side effects in both treatment arms while better tumor response was obtained with MFD. It is argued that the better tumor response in the MFD might be due to a (67%) higher daily dose of cisplatin concomitant with RT being given in a 3-week period (13). Hao et al. (119) updated the meta-analyses outcome of concomitant CHT trials to date in SCC of the head and neck. They confirmed an 8% benefit in 5-year absolute survival. Toxicity in general seems to be more pronounced with combined modality regimens using hyperfractionated RT or when the concomitant CHT regimen included carboplatin plus 5-FU. Several other randomized studies (eg, Horiot et al. [139] or Fu et al. [93]) have demonstrated the beneficial effect of hyperfractionation and/or accelerated fractionation over standard fractionation. Also, Calais (42,43) demonstrated better locoregional control when altered fractionation is used with concurrent CHT. According to Hao et al. (119), the current state of the evidence supports strongly to offer platinum-based concurrent CHT with conventional fractionated RT as a treatment option for patients with advanced head and neck cancers treated outside a clinical trial.
Three-Dimensional Conformal RTIMRT
The introduction of the multileaf collimator and three-dimensional treatment planning systems (TPS) in the 1990s has been instrumental for the development and application of three-dimensional conformal radiation therapy and IMRT. The major advantages of IMRT for irradiation of the complex head and neck anatomy are now generally recognized. The possibility of tightly shaping the higher isodose surfaces around the often concave target volumes allows for substantial sparing of critical structures. The use of electrons for irradiating the posterior neck, without exceeding the cord dose, has become almost obsolete. In this section, procedures are described for a safe and beneficial application of this powerful tool with focus on the IMRT techniques as used in the Erasmus MC.
IMRT
Pianificazione del trattamento
In the Erasmus MC, in case of radical radiation therapy of oropharyngeal cancer, IMRT is used to deliver a total dose of 46 Gy, 2 Gy per fraction, 6 fractions per week, to the primary tumor and neck, generally followed by a BT- or CyberKnife boost (Fig. 42.19). In line with the International Commission on Radiation Units and Measurements criteria for dose homogeneity in the PTV, it is generally required that 100% of the PTV must


obtain more than 95% of the prescribed dose (143), although small underdosages (eg, around the salivary glands) are acceptable in specific cases. Tolerating minor PTV underdosages has also been described by Fogliata et al. (83) and Wu et al. (325). Recently, we have studied this trade-off between full PTV coverage and sparing of the parotid glands, using a model for calculation of the subclinical disease control probability (163). For the patients in the study, the mean parotid gland dose decreased by more than 10 Gy by allowing for a small underdosage in the PTV, corresponding with a reduction in the calculated subclinical disease control probability of typically 1% and a little higher.

The applied planning constraints for the critical structures for IMRT as used in Erasmus MC are presented in Table 42.19 and compared with the RTOG H-0022 protocol (247). For plan design, the constraints for the cord and the PTV are overriding, and the criteria for the parotids and oral cavity are planning objectives rather than hard constraints. To create a safety margin, the cord constraint is set for the spinal canal, rather than for the cord per se.
Depending on the patient geometry, different planning strategies are used. The most favorable strategy is to spare both parotid glands. This is done using a nonequiangular, five-field technique, with gantry angles of 0 degrees, ±60 degrees and ±140 degrees (optimized for each individual patient), using 6-MV beams. Especially when the boost is also delivered with IMRT, significant sparing of both parotids is frequently not feasible. It may then be decided to largely relax the constraint for the ipsilateral parotid gland and to focus on sparing of the contralateral gland. Generally, a nonsymmetrical four-field technique is then applied, with two parallel-opposed beams at gantry angles of around 350 degrees and 160 degrees (or 10 degrees and 200 degrees, depending on tumor position). With such an approach, that is, sparing of a single parotid gland structure Eisbruch et al. (73) observed a salivary flow increase after 2 years.
In the absence of positive nodes, the lower neck region is treated with two non-IMRT anterior fields, positioned on either side of the cord with sparing of the larynx (midline block) (Fig. 42.33). The International Commission on Radiation Units and Measurements dose homogeneity criterion is then less strictly enforced. Another technique to cover the lower neck region is to extend the upper IMRT fields.
Figures 42.27 and 42.30 show a five-field technique (0 to 46 Gy) for a patient with a TF tumor (T2N1) to be treated by RT to the primary and bilateral neck. For this bilateral parotid sparing treatment plan, mean doses to the parotids are 22 and 23 Gy, respectively. For comparison purposes, Figures 42.28 and 42.31 show a treatment plan with focus on maximum sparing of the contralateral parotid, yielding mean doses of 17 Gy (contralateral parotid gland) and 30 Gy (ipsilateral parotid gland).
Patient Setup Verification, Correction, and PTV-Margins
IMRT is most effective when used in combination with narrow PTV margins that have to be in line with the geometrical uncertainties for the patient involved. This implies a proper knowledge of the setup variations. Each patient has a setup error that occurs during all fractions (the systematic or mean error) and day-to-day variations around this mean setup error (the random errors) (26,278). By its nature, the systematic error of an individual patient can be obtained only from measurements during each fraction, and is therefore not known at the time of treatment planning. The setup uncertainties are generally quantified by three standard deviations Σx, Σy, and Σz, describing the distribution of systematic setup errors in the patient group, and the standard deviations σx, σy, and σz that represent the day-to-day variations. For head and neck cancer patients, these standard deviations are mostly derived from measurements with electronic portal imaging devices (EPIDs). Stroom et al. (289,290), from our institution, derived for each direction, i, the required PTV margin, Mi, given by:
Mi = 0.7•σI + 2•Σi.
In this approach, the PTV margin of each new patient is fully based on setup measurements performed for previously treated patients. The formula reflects the idea that systematic errors, potentially leading to an underdosage of a specific part of the tumor in all fractions, are more severe than random errors. The equation was confirmed by the work of van Herk et al. (132). Setup errors can be minimized using EPID measurements and a correction protocol. Deviations in the patient setup are then quantified by comparison of the EPID images with digitally reconstructed radiographs derived from the planning CT scan. It is essential that the demarcations on the patient's skin or mask, used for setup at the linac, are in exact agreement with the isocenter of the planning CT scan. These demarcations should not be adjusted in a session at a conventional simulator, neither should verification be based on acquired simulator images (19). In an online protocol, the patient setup error is assessed in each fraction using a few monitor units (MUs), followed by a subsequent correction and delivery of the remainder of the MUs. With such a protocol, both the systematic error and the random component can be substantially reduced. However, a disadvantage of online protocols is the involved workload at the treatment unit and the unavoidable increase of the fraction time. For this reason, so-called off-line protocols are more often applied than online protocols. In an off-line protocol, EPID images are only acquired in a limited number of fractions, and all image analyses are performed off-line, that is, not during the time of the delivery of the fractions. The latter excludes the possibility of reduction of random errors, which is


of lesser relevance for the determination of the required margin (equation). Instead, the aim of an off-line protocol is to reduce the more important systematic patient setup errors by estimating the optimal a priori setup correction for subsequent fractions.

In the Erasmus MC we have developed and implemented the no-action level (NAL) protocol for off-line corrections (63), which is now applied for most patient groups, including those with oropharyngeal cancer. For each patient, the protocol starts with acquisition of EPID images during the first Nm fractions (Erasmus MC Nm = 2 for head and neck sites), without applying any setup corrections. The involved systematic setup error for the complete fractionated treatment is then estimated by calculation of the mean setup error in these first Nm fractions. In the remainder of the fractions, the patient is first set up using the (original) marks on the patient mask. Then, prior to dose delivery, an a priori setup correction is performed as prescribed by minus the (estimated systematic error), followed by irradiation; no images are acquired. The first application of the NAL protocol for head and neck cancer was described by de Boer et al. (65). The patients in this study were treated with parallel-opposed laterals, and the NAL protocol was therefore only applied in two directions. Table 42.20 shows the setup errors for IMRT patients, as derived in a recent analysis (not published). As previously outlined, for each patient, the setup correction is based on an estimate of the systematic setup error, derived from measurements in only two fractions. As a consequence, application of the NAL protocol will diminish the systematic errors, but not cancel them out. In Table 42.20, both the distribution of the residual systematic errors, ΣNAL, and the distribution of (calculated) initial systematic errors, Σinit, that would have occurred without application of NAL, are presented. The presented margins are calculated with the equation provided. In clinical practice, margins of 5 mm are used for all directions, leaving some room for delineation uncertainty. Recently, the NAL protocol has been extended (eNAL) to systematically update setup corrections based on weekly follow-up measurements (64).

Dosimetric Quality Assurance
In our institution, IMRT is delivered with dynamic multileaf collimation (DMLC), using the sliding window technique. Because of the complexity, a dedicated quality assurance (QA) protocol is instituted, supplementing the QA procedures for non-IMRT treatments. All involved dosimetric measurements for IMRT are performed with EPIDs (Fig. 42.44) (89,90,131). For daily linac QA, the sliding-gap method as proposed by LoSasso et al. (181), measuring the leaf positioning accuracy with an ionization chamber for a single leaf pair, has been extended to two-dimensional, using the EPID (305). The measurements take 3 minutes, including the analyses. Errors in leaf positioning as small as 0.1 to 0.2 mm can be detected. Apart from the daily verification of the leaf motions, QA procedures are performed for each individual IMRT patient (228,304,306,328,329). These procedures aim at (a) verification of the final TPS dose calculation for the optimized treatment parameters such as the leaf


trajectories, and (b) verification of the correct execution of the plan at the linac. Currently, the TPS dose is only verified by an independent dose calculation for a single or few points in the center of the tumor. A fully three-dimensional procedure is being developed. For verification of the correct fluence delivery at the linac, EPID dose measurements are performed both prior to the first treatment fraction (pretreatment verification [229,306]), and during treatment (“in vivo” verification [305]). For pretreatment verification, portal dose images (a two-dimensional dose distribution in the plane of the fluorescent screen of the EPID) measured with the EPID are compared with predictions. Differences point at errors in leaf sequencing, data transfer from the TPS to the linac, or to dosimetric/mechanical linac performance problems. Presently, portal dose image comparison (Fig. 42.45) has been fully integrated in the applied EPID software (Theraview NT, Cablon Medical, Heusden, The Netherlands); a method for automated image analysis also has been implemented. Images are only reviewed by a physicist in case of a failure to pass the automated test. Because of the high spatial resolution, EPIDs are suited for detection of tongue-and-groove underdosage effects. For a group of 270 IMRT patients, the pretreatment procedure has revealed four serious errors prior to the start of treatment (329). Recently, methods have been developed for back-projection of fluence profiles, measured with the EPID, in the planning CT scan or in an in-room acquired cone beam CT scan, allowing full three-dimensional analyses (328).
Deviations in in vivo measured PDIs may be due to errors in fluence delivery, but may also be caused by changes in patient anatomy or variations in patient setup. To discriminate between the two, the split IMRT field technique (305) has been developed, which is now routinely applied for all head and neck cancer patients.

Alternative IMRT Approaches
Beam Orientations
Instead of dedicated orientations, often a relatively large number of equiangular beams are used. Whereas some articles report techniques with seven equiangular beams for oropharynx tumors (62,239), others advocate nine beams (324). Generally, an odd number is used to avoid opposing beams.
Simultaneous Integrated Boost
For oropharyngeal cancer patients treated in the Erasmus MC, the boost is generally delivered with BT or the CyberKnife after 46 Gy. When using IMRT for full-dose delivery, a simultaneous


integrated boost technique may be applied (166,247,325). The involved simultaneous optimization of the large field and the boost technique does generally result in superior plans, compared with sequential optimization (211). With the simultaneous integrated boost technique, an enhanced fraction dose may be selected for the primary tumor, yielding two simultaneous opportunities for biologic dose escalation: a shortening of the total treatment duration and an increased LC as a result of the higher daily tumor dose. However, the possibilities for application of escalated fraction doses are limited by the risk of increased toxicity (166,325). Alternatively, to minimize complications, the fraction dose in the elective regions may be reduced. The current RTOG study H-0022 applies a simultaneous integrated boost technique, prescribing a GTV total dose of 66 Gy at 2.2 Gy/fraction, and a dose for the subclinical disease region of 54 Gy (1.8 Gy/fraction) (247).
Plan Optimization and Evaluation Using Radiobiologic Models
Instead of using dose- and dose-volume–based objectives and constraints, plan optimization and evaluation can, in principle, also be done using radiobiologic criteria such as the tumor control probability, normal tissue control probabilities, and the equivalent uniform dose for the tumor and organs at risk. For the head and neck region, several parameter sets for biologic models exist, derived from observed tumor control and toxicity data (76,77,259,269) (also used in tumor control probability/normal tissue control probabilities calculating modules [315]). Unfortunately, the results vary considerably with the applied parameter set: for a group of oropharynx cancer patients, van Vulpen et al. (310) reported predicted normal tissue control probabilities differences for the parotid glands ranging from -3% to +35% when applying different parameter sets. To our knowledge, articles describing a decisive role in clinical decision-making for the treatment of oropharyngeal cancer patients have not yet been published.
Step-and-Shoot or Segmental IMRT (SMLC)
Apart from the DMLC technique, intensity-modulated profiles can also be generated by sequential delivery of static field segments, with a variable shape and number of monitor units (SMLC). In the transition period from end of delivery of one segment to shaping of the next segment, the beam is switched off. DMLC allows for more precise realization of the optimized fluence profiles. However, some studies have concluded that the differences are of minor clinical importance (4,55,83). It has also been reported that DMLC treatments require more MUs and SMLC treatments take more time.
A leaf-sequencing algorithm for DMLC has been developed that fully prevents the occurrence of tongue-and-groove underdosage reported by van Santvoort et al. (266). Currently, we use the Cadplan TPS (Varian Medical Systems, Espoo, Finland) for inverse planning and leaf sequencing. It was demonstrated that for extreme profiles, tongue-and-groove underdosage of up to 30% may occur with this TPS (80). However, the protocol for pretreatment verification of the fluence profiles of each individual IMRT patient has never revealed a clinically relevant tongue-and-groove error. Also for SMLC, leaf-sequencing algorithms have been developed that reduce or prevent the occurrence of tongue-and-groove underdosage (61,182).

Risultati clinici
Some of the clinical results are presented in the section Xerostomia. Excellent reviews are presented by Puri et al. (243) and Lee et al. (168). Table 42.21 summarizes the preliminary clinical results of several studies of IMRT treatment for oropharyngeal carcinoma. The studies confirm the high rates for (loco-) regional control, distant metastases-free survival, disease-free survival, and OS in combination with reduced toxicity in comparison to conventional radiotherapy. Finally the multi-institutional RTOG study (H-0022) using IMRT for early-stage oropharyngeal cancer has completed accrual, and final results are to be expected shortly (247). IMRT allows dose to be concentrated in the tumor volume while sparing normal tissues. However, the downside to IMRT is the potential to increase the number of radiation-induced second cancers. The reasons for this potential are more MUs and, therefore, a larger total-body dose because of leakage radiation and, because IMRT involves more fields, a larger volume of normal tissue is exposed to lower radiation doses. In fact, Hall (114) calculated that IMRT may double the incidence of solid cancers in long-term survivals. In contrast to older patients, if balanced by an improvement of local tumor control, the use of IMRT might not be acceptable in children. An alternative might be to replace x-rays with protons in case of scanning pencil beams.
Alternative External Beam Approaches
Helical Tomotherapy
Apart from IMRT with linear accelerators, helical tomotherapy (186) (HiArt, TomoTherapy Inc., Madison, WI) can also be used for highly conformal dose delivery. Several articles report on dose distributions for head and neck cancer patients that might be superior to those obtained with linacs, regarding sparing of critical structures (82,230,310). Long-term clinical evaluations are not available as yet. Compared to linac-based IMRT, tomotherapy requires more MUs to deliver the same target dose, because of the applied fan-beam (212). This increases the whole-body dose equivalent, which may increase the risk for radiation-induced secondary malignancies (84). The clinical


implications of irradiating larger volumes to lower doses with tomotherapy, compared with smaller volumes with intermediate doses in linac IMRT, are unknown.

CyberKnife
The robotic CyberKnife system (Accuray Inc., Sunnyvale, CA) is another means of applying high dose of radiation with high accuracy (2). Some preliminary experience with the CyberKnife is available from the Erasmus MC for cancer in the oropharynx (Fig. 42.19 shows the protocol). This regards the delivery of a boost treatment of three fractions of 5.5 Gy on each consecutive day, prescribed at the 80% isodose. Patients are immobilized with the regular thermoplastic mask with a three-point fixation. Highly conformal plans with steep dose gradients are generated using 100 to 200 noncoplanar and nonisocentric coned beams. Figure 42.46 shows a typical dose distribution for a CyberKnife boost with the applied beam orientations. The CyberKnife image-guidance system and the patient skull are used for frequent measurement of the patient setup during treatment. Observed translations and rotations are used for immediate correction of the position and direction of the next beams. Because of these continuous adjustments, a PTV margin of only 2 mm was applied originally. Recently, the images obtained with the CyberKnife image-guidance system have been retrospectively analyzed, to quantify patient motion during delivery of a treatment fraction (135). For head and neck cancer and brain cancer patients, the maximum observed displacement in a 2-minute period was 2.8 mm in a single direction; a maximum rotation of 2.3 degrees was observed after 3 minutes. The overall systematic and random three-dimensional errors after 15 minutes are 1.3 and 1.2 mm (2 SD), respectively. With the CyberKnife image-guidance system, these in-fraction patient movements are automatically compensated using the robotic manipulator.
Cone-Beam CT
An important next step in image-guided RT for head and neck tumors may be the use of the recently introduced cone-beam CT scanners, integrated in linacs (Fig. 42.44) (146,172,202). In contrast to EPIDs, these systems allow for visualization of soft tissues. So far, the image quality is not as good as for modern diagnostic scanners. During the fractionated head and neck treatment, various processes may result in a gradual change of the patient anatomy, such as postoperative changes/edema, weight loss, and shrinking of the primary tumor and/or nodal masses (11,118). Large changes in the size of the GTV and the size and position of the parotid glands have been observed. These changes may result in suboptimal treatment as the dose delivery in all fractions is usually based on a treatment plan that is designed for the patient anatomy in the planning CT scan, which is acquired prior to the start of treatment. Studies have been performed to investigate the impact of replanning based on, or triggered by, anatomy changes observed in acquired cone beam CT scans (118,210). A major clinical question to be answered is the target definition in case of a shrunken gross target volume.
As part of the IMRT QA protocol, cone-beam CT scans may also be used to assess the “dose of the day” (328).
Future Technical Developments
Dose-Calculation Algorithms
It is well known that, especially in the presence of low-density inhomogeneities, significant dose-calculation errors may occur for single beams, even when using a modern commercial TPS. Such errors have also been observed for clinical, multibeam head and neck treatment plans (34,251,270). Improved accuracies can be obtained with Monte Carlo dose-calculation algorithms, and vendors of TPSs have started to offer this tool (129,251). However, to obtain clinically acceptable calculation times, approximations and simplifications are often used that could jeopardize the potential advantages of the full Monte Carlo technique. A comprehensive overview is provided by Reynaert et al. (252).



Paperless Electronic Records
In the previous section one is confronted with innovative, highly technological care, but also with clinical research regarding QOL issues. These processes will undoubtedly go on with virtually no limitations. From the organizational (data-retrieval) point of view, one could envisage that most departments of radiation oncology will eventually be structured as a “paperless office” (Fig. 42.47). Direct architecture changes the conventional workflow into a productive workspace environment; that is, with a click of a button it combines the ease of the use of Windows with access to all types of vendor applications, including record and verify, e-mail, IMRT-QA, and office applications. This server client architecture gives users the freedom to access their applications anywhere in the hospital or in the world for collaboration, consultation, or to access particular applications for personal use. Features like pen-enabled computing, centralized storage, and secure remote access of the applications via broadband are not new in the information technology arena, but definitely are not routine to radiation therapy. It is setting a stage for any type of new application to fit into the existing infrastructure without adding new workstations or PCs in the already fully taken workspace. The future generation of connectivity between radiotherapy applications is true flexibility at the physician's desk, a solution without constraints.