A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck

<p>Abstract</p> <p>Background</p> <p>Concomitant chemotherapy and radiotherapy (chemoradiation; CRT) is the standard treatment for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). CRT improves local control and overall survival (OS) when compared to radiotherapy (RT) alone. Induction chemotherapy (IC) reduces the risk of distant metastases (DM) and improves OS by 5% with the use of cisplatin/infusional 5 fluorouracil (PF) in meta-analysis. Adding a taxane to PF in the IC regimen confers a better outcome. Sequential treatment (ST) of IC followed by CRT is therefore under active investigation in multiple phase III trials.</p> <p>Methods</p> <p>We compared the outcome of two cohorts of patients (pts) with LA-SCCHN treated at our institution with CRT (n = 27) or ST (n = 31), respectively. CRT consisted of GEM 100 mg/m²weekly + conventional RT (70 Gy); ST consisted of the same CRT preceded by platinum-based IC.</p> <p>Results</p> <p>Response to IC: complete 8 (26%), partial 20 (65%), stable 1, progressive 1, not evaluable 1. Median follow up of the surviving pts: for CRT 73 months, for ST 51 months. Median time to distant metastasis (TDM) was for CRT 23.6 months, for ST not reached. Median OS was for CRT 20.2 months, for ST 40.2 months. Cox regression analysis, taking into account age, T and N stage and tumor site, showed a hazard ratio with ST of 1.190 for time to locoregional failure (p = 0.712), 0.162 for TDM (p = 0.002), and 0.441 for overall survival (OS) (p = 0.026).</p> <p>Conclusion</p> <p>TDM and OS were found significantly longer in the ST cohort without a reduced locoregional control. Notwithstanding the limitations of a non-randomized single-center comparison, the results are in line with very preliminary data of randomized comparisons suggesting an improved outcome with ST.</p

cTNM vs. pTNM: the effect of not applying ultrasonography in the identification of cervical nodal disease

Accurate clinical staging of oral squamous cell cancer can be quite difficult to achieve especially if nodal involvement is identified. Radiologically-assisted clinical staging is more accurate and informs the clinician of loco-regional and distant metastasis

Outcome in recurrent head neck cancer treated with salvage-IMRT

BACKGROUND: Recurrent head neck cancer (rHNC) is a known unfavourable prognostic condition. The purpose of this work was to analyse our rHNC subgroup treated with salvage-intensity modulated radiation therapy (IMRT) for curable recurrence after initial surgery alone. Patients Between 4/2003-9/2008, 44 patients with squamous cell rHNC were referred for IMRT, mean/median 33/21 (3-144) months after initial surgery. None had prior head neck radiation. 41% underwent definitive, 59% postoperative IMRT (66-72.6Gy). 70% had simultaneous chemotherapy. METHODS: Retrospective analysis of the outcome following salvage IMRT in rHNC patients was performed. RESULTS: After mean/median 25/21 months (3-67), 22/44 (50%) patients were alive with no disease; 4 (9%) were alive with disease. 18 patients (41%) died of disease. Kaplan Meier 2-year disease specific survival (DSS), disease free survival (DFS), local and nodal control rates of the cohort were 59/49/56 and 68%, respectively. Known risk factors (advanced initial pTN, marginal initial resection, multiple recurrences) showed no significant outcome differences. Risk factors and the presence of macroscopic recurrence gross tumor volume (rGTV) in oral cavity patients vs others resulted in statistically significantly lower DSS (30 vs 70% at 2 years, p=0.03). With respect to the assessed unfavourable outcome following salvage treatment, numbers needed to treat to avoid one recurrence with initial postoperative IMRT have, in addition, been calculated. CONCLUSION: A low salvage rate of only ~50% at 2 years was found. Calculated numbers of patients needed to treat with postoperative radiation after initial surgery, in order to avoid recurrence and tumor-specific death, suggest a rather generous use of adjuvant irradiation, usually with simultaneous chemotherapy

In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

<p>Abstract</p> <p>Background</p> <p>Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This <it>in vitro </it>study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules.</p> <p>Methods</p> <p>The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed.</p> <p>Results</p> <p>Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect.</p> <p>Conclusions</p> <p>Results from our <it>in vitro </it>model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an <it>in vivo </it>setting, possibly provide the greatest benefit in the clinic.</p

Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β1, talin and FAK pathways that regulate NF-kB nuclear activity

Clinicopathological parameters, recurrence, locoregional and distant metastasis in 115 T1-T2 oral squamous cell carcinoma patients

The incidence of oral squamous cell carcinoma remains high. Oral and oro-pharyngeal carcinomas are the sixth most common cancer in the world. Several clinicopathological parameters have been implicated in prognosis, recurrence and survival, following oral squamous cell carcinoma. In this retrospective analysis, clinicopathological parameters of 115 T1/T2 OSCC were studied and compared to recurrence and death from tumour-related causes. The study protocol was approved by the Joint UCL/UCLH committees of the ethics for human research. The patients' data was entered onto proformas, which were validated and checked by interval sampling. The fields included a range of clinical, operative and histopathological variables related to the status of the surgical margins. Data collection also included recurrence, cause of death, date of death and last clinic review. Causes of death were collated in 4 categories (1) death from locoregional spread, (2) death from distant metastasis, (3) death from bronchopulmonary pneumonia, and (4) death from any non-tumour event that lead to cardiorespiratory failure. The patients' population comprised 65 males and 50 females. Their mean age at the 1 diagnosis of OSCC was 61.7 years. Two-thirds of the patients were Caucasians. Primary sites were mainly identified in the tongue, floor of mouth (FOM), buccal mucosa and alveolus. Most of the identified OSCCs were low-risk (T1N0 and T2N0). All patients underwent primary resection neck dissection and reconstruction when necessary. Twenty-two patients needed adjuvant radiotherapy. Pathological analysis revealed that half of the patients had moderately differentiated OSCC. pTNM slightly differed from the cTNM and showed that 70.4% of the patients had low-risk OSCC. Tumour clearance was ultimately achieved in 107 patients. Follow-up resulted in a 3-year survival of 74.8% and a 5-year survival of 72.2%. Recurrence was identified in 23 males and 20 females. The mean age of 1 diagnosis of the recurrence group was 59.53 years. Most common oral sites included the lateral border of tongue and floor of mouth. Recurrence was associated with clinical N-stage disease. The surgical margins in this group was evaluated and found that 17 had non-cohesive invasion, 30 had dysplasia at margin, 21 had vascular invasion, 9 had nerve invasion and 3 had bony invasion. Severe dysplasia was present in 37 patients. Tumour clearance was achieved in only 8 patients. The mean depth of tumour invasion in the recurrence group was 7.6 mm. An interesting finding was that 5/11 patients who died of distant metastasis had their primary disease in the tongue. Nodal disease comparison showed that 8/10 patients who died of locoregional metastasis and 8/11 patients who died from distant metastasis had clinical nodal involvement. Comparing this to pathological nodal disease (pTNM) showed that 10/10 patients and 10/11 patients who died from locoregional and distant metastasis, respectively, had nodal disease. All patients who died from locoregional and distant metastasis were shown to have recurrence after the primary tumour resection. Squamous cell carcinoma of the oral cavity has a poor overall prognosis with a high tendency to recur at the primary site and extend to involve the cervical lymph nodes. Several clinicopathological parameters can be employed to assess outcome, recurrence and overall survival. © 2010 Jerjes et al; licensee BioMed Central Ltd