High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer

Background

Prior studies highlighted cyclin D1 as a key biomarker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This study builds on prior work by examining the roles of cyclin D1, cyclin D3, and cyclin E in mediating erlotinib sensitivity or resistance.

Methods

Expression plasmids for G1 cyclins were independently transfected into NIH 3T3 cells and effects on erlotinib sensitivity were examined. The expression profiles of G1 cyclins were compared in erlotinib-sensitive and erlotinib-resistant lung cancer cell lines. A549 and H358 cells were treated with erlotinib and changes in cyclin protein expression were assessed. Cyclin D3 immunohistochemical staining was measured in biopsy tissues obtained from patients before and after treatment with erlotinib. Erlotinib-sensitive lung cancer cells were transfected with cyclin D3 and changes in erlotinib sensitivity were examined.

Results

Individual transfection of cyclin D1, cyclin D3, and cyclin E expression plasmids each significantly reduced erlotinib sensitivity in NIH-3T3 cells. The erlotinib-resistant A549 cell line expressed high basal levels of cyclin D3 mRNA and protein. Comparison of tumor biopsies obtained from patients before and after treatment with erlotinib indicated an increase in the percentage of cancer cells expressing cyclin D3 following treatment with erlotinib (P = .02). Transfection of cyclin D3 into an erlotinib-sensitive lung cancer cell line inhibited erlotinib-induced signaling changes and reduced the growth-suppressive effects of erlotinib.

Conclusions

High expression of cyclin D3 confers resistance to erlotinib in vitro and in vivo. Cyclin D3 immunohistochemical staining warrants investigation as a biomarker for predicting erlotinib resistance.     

Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer

Background and purpose

Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN.

Materials and methods

Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n = 40 plans) and dose-volume histograms were generated.

Results

The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p = 0.020) and mean doses to the contralateral parotid gland (p = 0.049) and larynx (p = 0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p < 0.002 for both) and brainstem (p < 0.002 for both) and mean doses to the larynx (p < 0.002 for both) and ipsilateral (p = 0.004 IMRT, p = 0.050 adaptive) and contralateral (p < 0.002 IMRT, p = 0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT.

Conclusions

Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.     

Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer

Background

Minichromosome maintenance (MCM) proteins 2-7 form a complex essential for the initiation of DNA replication. In the process to screen expression changes related to growth suppression of non-small cell lung cancer (NSCLC) cells by a cJun dominant-negative mutant, we found that reduced expression of MCM4 was correlated with this growth suppression.

Method

We determined the relevance of MCM4 in proliferation of NSCLC by downregulating its expression with small-interfering RNA in three NSCLC cell lines. We then immunohistochemically analyzed MCM4 expression in 156 surgically resected NSCLCs to correlate clinicopathologic characteristics.

Results

MCM4 downregulation reduced proliferation in two cell lines. MCM4 expression was higher in cancer cells than in adjacent normal bronchial epithelial cells (p < 0.001). High MCM4 expression was correlated with male gender, heavy smoking, poorer differentiation and non-adenocarcinoma histology (p < 0.001, respectively). High MCM4 expression was also correlated with proliferation markers, Ki-67 and cyclin E expression (p < 0.001, respectively). MCM4 expression was not associated with survival.

Conclusion

MCM4 may play an essential role in the proliferation of some NSCLC cells. Taken together with higher expression in NSCLCs and its correlation with clinicopathologic characteristics such as non-adenocarcinoma histology, MCM4 may have potential as a therapeutic target in certain population with NSCLCs.     

3D cell cultures of human head and neck squamous cell carcinoma cells are radiosensitized by the focal adhesion kinase inhibitor TAE226

Background and purpose

Focal adhesion kinase (FAK), a main player in integrin signaling and survival, is frequently overexpressed in human cancers and therefore postulated as potential target in cancer therapy. The aim of this study was to evaluate the radiosensitizing potential of the FAK inhibitor TAE226 in three-dimensional (3D) tumor cell cultures.

Materials and methods

Head and neck squamous cell carcinoma (HNSCC) cells (FaDu, UT-SCC15, UT-SCC45), lung cancer cells (A549), colorectal carcinoma cells (DLD-1, HCT-116) and pancreatic tumor cells (MiaPaCa2, Panc1) were treated with different concentrations of TAE226 (0-1 μm; 1 or 24 h) without or in combination with irradiation (0-6 Gy, X-ray, single dose). Subsequently, 3D clonogenic survival assays (laminin-rich extracellular matrix) and Western blotting (expression/phosphorylation, e.g. FAK, Akt, ERK1/2) were performed.

Results

All investigated 3D cell cultures showed a dose-dependent reduction in clonogenic survival by TAE226. Intriguingly, TAE226 only significantly radiosensitized 3D HNSCC cell cultures accompanied by a pronounced dephosphorylation of FAK, Akt and ERK1/2.

Conclusions

Our data demonstrate TAE226 as potent FAK inhibitor that enhances the cellular radiosensitivity particularly of HNSCC cells grown in a 3D cell culture model. Future in vitro and in vivo investigations will clarify, to which extent this approach might be clinically relevant for radiotherapy of HNSCC.     

Biologic correlates of F-FDG uptake on PET in pulmonary pleomorphic carcinoma

Background

Pulmonary pleomorphic carcinoma is a rare epithelial tumor, and little is also known about the information on the usefulness of 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET). Therefore, we conducted the study including the underlying biologic analysis of ¹⁸F-FDG uptake.

Methods

Fifteen patients with pulmonary pleomorphic carcinoma who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); cell proliferation (Ki-67 labeling index); vascular endothelial growth factor (VEGF); microvessels (CD34); cell cycle control marker (p53); and apoptosis marker (bcl-2). These parameters were correlated with a control group of patients with other non-small cell lung cancer (NSCLC) (n = 33).

Results

The maximal standardized uptake value (SUV_max) of the primary tumors in 15 patients ranged from 6.1 to 26.8 (median 19.3). There were positive correlation between ¹⁸F-FDG uptake and Glut1 (p = 0.0016), Glut3 (p = 0.0080), VEGF (p = 0.0048), and microvessel density (MVD) (p = 0.0005). HIF-1α, p53 and bcl-2 showed no positive correlation with ¹⁸F-FDG uptake. ¹⁸F-FDG uptake, Glut1, Glut3, HIF-1α, VEGF and Ki-67 were significantly higher in patients with pulmonary pleomorphic carcinoma than those with other NSCLC.

Conclusion

¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma is closely associated with the presence of glucose metabolism (Glut1 and Glut3) and angiogenesis (VEGF and MVD). The relationship between ¹⁸F-FDG uptake and these biomarkers may lead to a more rational use of PET scan in pulmonary pleomorphic carcinoma.     

Carbon ion radiotherapy performed as re-irradiation using active beam delivery in patients with tumors of the brain, skull base and sacral region

Introduction

To asses carbon ion radiation therapy (RT) performed as re-irradiation in 28 patients with recurrent tumors.

Materials and methods

Twenty-eight patients were treated with carbon ion RT as re-irradiation for recurrent chordoma and chondrosarcoma of the skull base (n = 16 and n = 2), one chordoma and one chondrosarcoma of the os sacrum, high-risk meningioma (n = 3), adenoid-cystic carcinoma (n = 4) as well as one SCCHN.All patients were treated using active raster scanning, and treatment planning was performed on CT- and MRI-basis.All patients were followed prospectively during follow-up.

Results

In all patients re-irradiation could be applied safely without interruptions. For skull base tumors, local tumor control after re-irradiation was 92% at 24 months and 64% at 36 months. Survival after re-irradiation was 86% at 24 months, and 43% at 60 months. In all three meningiomas treated with C12 for re-irradiation, the tumor recurrence was located within the former RT-field. Two patients developed tumor progression at 6 months, and in one patient the tumor remained stable for 67 months. In patients with head-and-neck tumors, three patients developed local tumor progression at 12, 24 and 29 months after re-irradiation. Median local progression-free survival was 24 months.For sacral tumors, re-irradiation offered palliation with tumor control for 24 and 36 months.

Conclusion

Due to the physical characteristics particle therapy offers a new treatment modality in cases with tumor recurrences. With carbon ions, the additional biological benefits may be exploited for long-term tumor control. Further evaluation in a larger patients’ cohort will be performed in the future.     

Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary

Purpose

To compare the impact of an unilateral post-operative irradiation or a bilateral irradiation in terms of loco-regional control and survival in patients with cervical lymph node of squamous cell carcinoma from an unknown primary (CUP).

Methods and materials

Ninety five patients with epidermoid carcinoma involving unilateral cervical lymph nodes from an unknown primary were treated in two institutions from 1990 to 2007. Post-operative radiation therapy was delivered to one side of the neck in 59 cases, to both sides of the neck in 36 cases. There were 11 women and 84 men ranging in age from 38 to 80 years (median 59 years). Neck dissection was performed in 79 patients while 16 patients underwent single lymph node sampling only.

Results

After a median follow-up of 3.3 years, the nodal relapse rate was 34% after unilateral neck irradiation and 25% after bilateral radiotherapy (p = 0.21). Six contralateral lymph node relapses occurred after unilateral irradiation (10%). The 5-year overall survival rate of the entire group was 24%. The 5-year OS rates were 22% after unilateral irradiation and 23%, after bilateral radiotherapy (p = 0.944). The occult primary occurred in 12% after unilateral irradiation and 6% after bilateral radiotherapy. The radiation technique (3D-CRT or IMRT vs. 2D: p = 0.026) was prognostic on loco-regional control. Independent prognostic determinants on overall survival were the WHO status (p = 0.013) and the radiation technique (2D vs. 3D-CRT or IMRT; p = 0.029). There was no difference in loco-regional control (p = 0.639) and no difference in survival (p = 0.493) when chemotherapy was associated.

Conclusions

Retrospective comparisons between bilateral and unilateral neck radiotherapies did not show differences in terms of loco-regional control and survival. However, patient’s local regional control and survival are significantly improved after 3D-CRT or IMRT.     

Dose-effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy

Background and purpose

To analyse dose-response relationships for local control of cervical cancer after MR image-guided brachytherapy (IGBT) based on dose-volume histogram parameters.

Methods and materials

The analysis includes 141 patients with cervix cancer (stages IB-IVA) treated with 45-50.4 Gy EBRT ± cisplatin plus 4 × 7 Gy IGBT. Gross tumour volume (GTV), high risk clinical target volume (HR CTV) and intermediate risk CTV (IR CTV) were delineated and DVH parameters (D90, D100) were assessed. Doses were converted to the equivalent dose in 2 Gy (EQD2) using linear-quadratic model (α/β = 10 Gy). Groups of patients were formed according to tumour size at diagnosis (GTV_D) of 2-5 cm (group 1) or >5 cm (2), with subgroups of the latter for HR CTV size at first IGBT 2-5 cm (2a) or >5 cm (2b). Dose-response dependence for local recurrence was evaluated by logit analysis.

Results

Eighteen local recurrences in the true pelvis were observed. Dose-response analyses revealed a significant effect of HR CTV D100 (p = 0.02) and D90 (p = 0.005). The ED50-values for tumour control were 33 ± 15 Gy (D100) and 45 ± 19 Gy (D90). ED90-values were 67 Gy (95% confidence interval [50;104]) and 86 Gy [77;113], respectively.

Conclusions

A significant dependence of local control on D100 and D90 for HR CTV was found. Tumour control rates of >90% can be expected at doses >67 Gy and 86 Gy, respectively.     

Local failure after complete resection of N0-1 non-small cell lung cancer

Purpose

To estimate the risk of local-regional failure (LRF) after surgery for operable NSCLC, and the effect of clinical/pathologic factors on this risk.

Methods

Records of 335 patients undergoing complete resection (lobectomy, pneumonectomy) for pathological T1-4 N0-1 NSCLC (without post-operative radiation) from 1996 to 2006 were reviewed. Crude and actuarial estimated failure rates were computed; local-regional sites included ipsilateral lung, surgical stump, hilar, mediastinal, or supraclavicular nodes. Failure times in sub-groups were calculated with the Kaplan-Meier method and compared via log-rank test. Independent factors adversely affecting LRF were determined with Cox regression.

Results

The median follow-up duration for event-free surviving patients was 40 months (range: 1-150). The crude and actuarial 5-year probability of any failure (LR or distant) were 33% and 43%, respectively. Of all failures; 37% were LR only, 35% LR and distant and 28% distant only. The 5-year crude and actuarial probability of LRF were 24% and 35% (95% CI: 29-42%). Five-year crude LRF rates for T1-2N0, T1-2N1, T3-4N0 and T3-4N1 disease were 19% (41/216), 27% (16/59), 37.5% (15/40) and 40% (8/20), respectively. The corresponding actuarial estimates were T1-2N0 28%, T1-2N1 39%, T3-4N0 50% and T3-4N1 67%. In Cox multiple regression analysis, lymphovascular space invasion (p = 0.03, HR: 1.7) and tumor size (p = 0.01, HR: 1.67 for 5 cm increment) were associated with an increased risk of LRF.

Conclusion

Five-year LRF rates are ≥19% in essentially all patient subsets.     

Dose-volume analysis of locoregional recurrences in head and neck IMRT, as determined by deformable registration: A prospective multi-institutional trial

Background and purpose

Although IMRT for head and neck cancer is widely accepted, the implications of sparing normal tissue immediately adjacent to target volumes are not well known.

Materials and methods

Between 2002 and 2007, 124 patients with head and neck cancer were treated with surgery and postoperative IMRT (n = 79) or definitive RT (n = 45). Locoregional recurrences were analyzed for location relative to target volumes, and dosimetry.

Results

With a median follow-up of 26.1 months, a total of 16 locoregional recurrences were observed. The five-year actuarial locoregional disease-free survival was 82% [95% CI, 72-90%]. Analysis of 18 distinct sites of locoregional failure revealed that five of these failures were within the high dose clinical target volume (CTV), nine failures were at the margin of the CTV, and four recurrences were outside the CTV. The mean dose delivered to these recurrent volumes was 63.1 Gy [range: 57-68 Gy], while the mean dose to the coolest 1 cc within each recurrence was 60.0 Gy [range: 51-67 Gy]. There were two periparotid recurrences observed.

Conclusions

We observed excellent locoregional control rates overall. The majority of recurrences occur within high dose regions of the neck and not near the spared parotid glands.     

Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background and purpose

To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN.

Materials and methods

In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250 mg/day, 500 mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2 years; secondary endpoints were LDCR at 1 year, objective response rate, progression-free survival, overall survival, and safety and tolerability.

Results

Gefitinib (250 and 500 mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p = 0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p = 0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy.

Conclusion

Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.     

Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma

Background

Overexpression of EGFR correlates with decreased survival after radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the contribution of the activated form, pEGFR, and its downstream signaling (PI3-K/AKT) pathway is not clear yet.

Methods

Fifty-eight patients with HNSCC were included in the study. pEGFR, pAKT, hypoxia, and vessels were visualized using immunohistochemistry. Fractions (defined as the tumor area positive for the respective markers relative to the total tumor area) were calculated by automated image analysis and related to clinical outcome.

Results

Both pEGFR (median 0.6%, range 0-34%) and pAKT (median 1.8%, range 0-16%) expression differed between tumors. Also, a large variation in hypoxia was found (median pimonidazole fraction 3.9% 0-20%). A significant correlation between pEGFR and pAKT (r_s 0.44, p = 0.004) was seen, however, analysis revealed that this was not always based on spatial coexpression. Low pAKT expression was associated with increased risk of regional recurrence (p < 0.05, log-rank) and distant metastasis (p = 0.04).

Conclusion

The correlation between expression of pEGFR and pAKT is indicative of activation of the PI3-K/AKT pathway through phosphorylation of EGFR. Since not all tumors show coexpression to the same extent, other factors must be involved in the activation of this pathway as well.     

Histopathologic validation of 3′-deoxy-3′-F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude miceF-FLT PET repopulation -->

Background and purpose

FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing ¹⁸F-FLT PET.

Material and methods

Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm] = 3.0 Gy), either daily or every second day. ¹⁸F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results.

Results

Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P < 0.05) and 18 fractions in 18 days (P < 0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P > 0.05) and 18 fractions in 36 days (P > 0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P < 0.05), and increases with every-second-day irradiation (P > 0.05). ¹⁸F-FLT parameters correlated strongly with proliferation markers (r²: 0.679–0.879, P < 0.001).

Conclusions

¹⁸F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for ¹⁸F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy.     

Synchronous chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck using capecitabine: a single-centre, open-label, single-group phase II study

Aim

To evaluate the efficacy of concurrent oral capecitabine with accelerated hypofractionated radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Materials and methods

Between 2001 and 2004, 50 patients with stage III/IV SCCHN (0 to 2 performance status) were enrolled into this study. The capecitabine dose was between 450 and 550 mg/m² twice daily, continuously for 28 days. The radiotherapy dose was 5500 cGy in 20 fractions over 4 weeks. No intensity-modulated radiation was used. We evaluated the complete response rate, toxicity, locoregional control, overall survival, disease-free survival and cancer-specific survival.

Results

The median age was 55 (range 38-76) years; 72% had stage IV disease. The median follow-up was 6 years on the 30 surviving patients. Eighty-two per cent of patients completed the course of capecitabine and 94% completed prescribed radiotherapy. There were no treatment-related deaths, grade 3/4 haematological or renal toxicity. Five patients developed drug-related grade 3/4 acute toxicity (cardiac, skin, bowel); 47 developed grade 3/4 mucositis from chemoradiotherapy. Twenty-two (44%) patients required tube feeding and the tube dependency rate at 1 year was 6%. The complete response rate at 3 months was 90% (45/50 patients). Relapse occurred in 17/50 (34%) patients by 5 years. The locoregional control, overall survival, cancer-specific survival and disease-free survival rates at 3 years were 78, 72, 82 and 62%, respectively, and at 5 years were 72, 64, 75 and 56%, respectively.

Conclusion

This schedule of synchronous capecitabine for locally advanced SCCHN is well tolerated. The local control in this series compares favourably with other synchronous chemoradiotherapy reports. Chronic dysphagia and tube dependence is uncommon with this approach. Capecitabine as targeted therapy given with each fraction of radiotherapy and administered orally may have significant advantages over intravenous, 3 weekly cisplatin.     

Comparative study of respiratory motion correction techniques in cone-beam computed tomography

Background and purpose

To validate the clinical usefulness of motion-compensated (MC) cone-beam (CB) computed tomography (CT) for image-guided radiotherapy (IGRT) in comparison to four-dimensional (4D) CBCT and three-dimensional (3D) CBCT.

Material and methods

Forty-eight stereotactic body radiation therapy (SBRT) patients were selected. Each patient had 5-12 long CB acquisitions (4 min) and 1-7 short CB acquisitions (1 min), with a total of 349 and 150 acquisitions, respectively. 3D, 4D and MC CBCT images of every acquisition were reconstructed. Image quality, tumor positioning accuracy and tumor motion amplitude were quantified.

Results

The mean image quality of long short acquisitions, measured using the correlation ratio with the planning CT, was 74%/70%, 67%/47% and 79%/74% for 3D, 4D and MC CBCT, respectively; both 4D and MC CBCT were corrected for respiratory motion artifacts but 4D CBCTs suffered from streak artifacts. Tumor positioning with MC CBCT was significantly closer to 4D CBCT than 3D CBCT (p < 0.0001). Detailed patient analysis showed that motion correction was not required for tumors with less than 1 cm motion amplitude.

Conclusions

4D and MC CBCT both allow accurate tumor position analysis under respiratory motion but 4D CBCT requires longer acquisition time than MC CBCT for adequate image quality. MC CBCT can therefore advantageously replace 4D CBCT in clinical protocols for patients with large motion to improve image quality and reduce acquisition time.     

Validation of the Total Dysphagia Risk Score (TDRS) as a predictive measure for acute swallowing dysfunction induced by chemoradiotherapy for head and neck cancers

Background and purpose

Methods for predicting acute swallowing dysfunction in patients with head and neck cancers undergoing definitive chemoradiotherapy have not been established. We investigated the validity of the Total Dysphagia Risk Score (TDRS) as a predictive measure for this morbidity.

Materials and methods

Forty-seven patients with head and neck cancers who underwent definitive chemoradiotherapy between December 1998 and March 2006 were reviewed retrospectively. Median age was 63 years (range, 16-81). Almost all patients underwent platinum-based concomitant chemoradiotherapy. Factors of the TDRS were as follows: T-classification, neck irradiation, weight loss, primary tumour site and treatment modality. Patients were classified into three risk groups according to the TDRS.

Results

Swallowing dysfunction was observed in 27 patients (57%) as RTOG grade 2 or higher acute morbidity. This classification was significantly associated with grade 2 or higher acute swallowing dysfunction (P < 0.001). In ROC (receiver operator characteristic) analysis, the cut-off value of TDRS was set at 18 (sensitivity = 0.81; specificity = 0.85). Prediction of severe (grade ? 3) acute swallowing dysfunction was similarly obtained.

Conclusion

The TDRS is a useful tool to predict acute swallowing dysfunction induced by chemoradiotherapy for head and neck cancers.     

Impact of the prophylactic gastrostomy for unresectable squamous cell head and neck carcinomas treated with radio-chemotherapy on quality of life: Prospective randomized trial

Background and purpose

Concomitant radio-chemotherapy is the gold standard treatment for unresectable head and neck carcinomas. Placement of prophylactic gastrostomy has been proposed to provide adequate nutrition during the therapeutic sequence. The objectives of this study were to assess the impact of prophylactic gastrostomy on the 6-month quality of life, and to determine the factors related to this quality of life.

Materials and methods

Design. randomized, controlled, open study (“systematic percutaneous gastrostomy” versus “no systematic gastrostomy”). Patients. squamous cell head and neck carcinoma (stages III and IV, UICC 1997). Setting. oncological departments of French university teaching hospitals. Treatment. optimal concomitant radio-chemotherapy. Evaluations. T0 baseline evaluation, T1 during the treatment, T2 end of the treatment, and T3 6-month post-inclusion. Primary endpoint. 6-month quality of life (Qol) assessed using SF36, EORTC QLQ-C30, EORTC QLQ H&N35 questionnaires.

Results

The Qol changes from baseline included a decline (T1 and T2) followed by an improvement (T3). Qol at 6 months was significantly higher in the group receiving systematic prophylactic gastrostomy (p = 10⁻³). Higher initial BMI and lower initial Karnofsky index were significant factors related to a higher 6-month Qol.

Conclusions

The study results suggest that prophylactic gastrostomy improves post-treatment quality of life for unresectable head and neck cancer patients, after adjusting for other potential predictive quality of life factors.     

Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: Comparison between loose and stranded seed implants

Background and purpose

In permanent prostate brachytherapy the dose distributions 4 weeks post implant differ from the intraoperative dose distributions. The purpose of this study is to compare intraoperative planning and post implant dosimetry for loose and stranded seed implants.

Materials and methods

This study investigates prostate dose coverage in 389 patients with stage T1 or T2 prostate cancer treated in the years 2005, 2006 and 2007. The patients received either a loose seed or a stranded seed implant. All patients had US-based intraoperative planning and CT/MRI-based post implant dosimetry after 4 weeks.

Results

Intraoperative and post implant D₉₀ values amounted 183 ± 13 Gy (mean ± standard deviation) and 161 ± 30 Gy, respectively. Decline of D₉₀ values (mean and 95% confidence interval) between intraoperative planning and post implant dosimetry for RAPID strand (n = 67), Intersource strand (n = 136) and loose selectSeeds (n = 186) implants amounted to −40 (−45 to −34) Gy, −25 (−28 to −21) Gy and −15 (−18 to −21) Gy, respectively.

Conclusions

The patients treated in the period 2005-2007 with stranded or loose seed implants had on average adequate D₉₀ values of 161 ± 30 Gy. Post implant D₉₀ values were 22 ± 27 Gy lower compared to intraoperative planning. Decline of dose coverage between intraoperative planning and post implant dosimetry was significantly larger for the stranded seed implants.     

Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy

Background and purpose

Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck.

Material and methods

In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model.

Results

For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D₅₀ = 61.5 Gy (52.9-84.9 Gy), γ = 1.4 (0.8-2.6) and s = 0.1 (0.01-0.3).

Conclusions

Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.