For locally advanced oropharyngeal cancers the primary treatment option is concurrent chemoradiation at 70 Gy in 35 fractions with cisplatin every 3 weeks as per the Adelstein trial.
If the patient can not tolerate chemotherapy than there are two reasonable options either altered fractionation as per the Fu RTOG 90-03 study or combining cetuximab with radiation as per the Bonner study.
Finally, induction taxotere, cisplatin, and 5-FU chemotherapy can be considered for locally advanced tumors provided the patient can tolerate the expected toxicities.
Conventional radiation alone is a poor choice given the number of options listed above as it is proven to be inferior for both survival and local control.
Surgery should generally be reserved for salvage as the associated morbidity is universally unacceptable.
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Locally advanced oropharyngeal cancers include stage III and stage IV tumors
Stage III = T3N0, T1-3N1
Stage IVA = T4aN0, T4aN1, T1-4aN2
Stage IVB = T4bNx, TxN3
These tumors have a 5 year overall survival of 30-40%. Local recurrence remains high and radiation therapy alone is not sufficient for adequate tumor control.
Treatment options include:
- Chemoradiation - 70 Gy in 35 fractions with cisplatin
- Altered fractionation - concomitant boost or hyperfractionation
- Radiation and cetuximab
- Induction chemotherapy followed by radiation or chemoradiation
- Conventional radiation alone
- Surgery +/- post-operative chemotherapy and radiation as indicated
Concurrent chemoradiation is the mainstay of treatment in most locally advanced head and neck tumors and oropharyngeal cancers is no exception. The MACH-NC meta-analysis of 93 randomized trials by Pignon of locally advanced head and neck trials have demonstrated a significant benefit of chemoradiation compared to radiation alone. The latest 2009 update shows an absolute improvement of 6.5% in overall survival when concurrent radiation is used.
The French GORTEC study is an oropharynx specific study consisting of stage III and IV tumors. It compared conventional radiation to concurrent carboplatin/5-FU and conventional radiation. This demonstrated an improvement in 5 year overall survival from 16% to 22% and an improvement in local control from 25% to 50%.
A standard regimen is based of the Adestein Intergroup trial. This 2-arm study compared conventional radiation to concurrent chemoradiation and to split-course concurrent chemoradiation in unresectable head and neck cancers. This study demonstrated worse toxicity for the chemoradiation arm, but an improved 3 year overall survival of 40% to 20% in favor of the chemoradiation arm. The split-course arm was worse compared to the concurrent arm and was most likely due to tumor repopulation during the treatment break. The concurrent radiation arm gives cisplatin every three weeks on days 1, 22, 43.
Altered Fractionation:
This includes either concomitant boost or hyperfractionation with the goal of shortening treatment time or dose escalation, respectively. The RTOG 90-03 study by Fu provides level I evidence to support the use of either concomitant boost or hyperfractionation. In this study of locally advanced head and neck cancers these two regimens were superior when compared to conventional fractionation and split course hyperfractionation. Overall survival was improved at 8 years from 30% to 35%. Local control was improved at 8 years from 40 to 50%.
An EORTC study by Horiot included Stage II and III oropharyngeal cancers. This study compared hyperfractionated treated 80.5 Gy using 1.15 Gy fractions BID to conventional 70 Gy in 35 fractions. This also demonstrated a trend for improvement in 5 year overall survival 3o% to 38% and a significant improvement in local control 40% to 60%.
Cetuximab and Radiation
Bonner compared conventional radiation alone to conventional radiation combined with cetuximab (250mg/m2 weekly). The 2009 update demonstrated a 5 year overall survival of 45% vs 35%. Local control rates are improved from 40 to 50%. The update also correlated cetuximab related rash with an improvement in survival (HR = 0.5).
Induction Chemotherapy
Induction chemotherapy is largely used to reduce tumor burden and to improve rates of organ preservation. The MACH-NC meta-analysis shows a small absolute benefit of 2% for overall survival when induction chemotherapy is added. This is an option for patients with locally advanced tumors who can tolerate induction chemotherapy in addition to definitive treatment.
The two principal studies looking at induction chemotherapy added taxotere to a cisplatin and 5-FU regimen. Vermorken's EORTC trial compared cisplatin 5-FU induction to taxotere, cisplatin and 5-FU for three cycles. This study followed the induction chemotherapy with conventional or altered fractionation radiotherapy. The results demonstrated an improvement in overall survival of 37% vs 24%% and improved response rates 68% vs 54%. The TPF regimen was less toxic likely due to the decreased doses of cisplatin and 5-FU.
A second study published in the same issue was Posner's study. This study was essentially the same as Vermorken's study in regards to the induction chemotherapy. This study used concurrent chemoradiation instead of radiation alone after the induction chemotherapy. This study showed 3 year overall survval of 60% vs 50% in favor of the docetaxel/taxotere arm. Local control was better as well at 50% vs 40%.
Volumes:
All cases should be treated by IMRT.
GTV = gross tumor
CTV70 = GTV + 2 cm
CTV64 = Adjacent lymph node levels
CTV 56 = Elective nodal irradiation
PTV = CTV + 0.5 mm
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