Primož Strojan (Institute of Oncology Ljubljana)
**Introduction of the study:** In LASCCHN, a combination of radiotherapy (RT) and CMb: (1) significantly improves overall survival rate compared with RT alone; (2) CMb-treated patients with a prominent CMb-induced rash survived significantly better than patients with no or grade 1 rash, who experience no survival advantage compared to irradiated only patients. Comparing the benefits of concomitant immunoradiotherapy and chemoradiotherapy with RT alone, the outcome in CMb-treated patients with a skin rash of grade 2-4 (hazard ratio [HR] 0.49; Bonner et al, Lancet oncol 2010.) seems more favorable than in cisplatin (CP)-treated patients (HR 0.74; Pignon et al, Radiother Oncol 2009). The aim of the present single-institution non-randomized prospective phase II study was to test the hypothesis that early assessment of a CMb-induced skin rash can be used for treatment stratification of patients with LASCCHN: in patients who would develop a grade 2-4 skin rash after concomitant CMb administration, the treatment results will be improved compared with RT-CP combination. In patients without a prominent skin rash no beneficial effect of CMb is expected and concomitant chemoradiotherapy with CP should be more effective. **Methodology:** Patients with LASCC (stages III-IVB) of the oral cavity, oro- hypopharynx or larynx and WHO PS 0-2 were considered eligible. In the week before RT, all patients received a loading dose of CMb (400 mg/m2). During the first week of RT, a combination of CMb (250 mg/m2) and CP (30 mg/m2) was concurrently administered. At the end of the second week of RT, a multidisciplinary assessment of the skin rash was done: CTCAE v3.0 grade 0-1 – patients proceeded with chemoradiotherapy with CP (arm A); CTCAE v3.0 grade 2-4 – patients proceeded with immunoradiotherapy with CMb (arm B). Concomitant boost IMRT was used in all patients (56-63-70 Gy/35 fractions). The planned number of patients in the study: 120 (recruited over 3 years). The primary objective: the radiological complete response (CR) rate at 12-14 weeks post-therapy. Secondary objectives: locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) at 2 years after therapy, acute and late toxicity. **Results:** Between 12/2011 and 7/2013, 39 patients (males 87%; median age 57 years, range 42-75) entered the study which was prematurely terminated due to an unexpectedly high number of CTCAE v3.0 grade 3/4 allergic reactions to CMb. There were 31 active smokers; sites of origin were the oropharynx 30 (p16/HPV positive 8, status unknown 4), hypopharynx 5, oral cavity 2, and larynx 2. The majority (89.7%) of tumors were of TNM stage IV (T4 53.8%, N2b-3 71.8%). The RT dose was 70 Gy in all patients. During administration of the CMb loading dose, an allergic reaction of CTCAE v3.0 grade 3/4 developed in 11 patients (28.2%) who proceeded with chemoradiotherapy with CP (4-8 cycles, median 6); at 12-14 weeks post-therapy, a locoregionally CR was determined in 6 patients (54.5%). A grade 0-1 skin rash was recorded in 10 patients (35.7%) who continued with RT-CP (6-8 cycles, median 7); 8 patients (80%) from this group had a CR. A grade 2-4 skin rash was recorded in 18 patients (64.3%) who proceeded with RT-CMb (3-8 cycles, median 7) and 10 of them (55.6%) were complete responders. The difference in CR rates between the three groups was not significant. No differences in distribution of the primary tumor sites, T- and N-stage, or HPV status were found between the two arms or those with allergic reaction to CMb. The median follow-up time was 39 months (range, 26-49). Actuarial survival rates at 2 years in patients treated with chemoradiotherapy (arm A and patients allergic to CMb, N=21) and those treated with immunoradiotherapy (N=18) were as follows: LRC 38% (95% confidence interval [CI], 17-58) vs. 39% (95% CI, 16-61), P>0.05; PFS 35% (95% CI, 14-56) vs. 39% (95% CI, 16-61), p>0.05; and OS 52% (95% CI, 31-74) vs. 44% (95% CI, 21-67), p>0.05. Acute toxicity was assessed separately for patients who received concomitantly with RT either CP or CMb. Evaluation of late toxicity was done only in patients who survived 6+ months post-therapy and had no residual or recurrent disease above the clavicles (Table). **Conclusion:** CMb administration resulted in an unexpectedly high rate (28.2%) of grade 3/4 allergic reactions. A prominent CMb-induced skin rash developed in two thirds of the patients. Immunoradiotherapy in these patients did not result in a survival advantage over chemoradiotherapy with CP but increased acute toxicity.
|Institution||Institute of Oncology Ljubljana|
Primož Strojan (Institute of Oncology Ljubljana)
Barbara Žumer (Institute of Oncology Ljubljana) Boris Jančar (Institute of Oncology Ljubljana) Branko Zakotnik (Institute of Oncology Ljubljana) Cvetka Grašič Kuhar (Institute of Oncology Ljubljana) Katarina Karner (Institute of Oncology Ljubljana) Marta Dremelj (Institute of Oncology Ljubljana) Simona Jereb (Institute of Oncology Ljubljana)