Skin Reaction to Cetuximab as a Criterion for Treatment Selection in Head and Neck Cancer.

BACKGROUND/AIM: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.

Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m2) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m2 cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m2 cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m2 (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m2 cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

Comparison of weekly administration of cisplatin versus three courses of cisplatin 100 mg/m(2) for definitive radiochemotherapy of locally advanced head-and-neck cancers.

BACKGROUND: To compare definitive radiochemotherapy with weekly administration of 30-40 mg/m(2) of cisplatin to 100 mg/m(2) of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. METHODS: Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30-40 mg/m(2)) were compared to 58 patients receiving radiochemotherapy with 100 mg/m(2) cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. RESULTS: On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m(2) (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0-1 (HR 5.63; p < 0.001) and histological grade 1-2 (HR 1.81; p = 0.002). On multivariate analysis, improved OS was associated with cisplatin 100 mg/m(2) (HR 1.33; p = 0.023), ECOG performance score 0-1 (HR 2.15; p = 0.029) and female gender (HR 1.98; p = 0.026). Cisplatin 100 mg/m(2) was associated with higher rates of grade ≥3 hematotoxicity (p = 0.004), grade ≥2 renal failure (p = 0.004) and pneumonia/sepsis (p = 0.033). CONCLUSIONS: Radiochemotherapy with 100 mg/m(2) of cisplatin every 3 weeks resulted in better LRC and OS than weekly doses of 30-40 mg/m(2). Given the limitations of a retrospective study, 100 mg/m(2) of cisplatin appears preferable. Since this regimen was associated with considerable acute toxicity, patients require close monitoring.

Chemoradiation of locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN): Is 20mg/m(2) cisplatin on five days every four weeks an alternative to 100mg/m(2) cisplatin every three weeks?

OBJECTIVES: To compare chemoradiation with 100mg/m(2) cisplatin every three weeks to 20mg/m(2) on five days every four weeks for locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN). MATERIALS AND METHODS: In 230 patients receiving chemoradiation for LASCCHN, 100mg/m(2) cisplatin every three weeks (N=126) and 20mg/m(2) cisplatin on five days every four weeks (N=104) were retrospectively compared. Chemoradiation plus eleven characteristics (T-/N-classification, performance score, gender, age, tumor site, grading, surgery, radiation technique, pre-chemoradiation hemoglobin, cumulative cisplatin dose) were analyzed for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Chemoradiation groups were compared for adverse events. RESULTS: On univariate analyses, chemoradiation had no impact on LRC (p=0.53), MFS (p=0.67) and OS (p=0.14). On multivariate analysis of LRC, T-classification (p=0.045) and hemoglobin (p<0.001) were significant. On multivariate analysis of MFS, performance score (p=0.028) was significant. On multivariate analysis of OS, performance score (p=0.009) and hemoglobin levels (p=0.002) achieved significance. Chemoradiation with 100mg/m(2) cisplatin was associated with more pneumonia/sepsis (p=0.003), grade ⩾2nausea/vomiting (p<0.001), grade ⩾2 nephrotoxicity (p=0.005), grade ⩾2 xerostomia (p=0.002), grade ⩾3 hematotoxicity (p=0.052) and grade ⩾2 ototoxicity (p=0.048). CONCLUDING STATEMENT: 20mg/m(2) cisplatin on five days every four weeks was associated with fewer adverse events than 100mg/m(2) cisplatin every three weeks. 100mg/m(2) cisplatin was not significantly superior to 20mg/m(2) cisplatin regarding LRC, MFS and OS. Given the limitations of a retrospective study, 20mg/m(2) cisplatin appeared preferable. The results should be confirmed in a randomized trial.

TPF induction chemotherapy and concomitant irradiation with cisplatin and cetuximab in unresectable squamous cell carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of docetaxel, cisplatin/5-fluorouracil (TPF) induction chemotherapy and concomitant immunochemoradiotherapy with cetuximab and cisplatin in unresectable head and neck carcinoma. METHODS: Treatment consisted of TPF induction chemotherapy (docetaxel 75 mg/m(2) day 2; cisplatin, 75 mg/m(2) day 2; and 5-fluorouracil 750 mg/m(2) days 1-4; 4 cycles), followed by radiotherapy (RT) and concomitant weekly cetuximab, (250 mg/m(2), after a loading dose of 400 mg/m(2)) and cisplatin (30 mg/m(2)). RESULTS: Twenty-five of 30 patients completed 4 cycles of induction chemotherapy. Six or more concomitant infusions of cisplatin and cetuximab were administered in 13 of 25 and 18 of 25 patients, respectively. The 2-year locoregional control, disease-free survival (DFS), and overall survival (OS) were 47%, 47%, and 50%, respectively. Patients with grade ≥ 2 skin reaction to cetuximab had a superior outcome. CONCLUSION: The tested regimen was effective; however, cetuximab and low-dose cisplatin after induction TPF increased the treatment toxicity. A grade ≥ 2 skin rash correlated with improved efficacy.

Adjuvant radiotherapy for palpable melanoma metastases to the groin: when to irradiate?

PURPOSE: To determine the efficacy of and criteria for postoperative radiotherapy (PORT) in patients with palpable melanoma metastases to the groin. METHODS AND MATERIALS: Patients with palpable metastases to the groin who were treated with therapeutic nodal dissection during 2000 to 2006 were identified in a prospective institutional database. RESULTS: In 101 patients, 103 therapeutic nodal dissections were performed; 37 of these were treated with PORT to a median equivalent dose (eqTD(2)) of 50.6 Gy (range, 50-72 Gy). In the surgery-only and PORT groups, 2-year regional control rates were 86% (95% confidence interval [CI] 76-95%) and 91% (95% CI, 81-100%), respectively (p = 0.395). Of five recurrences in radiation-treated patients, four were of dermal type, and in three of these cases, no bolus over the operative scar was used. PORT improved 2-year regional control (46% [95% CI, 11-82%] vs. 82% [95% CI, 63-100%], p = 0.022) among patients in which the sum of risk factors present (i.e., risk factor score) was ≥2. In multivariate analysis, risk-factor score (<2 vs. ≥2: HR, 2.93; 95% CI, 1.00-8.56; p < 0.0001) and PORT (yes vs. no: HR, 7.81; 95% CI, 2.83-21.74; p = 0.050) was predictive for regional control and on logistic-regression testing, number of involved lymph nodes was predictive for systemic dissemination (p = 0.011). CONCLUSIONS: PORT should follow therapeutic nodal dissection in cases with two or more adverse factors. More conventional fractionation (≤2.5 Gy), cumulative eqTD(2) <60 Gy and use of bolus over the operative scar are recommended.

concomitant chemoradiotherapy with mitomycin C and cisplatin in advanced unresectable carcinoma of the head and neck: phase I-II clinical study.

PURPOSE: To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m(2) IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m(2)/d IV, applied during the last 10 fractions of irradiation ("chemoboost"). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m(2)/d up to the maximum tolerated dose (MTD) or at the most 14 mg/m(2)/d (Phase I study), which was tested in the subsequent Phase II study. RESULTS: All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m(2)/d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m(2)/d, the corresponding rates were 40%, 20%, and 22%, respectively. CONCLUSION: Concomitant chemoradiotherapy with mitomycin C and cisplatin "chemoboost" at 14 mg/m(2)/d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

Antitumour effectiveness of hyperthermia is potentiated by local application of electric pulses to LPB tumours in mice.

BACKGROUND: The aim of our study was to determine whether local application of electric pulses to tumours, which induce transient reduction of tumour perfusion, could potentiate the antitumour effectiveness of hyperthermia. MATERIALS AND METHODS: The antitumour effectiveness of local application of electric pulses (1300 V/cm, 100 micros, 1 Hz) and 910 MHz local hyperthermia at 43.5 degrees C, alone or in combination, was determined on LPB tumours in C57Bl/6 mice by measurement of tumour growth delay, changes in tumour perfusion using the Patent blue technique and extent of tumour necrosis. RESULTS: When hyperthermia was performed immediately after application of electric pulses, at a time of maximally reduced tumour perfusion, greater than additive antitumour effectiveness was observed, resulting in 14.5 +/- 3.1 days growth delay of tumours that regrew and 43% complete responses. Single treatment, application of electric pulses or hyperthermia had minor or no effect on tumour growth. When hyperthermia was performed 24 hours after application of electric pulses, at a point when tumour perfusion was restored, the effect of both treatments was additive, resulting in 4.1 +/- 1.1 days growth delay and no cures. CONCLUSION: The probable mechanisms for the observed, more than additive, interaction when hyperthermia was performed immediately after application of electric pulses are the potentiation of thermic cytotoxicity, due to the reduced tumour perfusion induced by application of electric pulses and prolonged tumour perfusion reduction after combined treatment leading to additional cell kill, due to the protracted ischemia.