Treatment/Prognosis

Question 1

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

Answer 1

Based on RTOG 0129 and AJCC 8th edition staging:

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

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

Advanced/unfavorable: HPV(–) smokers with stages III–IV Dz, T4 Dz regardless of HPV/smoking status

Question 2

What are the Tx paradigms for early oropharyngeal tumors?

Answer 2

Early oropharyngeal tumor Tx paradigm: surgical resection with selective neck dissection +/- PORT or definitive RT alone

Question 3

What are the Tx paradigms for intermediate oropharyngeal tumors?

Answer 3

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

Question 4

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

Answer 4

Advanced/unfavorable oropharyngeal tumor Tx paradigm: CRT (conventional)

Question 5

When is WLE alone appropriate for OPC?

Answer 5

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

Question 6

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

Answer 6

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.

Question 7

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

Answer 7

Historically, labiotomy and mandibulotomy were required to gain access to the OPX, but there is growing experience with transoral approaches with transoral laser microsurgery (TLM) and transoral robotic surgery (TORS).

Question 8

When is PORT indicated for OPC? When is postop CRT indicated for OPC?

Answer 8

Similar to other H&N sites, PORT is generally for intermediate-risk factors such as T3–T4, LN+, LVSI, and PNI, while postop CRT is indicated for +margin or +ENE.

Question 9

When can unilat neck Tx be considered for OPC pts?

Answer 9

Unilat neck Tx can be considered if the lesion is well lateralized (T1–T2, <1 cm soft palate extension, no BOT involvement) and 1 or few regional ipsi nodes <6 cm based on multiple retrospective reviews showing a very low contralat failure rate (<3%).

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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).

Question 12

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

Answer 12

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

Question 13

How should OPC pts be set up for simulation?

Answer 13

OPC pts should be simulated supine, with arms pulled inferiorly and the head extended with a bite block or stent. Contrast is recommended with CT.

Question 14

What type of custom stent can be used?

Answer 14

Mouth opening, tongue depressing stent

Question 15

What should the pre-RT evaluation/preparation include?

Answer 15

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

Question 16

What are the typical CTVs for IMRT planning?

Answer 16

CTV high dose (CTVHD): primary tumor and nodal GTV with 0.5–1-cm margin

CTV intermediate dose (CTVID): soft palate, adjacent parapharyngeal space, sup tonsillar pillars for lat tumors, and nodal levels adjoining involved nodes

CTV elective dose (CTVED): levels II–IV, RP nodes. If node+, most include ipsi IB and V.

Question 17

What are the typical RT doses and volumes used for OPC?

Answer 17

T1 and superficial T2N0: 66–70 Gy to CTVHD, 60 Gy to CTVID, and 54 Gy to CTVED, given in 30–35 fx over 6–7 wks

> T2+ without chemo: (1) 70 Gy to CTVHD, 63 Gy to CTVID, and 56 Gy to CTVED given in 35 fx over 6 wks (per Danish Head and Neck Cancer Group [DAHANCA]); (2) 70 Gy to CTVHD, 60 Gy to CTVID, and 57 Gy to CTVED given in 33 fx

> T3 or >N2 with chemo: 70 Gy to CTVHD, 63 Gy to CTVID, and 59.5 Gy to CTVED in 35 fx

Question 18

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

Answer 18

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

Question 19

What were the RT techniques and doses employed in RTOG 00–22? How was the N stage established?

Answer 19

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 PTV and 54–60 Gy in 30 fx (1.8–2 Gy/fx) to the secondary PTV. Neck staging was clinical (not from CT); however, pts “upstaged” by CT (e.g., cN1 but N2 after CT) were also eligible.

Question 20

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

Answer 20

RTOG 90–03 (Fu KK et al., IJROBP 2000): 1,073 pts with H&N cancers (10% 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.

Question 21

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

Answer 21

RTOG 90–03 (Fu KK et al., IJROBP 2000): see above.

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.

Question 22

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

Answer 22

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

Question 23

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

Answer 23

GORTEC 94–01 (Calais G et al., JNCI 1999): 222 pts with stages 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 grades 3–4 mucositis and weight loss/feeding tube use in the CRT arm.

Head and Neck Intergroup Study (Adelstein DJ et al., JCO 2003): 295 pts with unresectable stages III–IV H&N cancers (15% OC, 55% OPX, 20% HPX), RT alone vs. CRT with cisplatin 100 mg q3 wks × 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.

Question 24

Pooled analysis from which 2 important RCTs support adding chemo to PORT in H&N cancers for +margin and ECE?

Answer 24

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 levels 4–5 +N from OCC/OPC. There was better OS, DFS, and 5-yr LC with CRT but ↑ grades 3–4 toxicity.

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%).

Question 25

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

Answer 25

Bonner JA et al. (NEJM 2006): 424 pts with stages III–IV SCC of the OPX, laryngeal cancer, or HPX 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).

Question 26

What studies are looking at Tx deintensification for HPV+ OPX?

Answer 26

1. E1308: Phase II, stages III/IV, induction chemo (paclitaxel, cisplatin, cetuximab) f/b 54 Gy in 27 fx if CR or 69.3 Gy in 33 fx if PR, both with concurrent cetuximab. Although the study (Marur S et al., J Clin Oncol 2017) met its 2-yr PFS target based on historical control, other phase III trials indicate induction chemo adds toxicity without survival benefit (PARADIGM, DeCIDE).
2. RTOG 1016: Phase III, stages III/IV, treated with accelerated IMRT to 70 Gy/6 wks randomized to concurrent cisplatin vs. cetuximab.
3. NRG HN002: Phase II, stages III/IV, randomized to dose-reduced cisplatin CRT (60 Gy in 6 wks) vs. accelerated RT alone (60 Gy in 5 wks).

Question 27

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

Answer 27

TAX 324 study (induction chemo → CRT) (Posner MR et al., NEJM 2007): 501 pts, unresectable stages 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% rcvd 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 stages 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 grades 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.

Question 28

What study compared induction chemo vs. upfront CRT?

Answer 28

PARADIGM study (induction TPF → CRT vs. CRT) (Haddad H et al., Lancet Oncol 2013): 145 pts, stages III–IV (55% OPX), randomized to induction TPF → CRT vs. CRT. At a median follow-up of 49 mos, there was no difference in 3-yr OS (73% for induction vs. 78% for CRT), with a higher rate of febrile neutropenia observed in the induction arm.

Question 29

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

Answer 29

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.

Question 30

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

Answer 30

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.

Question 31

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

Answer 31

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

Question 32

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

Answer 32

According to Bese NS 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)