Supplementary table 1: Management of toxicity (CTC-NCI v.4.0)

Patients are evaluated before each cycle for treatment validation.

Dose reductions are calculated based in percentage of total initial dose.

Haematological toxicities:

Treatment delay / Dose reduction
Paclitaxel / Epirubicin / Cisplatin
Neutrophil ≥ 1 x 109/L and plat ≥ 70 x 109/L / Full dose
Neutrophil ≥ 0.5 x 109/L and < 1 x 109/L,
or plat ≥ 50x109/L and <70 x 109/L / No delay. / Reduction of 30%
Neutrophil < 0.5 x 109/L, febrile neutropenia, or plat < 50x109/L / Delay until recovery / Reduction of 30%

STOP treatment if no recovery (neutrophil ≥ 1 x 109/L, or plat ≥ 75 x 109/L) after 3 weeks of delay

Subsequent dose increase is not allowed in case of grade IV toxicities

Non-haematological toxicities:

Neurotoxicity

Paclitaxel / Epirubicin / Cisplatin
Grade I / Full dose
Grade II, 1st episode / Reduction of 25% / Full dose / Full dose
Grade II, 2nd episode or persistence after 1st reduction / Reduction of 50% / Full dose / Reduction of 25%
Grade II, persistence after 2nd reduction of paclitaxel / STOP / Full dose / Reduction of 25%
Grade III / STOP / Delay until recovery, then full dose / Delay until recovery, then reduction of 25%
Grade IV / STOP treatment and perform surgery 4-6 weeks from last cycle

Mucositis

Paclitaxel / Epirubicin / Cisplatin
Grade I / Full dose
Grade II / Reduction of 25% / Redaction of 25% / Redaction of 25%
Grade III / Delay until resolution, then reduction of 25% / Delay until resolution, then reduction of 25% / Delay until resolution, then reduction of 25%
Grade IV / STOP treatment and perform surgery 4-6 weeks from last cycle

Diarrhoea

Paclitaxel / Epirubicin / Cisplatin
Grade I / Full dose
Grade II / Full dose
Grade III / Delay until resolution, then reduction of 25%
Grade IV / STOP treatment and perform surgery 4-6 weeks from last cycle

Skin reaction

Paclitaxel / Epirubicin / Cisplatin
Grade I / Anti H1 and corticotherapy / Full dose / Full dose
Grade II / Anti H1 and corticotherapy / Full dose / Full dose
Grade III / STOP / Delay until resolution, then full dose / Delay until resolution, then full dose
Grade IV / STOP treatment and perform surgery 4-6 weeks from last cycle

Immediate Hypersensitivity

Paclitaxel / Epirubicin / Cisplatin
Grade I / Conventional surveillance / Full dose / Full dose
Grade II / Conventional treatment (antiH1, antiH2, corticotherapy) and restart perfusion after complete resolution / Full dose / Full dose
Grade III / STOP / Delay until resolution, then full dose / Delay until resolution, then full dose
Grade IV / STOP treatment and perform surgery 4-6 weeks from last cycle

Immediate cardiac ultrasonography is mandatory in case of suspicion of cardiac failure.