Randomized phase 3 noninferiority trial of radiotherapy and cisplatin vs radiotherapy and cetuximab after docetaxel-cisplatin-fluorouracil induction chemotherapy in patients with locally advanced unresectable head and neck cancer.

OBJECTIVES: Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT. MATERIALS AND METHODS: This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of < 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL). RESULTS: Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153). CONCLUSION: Noninferiority of cet+RT over cis+RT was not demonstrated.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC).

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.

Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group.

PURPOSE Cisplatin plus fluorouracil (PF) induction chemotherapy has been compared with taxane (docetaxel or paclitaxel), cisplatin, and fluorouracil (Tax-PF) in randomized trials in locoregionally advanced head and neck cancers (LAHNCs). The aim of this meta-analysis was to study the efficacy and toxicity of Tax-PF and PF and identify differences in outcomes in subsets of patients. METHODS Five randomized trials representing 1,772 patients were identified. Updated individual patient data (IPD) were retrieved for all trials. The log-rank test, stratified by trial, was used for comparison. Interaction or trend tests were used to study the interaction between covariates and treatment. Results Median follow-up was 4.9 years. The hazard ratio (HR) of death was 0.79 (95% CI, 0.70 to 0.89; P < .001; absolute benefit at 5 years: 7.4%) in favor of Tax-PF. Heterogeneity was significant (P = .08, I(2) = 51%) and related to one trial. There was no more heterogeneity after exclusion of this trial (P = .99, I(2) = 0%), and HR of death was 0.72 (95% CI, 0.63 to 0.83) in favor of Tax-PF. There was no interaction between treatment effect and the following patient covariates: age, sex, performance status, tumor stage, or site. Tax-PF was associated with significant reductions of progression, locoregional failure, and distant failure compared with PF, with HRs of 0.78 (95% CI, 0.69 to 0.87; P < .001), 0.79 (95% CI, 0.66 to 0.94; P = .007), and 0.63 (95% CI, 0.45 to 0.89; P = .009) respectively. CONCLUSION This IPD meta-analysis shows the superiority of Tax-PF over PF as induction chemotherapy. Its precise role in the management of LAHNC remains to be determined.

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m(2) ) plus cisplatin (75 mg/m(2) ; n = 398) or placebo plus cisplatin (75 mg/m(2) ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers.

Update on the diagnosis of cancer of unknown primary (CUP) origin.

The cancer of unknown primary (CUP) concept encompasses a heterogeneous group of cancers that are difficult to diagnose and that show diverse clinical and histopathological features. Currently, CUP is the fifth most frequent cancer diagnosis in women and the eighth in men. The ongoing development of new therapies specific to the various cancer types makes mandatory the identification of the primary tumour in CUP patients, so that they may benefit from advances in therapy and improvements in prognosis. Molecular detection techniques provide very useful tools in the prediction of primary tumour types and must be used together with clinical, histopathological and IHC diagnostic techniques. Steady collaboration and fluid communication between oncologists and pathologists is of the utmost importance for the correct interpretation of tests and the personalised approach required by each individual case. Work in multidisciplinary teams will result in significant changes in the diagnosis and treatment of these patients.

Diagnosis of unknown primary cancer based on molecular techniques may influence therapeutic approach and improve survival.

Unknown primary cancer (UPC) is a common clinical syndrome classically associated with a poor prognosis. Pathological examination including immunohistochemistry continues to be essential in tumour origin characterization, although in many cases primary tumour site remains unknown. Gene expression based analysis may offer important diagnostic information that could lead to therapeutic decisions.

Tyrosine kinase inhibitors in treating soft tissue sarcomas: sunitinib in non-GIST sarcomas.

Sarcomas are uncommon malignancies that represent more than 50 different tumor types. Surgery remains the mainstay of treating localised disease. Anthracycline and ifosfamide-based chemotherapy is an option for advanced disease; however, effective treatment of advanced soft tissue sarcoma remains a challenge. Advances in understanding the genetic nature of cancer have led to the development of new treatment options for sarcoma. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic properties and promising activity in the treatment of GIST refractory to imatinib, however in either soft tissue sarcoma, experience with sunitinib is under development in different clinical trials. In this review we offer the experience with this small molecular target in non-GIST sarcomas.

Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma.

BACKGROUND: Treatment of high-grade osteosarcoma remains a challenge. The prognostic significance of the pre-treatment serum lactate dehydrogenase (LDH) level is currently controversial. PATIENTS AND METHODS: We reviewed records from all patients diagnosed with conventional high-grade osteosarcoma at our institution over a 25-year period and analysed the prognostic significance of LDH in high-grade localised extremity osteosarcomas treated with chemotherapy. RESULTS: Between June 1977 and March 2003, 66 patients for whom follow-up was available were diagnosed with localised high-grade extremity osteosarcoma and treated with chemotherapy. The median age was 15 years, with only 3% older than 40 years, and the median follow-up was 100 months. The median progression-free survival (PFS) was 67 months and the median overall survival (OS) was 113 months. The absence of a response to chemotherapy was correlated with a trend toward lower PFS and OS. High serum pre-treatment LDH level was associated in multivariate analyses with a poorer prognosis for both PFS (HR=8.623, 95%CI: 1.71-43.37; p=0.009) and for OS (HR=9.38; 95%CI: 1.73-50.74; p=0.009). CONCLUSION: In this series, the pre-treatment serum LDH level had an independent prognostic value for both PFS and OS in patients with high-grade localised extremity osteosarcoma. This measurement should be included in a large prospective prognostic series.

Quimioterapia basada en platino más cetuximab en el cáncer de cabeza y cuello / Platinum plus cetubimab based quimiotherapy in head and neck cancer

Antecedentes: Cetuximab resulta efectivo en el carcinoma metastático o recurrente de células escamosas de cabeza y cuello, resistente al platino. Se investigó la eficacia de cetuximab más quimioterapia basada en platino como tratamiento de primera línea en pacientes con carcinoma metastático o recurrente de células escamosas de cabeza y cuello. Métodos: Se asignaron al azar 220 pacientes de 442 pacientes elegibles con carcinoma metastático o recurrente de células escamosas de cabeza y cuello sin tratamiento, para recibir cisplatino (a una dosis de 100mg por metro cuadrado de área de superficie corporal el día 1) o carboplatino (en un área por debajo de la curva de 5mg por mililitro por minuto, como infusión intravenosa de 1 hora el día 1) más fluorouracilo (a una dosis de 1000mg por metro cuadrado por día, durante 4 días) cada 3 semanas, por un máximo de 6 ciclos, y 222 pacientes para recibir la misma quimioterapia más cetuximab (a una dosis de 400mg por metro cuadrado en forma inicial, como infusión intravenosa de 2 horas, luego 250mg por metro cuadrado, como infusión intravenosa de 1 hora por semana) durante un máximo de 6 ciclos. Los pacientes con enfermedad estable que recibieron quimioterapia más cetuximab continuaron recibiendo cetuximab hasta la progresión de la enfermedad o hasta la aparición de efectos tóxicos inaceptables, lo que ocurriera primero. Resultados: El agregado de cetuximab a la quimioterapia basada en platino con fluorouracilo (platino-fluorouracilo) prolongó de manera significativa la mediana de la supervivencia global, de 7.4 meses en el grupo de quimioterapia sola a 10.1 meses en el grupo que recibía quimioterapia más cetuximab (índice de riesgo para muerte = 0.80; intervalo de confianza 95%: 0.64-0.99; p = 0.04). El agregado de cetuximab prolongó la mediana del tiempo de supervivencia libre de progresión de 3.3 meses a 5.6 meses (índice de riesgo para la progresión = 0.54; p < 0.001) y aumentó la tasa de respuesta de 20% a 36% (p < 0.001).

Platinum-based chemotherapy plus cetuximab in head and neck cancer.

BACKGROUND: Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. METHODS: We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. RESULTS: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. CONCLUSIONS: As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy.

PURPOSE: To evaluate the efficacy and safety of the epidermal growth factor receptor-directed monoclonal antibody cetuximab administered as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who experience disease progression on platinum therapy. PATIENTS AND METHODS: An open-label multicenter study in which patients with disease progression on two to six cycles of platinum therapy received single-agent cetuximab (initial dose 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) for > or = 6 weeks (single-agent phase). Patients who experienced disease progression could receive salvage therapy with cetuximab plus platinum (combination-therapy phase). From June 2001 to December 2002, 103 patients were enrolled and treated with cetuximab, 53 of whom subsequently received combination therapy. RESULTS: In the single-agent phase, response rate was 13%, disease control rate (complete response/partial response/stable disease) was 46%, and median time to progression (TTP) was 70 days. During the combination-therapy phase, the objective response rate was zero, disease control rate was 26%, and TTP was 50 days. Median overall survival was 178 days. Treatment was well tolerated. The most common cetuximab-related adverse events in the single-agent phase were skin reactions, particularly rash (49% of patients, mainly grade 1 or 2). There was one treatment-related death due to an infusion-related reaction. CONCLUSION: Single-agent cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic SCCHN that progressed on platinum therapy. Response was comparable to that seen with cetuximab plus platinum combination regimens in the same setting.

Primary pulmonary artery sarcoma: report of three cases and review of the literature.

Pulmonary artery sarcomas (PASs) are rare tumors of the vasculature of the lung that usually present as a thromboembolism. Failure of anticoagulant therapy to relieve all of a patient's symptoms suggests the diagnosis. Approximately 75% of patients with PAS present with dyspnea, and slightly > 50% also experience chest pain or cough. Imaging studies (chest computed tomography with 3-dimensional reconstruction, magnetic resonance imaging, perfusion lung scan, and pulmonary angiogram) are usually unspecific. A definitive diagnosis requires pathologic examination of tissue obtained by intravascular, percutaneous, or surgical biopsy. Treatment of primary PAS is usually surgical with or without adjuvant chemotherapy or radiation therapy. Because these tumors are rare, data from large randomized trials are not available. Palliative chemotherapy with anthracyclines and ifosfamide is the usual treatment in advanced disease, with response rates of approximately 50%. The mean survival time ranges from 14 months to 18 months. We report 3 cases of PAS treated with surgery and chemotherapy (anthracyclines and ifosfamide) with different outcomes.

Molecular biology in head and neck cancer.

Major changes in the treatment of head and neck cancer are possible today because of the knowledge that we have on the molecular biology of these tumors. Different pathways are active in the development of this cancer and field cancerization is a major problem for the cure in early stage disease. Epidermal growth factor signal transduction pathway is now the principal target for this disease. New therapeutic strategies such as monoclonal antibodies and small molecules have appeared, however no more than 20% of the patients have objective responses with these therapies. Consequently, new alternatives of treatment in the basis of the understanding of molecular biology are necessary to increase the number of patients that can be cured in the future.

DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy.

PURPOSE: Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. We studied whether single nucleotide polymorphisms (SNPs) of DNA repair genes predict the response to cisplatin or prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: A polymerase chain reaction-restriction fragment length polymorphism (RFLP) approach was used to determine the frequency of the SNPs: XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and XRCC1-Arg399Gln in DNA from peripheral lymphocytes of 103 stage IV SCCHN patients. RESULTS: The frequencies of the distinct genotypes were, respectively, for the homozygous common allele, heterozygous and homozygous polymorphic variant: 53%, 40%, and 7% for ERCC1; 50%, 42%, and 8% for XPD-312; 35%, 57%, and 8% for XPD751; and 35%, 51%, and 13% for XRCC1. Patients with only common alleles at all the SNPs tested had a median overall survival of 5.1 months (range, 4.3 to 6.0 months) as compared with not reached for patients with at least one polymorphic variant (P < .001). Estimates from Cox's multivariate analysis suggest that the accumulation of each polymorphic variant decreases the probability of dying by a factor of 2.1 (P < .001; the presence of seven polymorphic variants confers a 175-fold protection). The accumulation of polymorphic variants increases by 2.94-fold the probability of achieving a complete response to treatment (P = .041). CONCLUSION: Using a multivariate model, the presence of polymorphic variants in DNA-repair genes are powerful prognosis factors and response to cisplatin predictors among SCCHN patients.

Breast cancer-specific mRNA transcripts presence in peripheral blood after adjuvant chemotherapy predicts poor survival among high-risk breast cancer patients treated with high-dose chemotherapy with peripheral blood stem cell support.

PURPOSE: To study the prognostic significance of the presence of breast cancer-specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. METHODS: From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. RESULTS: Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). CONCLUSION: PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.

Cetuximab in squamous cell carcinoma of the head and neck.

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemotherapy and chemoradiotherapy are new alternatives for locally advanced disease, particularly induction chemotherapy for patients with unresectable tumors. In recurrent/metastatic disease and after progression to platin-based regimens, no treatments other than best supportive care are currently available. Most SCCHN tumors overexpress the epidermal growth factor receptor (EGFR). This is a tyrosine kinase membrane receptor and has a clear implication in angiogenesis, tumor progression and resistance to different cancer treatments. Cetuximab is a monoclonal antibody that binds to EGFR and alters the tyrosine kinase-mediated signal transduction pathway. The drug is active in colon cancer and is currently being tested in SCCHN patients. For locally advanced disease, cetuximab/radiotherapy combination has demonstrated a benefit in survival when compared with radiotherapy alone as radical treatment. Cetuximab is an active treatment in platin-refractory patients with recurrent/metastatic disease.

Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Treatment comprised cetuximab (initial dose 400 mg/m2 with subsequent weekly doses of 250 mg/m2) in combination with 3-week cycles of either cisplatin (100 mg/m2) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m2/d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were enrolled onto the study. The incidence of dose-limiting toxicities in phase A was acceptable. The most common grade 3/4 adverse events in both groups were leucopenia (38%), asthenia (25%), vomiting (14%), and thrombocytopenia (15%), which are consistent with the known safety profiles of cetuximab, cisplatin/carboplatin, and FU. The overall response rate among patients was 36%, with no clear trend toward an increased efficacy at the highest dose of FU, and no impact of the concomitant chemotherapy regimens on cetuximab pharmacokinetics. CONCLUSION: The combination of cetuximab, cisplatin/carboplatin, and FU was reasonably well tolerated and active in recurrent/metastatic SCCHN, and merits additional investigation. An FU dose of 1,000 mg/m2/d in combination with cisplatin or carboplatin can be recommended for additional studies.

Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this study was to assess the antitumor activity and toxicity profile of weekly docetaxel in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Patients with recurrent, metastatic, incurable squamous cell carcinoma of the head and neck were enrolled. Weekly docetaxel (30 mg/m2) was administered for 4 weeks every 5 weeks for a maximum of 6 cycles. RESULTS: The activity and toxicity of docetaxel were assessed in all 38 patients who were entered on the study. No Grade 3-4 toxicities were recorded. No treatment delays were required because of toxicity or dose reductions. Responses were observed in 42% of patients (95% confidence interval, 26-58%). The median duration of response was 8.39 months, the estimated median overall survival was 11.3 months, and the 1-year survival rate was 39%. CONCLUSIONS: The results of this study suggested that weekly docetaxel was an active agent for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer.

PURPOSE: To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). PATIENTS AND METHODS: Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1000 [corrected] mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). RESULTS: A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). CONCLUSION: Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment.