# Radiation Oncology/Head & Neck/Neoadjuvant Chemo

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Head & Neck Cancer: Neoadjuvant Chemotherapy
    For neoadjuvant chemotherapy combined with concurrent chemo-RT see page at Concurrent Chemo-RT

## Induction Chemotherapy vs RT Alone

* DAHANCA 4 (1986-1991) -- neoadjuvant cisplatin + 5-FU and RT vs RT alone
** 461 pts (tumors of OC,OP,HP,L). Randomized to: 1) RT alone (64-70 Gy) (or RT + surgery if OC) vs 2) 3 cycles cisplatin + 5-FU followed by RT.
** 1997 PMID 9165133 Full text -- "Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study." (Lewin F, Radiother Oncol. 1997 Apr;43(1):23-8.)
*** Reponse rate 71% (neoadj chemo) vs 66% (RT only), NS; CR in 48% vs 39%. No difference in OS or LRC.
*** Conclusion: no benefit to neoadj chemo followed by RT
* Wayne State; 1985 - PMID 4038469 — "Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin." Rooney M et al. Cancer. 1985 Mar 1;55(5):1123-8.
** Pilot study. Pts received one of several regimens of induction chemotherapy: 2 courses cisplatin + vincristine + bleomycin (COB), 2 courses cisplatin + 96-hr 5-FU infusion, or 3 courses cisplatin + 120-hr 5-FU infusion. Pts went on to surgery or RT.
** High overall response rate in all 3 arms. CR rate higher in 120-hr 5-FU/Cisplatin regimen, 54% vs 29% (COB) and 19% (96-hr). Also higher survival for that regimen. Responders to initial chemo have higher survival vs non-responders.
** Conclusion: multimodality treatment is feasible.
* VA Larynx Trial - PMID 2034244
** Randomized. Pts with Stage III or IV laryngeal carcinoma randomized to induction chemo + XRT or surgery + XRT.
** See details at Larynx.
* RTOG 91-11 - PMID 14645636
** Larynx. 3 arms: induction chemo + RT, concurrent chemo/RT, XRT alone.
** See details at Larynx.
* Rush Presbytarian, Chicago (1976-1982) -- Induction chemo vs surgery +/- postop RT
** Randomized. 95 patients, poor prognosis Stage II, Stage III-IV. Arm 1) Induction chemo x2 weeks vs Arm 2) Regional therapy only (surgery +/- postop RT). Adjuvant chemo q3months x1 year. Initially received methotrexate / leucovorin, but was changed to Adriamycin + cisplatin because of toxicity concerns.
** 1985 PMID 3889230 — "A randomized trial of adjuvant chemotherapy in head and neck cancer." (Taylor SG et al. J Clin Oncol. 1985 May;3(5):672-9.)
*** Outcome: No difference in disease control or survival.
*** Conclusion: Induction chemotherapy doesn't improve outcomes
* RTOG 68-01 -- Methotrexate
** Randomized. 638 patients, Stage III-IV oral cavity (23%), oropharynx (55%), supraglottic larynx (12%), hypopharynx (10%). Arm 1) RT alone vs. Arm 2) IV MTX 25 mg q3d x5 followed by RT. RT 55-80 Gy
** 1980 PMID 7410127 -- "Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx." (Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 May;6(5):533-41.)
*** Outcome: median OS RT vs. MTX-RT: oral cavity 11.8 mo vs. 12.4 mo, oropharynx 13.6 mo vs. 13.1 mo, SGL 17.2 mo vs. 19.2 mo, hypopharynx 9.7 mo vs. 13.4 mo
*** Conclusion: Minimal gain, induction methotrexate should not be used

## Induction Chemotherapy: Combinations

* EORTC 24971 / TAX 323 -- PF vs TPF, followed by RT
** Randomized. 358 patients with unresectable Stage III/IV disease and no mets (Oropharynx 46%, hypopharynx 29%, oral cavity 18%, larynx 7%) Induction PF (cisplatin 100mg/m2, 5-FU 1000mg/m2) vs. TPF (docetaxel 75mg/m2, cisplatin 75mg/m2, 5-FU 750 mg/m2) x4 cycles. If no progression, RT start within 4-7 weeks after completing chemo. RT standard (66-70 Gy) or accelerated (max 70 Gy) or hyperfractionated (max 74 Gy). No concurrent chemo (?)
** Protocol compliance: PF 66% completed induction vs. TPF 76%. Progressive disease PF 7% vs. TPF 8%; adverse events PF 12% vs. TPF 6%; death PF 7% vs. TPF 3%
** 2007 PMID 17960012 -- "Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer" (Vermorken JB, N Engl J Med 2007 Oct 25; 357(17):1695-704). Median F/U 2.7 years
*** Outcome: median PFS TPF 11 months vs. PF 8.2 months (SS); median OS 14 months vs. 19 months (SS), risk of death decreased by 27%
*** Toxicity: TPF leukopenia and neutropenia vs. PF thrombocytopenia, N/V, stomatitis, hearing loss
*** Conclusion: Induction with TPF superior over induction with PF
* TAX 324 -- PF vs TPF, followed by Chemo-RT
** Randomized. 501 patients with Stage III/IV disease (resectable and unresectable) and no mets. Induction with PF (cisplatin 100mg/m2, 5-FU 1000mg/m2) vs. TPF (docetaxel 75mg/m2, cisplatin 100mg/m2, 5-FU 1000mg/m2) x3 cycles. If response (>25% tumor reduction), chemo-RT start within 3-8 weeks. RT 70-74 Gy in 2 Gy/fx, involved LNs 60-74 Gy, uninvolved LNs >=50 Gy. Concurrent carboplatin AUC 1.5. Surgery 6-12 weeks after RT if N2 and PR, if N3, or if residual disease
** Protocol compliance: 98% completed induction, completion per protocol TPF 73% vs. PF 68%
** 2007 PMID 17960013 -- "Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer" (Posner MR, N Engl J Med 2007 Oct 25; 357(17):1705-15). Minimum F/U 2 years
*** Outcome: median OS TPF 5.9 years vs. PF 2.5 years (SS); 3-year OS 62% vs. 48% (SS). Locoregional control 70% vs. 62% (SS), no difference in DM
*** Toxicity: TPF neutropenia vs. PF hematologic adverse events
*** Conclusion: Induction with TPF superior over induction with PF