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  • Radiotherapy & Oncology Volume 109, Issue 2 , Pages 286-292, November 2013


    Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation


    Simon Laban, Leonhard Steinmeister, Lisa Gleißner et al




    Background and purpose

    There is a great need to improve the outcome of locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). Standard treatment includes a combination of surgery, radio- and chemotherapy. The addition of molecular targeting agents to conventional treatment may improve outcomes. In this study the Raf inhibitor sorafenib was used to increase the radiosensitivity of HNSCC cell lines.


    Material and methods

    In a panel of six cell lines (A549, FaDu, UTSCC 60A, UTSCC 42A, UTSCC 42B, UTSCC 29) radiosensitivity was measured by colony formation assay and apoptosis and cell cycle analysis were performed by flow cytometry. DNA repair was analyzed by 53BP1 immunohistochemistry.



    Sorafenib added prior to irradiation resulted in an increased cellular radiosensitivity (DEF0.5=1.11–1.84). Radiosensitization was not caused by an enhanced rate of apoptosis or cell cycle effects. In contrast, sorafenib was shown for the first time to block the repair of DNA double-strand breaks (DSB).



    Our data suggest that sorafenib may be used to overcome the radioresistance of HNSCC through the inhibition of DSB repair.







  • Radiotherapy & Oncology Volume 109, Issue 2 , Pages 269-274, November 2013

    The effect of induction chemotherapy on tumor volume and organ-at-risk doses in patients with locally advanced oropharyngeal cancer


    Patricia Doornaert, Max Dahele, Wilko F.A.R. Verbakel et al:




    Background and purpose

    To retrospectively report changes in gross tumor volume (GTV) and organ-at-risk (OAR) doses after induction chemotherapy (IC) in oropharyngeal cancer using different contouring strategies.


    Materials and methods

    GTV and OARs were delineated on pre- and post-IC planning CT. Two post-IC GTV contours were made: (1) a ‘consensus set’ using published guidelines (GTVconsensus), and (2) ‘visible set’, delineating only visible post-IC GTV (GTVvisible). Pre-IC interactively optimized volumetric modulated arc therapy plans were generated. The pre-IC planning constraints served as the starting point for both post-IC plans. Results reflect pooled data from all 10 patients.



    Mean reduction in volume post-IC was 24% and 47% for consensus and visible primary tumor and 57% and 60% for consensus and visible nodes. Compared to pre-IC plans, average mean OAR dose for post-IC GTVconsensus plans was significantly lower for CL parotid. For GTVvisible plans both parotids, upper/lower larynx, inferior pharyngeal constrictor and cricopharyngeal muscles were significantly lower. However reductions compared with post-IC GTVconsensus plans were modest (1.6/1.5/1.2/3.7/5.9/2.6 Gy, respectively).



    IC in patients with oropharyngeal carcinoma results in substantial reductions in GTVs. If post-IC GTVs are used, which is contrary to current consensus, statistically significant but relatively small OAR dose reductions are observed.




  • Radiotherapy & Oncology Volume 109, Issue 2 , Pages 262-268, November 2013

    Malignant salivary gland tumours: Can fast neutron therapy results point the way to carbon ion therapy?


    Clare Stannard, ,Frederik Vernimmen, Henri Carrara et al:




    Background and purpose

    To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams.


    Materials and methods

    Neutrons at iThemba LABS are produced by the reaction of 66 MeV protons on a beryllium target. A median dose 20.4 Gy, in 12 fractions in 4 weeks or 15 fractions in 5 weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours.



    Locoregional control was 60.6% at 5 years and 39.1% at 10 years and DSS was 66.8% and 53.7% at 5 and 10 years respectively.

    In the univariate analysis T4, >4 cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6 cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6 cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease.



    Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.




  • Radiotherapy & Oncology Volume 109, Issue 2 , Pages 281-285, November 2013

    Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer


    Eric F. LartigauEmmanuelle Tresch, Juliette Thariat et al:




    Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival < 1 year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2 weeks) in order to get the same local control as the one demonstrated with longer protocols.


    Methods and materials

    Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO < 3). Reirradiation (RT) dose was 36Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy.



    Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT + RT, 3 were not treated and 1 received only CT. Median age was 60 (42–87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38 months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4 months. At 3 months, response rate was  58.4% (95% CI: 43.2–72.4%) and disease control rate was 91.7% (95% CI: 80.0–97.7%). The one-year OS rate was 47.5% (95% CI: 30.8–62.4).



    These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.




  • Radiotherapy & Oncology Volume 109, Issue 3 , Pages 463-468, December 2013

    Adaptive radiotherapy with an average anatomy model: Evaluation and quantification of residual deformations in head and neck cancer patients


    Simon van Kranen, Angelo Mencarelli, Suzanne van Beek et al:




    Background and purpose

    To develop and validate an adaptive intervention strategy for radiotherapy of head-and-neck cancer that accounts for systematic deformations by modifying the planning-CT (pCT) to the average misalignments in daily cone beam CT (CBCT) measured with deformable registration (DR).


    Methods and materials

    Daily CBCT scans (808 scans) for 25 patients were retrospectively registered to the pCT with B-spline DR. The average deformation vector field (<DVF>) was used to deform the pCT for adaptive intervention. Two strategies were simulated: single intervention after 10 fractions and weekly intervention with an <DVF> from the previous week.

    The model was geometrically validated with the residual misalignment of anatomical landmarks both on bony-anatomy (BA; automatically generated) and soft-tissue (ST; manually identified).



    Systematic deformations were 2.5/3.4 mm vector length (BA/ST). Single intervention reduced deformations to 1.5/2.7 mm (BA/ST). Weekly intervention resulted in 1.0/2.2 mm (BA/ST) and accounted better for progressive changes. 15 patients had average systematic deformations >2 mm (BA): reductions were 1.1/1.9mm (single/weekly BA). ST improvements were underestimated due to observer and registration variability.



    Adaptive intervention with a pCT modified to the average anatomy during treatment successfully reduces systematic deformations. The improved accuracy could possibly be exploited in margin reduction and/or dose escalation.





  • International Journal of Radiation Oncology Biology Physics Volume 87, Issue 4 , Pages 676-682, 15 November 2013


    Parotid Glands Dose–Effect Relationships Based on Their Actually Delivered Doses: Implications for Adaptive Replanning in Radiation Therapy of Head-and-Neck Cancer


    Klaudia U. Hunter, MD, Laura L. Fernandes, MS, Karen A. Vineberg, MS et el




    Doses actually delivered to the parotid glands during radiation therapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help make decisions regarding adaptive radiation therapy (ART) aimed at reducing the delivered doses.


    Methods and Materials

    In this prospective study, oropharyngeal cancer patients treated definitively with chemoirradiation underwent daily cone-beam computed tomography (CBCT) with clinical setup alignment based on the C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy.



    Thirty-six parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy, and differences from planned to delivered mean gland doses were −4.9 to +8.4 Gy, median difference +2.2 Gy in glands in which delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with posttreatment salivary outputs at almost all posttherapy time points, without statistically significant differences in the correlations. Large dispersions (on average, SD 3.6 Gy) characterized the dose–effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident at first fraction (r=.92, P<.0001) because of complex setup deviations (eg, rotations and neck articulations), uncorrected by the translational clinical alignments.



    After daily translational setup corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose–saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed at first treatment, indicating potential benefit for more complex setup corrections or adaptive interventions in the minority of patients with large deviations detected early by CBCT.




  • International Journal of Radiation Oncology Biology Physics Volume 87, Issue 4 , Pages 683-689, 15 November 2013

    Two-Year and Lifetime Cost-Effectiveness of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Head-and-Neck Cancer


    Racquel E. Kohler, MSPH, Nathan C. Sheets, MD, Stephanie B. Wheeler, PhD, MPH, Chris Nutting, FRCP, FRCR, MD, PhD



    To assess the cost-effectiveness of intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3D-CRT) in the treatment of head-and neck-cancer (HNC).


    Methods and Materials

    We used a Markov model to simulate radiation therapy-induced xerostomia and dysphagia in a hypothetical cohort of 65-year-old HNC patients. Model input parameters were derived from PARSPORT (CRUK/03/005) patient-level trial data and quality-of-life and Medicare cost data from published literature. We calculated average incremental cost-effectiveness ratios (ICERs) from the US health care perspective as cost per quality-adjusted life-year (QALY) gained and compared our ICERs with current cost-effectiveness standards whereby treatment comparators less than $50,000 per QALY gained are considered cost-effective.



    In the first 2 years after initial treatment, IMRT is not cost-effective compared with 3D-CRT, given an average ICER of $101,100 per QALY gained. However, over 15 years (remaining lifetime on the basis of average life expectancy of a 65-year-old), IMRT is more cost-effective at $34,523 per QALY gained.



    Although HNC patients receiving IMRT will likely experience reduced xerostomia and dysphagia symptoms, the small quality-of-life benefit associated with IMRT is not cost-effective in the short term but may be cost-effective over a patient's lifetime, assuming benefits persist over time and patients are healthy and likely to live for a sustained period. Additional data quantifying the long-term benefits of IMRT, however, are needed.




  • International Journal of Radiation Oncology Biology Physics Volume 87, Issue 5 , Pages 867-868, 1 December 2013

    Improved Long-Term Outcomes With IMRT: Is It Better Technology or Better Physics?


    Michael J. Zelefsky, MD, Joseph O. Deasy, PhD


    Intensity modulated radiation therapy (IMRT) for the treatment of localized prostate cancer has now been in use for almost 15 years. There has been evidence during this time that this form of treatment delivery is more accurate and is associated with fewer side effects compared with previous forms of radiation therapy applications. Zelefsky et al (1) reported their observations over a decade ago that acute and late rectal side effects were significantly reduced after high-dose IMRT compared with historical controls treated with 3-dimensional conformal techniques (3D-CRT) to similar dose levels. More recently, they have noted that these differences in toxicity outcomes persisted with follow-up beyond 10 years (2).


    In this issue, Michalski et al (3) report on the toxicity outcomes of Radiation Therapy Oncology Group (RTOG) 0126 and provide for the first time evidence that IMRT-treated patients experience less toxicity after therapy than do a concurrently treated cohort of patients treated with similar doses with the use of 3D-CRT. It is important to note that although RTOG 0126 never intended to compare IMRT with 3D-CRT, thanks to a later amendment in the protocol that allowed practitioners to use IMRT for accrued patients, an opportunity eventually existed to compare these 2 cohorts of patients retrospectively. Notwithstanding significant differences in the treatment volumes between the IMRT and 3D-CRT cohorts and in the margins used to create planning target volumes, these investigators still noted that the combined gastrointestinal and genitourinary toxicities were lower among the IMRT-treated patients.


    Yet, what is most revealing about this study is that when the authors performed a multivariable analysis for predictors of toxicity and added dosimetric-based variables to the regression model, the treatment technique was no longer a significant factor. The authors found instead that dosimetric parameters were the most important predictors of late toxicity—namely, that a dose of >70 Gy to more than 15% of the rectal volume was an independent predictor for late grade 2 rectal toxicity (P=.034). These findings suggest, as we expected, that a critical predictor of late toxicity after radiation therapy was the volume of normal tissue exposed to the high doses of radiation therapy. Conformal delivery systems such as IMRT may simply represent a means to achieve that aim—a meaningful reduction of the volume of rectum exposed to the high doses of irradiation.


    We believe there is an important message here. There is nothing magical about 3D-CRT, IMRT, image guided radiation therapy, or novel radiation therapy delivery systems and no guarantee that these approaches spare the patient from toxicity. Yet, these delivery systems are all important means to achieve the end result of applying a high dose of irradiation with concomitant reduction of exposure to normal tissue. Recently it has been reported that enhanced accuracy using daily image guidance with the placement of fiducial markers resulted in less urinary toxicity during the application of ultra-high-dose radiation therapy (4). This observed reduction in toxicity was achieved without a tightening of the margins used around the clinical target volume. Conformality enhancements in the delivery of radiation therapy have facilitated improved dose distributions and greater accuracy of treatment. Accordingly, this allows the radiation oncologist to safely deliver the required high radiation doses into the tumor.


    In the study by Michalski et al (3), the IMRT cohort in general was actually treated with a larger high-dose target volume according to protocol stipulations; yet, despite that requirement, treatment was associated with a 27% reduction in late gastrointestinal toxicities. It appears that the reason for this may be related to IMRT more effectively and more frequently being able to reduce the V70 exposed to 15% or more of the rectum. This is consistent with the QUANTEC recommendations that the volume of rectal high dose overlap in the treatment plan be constrained to V70 <20% and V75 <15% (5). Furthermore, studies that attempt to reduce the risk of treatment-related rectal toxicities after radiation therapy should consider the incorporation of dose–volume endpoints such as the V70 >15% of the rectal volume for identifying patients in whom rectal toxicity may more likely develop after conventionally fractionated IMRT.


    Although these findings underscore the benefit of using IMRT to achieve greater conformality to obtain the desired dosimetric outcome, they also suggest that some patients with “geometrically favorable target volumes” that do not significantly overlap with the rectum may safely receive high-dose radiation therapy without the need for IMRT. On the other hand, patients who are identified as being at high risk for rectal toxicity (by virtue of the fact that despite careful planning they still receive V70 Gy >15% of the rectal volume) may benefit from interventions and new technologies currently being tested to improve the geometry of the rectum and its juxtaposition with the target volume. For instance, physical manipulation methods have also been suggested that could potentially reduce rectal toxicity. Prada et al (6) have reported reduced rectal toxicity based on endoscopic posttreatment evaluations with the transperineal injection of hyaluronic acid in the space between the anterior rectal wall and the posterior aspect of the prostate to create a greater separation between these 2 organs. More recently, several investigators have shown marked reduction in rectal wall doses with the transperineal insertion of a biodegradable balloon that could provide a separation of as much as 1 cm, effectively reducing rectal doses during radiation therapy 7, 8. Thus, the use of IMRT does not routinely prevent rectal toxicity; however, with a carefully designed treatment plan, effective image guidance, and potential “man-made” improvements in the geometry of the target and organs at risk, it is an effective tool for producing a superior dosimetric outcome.


    Although Michalski et al (3) have shown reductions in rectal toxicities, it seems that IMRT has not yet effectively reduced bladder-related toxicity after high-dose radiation therapy. In the Memorial Sloan-Kettering Cancer Center experience, reduced urinary toxicities after radiation therapy to the prostate have also not been observed with the use of IMRT 1, 2. These findings may be related to our ignorance of the critical anatomic component or subunit responsible for post-radiation therapy bladder-related toxicity. The recent observation of reduced urinary toxicity with image guided radiation therapy could possibly be related to less dose delivered to the bladder trigone rather than any relationship to whole bladder or urethra doses (4). Acute symptoms could possibly be related to swelling and inflammation to the prostatic urethra, but late toxicity may more likely be related to bladder neck and dose to the trigone region. In a recent analysis we observed that dose to the trigone was in fact an independent predictor for late grade 2 urinary toxicity after high-dose IMRT (unpublished data). Clearly, this endpoint requires further study.


    The resurgence of interest in proton therapy for prostate cancer has also raised interesting questions about the potential for this technology to reduce the risk of late toxicity after treatment. The Bragg peak effect of protons poses a unique biologic advantage for reducing the integral dose and exposure to normal tissues. Yet, to date there is no convincing evidence that this inherent advantage of the proton beam has translated into reduced late complications or secondary malignancies for prostate cancer patients. Techniques for improving conformality of the proton beam with intensity modulation in proton therapy and with adaptive image guidance remain in their infancy and will certainly require more research and clinical experience. In the meantime, the results of ongoing prospective studies comparing outcomes between IMRT and proton therapy for patients with prostate cancer will help sort these issues out.


    It is likely that new developments in treatment planning and delivery systems have reached a plateau, and it is unclear whether any new radiation therapy intervention or technique will produce further dramatic reductions in side effect profiles of treated patients. Radiation therapy may only produce further reductions in side effects with the recognition or identification of the critical elements of the normal tissue structure or dose patterns most closely associated with treatment-related dysfunction. This information would then need to be used to drive accurate image guided interventions. In the future, with the help of functional imaging and biologically based outcome-driven treatment planning, we may need to explore image guided dose de-escalation in the critical locations to have a more meaningful impact.



  • Volume 87, Issue 5 , Pages 1078-1085, 1 December 2013

    Temporal Nodal Regression and Regional Control After Primary Radiation Therapy for N2-N3 Head-and-Neck Cancer Stratified by HPV Status


    Shao Hui Huang, MD, MRT(T), Brian O'Sullivan, MD ,  Wei Xu, PhD et cols:



    To compare the temporal lymph node (LN) regression and regional control (RC) after primary chemoradiation therapy/radiation therapy in human papillomavirus-related [HPV(+)] versus human papillomavirus-unrelated [HPV(−)] head-and-neck cancer (HNC).


    Methods and Materials

    All cases of N2-N3 HNC treated with radiation therapy/chemoradiation therapy between 2003 and 2009 were reviewed. Human papillomavirus status was ascertained by p16 staining on all available oropharyngeal cancers. Larynx/hypopharynx cancers were considered HPV(−). Initial radiologic complete nodal response (CR) (≤1.0 cm 8-12 weeks after treatment), ultimate LN resolution, and RC were compared between HPV(+) and HPV(−) HNC. Multivariate analysis identified outcome predictors.



    A total of 257 HPV(+) and 236 HPV(−) HNCs were identified. The initial LN size was larger (mean, 2.9 cm vs 2.5 cm; P<.01) with a higher proportion of cystic LNs (38% vs 6%, P<.01) in HPV(+) versus HPV(−) HNC. CR was achieved is 125 HPV(+) HNCs (49%) and 129 HPV(−) HNCs (55%) (P=.18). The mean post treatment largest LN was 36% of the original size in the HPV(+) group and 41% in the HPV(−) group (P<.01). The actuarial LN resolution was similar in the HPV(+) and HPV(−) groups at 12 weeks (42% and 43%, respectively), but it was higher in the HPV(+) group than in the HPV(−) group at 36 weeks (90% vs 77%, P<.01). The median follow-up period was 3.6 years. The 3-year RC rate was higher in the HPV(−) CR cases versus non-CR cases (92% vs 63%, P<.01) but was not different in the HPV(+) CR cases versus non-CR cases (98% vs 92%, P=.14). On multivariate analysis, HPV(+) status predicted ultimate LN resolution (odds ratio, 1.4 [95% confidence interval, 1.1-1.7]; P<.01) and RC (hazard ratio, 0.3 [95% confidence interval 0.2-0.6]; P<.01).



    HPV(+) LNs involute more quickly than HPV(−) LNs but undergo a more prolonged process to eventual CR beyond the time of initial assessment at 8 to 12 weeks after treatment. Post radiation neck dissection is advisable for all non-CR HPV(−)/non-CR N3 HPV(+) cases, but it may be avoided for selected non-CR N2 HPV(+) cases with a significant LN involution if they can undergo continued imaging surveillance. The role of positron emission tomography for response assessment should be investigated.



  • Strategies to reduce long-term postchemoradiation dysphagia in patients with head and neck cancer: An evidence-based review

    Comentario del Dr. Joaquín Cabrera
    Hospital Infanta Cristina ( Badajoz)


    Head and Neck. Article first published online: 4 JUL 2013 DOI: 10.1002/hed.23251

    Strategies to reduce long-term postchemoradiation dysphagia in patients with head and neck cancer: An evidence-based review.

    Vinidh Paleri MS, Justin W. G. Roe, Primož Strojan,  June Corry,  Vincent Grégoire, Marc Hamoir, Avraham Eisbruch, William M. Mendenhall, Carl E. Silver,  Alessandra Rinaldo,  Robert P. Takes,  Alfio Ferlito .




    Background. Swallowing dysfunction following chemoradiation for head and neck cancer is a major cause of morbidity and reduced quality of life. This review discusses 3 strategies that may improve posttreatment swallowing function.


    Methods. The literature was assessed by a multiauthor team that produced evidence-based recommendations.


    Results (1) Prospective and randomized studies with small cohorts show a trend toward benefits for a preventative exercise program addressing oral and pharyngeal structures. (2) Prospective and retrospective data indicate that better swallowing outcomes are likely when nasogastric tubes are used in preference to gastrostomy tubes to supplement enteral nutrition during chemoradiation. (3) Emerging prospective data with mature results on small cohorts support the hypothesis that radiation dose restriction to swallowing structures using intensity-modulated radiation therapy techniques leads to better swallow outcomes.




    This study discusses 3 strategies for improving swallow-related outcomes in patients undergoing chemoradiation for head and neck cancer and identifies areas for future research.




  • Oral Oncology 2012. Haigentz M, Cohen EEW, Wolf GT, Strojan P, Eisbruch A, Ferlito A. Editorial. The future of induction chemotherapy for head and neck squamous cell carcinoma. Publicado on line 14 de

    Comentario del Dr. Joaquín Cabrera
    Hospital Infanta Cristina ( Badajoz)


    No hay abstract disponible, se reproduce a continuación la introducción del artículo:


    Over the past decade, the rapid evolution of chemoradiotherapy for locoregionally advanced head and neck cancer has resulted in multiple approaches with several demonstrating improved survival over radiotherapy alone in randomized studies. Indeed, the National Comprehensive Cancer Network (NCCN) currently lists nine acceptable chemotherapy regimens in combination with radiation for primary treatment of non-nasopharyngeal squamous cell cancers, including four with category 1 (highest level) evidence.1 Unfortunately, there is a lack of randomized trial evidence comparing these new approaches, resulting in several possible treatment protocols for the same patient that though effective, are considerably different in chemotherapeutic agents and treatment duration, and therefore result in differences in toxicities and potentially in outcome. The choice of optimal therapy becomes especially daunting for the oncologist who treats a small number of head and neck cancer patients per year and does not have the opportunity to develop extensive personal experience.


    Among the therapeutic protocols generating interest in recent years has been induction/sequential chemoradiotherapy, involving systemic doses of chemotherapy prior to concurrent chemoradiotherapy. The rationale for introducing aggressive induction chemotherapy in curative-intent settings has been (1) to increase efficacy of subsequent chemoradiotherapy resulting from its down-staging effects on the gross tumor volume, (2) to act as a test of tumor radiosensitivity, and (3) to possibly eradicate systemic micrometastases. In two phase III trials, the addition of docetaxel (T) to traditional cisplatin/5 fluorouracil (PF) during induction resulted in improved progression-free and overall survival,2,3 making TPF the preferred induction regimen over PF and launching three randomized trials testing sequential approaches with TPF induction followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. The first of these studies was presented in 2009, with several concerns raised in its methodology, and the results remain unpublished.4 During the most recent Annual Meeting of the American Society of Clinical Oncology (ASCO), the longawaited results of the remaining two randomized phase III trials were presented.5,6 Though neither study completed accrual as initially planned, the results nevertheless were widely anticipated in hopes that a more definitive validation of a single standard of care could be established.


    Artículo referido a los abstract presentados en ASCO 2012:


    - Cohen EEW, Karrison T, Kocherginsky M, Huang CH, Agulnik M, Mittal BB, et al. DeCIDE: a phase III randomized trial of docetaxel (D), cisplatin (P), 5- fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol:30. [suppl., abstr. 5500].


    Background: IC is associated with lower distant failure (DF) rates in SCCHN but an improvement in overall survival (OS) has not been validated. The goal of this trial was to determine whether IC prior to chemoradiotherapy (CRT) improves survival compared to CRT alone. Methods: In this phase 3, open-label trial, subjects with pathologically confirmed SCCHN; N2/N3 disease without metastases; no prior therapy; KPS ³ 70%; and intact organ function were randomized to CRT alone (CRT arm) [5 days of D (25 mg/m2), F (600 mg/m2), hydroxyurea (500 mg BID), and RT (150 cGy BID) followed by a 9 day break] or to 2 cycles of IC [D (75 mg/m2), P (75 mg/m2), F (750 mg/m2 day 1-5)] followed by the same CRT (IC arm). Primary endpoint was OS. Secondary endpoints included DF free survival, failure pattern, and recurrence-free survival (RFS). 280 subjects provided 80% power to detect a hazard ratio HR=0.5 for OS (a=0.05). Results: 280 subjects were accrued from 2004-09 with minimum follow-up 24 months. Of 142 patients randomized to IC, 91% received 2 cycles and 87% continued to CRT. Treatment adherence during CRT was high for docetaxel and hydroxyurea, but fewer than 75% of the patients received target dose of 5FU in both arms. RT was delivered without major deviations in 94% and 95% of patients on IC and CRT arms, respectively. The most common grade 3-4 toxicities during IC were febrile neutropenia (9%) and mucositis (8%), and during CRT (both arms combined) they were mucositis (45%), dermatitis (19%), and leukopenia (17%). Only grade 3-4 leukopenia and neutropenia rates were significantly higher in IC (p=0.002 and p=0.02, respectively). Table shows efficacy. 


    Conclusions: High survival rates were observed in both arms. Further analysis and follow-up may provide insight into why the significant decrease in DF did not translate into improved OS.



    3-year outcomes.


    IC arm (%)

    CRT arm (%) 


    95% CI

    p value







    DF-free survival












    Cumulative incidence of DF






    Cumulative incidence of 
    locoregional failure








    - Haddad RI, Rabinowits G, Tishler RB, Adkins D, Khuri FR, Clark J, et al. The PARADIGM trial: a phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC). J Clin Oncol:30. [suppl., abstr. 5501]


    Background: PARADIGM is a multicenter phase III study comparing TPF (docetaxel, cisplatin, and 5-fluorouracil)-based ST (Arm A) to upfront cisplatin CRT (Arm B) in patients (pts) with LAHNC. Pt accrual was terminated in 12/2008 due to slow enrollment with 145 of 300 planned analyzable patients accrued. Safety data was previously presented at the 2010 ASCO annual meeting showing no unusual pattern of toxicities in either arm. Here we present the survival results. Methods: Pts were randomized to receive arm A-ST (as induction chemotherapy (ICT) with TPF x 3) followed by CRT with either weekly carboplatin and once daily radiotherapy, or weekly docetaxel and accelerated boost radiotherapy based on adequate response to ICT; or arm B - accelerated boost CRT with bolus cisplatin x 2. The primary endpoint was survival. With original accrual target of 300 analyzable patients, this study was powered at 80% to detect an improvement in 3-year survival from 55% (arm B) to 70% (arm A). Results: A total of 145 previously untreated pts were enrolled (Arm A: 70; Arm B: 75), of whom 127 were male and 127 were Caucasian. Median age was 55; patients had PS of 0 (97) or 1 (48). Sites of disease were oropharynx: 80, larynx: 24, hypopharynx: 15, and oral cavity: 26. Disease stages were II (1 pt), III (20 pts) and IV (124 pts). After a median follow-up of 49 months, 41 pts have died (20 in arm A and 21 in arm B). Three-year survival was 73% (arm A) and 78% (arm B) (HR1.09; 95% CI 0.59 to 2.03 p=0.77). Three-year progression-free survival was 67% (arm A) and 73% (arm B) (HR 1.2; 95% CI 0.65 to 2.22; p=0.55). Patterns of failure will be presented at the meeting. 


    Conclusions: Althoughthese results suggest no survival differences between CRT and ST for patients with LAHNC, the study was terminated before the planned accrual could be reached. HPV status for the oropharynx cases which represented the majority of patients was not available for stratification; and excellent survival was seen in both arms. 



  • Intensity-Modulated Radiotherapy is Associated With Improved Global Quality of Life Among Long-term Survivors of Head-and-Neck Cancer

    Comentario del Dr. José Enrique Baquedano Baquedano
    Hospital Arnau de Vilanova (Lleida) 


    International Journal of Radiation Oncology  Biology  Physics - Volume 84 (1), Pages 170-175, 1 September 2012


    Intensity-Modulated Radiotherapy is Associated With Improved Global Quality of Life Among Long-term Survivors of Head-and-Neck Cancer



    To compare the long-term quality of life among patients treated with and without intensity-modulated radiotherapy (IMRT) for head-and-neck cancer.


    Methods and Materials

    The University of Washington Quality of Life instrument scores were reviewed for 155 patients previously treated with radiation therapy for locally advanced head-and-neck cancer. All patients were disease free and had at least 2 years of follow-up. Eighty-four patients (54%) were treated with IMRT. The remaining 71 patients (46%) were treated with three-dimensional conformal radiotherapy (3D CRT) by use of initial opposed lateral fields matched to a low anterior neck field.



    The mean global quality of life scores were 67.5 and 80.1 for the IMRT patients at 1 and 2 years, respectively, compared with 55.4 and 57.0 for the 3D CRT patients, respectively (p < 0.001). At 1 year after the completion of radiation therapy, the proportion of patients who rated their global quality of life as “very good” or “outstanding” was 51% and 41% among patients treated by IMRT and 3DCRT, respectively (p = 0.11). At 2 years, the corresponding percentages increased to 73% and 49%, respectively (p < 0.001). On multivariate analysis accounting for sex, age, radiation intent (definitive vs. postoperative), radiation dose, T stage, primary site, use of concurrent chemotherapy, and neck dissection, the use of IMRT was the only variable independently associated with improved quality of life (p = 0.01).



    The early quality of life improvements associated with IMRT not only are maintained but apparently become more magnified over time. These data provide powerful evidence attesting to the long-term benefits of IMRT for head-and-neck cancer.

    Keywords: Intensity-modulated radiation therapy, Head-and-neck cancer, Radiation therapy, Quality of life, Long-term survivors



  • HEAD AND NECK CANCER SEMINARS IN RADIATION ONCOLOGY Volumen 22. número 3. páginas 185-262. Julio 2012.

    Comentario del Dr. Miguel Martínez Carrillo
    Hospital Virgen de las Nieves (Granada)



    Biology of human papillomavirus-related oropharyngeal cancer.


    Howard JD, Chung CH.


    Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.



    Recent data show that human papillomavirus-positive oropharyngeal cancer (OPC) has a distinct biological and clinical behavior compared with human papillomavirus-negative OPC. As this subset of head and neck cancer represents an increasing public health concern, a thorough understanding of the causative and mechanistic differences between these diseases and how these distinctions impact clinical treatment is required. In this review, we will summarize recent data in epidemiology, the mechanism of viral carcinogenesis and differences in tumor biology that may provide insights to improve the clinical management of patients with human papillomavirus-positive OPC.



    Management of human papillomavirus-positive and human papillomavirus-negative head and neck cancer.


    Mehra R, Ang KK, Burtness B.


    Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA.



    A subset of squamous cell carcinomas of the head and neck is now known to be caused by oncogenic human papillomavirus (HPV) infection. Viral-associated malignancies arise predominantly from the oropharynx and are generally more responsive to treatment compared with non-HPV squamous cell head and neck carcinomas. Although many patients with HPV-positive disease lack the traditional risk factors of tobacco and alcohol use, retrospective recursive partitioning analysis indicates that patients with a >10 pack-year smoking history and HPV-positive disease may be at intermediate risk for survival. This warrants further study in a prospective clinical trial. Thus, current clinical trials that are being designed to study curative treatment regimens, such as transoral surgery or combinations of radiation with systemic therapy, are being developed separately for HPV-positive and HPV-negative disease with attention to tobacco history. This review will discuss some of the ongoing research efforts for HPV-positive and HPV-negative head and neck carcinomas.



    The role of chemotherapy in locally advanced head and neck squamous cell carcinoma.


    Nwizu T, Ghi MG, Cohen EE, Paccagnella A.


    SS Giovanni e Paolo Hospital, Medical Oncology Division, Department of Medicine, University of Chicago, Chicago, IL.



    The role of chemotherapy in multimodality treatment for locally advanced head and neck squamous cell carcinoma, although firmly established, presents several unresolved issues. Concomitant platinum-based chemoradiation (CRT) is a standard treatment for unresectable, resectable but nonsurgically treated, and postoperative high-risk patients with locally advanced head and neck squamous cell carcinoma. However, no clear conclusion can be drawn regarding the optimal platinum compound or combinations to use, the type of schedule, and number of cycles (ie, platinum total dose) to be delivered. Cetuximab administered concomitantly with radiotherapy has not been directly compared with CRT but offers a potential different approach using a noncytotoxic systemic agent. In the organ preservation setting, CRT, although yielding a superior 5-year larynx preservation rate, showed similar outcomes to induction chemotherapy (IC) followed by radiation in terms of 5-year laryngectomy-free survival and overall survival, with a higher incidence of grade 3-4 mucositis. The role of IC in nonorgan preservation programs has not yet been established. Phase III trials comparing concomitant CRT versus IC followed by CRT are ongoing with results anticipated in the near future.



    Molecular-targeted therapies in head and neck cancer.


    Rao SD, Fury MG, Pfister DG.


    Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.



    The increasing understanding of tumor biology has opened the door to a new class of biological agents directed at specific molecular targets in the treatment of squamous cell carcinomas of the head and neck. These targeted agents present the opportunity to more effectively attack the crucial cellular pathways contributing to tumor growth and survival, while minimizing toxicity. Cetuximab, which targets epidermal growth factor (EGF) receptor signaling, was the first such biological agent to be proven effective in head and neck squamous cell cancers. Currently, there are dozens of targeted agents at various stages of testing for use in the treatment of head and neck cancers. In this article, we review strategies aimed at key pathways, including EGF receptor signaling, the Vascular Endothelial Growth Factor (VEGF) pathway, and PI3K/AKT/mammalian target of rapamycin activation



    Retreatment of recurrent head and neck cancer in a previously irradiated field.


    Wong SJ, Bourhis J, Langer CJ.


    Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.



    During the past 2 decades, concurrent chemotherapy with reirradiation (reRT) has matured from a fear-provoking, rarely performed therapeutic strategy to an accepted mainstream option for selected patients with recurrent or second primary squamous cell head and neck cancer in previously irradiated fields. Attempts by investigators to advance and improve reRT have included multiple new approaches, such as the use of reRT in the postoperative setting, the integration of new radiation techniques, as well as the addition of targeted agents into reRT regimens. We review and discuss recent studies that address these areas. Although clinical research efforts to examine new reRT regimens are valuable, we have reached a plateau in the acquisition of significant new knowledge because of a paucity of prospective multicenter studies and a near total absence of randomized phase III trials. Analysis of recent reRT studies points out areas where incremental advances have been made, but more importantly, we provide a guide to the priorities on which future investigations should focus.



    Predictive and prognostic role of functional imaging of head and neck squamous cell carcinomas.


    Quon H, Brizel DM.


    Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD; Department of Oncology, Johns Hopkins University, Baltimore, MD.



    Predicting radiotherapy (RT) treatment response and eventual locoregional disease control is an important component of the ongoing effort to improve the therapeutic ratio in the management of head and neck squamous cell carcinomas. The development of clinically useful predictive and prognostic imaging biomarkers has been limited by significant tumor heterogeneity in both the tumor and its microenvironment. Various advanced imaging techniques have been evaluated in the head and neck squamous cell carcinoma patient, which now offer a strategy to identify and quantify this heterogeneity, characterizing the tumor at baseline and its response to RT. The most promising of these techniques include dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), DCE computed tomography, diffusion-weighted MRI, and (18)F-fluoromisonidazole positron emission tomography (PET) all relying on the spatiotemporal quantification of a contrast agent within a region of interest that can be further analyzed by various pharmacokinetic models. Despite the small study populations, several consistent observations have been reported that warrant further validation. Features associated with a favorable RT response include tumors with an effective vasculature characterized by rapid and high influx rates of the contrast agent and its effective clearance with little or no regions of hypoxia. (18)F-deoxyglucose-PET imaging remains an active area of investigation with the metabolic tumor volume parameter appearing to offer potential predictive value. Characterizing changes during a course of RT may offer greater predictive value. Both DCE-MRI and diffusion-weighted MRI can identify physiological changes within the first 1-2 weeks of treatment that are correlated with long-term clinical outcome. Identifying persistent hypoxia with (18)F-fluoromisonidazole-PET during a course of RT suggests an increased risk of relapse. Whether this is due to an inability to favorably remodel the tumor's vasculature has not been clearly demonstrated to date. Future research goals include the need to further validate these promising imaging biomarkers especially in larger cohorts of patients, characterizing the optimal threshold cutoffs and to refine the predictive value by incorporating the assessments of early tumor responses to therapy that offer the potential for increased specificity because it reflects the biological stress responses.



    Current management of nasopharyngeal cancer.


    Lee AW, Lin JC, Ng WT.


    Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong.



    Management of nasopharyngeal carcinoma is one of the greatest clinical challenges. Appropriate detection is not easy because of its anatomical location; sensitive biomarkers in addition to endoscopic and radiological examinations would be valuable. One useful biomarker (particularly for nonkeratinizing carcinoma) is the plasma level of Epstein-Barr viral deoxyribonucleic acid, and its role as a tool for prognostication and monitoring disease progress is presented. Radiotherapy is the primary treatment modality, and using radiation therapy in combination with chemotherapy is recommended for the treatment of locoregionally advanced tumors. Intensity-modulated radiotherapy techniques with image guidance to ensure setup precision are recommended if resources allow; adaptive replanning should be considered if major deviations from the intended dose distribution occur during the treatment course. Most contemporary series have reported encouraging results, with locoregional control exceeding 90%; the key problem is distant failure. The therapeutic margin is extremely narrow. Although significant reduction of some toxicities (eg, xerostomia) and better quality of life is now achievable especially for early stages, the risk of major late toxicities remains substantial. This review will focus on the primary treatment: the current consensus and controversies in the treatment strategy for different stages, the choice of chemotherapy regimen, and the key factors for improving the therapeutic ratio of radiotherapy will be discussed. Summary of the current achievement and direction for future improvement will be presented.



    Biology and management of salivary gland cancers.


    Adelstein DJ, Koyfman SA, El-Naggar AK, Hanna EY.


    Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.



    The salivary gland cancers are uncommon neoplasms of the head and neck, which exhibit considerable pathologic, biological, and clinical diversity. Surgical resection, often with postoperative radiation, is the standard therapeutic approach, and the results after treatment vary widely depending on the tumor histology. Chemotherapy has been of only limited palliative benefit in patients with advanced disease, and there has been little exploration of its use in definitive management. Recent investigation has focused on identification of the characteristic molecular signatures and genomic alterations of the specific histologic subtypes. These efforts have suggested the potential for molecularly targeted therapies, and clinical trials exploring this approach are currently underway.



    The role of external beam radiation and targeted therapy in thyroid cancer.


    Brierley J, Sherman E.


    Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, Toronto, Ontario, Canada.



    The initial management of thyroid cancer is usually surgery, followed by radioactive iodine in differentiated thyroid cancer. The role of external beam radiotherapy for gross residual or unresected disease is discussed. For both differentiated thyroid cancer and medullary thyroid cancer, the role of external beam radiotherapy after resection of gross disease when there is a high risk of local regional failure is reviewed. In anaplastic thyroid cancers, although most patients present with unresectable disease and radiotherapy is the mainstay of treatment, the benefits of the addition of chemotherapy to radiation therapy will be discussed. Patient selection, radiation volumes, and radiation doses will be discussed. As in other tumor sites, external beam radiation has an import role in the palliative management of patient with metastatic thyroid cancer of all histologies, especially of metastases to bone but also brain and lung, but this role is not described in the review.



  • FADD Expression as a Prognosticator in Early-Stage Glottic Squamous Cell Carcinoma of the Larynx Treated Primarily With Radiotherapy

    Comentario del Dr. José Enrique Baquedano Baquedano
    Hospital Arnau de Vilanova (Lleida)


    International Journal of Radiation Oncology  Biology Physics - Volume 83, Issue 4, Pages 1220-1226 , 15 July 2012



    We recently reported on the identification of the Fas-associated death domain (FADD) as a possible driver of the chromosome 11q13 amplicon and the association between increased FADD expression and disease-specific survival in advanced-stage laryngeal carcinoma. The aim of this study was to examine whether expression of FADD and its Ser194-phosphorylated isoform (pFADD) predicts local control in patients with early-stage glottic carcinoma primarily treated with radiotherapy only.


    Methods and Materials

    Immunohistochemical staining for FADD and pFADD was performed on pretreatment biopsy specimens of 92 patients with T1–T2 glottic squamous cell carcinoma primarily treated with radiotherapy between 1996 and 2005. Cox regression analysis was used to correlate expression levels with local control.



    High levels of pFADD were associated with significantly better local control (hazard ratio, 2.40; 95% confidence interval, 1.04–5.55; p = 0.040). FADD overexpression showed a trend toward better local control (hazard ratio, 3.656; 95% confidence interval, 0.853–15.663; p = 0.081). Multivariate Cox regression analysis showed that high pFADD expression was the best predictor of local control after radiotherapy.



    This study showed that expression of phosphorylated FADD is a new prognostic biomarker for better local control after radiotherapy in patients with early-stage glottic carcinomas.

    Keywords: FADD, Larynx, Prognostic marker, Radiotherapy, Squamous cell carcinoma


  • A prospective protocol for nasopharyngeal carcinoma in children and adolescents: The Italian Rare Tumors in Pediatric Age TREP project.
    Comentario del Dr. Joaquín Cabrera
     Hospital Infanta Cristina ( Badajoz)


    Cancer. 2012 May 15; 118(10):2718-2725. doi: 10.1002/cncr.26528. Epub 2011 Sep 14.


    A prospective protocol for nasopharyngeal carcinoma in children and adolescents:  The Italian Rare Tumors in Pediatric Age (TREP) project.


    Casanova M, Bisogno G, Gandola L, Cecchetto G, Di Cataldo A, Basso E, Indolfi P,  D'Angelo P, Favini F, Collini P, Potepan P, Ferrari A; on behalf of the Rare Tumors in Pediatric Age Group.


    Pediatric Oncology Unit, Foundation for the Research and Cure of Cancer, NationalCancer Institute, Milan, Italy.




  • Int J Radiat Oncol Biol Phys. 2012 Sep 1; 84 1 :176-82. doi:10.1016/j.ijrobp.2011.10.010. Epub 2012 Jan 13.

    Dosimetric predictors of radiation-induced acute nausea and vomiting in IMRT for nasopharyngeal cancer.


    Lee VH, Ng SC, Leung TW, Au GK, Kwong DL.


    Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong. vhflee@hku.hk


  • Int J Radiat Oncol Biol Phys. 2012 Sep 1; 84 1 :183-8. doi: 10.1016/j.ijrobp.2011.11.044. Epub 2012 Feb 11.

    Active tobacco smoking and distant metastasis in patients with oropharyngeal cancer.


    McBride SM, Ali NN, Margalit DN, Chan AW.


    Harvard Radiation Oncology Program, Boston, Massachusetts, USA.


  • Int J Radiat Oncol Biol Phys. 2012 Nov 15; 84 4: 983-9.doi: 10.1016/j.ijrobp.2012.03.005.

    Hypopharyngeal Dose Is Associated With Severe Late Toxicity in Locally Advanced Head-and-Neck Cancer: An RTOG Analysis.


    Machtay M, Moughan J, Farach A, Martin-O'Meara E, Galvin J, Garden AS, Weber RS, Cooper JS, Forastiere A, Ang KK.


    University Hospitals Seidman Cancer Center and Case Western Reserve University School of Medicine, Cleveland, Ohio. Electronic address: mitchell.machtay@uhhospitals.org.



  • Head Neck. 2012 Jan; 34 1: 23-33. doi: 10.1002/hed.21686. Epub 2011 Mar 3.

    Transoral laser surgery versus radiotherapy: systematic review and meta-analysis for treatment options of T1a glottic cancer.


    Abdurehim Y, Hua Z, Yasin Y, Xukurhan A, Imam I, Yuqin F.


    Department of Otorhinolaryngology, First Teaching Hospital of Xinjiang Medical University, Urumqi, China.


  • Head Neck. 2012 Jan; 34 1: 78-87. doi: 10.1002/hed.21685. Epub 2011 Apr 5.

    Anterior craniofacial resection for malignant paranasal tumors: a monoinstitutional experience of 366 cases.


    Cantu G, Solero CL, Miceli R, Mattana F, Riccio S, Colombo S, Pompilio M, Lombardo G, Formillo P, Quattrone P.


    Cranio-Maxillo-Facial Unit, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milano, Italy. gcantu43@gmail.com


    Our data indicated that craniofacial resection and postsurgical radiotherapy remain the primary option for malignant tumors involving the anterior skull base.




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