(1)IMRT for Carcinomas of the Nasopharynx Benjamin D

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IMRT for Carcinomas of the Nasopharynx

Benjamin D. Rosenbluth, William W. Chou, Nancy Y. Lee

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Contents

3.1 Introduction – The Clinical Problem

and the Potential Beneﬁts of IMRT . . . 319

3.2 Unique Anatomical Challenges in the Treatment of Nasopharyngeal Carcinoma . . . 321

3.3 Target Volume Delineation – Deﬁnition of Organs at Risk . . . 322

3.4 Planning and Dose Prescriptions – Optimization Strategies . . . 324

3.4.1 Dose Speciﬁcation . . . 326

3.4.2 Planning Goals . . . 327

Treatment Delivery Issues . . . 328

3.5 Clinical Experiences Deﬁning the Role of IMRT . . . . 329

3.6 Future Directions . . . 330

References . . . 332

3.1 Introduction – The Clinical Problem and the Potential Beneﬁts of IMRT

Nasopharyngeal carcinoma (NPC) is common among Asians, especially the Southern Chinese, and is rarely seen among the Caucasian population, representing

< 1_%of all cancers in the United States [1].

The nasopharynx is a cuboidal chamber located below the base of the skull and behind the nasal cavity. The posterior wall lies at the level of the first two cervical vertebrae and is continuous with the roof, which is formed by the basisphenoid, basiocciput, and the anterior arch of the atlas. The lymphoid tissue in this area forms the pharyngeal tonsil (adenoids). Each lateral wall contains a eustachian tube orifice, which is surrounded by the torus tubarius, a prominence in the cartilaginous portion of the tube. Behind the torus tubarius is a recess called Rosenmüller’s fossa (Fig. 1). The lateral walls, including Rosenmüller’s fossa, are the most common sites of origin of nasopharyngeal carcinoma. The floor of the nasopharynx consists of the upper surface of the soft palate and communicates with the oropharynx via the pharyngeal isthmus.

Lymphatic spread to the ipsilateral nodes is common in NPC and is present in 85–90% of cases [2]. Bilat- eral spread occurs in about 50% of cases. Metastasis to the contralateral nodes only is uncommon. Spread to the lateral and posterior retropharyngeal lymph nodes occurs early and is frequently seen on MRI or CT scans, although the nodes are not palpable (Fig. 1D).

Metastasis to the jugulodigastric and superior posterior cervical nodes is also common. From these ﬁrst ech- elon nodes, further metastasis to the midjugular and posterior cervical, lower jugular, and posterior cervical and supraclavicular nodes can occur. Occasionally, spread to the submental and occipital nodes occurs as a result of lymphatic obstruction due to extensive cervical lymphadenopathy. Spread to the parotid nodes can occur via the lymphatics of the eustachian tube.

Metastasis to the mediastinal lymph nodes may occur when supraclavicular lymphadenopathy is present. Dis- tant lymph node metastasis is often reported in autopsy series. Survival decreases as cervical lymph node involvement progresses from the upper to the middle and lower nodes [3].

Both MRI and CT scans are useful in radiotherapy treatment planning. However, MRI is capable of mul- tiplanar display of tumor extent and is superior to CT scans in delineating muscle and other soft tissue involvement. In post-treatment follow-up examinations, MRI can help differentiate radiation ﬁbrosis from per- sistent or recurrent tumor based on T2-weighted signal intensities and with gadolinium enhancement and fat suppression [4]. MRI and CT scans can also detect lymph node metastasis that may not be evident on clinical ex- amination (see Fig. 1D) [5]. CT, however, is superior to MRI in the detection of early bone invasion [6, 7], and a CT scan with bone windows is useful to demon- strate the extent of invasion of the base of the skull or the cervical vertebrae. The major limitation of CT is its poor tissue differentiation. Thus, ideally both CT and MRI should be used in planning radiation treatment for patients with NPC.

The standard treatment for nasopharyngeal carcinoma is deﬁnitive radiotherapy, +|− chemotherapy, with chemotherapy reserved for more advanced le-

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Fig. 1a–d.Normal computed tomography (CT) and magnetic res- onance imaging (MRI) images of the nasopharynx: (a) axial postcontrast CT scan of the midnasopharynx. Just posterior to the medial pterygoid plate (PP), there is a small recess representing the oriﬁce of the eustachian tube (E). Posterior to this and separating the fossa of Rosenmüller (R) from the eustachian oriﬁce is a pro- tuberance extending into the nasopharyngeal airway, the torus tubarius (T). Lateral to the pterygoid plates is the lateral pterygoid muscle (P). Note the normal asymmetry of the fossa of Rosenmüller (double white arrows), which can occasionally simulate early car- cinoma. Also of importance is the symmetrical parapharyngeal space that contains branches of the internal maxillary artery and small veins of the pterygoid plexus. The parapharyngeal space sep- arates the deep lobe of the parotid gland from the soft tissues of the nasopharynx and serves as a landmark for deep invasion from carcinoma of the nasopharynx;(b)axial proton density-weighted MRI scan through the nasopharynx showing soft tissue contrast achieved with MRI scanning in this region. Note the higher-signal- intensity mucosal adenoidal tissue, which is easily separated from

the underlying musculature of the deep pharyngeal soft tissues.

Also note the musculature of the masticator space, including the masseter muscle, deep head of the temporalis muscle, lateral and medial pterygoid muscles, and the tensor veli and levator veli palatini muscles. Note the symmetrical convex appearance of the longus capitis muscles (L) positioned directly behind the mucosa of the nasopharynx and Rosenmüller’s fossa (R). Posterior and lateral to the torus tubarius (T) is the parapharyngeal space (P), containing fat and separating the deep structures from the deep lobe of the parotid gland;(c)coronal T2-weighted MRI scan demonstrating the close relationship of the superior recess of the nasopharynx to the skull base, the torus tubarius (T), the levator veli palatini mus- cle (double arrows), the medial pterygoid muscle (M), the lateral pterygoid (LP) muscle, the mandible, and the masseter muscle. Po- sitioned in the midline are the tongue and the soft palate;(d)axial T2-weighted MRI scan through the midnasopharynx showing the presence of a metastatic right lateral retropharyngeal lymph node (N). Note its location lateral and posterior to the tumor (T) in the right fossa of Rosenmüller

sions [8, 9]. Radiotherapy’s use as primary therapy for nasopharyngeal carcinoma is largely attributable to the nasopharynx’s anatomical location, as well as the propensity of NPC for early bilateral lymph node metastases and involvement of the lateral retropha-

ryngeal node of Rouvière , which usually cannot be surgically removed. Furthermore, cervical lymph node metastases from nasopharyngeal carcinoma, even when they are bulky, are very radioresponsive and locally radiocurable.

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Utilizing conventional radiation, the local control rate for T1 and T2 tumors ranges from 64 to 95%;

however, the control rate drops to 44–68% in more advanced T3|T4 lesions. Five-year survival is reported to be between 36 and 58% [11–17].

Tumor control for carcinoma of the nasopharynx has been highly correlated with the dose delivered to the tumor [18, 19]. In a series of 107 patients with NPC treated with conventional radiation, local control was signiﬁcantly improved when > 67 Gy was delivered to the tumor target. In another series of 118 patients, the improvement of tumor control was not only attributed to the prescription of higher doses of radiation, but also to improvements in technical accuracy. Technical accuracy is desirable in the treatment of NPC for another reason: as mentioned above, the nasopharynx is surrounded by many normal critical structures, including the brainstem, optic chiasm, optic nerves, and the spinal cord [20–29].

It is therefore apparent why intensity modulated radiation therapy (IMRT) has gained its popularity in the treatment of head and neck cancers. With this technique, multiple radiation beams can be modulated and shaped, such that a high dose can be delivered to the tumor while signiﬁcantly reducing the dose to the surrounding normal tissue. The proximity of NPC to critical normal tissues, its dose responsiveness, and its improved control with greater technical accuracy all argue for the use of IMRT in obtaining good local control for these tumors. Also, due to the relative lack of organ motion within the head-and-neck region, accurate reproduc- tion of daily patient setups is quite feasible, provided adequate immobilization is utilized.

This ability of IMRT to safely and effectively treat primary tumor which may approximate critical normal structures, is predominantly manifest in the treatment of more advanced NPC tumors, namely T3 and T4 tumors.

Another major benefit of IMRT in the treatment of NPC, and one which benefits patients with all T stages, is its ability to spare the parotids and maintain salivary function (see next section). This benefit is applicable to the treatment of both early and locally invasive tumors, as all patients previously required opposed lateral radiation fields, which inevitably treated the parotid glands to toxic doses. Thus, for patients with T1 and T2 disease, while treatment with IMRT provides target coverage and control which may not differ significantly from that with conventional radiation, it is superior in sparing the parotid glands. On the other hand, for patients with T3 and T4 disease, IMRT can help us accomplish two goals, namely parotid sparing and adequate dose to the GTV without significant normal-tissue toxicity.

As mentioned previously, chemotherapy has been shown to play a role, along with radiation, in the manage- ment of more advanced lesions. A recent phase III trial by the Head and Neck Intergroup in the United States

compared radiotherapy alone to radiotherapy plus concurrent and adjuvant chemotherapy for stage III and IV disease. Chemotherapy consisted of cisplatin 100 mg/m² on days 1, 22 and 43 during radiotherapy. Following completion of radiotherapy, treatment continued with cisplatin 80 mg/m²on day 1 plus 5-fluorouracil (5-FU) 1,000 mg/m²/day on days 1 to 4 every four weeks for three courses. Radiotherapy in both arms was conventional, given as 1.8 to 2.0 Gy per fraction per day, five days a week, to a total dose of 70 Gy. At five years, the overall survival was 37% vs 67% (P < 0. 001) and progression-free survival was 29% vs 58% in favor of the chemotherapy arm (P < 0. 001) [30]. These results have been confirmed by several other studies, including four meta-analyses [31–38].

It should be noted, however, that, although the intergroup trial demonstrated an improvement in local control and survival, about 1|3 of the patients did not complete the prescribed therapy due to toxicity. As IMRT may also decrease the toxicities associated with radiation therapy, it may therefore improve patient compliance with combined modality therapy. This theory is currently being tested in an ongoing phase II trial (RTOG 0225), examining IMRT +|- chemotherapy for NPC.

Yet another role for IMRT in NPC treatment is in the re-treatment of patients with recurrent disease. Pa- tients with recurrences have often already received very high doses of radiation and are usually not considered surgically resectable. Therefore, their only chance of control frequently lies in the radiation oncologist’s ability to delimit with extreme precision the volume which receives additional radiation. Close collaboration with one’s physics department can help determine the extent to which a patient can be re-treated, and can offer these patients their best chances of salvage.

3.2 Unique Anatomical Challenges in the Treatment of Nasopharyngeal Carcinoma

Many of the common acute and late side effects of conventional radiation for NPC are directly related to the proximity and radiosensitivity of multiple normal tissues in the area of the tumor. Many of these organs, while not critical for survival, are extremely important when it comes to quality of life for these patients.

Among the more common side effects are xerostomia, temporal lobe necrosis, hearing loss and pituitary hy- pofunction. Less commonly seen in recent data are oral and dental complications, neuro-ophthalmologic complications, and soft or hard-tissue complications.

One of the major complaints of patients undergo- ing conventional external beam radiation therapy to the nasopharynx is xerostomia. Standard radiation deliv- ers a high dose to the bilateral major salivary glands.

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Salivary ﬂow is markedly reduced following 10–15 Gy of radiation delivered to most of the gland [39, 40].

The recovery of the salivary function is possible over time even with doses up to 40–50 Gy. However, higher doses to most of the gland will result in irreversible and permanent xerostomia. The degree of xerostomia is largely dependent on the radiation dose and the volume of the salivary gland that is in the radiation ﬁeld.

As a result, patients’ quality of life is compromised as they experience changes in speech and taste. The oral dryness also predisposes the patients to ﬁssures, ul- cers, dental caries, infection, and even in worst cases, osteoradionecrosis [41–44]. Thus, IMRT has the potential to reduce the dose to the salivary glands while simultaneously delivering a high dose to the tumor target.

In the cases of locally advanced NPC, there is often involvement of critical intracranial structures, especially once margin is added to the gross tumor volume (GTV).

If there is any chance of toxicity to these organs, they must be contoured and monitored for toxic doses. The organs particularly at risk for radiation damage include the temporal lobes, spinal cord, cochleae, optic nerves, optic chiasm and mandible (including the mandibular horns). Usually the brainstem is the area of greatest con-

Fig. 2. CT delineation of tumor volume with correlating MR images.

GTV, light blue; PTV1, yellow; PTV2, red; right parotid gland, dark blue;

left parotid gland, orange

cern, given the usual areas involved by NPC. For further details, including dose speciﬁcations to the organs at risk, see “Planning Goals” below.

3.3 Target Volume Delineation – Deﬁnition of Organs at Risk

One of the most important issues in the application of IMRT is the accurate and adequate definition of target volumes. The precise delineation of these volumes, especially the subclinical volumes, is crucial in treatment planning. When compared to standard techniques, the very tight and conformal isodose curves around the outlined target volumes in IMRT increase the risk of missing areas containing subclinical disease if the treatment volumes are not drawn accurately. Consequently, there is an increased risk of marginal or out-of-field recurrence. As there is significant variation among physicians regarding the definitions of head and neck nodal volumes, efforts to define accurately the location of lymph nodes in the head and neck, using cadaver CT scans, have been described [45–48].

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Fig. 3. CT and MRI supple- mented by PET information.

GTV, light blue; PTV1, yellow;

PTV2, red; right parotid gland, dark blue; left parotid gland, orange

Since precise delineation of both the tumor and normal structures is crucial in treatment planning [37, 49, 50], fusion of MRI and|or PET images may be performed to supplement CT for better determination of gross tumor volume (GTV) and the surrounding normal tissue (Fig. 2). Information from the PET scan may further supplement MRI ﬁndings, especially regarding additional tumor manifestations (Fig. 3) [51]. All available imaging modalities should be used when outlining the gross extent of the disease. For example, PET scans may help ensure that a GTV outlined with the aid of MRI truly encompasses the entire area of high-metabolic activity, as detected on PET. Conversely, one must be sure not to make the GTV too small by basing contours only on the areas of high uptake on PET, as an MRI will often re-

Table 1.Suggested target volumes and margins

Target Deﬁnition Margin (prescription dose)

GTV CTV1 = Nasopharyngeal primary and Gross nodal disease+at least 5 mm margin (see CTV2: CTV1 should be encompassed by CTV2) except in areas adjacent to critical structure, i.e. brainstem, where margin can be as small as 1 mm

PTV1 (70 Gy)^∗=5 mm in all directions from CTV1 except for areas adjacent to critical structures, i.e.

brainstem, where margin can be as small as 1 mm

∗GTV will have at least a 1 cm margin in all directions, except for regions near critical structures.

High risk subclinical disease

CTV2 = Adjacent soft tissue|structures , i.e., entire nasopharynx, clivus, skull base, retropharyngeal nodal regions, pterygoid fossae, parapharyngeal space, sphenoid sinus, and posterior third of maxillary sinus and up to posterior 1|2 of nasal cavity (CTV2 should encompass CTV1) High risk nodal groups

a. Upper deep jugular b. Subdigastric c. Midjugular d. Posterior Cervical e. Retropharyngeal

f. Submandibular (may omit at discretion of treating physician if T1N0)

PTV2 (59.4 Gy^∗)= 5 mm in all directions of CTV2 except when near brainstem where margin can be as small as 1 mm

∗PTV2 should encompass PTV1 in all directions

Low risk subclinical disease

CTV3 = lower jugular nodes, supraclavicular lymph nodes

PTV3 (50.4 Gy)=low anterior AP ﬁeld

Alternatively, if PTV3 is encompassed in the IMRT field and there is no low anterior AP field, the prescription for PTV3 should be 54 Gy (see text under dose specification)

veal abnormalities which a PET scan is too insensitive to detect.

In addition, target volumes should be delineated slice by slice on the treatment CT axial images in conjunc- tion with a neuroradiologist (Fig. 4). GTV is deﬁned as all known gross disease determined from clinical information, endoscopic ﬁndings, and imaging studies.

This essentially includes the nasopharyngeal primary with any local extension, gross retropharyngeal lymphadenopathy, and any gross nodal disease greater than 1.0 cm or with a necrotic center. Close attention must be paid to the retropharyngeal nodal regions to detect any abnormal nodes. When in doubt, nodes in these regions should be considered GTV and should be outlined as such.

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Fig. 4. CTV delineation for a T2bN0M0 nasopharyngeal carcinoma receiving deﬁnitive IMRT. GTV, light blue; PTV2, red; right parotid gland, darkblue; left parotid gland, orange

Clinical tumor volume (CTV) is deﬁned as the GTV plus areas with potential microscopic spread as determined by the treating physician. A margin of at least 5.0 mm on the GTV should be used in all directions;

this may be reduced to 1.0 mm in situations where the GTV is adjacent to the brainstem, such as in the event of clivus inﬁltration. Three different CTVs are deﬁned, namely CTV1 for gross tumor volume, CTV2 for high- risk nodal regions and adjacent soft tissue, and CTV3 for low-risk nodal regions (Table 1).

At-risk adjacent tissues, deﬁned by the CTV2, include the entire nasopharynx, clivus, skull base, retropharyngeal nodal regions, pterygoid fossae, parapharyngeal space, sphenoid sinus, posterior third of maxillary sinus and up to the posterior one-half of the nasal cavity.

High-risk lymph-node groups in NPC include upper deep jugular (junctional, parapharyngeal), subdigastric (jugulodigastric), midjugular, posterior cervical,

retropharyngeal lymph nodes, and submandibular lymph nodes [46, 52].

Elective treatment of all cervical lymph nodes should be performed due to the high likelihood of cervical metastases including clinically N0 patients. This generally held approach is challenged by a randomized study by Ho demonstrating that survival of N0 patients receiving elective irradiation of the cervical lymphatics was not better than that of N0 patients not receiving neck irradiation [53]. Lee et al., however, reported that in 384 NPC patients with clinically negative necks, 11% (44 patients) of those receiving elective neck irradiation had regional failure compared with 40% (362 of 906) of those not electively treated [15]. (At the discretion of the treating physician, patients with stage T1N0 may be spared treatment of the level I nodes.) Lower risk lymph node groups such as lower neck and supraclavicular lymph nodes bilaterally are included in CTV3, which may be included in the AP ﬁeld.

The planning target volume (PTV) provides a margin around the CTV to compensate for internal organ motion and treatment-setup uncertainty. Studies should be performed by each institution to deﬁne the appropriate magnitude of compensation necessary for the variables related to the PTV. In our institution, 5.0 mm expansion around the CTV is utilized, except for situations where the CTV is adjacent to the brain stem, in which case the margins are reduced to 1.0 mm. Figure 4 shows serial GTV, PTV1, and PTV2 axial delineation in a T2bN0M0 NPC patient receiving deﬁnitive IMRT.

Critical normal structures, including the brain stem, spinal cord, optic nerves, optic chiasm, temporo- mandibular (T-M) joints, mandible, and brain must be outlined in three dimensions. The spinal cord contours should be 5.0 mm larger in the radial dimension than the spinal cord (i.e., the cord diameter on any given slice should be 10 mm larger than the cord itself). The brain stem and chiasm should be deﬁned as at least 1.0 mm larger in all directions than the corresponding structure. Important but less critical normal structures such as parotid gland, eyes, lens, middle and inner ears, tongue and glottic larynx should also be included.

3.4 Planning and Dose Prescriptions – Optimization Strategies

The fundamental sequential steps involved in IMRT planning, from simulation to treatment delivery, are illustrated in Fig. 5.

Target volumes and normal anatomy must be deﬁned by CT simulation to allow for accurate target deﬁ- nition, digital reconstruction and three-dimensional planning. Fusion of MR images may be used to supplement CT imaging for better delineation of gross

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Fig. 5. Flow chart of IMRT planning from simulation to plan evaluation and modiﬁcation

tumor and surrounding normal tissue. IMRT plans are sensitive to setup errors and patient movement, and therefore, they require stringent patient immobilization and daily setup reproducibility [37]. Special considera- tions during the simulation are required to address these concerns.

For immobilization, the head and neck should be im- mobilized using a thermoplastic mask; neck support may be needed if a thermoplastic head mask alone is not sufﬁcient for neck immobilization. Immobilization can be achieved with a headboard (Timo S-type, MED- TEC) for attachment of an Aquaplastic mask (Aquaplast, Wycoff Heights, NJ) that extends from the vertex of the scalp to the shoulders [25, 54]. The treatment immobilization device can also be used for MRI fusion scans. Due to the size of the head rest and the immobilization setup, diagnostic MRI with the head coil may not be compatible with these devices; however, in such cases, MRI with body coil setup should accommodate the immobilization devices and allowed for duplication of the CT simulation process with good image resolu- tion. Alternatively, image-registration methods may be employed to correlate diagnostic MRI with CT simula- tions.

The patient’s head should be hyperextended at the simulation to provide adequate separation between the primary lesion|retropharyngeal lymph node and the upper neck ﬁeld [27]. The tip of the uvula and the base of the occiput should be parallel to the beam axis [55].

A pair of orthogonal radiographs should be taken for isocenter localization at the initial simulation. A treatment planning CT scan in serial 3.0 mm thickness slices should be obtained from the head down to the clav- icles, with a minimum margin of 5–10 cm above and below the target. CT scan slice thickness for the GTV should be 3.0 mm or less while regions above and below the target volume can have slice thicknesses of 5.0 mm.

An isocenter for the conformal IMRT ﬁeld is chosen based on the patient’s anatomy and disease distribution.

Currently, at our medical center, the primary tumor and upper neck are treated with conformal IMRT field while the lower neck is treated with a conventional anterior field. These two fields are matched with a split-beam technique and the match line is set above the vocal cords.

Multiple radiotherapy techniques as well as IMRT methods in deﬁning the isocenter and match line have been described [55].

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An older technique only used IMRT for the primary tumor and retropharyngeal region, while the upper neck above the vocal cords was irradiated with opposed- lateral fields and the lower neck and supraclavicular fossae were treated with a single anterior field using conventional radiotherapy. In these cases, the IMRT field is matched with the opposed-lateral neck field using a split-beam technique. The opposed-lateral neck field is also matched to the lower neck and supraclavicular field with a split-beam technique.

At some centers, a third technique has evolved, stem- ming from concerns about dose uncertainties at the match lines. This technique uses an extended-field IMRT (EF-IMRT), which treats the primary tumor as well as all regional lymph nodes, including the supraclavicular nodes (see next section). However, due to the extended field size, application of this EF-IMRT technique may be limited by the field-size constraints of the available linear accelerators. General indications, as well as advantages and disadvantages for each of the three techniques (IMRT for the primary tumor alone, IMRT for the primary plus upper neck nodes, and IMRT for the entire tumor and neck volume) are presented in Table 2.

Regardless of the technique used, the aim of treatment is to deliver sufficient radiation to the PTVs while excluding the non-involved tissue. The treatment plan is based on an analysis of the volumetric dose, including a dose-volume histogram (DVH) analyses of the PTVs and critical normal structures. Due to the complexity and variations in clinical presentation, treatment plans should be customized for each patient. The method of inverse planning should be utilized to determine intensity optimizations and beam configurations. The number of fields should be determined by treatment planning to produce the best conformal plan. For the intensity optimization, the prescribed dose should encompass at least 95% of the involved and electively irradiated sites of disease.

Table 2.Indications and advantages for different IMRT planning techniques IMRT for the primary tumor alone IMRT for the primary plus upper neck

nodes

IMRT for the entire tumor and neck

Suitable for cases with no lymph node involvement

No need to contour lymph nodes

For cases when upper neck nodes are involved

Lower neck nodes can be treated at a lower dose but still at a standard fractionation

Simple in treatment setup No match-line problem

Lymph nodes can be treated at a lower dose (i.e., 54 Gy) but still at a standard dose fractionation

Improved dose conformity and uniformity

Simpler treatment setup

Dose uncertainties at match line

Suitable for cases with lymph node involvement

Longer ﬁeld lengths required:

20– 24 cm (for oropharynx); 22 – 28 cm (for nasopharynx); 26 –32 cm (for sinus) Complex treatment setup

Sensitive to patient movement during treatment

Dose uncertainties at match lines

Sensitive to patient motion during the treatment

Megavoltage machines, usually using a 6-MV photon beam, should be used for the irradiation of the primary tumor. Energy greater than 6 MV should not be used for the irradiation of cervical lymph nodes. Treatment must be delivered with megavoltage equipment capable of delivering dynamic intensity modulation with computer controlled auto-sequence multi-leaf collima- tors. Other techniques, including the use of partial block transmission blocks and sequential tomother- apy, have been previously described and are acceptable, as long as dose speciﬁcations and constraints are met [37].

3.4.1 Dose Speciﬁcation

The prescription dose is the isodose surface that encompasses at least 95% of the PTV. The gross tumor and involved lymph nodes along with margin for set-up error and organ motion (PTV1) should receive 70 Gy in 33 fractions at 2.12 Gy per fraction. PTV2 with high risk cervical lymph nodes or dissected neck area containing lymph node metastasis should receive 59.4 Gy in 33 fractions at 1.8 Gy per fraction. If possible, no more than 20% of any PTV1 should be treated with 110%

of the prescribed dose and no more than 1% of any PTV1 and PTV2 should exceed 93% of the prescribed dose. Dose greater than 110% of 70 Gy should be limited to 1% or 1.0 cc of the tissue outside the PTVs. Exam- ples of dose distribution and coverage are presented in Fig. 6–8.

This dose distribution or dose painting may allow for a differential radiobiologic advantage. GTV receives a higher dose per fraction when compared to CTV and all surrounding normal tissues potentially may beneﬁt from a greater radiobiologic effect. Other investigators have reported encouraging results from the differential dose delivery and minimization of toxicity [21, 22].

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Fig. 6a–d.IMRT dose distribution for a patient with a T2bN0 NPC:(a)superior axial;(b)infe- rior axial;(c)coronol;(d)sagittal.

PTV1, yellow; PTV2, red; 118%

isodose line (70 Gy), green; 114%, orange; 100% (59.4 Gy), yellow;

90%, dark blue; 70%, magenta;

50%, light blue

At our center, the lower neck and supraclavicular field (PTV3) is treated with a conventional AP field, beam split to the IMRT fields, as discussed previously. The conventional AP field is generally prescribed to a depth of 3 cm from the anterior surface and receives 50.4 Gy in 28 fractions of 1.8 Gy per fraction. As mentioned above, dose uncertainty at the match line has led to the use of extended-field IMRT that treats the primary tumor with all the regional lymph nodes including the supraclavicular nodes. A head, neck, shoulder immobilization device must be used in these situations. In these situations, the dose per fraction in PTV3 is 1.64 Gy; in order to compensate for fractionation lower than conventional fractionation of 1.8 Gy, the low neck and supraclavicular fields are treated to a higher total dose of 54.0 Gy in the IMRT plan (see Fig. 9). A third alternative is to plan to treat the low neck in the IMRT plan, defining the low neck|supraclavicular fossae as part of the PTV2 and, after 28 fractions, to close these fields and complete the remainder of the treatments using the same IMRT plan, following reoptimization and replanning.

3.4.2 Planning Goals

Conforming to the critical normal structure constraints followed by prescription goals must be the main treatment-planning priorities. Other planning goals include obtaining a low mean parotid dose, a reduced dose to submandibular glands and oral cavity, and meet- ing dose constraints for other normal structures. DVHs

Table 3.Dose constraints for critical normal structures (RTOG 0225)

Critical normal structure Dose constraints

Brainstem 54 Gy or 1 cc volume 60 Gy

Optic chiasm|optic nerves 54 Gy or 1 cc volume 60 Gy

Spinal cord 45 Gy or 1 cc volume 50 Gy

Mandible|^{T-M joint} 70 Gy or 1 cc volume 75 Gy Temporal lobes 60 Gy or 1% volume 65 Gy

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Fig. 7a,b.Dose volume histogram for the patient in Fig. 15:(a)critical normal structures;(b)lower priority normal structures

should be generated for all target volumes, critical normal structures and other unspeciﬁed tissues (Fig. 7 and 8). No more than 5% of the non-target tissue should receive more than 70 Gy, including all transmitted and scattered doses.

Dose constraints for critical normal structures are presented in Table 3. In cases where constraints to critical structures lead to under-dosing the tumor, these limits can be exceeded, at the discretion of the treating physician, but patients should be fully consented for the anticipated risk of injury to these normal structures.

Dose restraints for other normal structures, including tongue, inner|middle ear, eyes and glottic larynx, may be of lower priority and should not compromise the GTV or CTV coverage. Table 4 lists recommended dose for these lower-priority normal structures.

For the parotid glands, a mean dose of 26 Gy should be achieved in at least one gland; alternatively, at least 20 cc of the combined volume for both parotid

Fig. 8a,b.Patient with a T4N2 NPC treated using an IMRT plan with a separate supraclavicular ﬁeld:(a)isodose distribution. GTV, orange; PTV2, yellow; parotid glands, dark blue; 59.4 Gy isodose

line, green; 70 Gy isodose line, pink;(b)dose-volume histogram for the same patient. (Courtesy of Louise E. Braban, Ph.D., and Linda X. Hong, Ph.D.)

glands should receive less than 20 Gy. The degree of xerostomia is largely dependent on the radiation dose and the volume of the salivary gland irradiated. Sali- vary ﬂow is markedly reduced following 10–15 Gy of radiation delivered to most of the gland. Recov- ery of salivary function is possible over time with doses up to 40–50 Gy, although irreversible xerostomia occurs with higher doses [39, 56, 57]. Doses to the submandibular and sublingual glands should be as low as possible, without compromising target coverage.

Treatment Delivery Issues

Treatment is delivered once daily for a total of ﬁve fractions per week until completion. All targets are treated simultaneously, except for the supraclavicular area, which is usually stopped after 28 fractions when treated with a conventional low neck ﬁeld. During treat-

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Fig. 9. Patient with a T3N3 NPC treated using an IMRT-only plan.

Because the patient had bilateral and supraclavicular gross LNs, the decision in this case was made to increase the subclinical dose from 54 Gy to 59.4 Gy to the low neck. (Courtesy of Ping Xia, Ph.D.)

ment, port films (including an orthogonal pair) should be taken for each field on a weekly basis, to ensure accurate location of the isocenter. Patient position and MLC aperture should be monitored by weekly verification films.

For pre-treatment patient-specific quality assurance (QA), a thorough plan check and independent monitored unit (MU) calculations are performed, as is the case with conventional treatment. During radiation delivery, accelerator MLC position readout and the record and verify (RV) system should be monitored to verify the start- and stop-leaf positions of each field for the daily treatments. Routine film dosimetry for pretreatment delivery verification has been eliminated at our institution after long-term comparison between film and calcula- tion consistently demonstrated agreement to within 2%.

Film dosimetry is now reserved for new treatment sites, unusual intensity proﬁles or MU veriﬁcation checks with discrepancies in excess of 3%.

Table 4.Recommended dose limits for lower priority normal structures (RTOG 0225)

Normal structures Recommended constraints Parotid glands Mean dose 26 Gy in at least

one gland or 20 cc of both 20 Gy

Tongue 55 Gy or 1% volume 65 Gy

Inner|^{middle ear} Mean dose 50 Gy

Eyes Mean dose 35 Gy

Lens As low as possible

Glottic larynx Mean dose 45 Gy

3.5 Clinical Experiences Deﬁning the Role of IMRT

While the role of IMRT for the treatment of NPC continues to be defined, multiple studies over the last few years have helped explicate the specific benefits of IMRT, both on a technical|theoretical basis as well as on a clinical|practical basis.

Cheung et al. demonstrated that target coverage of the primary tumor was maintained and that nodal coverage was improved in 17 NPC patients planned with IMRT, as compared with conventional beam arrangements [58].

The ability of IMRT to spare the parotid glands was noted as well. Similar results were reported by Hunt et al. in 23 patients with primary NPC [27]. However, no attempt was made in their series to spare the parotids, and, as a result, the mean parotid dose was quite high, at 60.5 Gy. Subsequently, with the use of proper normal- tissue dose constraints, substantial improvements have been noted.

Xia et al. compared IMRT treatment plans with conventional treatment plans for a case of locally advanced nasopharyngeal carcinoma [25]. In their series, the coverage to the GTV a well as the CTV was superior with the inverse-planned IMRT plans. Also, with the use of proper normal-structure dose constraints, inverse- planned IMRT plans achieved the least dose delivered to the brain stem, chiasm, optic structures, and parotid.

In fact, the mean parotid dose was reduced to as low as 21.4 Gy. The authors concluded that IMRT provided improved tumor target coverage with signiﬁcantly better sparing of sensitive normal tissue structures in the treat-

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ment of locally advanced nasopharyngeal carcinoma.

A similar conclusion was reached in a study by Wolden et al., in which, due to a lack of major beneﬁt with conventional three-dimensional treatment planning used only during the boost phase of treatment for nasopharyngeal carcinoma, the authors recommend using IMRT to deliver the entire course of radiation [59]. It is worth noting that, although this study only investigated the use of a three-dimensional boost, the same lack of efﬁcacy would likely be found if an IMRT boost had been used.

This is because, in such a situation, the conventional portion of the treatment would already have treated certain critical structures (e.g., the spinal cord) to significant enough doses, such that further treatment with an IMRT plan would be compromised. It is therefore highly preferable to perform the entire treatment course using IMRT.

At UCSF, IMRT has been used for treatment of nasopharyngeal carcinoma since 1995. In their series, patients were treated with both forwardly planned as well as inversely planned IMRT. Radiation beams were delivered using partial transmission blocks, computer controlled auto-sequencing static multileaf collimator (MLC), or the Peacock system using a dynamic multi- vane intensity-modulating multileaf collimator, called the MIMiC. An update of their experience by Lee et al. reported that, in 87 patients treated with IMRT, the 4-year local progression-free survival, regional progression-free survival, distant metastasis-free survival, and overall survival were 94, 98, 66, and 73%, respectively, with a median follow up of 31 months [60].

IMRT achieved excellent locoregional control, provided excellent tumor coverage, and allowed the delivery of a high dose to the target with signiﬁcant sparing of the salivary gland and other nearby critical normal tissues (see Fig. 10).

Kwong et al., from Queen Mary Hospital in Hong Kong, presented their data on 50 patients with T1–2N0–

1M0 NPC treated with IMRT. With a median followup

Fig. 10. Salivary toxicity in 87 patients with NPC treated using IMRT in the series reported by Lee et al. [60]

of 14 months after completion of radiotherapy, the 2- year nasopharynx, neck, and distant failure-free survival rates were 100, 94.4, and 94.1%, respectively [61]. Again, good parotid-sparing was achieved in these patients.

In a recent report, Ozyigit and Chao provide an up- dated report of the Washington University-Mallinckrodt experience. Twelve patients with NPC were treated with IMRT between February 1997 and December 2000 [62].

T stages included one T1, three T2, three T3, and ﬁve T4;

N stages included one N0, three N1, four N2, and four N3. The patients received chemotherapy according to the Intergroup 0099 regimen. With a median follow-up time of 31 months (range 19–52 months), one neck recurrence was observed. Three patients developed distant metastases, and one patient dies of distant metastasis.

There were no failures in the nasopharynx.

3.6 Future Directions

While the potential beneﬁts of IMRT for treatment of NPC are well understood, the practical aspects of its implementation as well as the potential further minimization of treatment-related toxicities continue to be explored.

RTOG 0225 is a phase II study of IMRT +|^–

chemotherapy for stage I–IVB squamous cell carcinoma of the nasopharynx. The primary purpose of this study is to test the feasibility and transportability of delivering IMRT in a multi-institutional setting for the treatment of nasopharyngeal carcinoma. The rate of late xerostomia associated with the treatment regimen will also be assessed. The rationale of this study is that a potential reduction in radiation side effects using IMRT will increase patient compliance to combined therapy without compromising local-regional control. The study is on-going and the results are eagerly awaited at this time.

With the development of new technology comes the need for re-evaluation of older data. In 1991, Emami et al. collected and amended information on radiation tolerance of multiple normal tissues, with a special emphasis on partial volume effects [63]. At the time, the authors acknowledged that the work obviously was not and could not be comprehensive. We now know that, as the information collected in this seminal study was drawn from sources utilizing techniques which pre-dated IMRT, it is quite certain that the dosimetric analyses performed to arrive at those tolerance doses are not as accurate as the dosimetric analyses which can be performed using a computer-generated IMRT plan.

Emami and colleagues studied two-dimensional data for their study, and had no access to computer-derived dose-volume histograms; as a result, many of their out- comes were necessarily a result of close estimates. Now, as clinical data is collected and evaluated in the context

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of newer IMRT plans, it will become possible – and necessary – to validate, and perhaps amend, much of the vital data that Emami and colleagues have given us.

One area in which more accurate tissue-tolerance data would be particularly useful is in reirradiation of recurrent NPC. Five-year actuarial survival of select patients reirradiated for recurrent NPC, using conventional radiotherapy, has ranged from 20 to 45% [64–69].

However, long-term local control was noted in only 14–60% of the retreated patients. Five-year actuarial survival ranged from 13% (in patients who recurred

Fig. 11. IMRT plan for a patient with recurrent NPC. Patient previously received full-dose radiation therapy.

(Courtesy of Ping Xia, Ph.D.) within two years following initial radiotherapy) to 66%

(in patients who recurred later than two years following initial radiotherapy) [65]. Again, a dose-responsive el- ement was noted: ﬁve-year actuarial survival was 45%

with doses greater than or equal to 60 Gy and 0% with doses less than 60 Gy, although most patients treated with lower doses had more advanced disease at recurrence [65]. Severe complications following reirradiation occurred in 4–48% of the patients reported in the literature [19, 64–68, 70]. The incidence of severe complications from reirradiation increased with increasing

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total cumulative dose: incidence was 4% with doses less than or equal to 100 Gy, vs 39% with doses greater than 100 Gy [66]. The use of IMRT in these patients would theoretically lower the rate of late normal-tissue complications, allow better targeting of tumor, and ultimately enable the delivery of at least 60 Gy to tumors, even in advanced cases.

The practice at UCSF is to treat recurrent NPC patients with IMRT to a dose of 60 Gy at 1.44 Gy/fraction, twice-daily, 6 h apart, ﬁve days per week to the GTV, with concurrent cisplatin chemotherapy, while the CTV receives a dose of 50 Gy at 1.2 Gy/fraction twice-daily.

Alternatively, once-daily fractionation using IMRT to a dose of 60 Gy, with concurrent chemotherapy, can be used if an appropriate plan is formulated. An example of an IMRT plan for recurrent NPC is shown in Fig. 11.

Treatment for NPC recurrences must be evaluated on a case-by-case basis, in close collaboration with ones physics staff. Often, it is necessary to “recreate” pre- vious treatment ﬁelds, especially when a conventional plan was used previously, to approximate the cumulative dose which will be delivered to the target as well as to adjacent critical structures. Such a three-dimensional

“recreation” entails a thorough anatomic analysis of prior treatment ﬁelds, as well as a detailed knowledge of the treatment techniques used.

One area in the treatment for NPC which is not intrinsic, but is often complementary, to IMRT is chemotherapy. As mentioned earlier, the addition of chemotherapy to radiation improves locoregional control, distant metastasis-free rates, disease-free survival, and overall survival. These positive effects have especially been seen in patients treated with concurrent, as opposed to adjuvant, chemoradiotherapy. However, compliance has been a problem: there was only a 53–73% compliance rate in patients treated with concurrent cisplatin-based chemotherapy and radiotherapy, and only a 55–76% compliance rate seen in radiation- treated patients who received adjuvant cisplatin-based therapy. This poor compliance is in large part due to the toxicity associated with combined- modality therapy.

While IMRT has decreased this toxicity, improvements in the toxicity proﬁles of the chemotherapeutic regimens being used would further improve compliance rates.

Moreover, while local-control rates will improve with the higher radiation doses enabled by IMRT, further improvements in chemotherapy will result in improved distant-metastasis and overall-survival rates.

High distant-metastasis rates continue to be a problem for patients with NPC; this is especially apparent as patients’ tumors have a more effective local response to IMRT. As systemic chemotherapy for NPC continues to evolve, especially with the development of targeted chemotherapeutic agents (e.g., C225 [cetuximab], Iressa [geﬁtinib] and COX-2 inhibitors), the distant manifestations of NPC will be addressed. When delivered in combination with IMRT, these agents will help maximize

control of both local and distant disease in these patients.

The result will undoubtedly be further improvement in quality of life and overall survival for patients with NPC.

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