Radiation Oncology: A Question-Based Review

Oropharyngeal Cancer

Steven H. Lin and Giuseppe Sanguineti

image Background

What is the incidence of oropharyngeal cancer (OPC) in the U.S.?

~12,000 cases/yr of OPC in the U.S. (2008 data)

How does the incidence of OPC compare to that of other H&N sites?

The incidence of OPC is increasing, whereas cancer of other H&N sites is decreasing.

Is there a gender predilection for OPC?

Yes. Males are more commonly affected than females (3:1).

What are the 4 subsites of the oropharynx (OPX)?

Soft palate, tonsils, base of tongue (BOT), and pharyngeal wall

From which subsite do most OPCs arise?

The tonsil (ant tonsil pillar and fossa) is the most common primary site.

What are the borders of the OPX?

1.     Anterior: oral tongue/circumvallate papillae

2.     Superior: hard palate/soft palate junction

3.     Inferior: valleculae

4.     Posterior: pharyngeal wall

5.     Lateral: tonsil

What 3 structures make up the walls of the tonsillar fossa?

Walls of the tonsillar fossa:

1.     Ant tonsillar pillar (palatoglossus muscle)

2.     Post tonsillar pillar (palatopharyngeal muscle)

3.     Inf glossotonsillar sulcus

What are the 4 most important risk factors for the development of OPC?

Risk factors for developing OPC:

1.     Smoking

2.     Alcohol

3.     HPV infection (HPV 16)

4.     Betel nut consumption

What is the 1st-echelon drainage region for most OPCs?

The 1st-echelon drainage site for most OPCs is the level II (upper jugulodigastric) nodes.

Are skipped mets common for OPC?

No. Skipped mets are extremely rare in OPC (<1%).

What are the 2 most common histologies encountered in the OPX? Rare histologies?

1.     Most common histologies: squamous cell carcinoma (SCC) (90%), non-Hodgkin lymphoma (10% tonsil, 2% BOT)

2.     Rare histologies: lymphoepithelioma, adenoid cystic carcinoma, plasmacytoma, melanoma, small cell carcinoma, mets

What % of pts with OPC fail locoregionally vs. distantly?

50% of OPC pts fail locally, and 50% fail distantly.

How prevalent is HPV infection in OPC?

Depending on the series, ~40%–80% of OPCs are associated with HPV infection.

Which HPV serotype is most commonly associated with OPC?

HPV 16 is the most common serotype in OPC (80%–90%).

What is a surrogate marker of HPV infection in OPC that can be used as an indirect indication of HPV seropositivity?

The surrogate marker for HPV infection is p16 staining; E7 protein inactivates Rb, which upregulates p16.

Which pt population is most likely to present with HPV-related OPC?

Nonsmokers and nondrinkers are most likely to have HPV+ SCC of the OPX.

Do HPV+ or HPV+ OPC pts have a better prognosis?

HPVOPC pts have a better prognosis. Data from RTOG 0129 (Ang KK et al., NEJM 2010) showed better 3-yr OS (82.4% vs. 57.1%) and risk of death (HR 0.42) for HPV+ pts. Smoking was an independent poor prognostic factor.

What is the hypothesis behind why HPV+ OPC pts have a better prognosis?

HPV+ H&N cancers are usually in nonsmokers and nondrinkers, so p53 status is usually nonmutated; p53 mutation (which is common in non–HPV-related H&N cancers) predicts for a poor response to Tx.

image Workup/Staging

What nerves are responsible for otalgia in cancers of the oral tongue, BOT, and larynx/hypopharynx (HPX)?

1.     Oral tongue: CN V (auriculotemporal) → preauricular area

2.     BOT: CN IX (Jacobson nerve) → tympanic cavity

3.     Larynx/HPX: CN X (Arnold nerve) → postauricular area

What is the most common presentation of OPC?

The most common presentation is a neck mass, especially with HPV+ OPC.

What are additional common presenting Sx by OPX subsite?

1.     Base of tongue: sore throat, dysphagia, otalgia, neck mass

2.     Tonsils: sore throat, trismus, otalgia, neck mass

3.     Soft palate: leukoplakia, sore throat with swallowing, trismus/perforation, phonation defect with advanced lesions

4.     Pharyngeal wall: pain/odynophagia, bleeding

Describe the workup for a pt with an OPX mass.

OPX mass workup: H&P (bimanual exam of the floor of mouth), labs, direct laryngoscopy, CT/MRI H&N, tissue Bx (EUA if necessary), and CXR (or CT chest)

If the neck mass Bx is positive, is an additional Bx of the primary lesion necessary?

Yes. A Bx of the primary (or suspected primary) should also be done.

What % of OPC pts have clinically occult nodal mets?

30%–50% of OPC pts have clinically occult nodal mets.

What % of OPC pts present with clinically+ nodes, and what % present with bilat nodal Dz?

~75% of OPC pts have clinically+ nodes at presentation, with ~30% having bilat Dz (especially if lesions are BOT/midline).

What is the T staging of OPC?

T staging of OPC is similar to other SOOTH (salivary, oral cavity, oropharynx, thyroid, hypopharynx) H&N cancers:

1.     T1: ≤2 cm

2.     T2: 2–4 cm

3.     T3: >4 cm

4.     T4a (moderately advanced): invades larynx, deep/extrinsic tongue muscles, medial pterygoid, hard palate, mandible

5.     T4b (very advanced): invades lat pterygoid muscle, pterygoid plate, lat nasopharynx, skull invasion, carotid encasement

What are the 4 extrinsic tongue muscles, and what are their anatomic spans?

Extrinsic tongue muscles and anatomic spans:

1.     Genioglossus (ant mandible to tongue)

2.     Styloglossus (styloid process to tongue)

3.     Palatoglossus (palate to tongue; also forms ant tonsillar pillar)

4.     Hyoglossus (hyoid bone to tongue)

What is the N staging of OPC?

The nodal staging of OPC is the same as other H&N sites (except for nasopharyngeal):

1.     N1: single, ipsi, <3 cm

2.     N2a: single, ipsi, 3–6 cm

3.     N2b: multiple, ipsi, <6 cm

4.     N2c: bilat or contralat, <6 cm

5.     N3: any >6 cm

Describe the overall stage groupings for OPC.

1.     Stage I: T1N0

2.     Stage II: T2N0

3.     Stage III: T3N0 or T1-3N1

4.     Stage IVA: T4aN0-1 or T1-4aN2

5.     Stage IVB: T4b or N3

6.     Stage IVC: M1

Broadly speaking, what OPC pts/stage groups are deemed early, intermediate, and advanced?

1.     Early: stages I–II (cT1-2N0) and select III (T2N1)

2.     Intermediate/favorable: HPV+ stages III–IV (without T2N1) in nonsmokers/drinkers, T3N0 (exophytic) regardless of HPV/smoking status

3.     Advanced/unfavorable: HPV– smokers with stage III–IV Dz, T4 Dz regardless of HPV/smoking status

image Treatment/Prognosis

What are the Tx paradigms for early (e.g., cT1-T2, cN0) oropharyngeal tumors?

Early oropharyngeal tumor Tx paradigm: surgical resection +/− PORT or definitive RT alone

What are the Tx paradigms for intermediate-group oropharyngeal tumors?

Intermediate-group oropharyngeal tumor Tx paradigms: surgery +/− postop CRT, altered fractionation RT +/− cetuximab, and CRT (conventional fractionation)

What are the Tx paradigms for advanced/unfavorable oropharyngeal tumors?

Advanced/unfavorable oropharyngeal tumor Tx paradigm: CRT (conventional) +/− induction chemo

When is WLE alone appropriate for OPC?

Rarely. WLE may suffice in the rare instance of a small (<1 cm), ant tonsillar pillar lesion.

Is tonsillectomy ever adequate as a definitive Tx for tonsillar cancers?

Generally, no. Simple tonsillectomy is considered an excisional Bx and thus needs further definitive Tx. Radical tonsillectomy may be adequate in select cases but results in worse functional outcomes than RT.

What type of surgery is required for the surgical management of OPC?

The “commando” procedure is typically required for OPC, which consists of composite resection of the mandible with en bloc removal of the tumor and deep structures.

When is PORT indicated for OPC?

PORT is generally indicated in OPC with a +margin, ≥2 +LNs, +ECE, PNI, and LVSI.

When can unilat neck Tx be considered for OPC pts?

Unilat neck Tx can be considered if the lesion is well lateralized (at least 1.5 cm from midline) and the N stage is <N2a.

What data supports unilat neck irradiation for select OPX lesions?

PMH data (O–Sullivan B et al., IJROBP 2001): 228 pts with tonsillar lesions were treated with ipsi nodal irradiation (wedge-pair fields), most with T1-2N0 Dz. Contralat failure rates were low (3.5% overall, 0% for T1, and 1.5% for T2). There was increasing risk to the contralat neck if the medial one third of the palate and/or BOT were involved.

Which LN regions/levels should be irradiated in pts with an early T stage but N+ OPC?

Levels II–IV should always be included/irradiated; however, recent data (Sanguineti G et al., IJROBP 2009) suggests that levels I and V may be omitted due to a significantly lower incidence of nodal spread.

What is the main indication for a neck dissection after definitive CRT for OPC?

The main indication for a neck dissection after CRT is persistent nodal Dz that can be documented by fine-needle sampling, CT (at 4–6 wks), or PET/CT (at 10–12 wks).

What is the recommended timing for a neck dissection after CRT?

Neck dissection should typically occur at 6–8 wks (12–15 wks if evaluated by PET/CT).

How should OPC pts be set up for simulation?

OPC pts should be simulated supine, with arms along the body and the head extended with a bite block. Contrast is recommended with CT.

What should the pre-RT evaluation/preparation include?

Dental evaluation/fluoride prophylaxis, speech & swallow evaluation/exercises, and nutrition evaluation with a PEG tube if the pre-Tx weight loss is >10% over 3 mos

What is the classic sup RT field border for OPC?

1.     If N0: 2 cm above angle of mandible

2.     If N+: above mastoid tip, floor of sphenoid sinus (ant), inf edge of external auditory meatus (post)

3.     Include the entire pterygoids if a tonsillar/soft palate primary.

What are the classic inf and post RT field borders for OPC?

1.     Inferior: thyroid notch (junction above arytenoids, if possible, and avoid nodal splitting if N+)

2.     Posterior: behind spinous process

What is the classic ant RT field border for OPC?

The ant RT border should cover the medial pterygoid muscle insertion on the pterygoid plate, curve just ant to the hard palate to the base of skull superiorly, and end 2 cm beyond the tumor or at the 2nd molar inferiorly.

What are the typical RT doses used for OPC?

1.     T0-166 Gy

2.     ≥T170 Gy, or 81.6 Gy with hyperfractionation

What is the 2-yr LF rate after IMRT alone for early (T1-2N0-1) OPC?

RTOG 00-22 (Eisbruch A et al., IJROBP 2010) demonstrated excellent results with accelerated hypofractionated IMRT for early OPC: 2-yr LRF was 9% (if major deviations, 50%; otherwise 6%, SS).

What were the RT techniques and doses employed in RTOG 00-22?

In RTOG 00-22 (Eisbruch A et al., IJROBP 2010), RT was delivered with accelerated hypofractionated IMRT as follows: 66 Gy in 30 fx (2.2 Gy/fx) to the primary target PTV and 54–60 Gy in 30 fx (1.8–2 Gy/fx) to the secondary target PTV.

How was the N stage established in RTOG 00-22 for eligibility purposes?

For RTOG 00-22 (Eisbruch A et al., IJROBP 2010), neck staging was clinical (not from CT); however, pts “upstaged” by CT (e.g., cN1 but N2 after CT) were also eligible.

What did the RTOG 90-03 study demonstrate about the use of altered fractionation in H&N cancers?

RTOG 90-03 (Fu KK et al., IJROBP 2000): 1,073 pts with H&N cancers (10% oral cavity [OC], 60% OPX, 13% HPX) with stage III (28%) or stage IV (68%) Dz randomized to (a) conventional 70 Gy qd, (b) 81.6 Gy in 1.2 Gy/fx bid, (c) accelerated with split, and (d) concomitant boost (1.8 Gy/fx qd × 17, with last 12 fx bid with 1.8 Gy am, 1.5 Gy pm to 72 Gy). There was better LC with altered fx (54% vs. 46%) but no OS/DFS benefit. There was worse acute toxicity but no difference in late toxicity.

What randomized studies demonstrated better outcomes with hyperfractionated RT over conventional RT for OPC?

1.     RTOG 90-03 (Fu KK et al., IJROBP 2000): See above.

2.     EORTC 22791 (Horiot JC et al., Radiother Oncol 1992): 325 pts (all OPX, but no BOT): 70 Gy vs. 80.5 Gy at 1.15 Gy bid. There was better LC (60% vs. 40%) but no OS benefit. LC was best for T3 Dz.

What data showed good LC rates with RT alone for select advanced (stage III–IV) OPCs?

MDACC data (Garden AS et al., Cancer 2004): pts with small primaries but stage III–IV Dz by virtue of +LNs; treated with RT alone. There were acceptable 5-yr LF (15%), DM (19%), and OS (64%) rates.

What are 2 important randomized trials that demonstrated the importance of adding chemo to conventionally fractionated RT in OPC?

1.     GORTEC 94-01 (Calais G et al., JNCI 1999): 222 pts with stage III–IV OPC randomized to conventional RT alone vs. conventional RT + carboplatin/5-FU, no planned neck dissection for N2-3 Dz. The CRT arm had better 3-yr OS (51% vs. 31%), DFS (30% vs. 15%), and LC (66% vs. 42%); however, there was significantly worse grade 3–4 mucositis and weight loss/feeding tube use in the CRT arm.

2.     Cleveland Clinic data (Adelstein DJ et al., JCO 2003): 295 pts with unresectable stage III–IV H&N cancers (15% OC, 55% OPX, 20% HPX), RT alone vs. CRT with cisplatin 100 mg q3wks × 3. 3-yr OS was better in the CRT arm (37% vs. 23%). There also was improved DFS (51% vs. 33%) in the CRT arm.

What are the indications for adding chemo to PORT in H&N cancers, and what are 2 important RCTs that support this?

1.     Pooled analysis suggests +margin and ECE as the most important indications.

2.     EORTC 22931 (Bernier J et al., NEJM 2004): 334 pts randomized to PORT 66 Gy vs. PORT + cisplatin 100 mg/m2 on days 1, 22, and 43. Eligibility: ECE, + margin, PNI, LVI, and level 4–5 +N from OCC/OPC. There was better OS, DFS, and 5-yr LC with CRT but ↑ grade 3–4 toxicity.

3.     RTOG 95-01 (Cooper JS et al., NEJM 2004): 459 pts randomized to 60–66 Gy PORT vs. PORT + cisplatin 100 mg/m2 on days 1, 22, and 43. Eligibility: > 2 LN, ECE, +margin. There was better DFS (43% vs. 54%) and 2-yr LRC (72% vs. 82%) but only a trend to improvement in OS (57% vs. 63%).

What study demonstrated improvement in OS with the addition of cetuximab (C225) to RT in H&N cancers?

Bonner et al. (NEJM 2006): 424 pts with stage III–IV SCC of the OPX, laryngeal cancer (LCX), or HC randomized to RT vs. RT + C225. RT options were conventional to 70 Gy, 1.2 bid to 72–76.8 Gy, or concomitant boost to 72 Gy. There was better 3-yr LRC (47% vs. 34%) and OS (55% vs. 45%) with C225 + RT. Subset analysis showed improvement mostly in OPC and in the altered fractionation RT arms (~50% treated with altered fractionation).

What 2 randomized studies demonstrated a benefit with induction taxane/platinum/5-FU (TPF) chemo → RT or CRT in pts with unresectable H&N cancers?

TAX 324 study (induction chemo → CRT) (Posner MR et al., NEJM 2007): 501 pts, unresectable stage III–IV H&N cancers (52% OPX, ~13%–18% OC, larynx, HPX) randomized to induction platinum + 5-FU or TPF → CRT with carboplatin. There was better 3-yr OS (62% vs. 48%), MS (71 mos vs. 30 mos), and LRC (70% vs. 62%) in the TPF arm. Pts in the TPF arm had fewer Tx delays than in the platinum/5-FU arm despite higher myelotoxicity in the TPF arm (98% rcv planned Tx in the TPF arm vs. 90% in the PF arm).

TAX 323 study (induction chemo → RT) (Vermorken JB et al., NEJM 2007): 358 pts, unresectable stage III–IV H&N cancers (46% OPX, 18% OC, 29% HPX, 7% larynx) randomized to induction platinum + 5-FU or TPF → RT alone. TPF resulted in better median PFS (11 mos vs. 8.2 mos), MS (18.8 mos vs. 14.5 mos), and HR 0.73. The rate of toxic deaths was greater in the platinum/5-FU group (5.5% vs. 2.3%). Also, there was more grade 3–4 thrombocytopenia, anemia, stomatitis, n/v, diarrhea, and hearing loss in the platinum/5-FU arm. Neutropenia, leukopenia, and alopecia were more common in the TPF arm.

What are some advantages and disadvantages of split-field IMRT (vs. whole-field IMRT) in the Tx of H&N cancers?

There is potentially better laryngeal sparing with split-field IMRT techniques; however, the drawback is that the practitioner may have to junction the RT dose through involved nodes.

What are the advantages and disadvantages of IMRT “dose painting” (vs. sequential plans) in the Tx of H&N cancers?

The main advantage of IMRT dose painting is that better conformality can be achieved in a single plan. The drawback, however, is that nonstandard doses/fx are required.

How do unplanned RT interruptions in H&N cancer affect LC rates and why?

Each wk of Tx time prolongation reduces the LC rate by ~10%–12% in H&N cancer pts b/c of accelerated repopulation.

What is the best way to compensate for several/few missed RT sessions and avoid Tx time prolongation in H&N cancer pts?

According to Bese et al., the best way to compensate is by preserving total time, dose, and dose/fx (i.e., can treat bid on Fridays or extra fx on Saturdays). Alternatively, dose/fx can be increased (e.g., by ~0.5–0.7 Gy/day). (IJROBP 2007)

image Toxicity

What is the approximate long-term PEG tube dependency rate after CRT for OPC?

The long-term PEG tube dependency rate after CRT is ~15%–20%, which is reduced with swallowing exercises and the use of PEG on demand.

What are some typical RT dose constraints for the parotid glands?

Typical RT dose constraints for the parotid glands are (a) mean dose to either parotid <26 Gy or (b) at least 50% of either parotid gland <30 Gy.

What is the typical RT dose constraint for the inner ears?

The mean dose to the inner ears should be >50 Gy.

Approximately what % of pts receiving cisplatin-based chemo will experience hearing loss as a result of ototoxicity?

~30% of pts will experience hearing loss.

What is the typical RT dose constraint for the larynx?

Approximately one third of the larynx should not exceed a dose of 50 Gy (V50 <30%).

What were the xerostomia rates for OPC pts treated with IMRT in RTOG 00-22?

Xerostomia rates in RTOG 00-22 (Eisbruch A et al., IJROBP 2010) were 55% at 6 mos, 25% at 1 yr, and 16% at 2 yrs. Salivary output did not recover over time.

What was the observed rate of osteoradionecrosis with accelerated hypofractionated IMRT in RTOG 00-22?

The observed rate of osteoradionecrosis was 6% in RTOG 00-22 (Eisbruch A et al., IJROBP 2010), which is higher than expected for IMRT (potentially b/c of the accelerated hypofractionated approach). Other toxicities were acceptable (grade 2+ for mucosa [24%], salivary [67%], esophagus [19%]).

What is the follow-up paradigm for OPC pts?

OPC follow-up paradigm: H&P + pharyngolaryngoscopy (q1–3mos for yr 1, q2–4mos for yr 2, q4–6mos for yrs 3–5, q6–12mos if >5 yrs), imaging (for signs/Sx), TSH (if neck irradiated), speech/hearing/dental evaluation, and smoking cessation