Delayed DNA double-strand break repair following platin-based chemotherapy predicts treatment response in head and neck squamous cell carcinoma.

INTRODUCTION: The aim of this study was to investigate if defective repair of DNA double-strand break (DSB) in head and neck squamous cell carcinoma (HNSCC) could be used as an early predictor of treatment response. METHODS: Tumour biopsy 24-36 h following induction chemotherapy (IC) and pre-treatment biopsies were stained for RAD51 and geminin (S-phase marker) for immunofluorescence in patients with HNSCC. The difference between RAD51 score (percentage of geminin-positive cells that were also positive for RAD51) was calculated for the two specimens. Tumours with a percentage difference of⩽10% were deemed to have repaired IC-induced DSBs, and were classified as 'RAD51 negative'. Response at 3 months post treatment and human papilloma virus (HPV) status were assessed. RESULTS: Thirteen pairs of samples were available for analyses. Three samples were classified as RAD51 negative and 10 as RAD51 positive at 24 h post IC. All of the three patients with tumours classified as RAD51 negative had partial response or progressive disease and the 10 patients with tumours deemed RAD51 positive had a complete response. 100% of the HPV-positive tumours were RAD51 positive and had a complete response. CONCLUSIONS: We have demonstrated that impaired DSB DNA repair may underlie enhanced treatment sensitivity of HPV-positive HNSCC and repair capacity following platinum-induced DNA damage predicts response in HNSCC. This has potential as a biomarker for patient selection in trials of DNA damage response pathway modulation.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

AIM: The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. MATERIALS AND METHODS: 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. RESULTS: IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. CONCLUSION: This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

A phase II trial of induction chemotherapy and chemo-IMRT for head and neck squamous cell cancers at risk of bilateral nodal spread: the application of a bilateral superficial lobe parotid-sparing IMRT technique and treatment outcomes.

PURPOSE: To determine the feasibility of induction chemotherapy and chemo-IMRT in head and neck squamous cell cancers at risk of bilateral nodal spread (midline tumours) and to evaluate whether bilateral superficial lobe parotid-sparing IMRT can reduce the incidence of ⩾G2 subjective xerostomia. METHODS: Patients with midline tumours were enrolled to a phase II trial to receive induction platinum/5-fluorouracil and concomitant platinum with combined superficial lobe parotid-sparing IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions (f) and at risk nodal levels, 54 Gy/30f. Incidence of ⩾G2 subjective xerostomia was defined as the primary endpoint. Secondary endpoints included incidences of acute and late toxicities and survival outcomes dependent on human papilloma virus (HPV) status. RESULTS: One hundred and twenty patients with midline cancers completed treatment between December 2005 and May 2010 with median follow-up of 50 months. Incidences of ⩾G2 acute toxicities were: dysphagia 75%; xerostomia 65%; mucositis 86%; pain 83%; and fatigue 64%. At 12 months, ⩾G2 subjective xerostomia was observed in 21% (17% in HPV +ve). Two-year loco-regional progression-free survival (PFS) was 90.7% (95% CI: 85.2-96.2). According to HPV status, there was a significant difference for 2-year loco-regional PFS, 76.8% (HPV-negative) vs 98.6% (HPV-positive), P=0.001. 2-year overall survival was 93% for HPV-positive compared with 52% for HPV-negative cases, P<0.001. CONCLUSIONS: Sequential chemotherapy/chemo-IMRT for midline tumours is feasible, with excellent survival outcomes. At 1 year, 21% experience ⩾G2 subjective xerostomia. Two-year survival outcomes differ significantly between HPV-positive and HPV-negative disease, suggesting development of different treatment schedules for the different disease entities.

Recent advances in radiotherapy.

Radiation therapy has come a long way from treatment planning based on orthogonal radiographs with large margins around tumours. Advances in imaging and radiation planning software have led to three-dimensional conformal radiotherapy and, further, to intensity modulated radiotherapy (IMRT). IMRT permits sparing of normal tissues and hence dose-escalation to tumours. IMRT is the current standard in treatment of head and prostate cancer and is being investigated in other tumour sites. Exquisitely sculpted dose distributions (increased geographical miss) with IMRT, plus tumour motion and anatomical changes during radiotherapy make image guided radiotherapy an essential part of modern radiation delivery. Various hardware and software tools are under investigation for optimal IGRT.

Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months. PATIENTS AND METHODS: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed. RESULTS: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. CONCLUSIONS: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo.

Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC(50)=0.35 muM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiation-induced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4',6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gammaH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer.

We describe a retrospective series of patients with advanced head-and-neck cancer who were treated with induction chemotherapy followed by radical chemo-radiation. Patients treated with two cycles of induction chemotherapy followed by definitive chemo-radiation for squamous cell carcinoma of the head-and-neck region, from 2001 - 2006 at the Royal Marsden Hospital, formed the basis of this study. Cisplatin (75 mg m(-2)) on day 1 and 5-FU (1000 mg m(-2)) day 1 - 4 was the standard regimen used for induction treatment. Cisplatin (100 mg m(-2)) on day 1 and day 29 was used for concomitant treatment. The radiation was delivered using conformal technique. Tissues containing macroscopic and microscopic disease were treated to doses of 65 Gray (Gy) in 30 fractions and 50 Gy in 25 fractions, respectively. Data on patterns of relapse and acute toxicity (NCICTCv.3.0) were collected. A total of 129 patients were included, median age was 58 (range: 27 - 78). The site of tumour was: oropharynx 70 (54%), larynx 30 (23%), hypopharynx 24 (19%) and other 5 (4%). The median follow-up was 19 months (range: 4 - 58). Local control, disease-specific survival and overall survival at 2 years were 71%, 68% and 63%, respectively. The distant recurrence rate at 2 years was 9%. Ten patients required dose reduction during induction chemotherapy due to toxicity. The dose of 5-FU was reduced in six patients and that of cisplatin in four patients. The incidence of grade 3/4 toxicity was: neutropenia 5%, thrombocytopenia 1%, nausea and vomiting 3%. One cycle of concurrent cisplatin was omitted in 23 patients due to toxicity. Full-dose radiotherapy was administered to 98% of patients. The incidence of grade 3/4 toxicity was: skin 20%, dysphagia 65%, mucositis 60%, neutropenia 3%, anaemia 1%, nausea and vomiting 4%, nephrotoxicity 1%. Induction chemotherapy followed by radical chemo-radiation is a safe and tolerable regimen in the treatment of advanced head-and-neck cancer. Distant recurrence rates are lower with equivalent local control and survival compared to chemo-radiation alone (historical controls).

Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study.

BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.

Otological toxicity after postoperative radiotherapy for parotid tumours.

Radiotherapy is commonly used in the management of malignant parotid gland tumours that have adverse pathological risk factors after surgery. Radiation to the parotid bed is associated with predictable complications. In particular, the close proximity of the auditory apparatus, which receives a significant radiation dose, results in significant toxicity in a proportion of patients. Here we review auditory toxicity after radiation to the parotid bed.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Recovery of Salivary Function: Contralateral Parotid-sparing Intensity-modulated Radiotherapy versus Bilateral Superficial Lobe Parotid-sparing Intensity-modulated Radiotherapy.

AIMS: To establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. MATERIALS AND METHODS: A dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events - NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical - LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0-1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. RESULTS: Seventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29-0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6-30.5), k = 2.7 (0.9-4.5) (CLPS-IMRT) and 28.9 Gy (26.1-31.9), k = 2.4 (1.4-3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3-27.6), k = 1.9 (0.5-3.8); CLPS-IMRT 24.0 Gy (17.7-30.1), k = 2.1 (0.1-4.1). CONCLUSION: BSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.

Induction Chemotherapy Followed by Chemo-intensity-modulated Radiotherapy for Locally Advanced Nasopharyngeal Cancer.

AIMS: To determine the toxicity and tumour control rates after chemo-intensity-modulated radiotherapy (chemo-IMRT) for locally advanced nasopharyngeal cancers (LA-NPC). MATERIALS AND METHODS: Patients with LA-NPC were enrolled in a trial to receive induction chemotherapy followed by parotid-sparing chemo-IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions and at risk nodal levels received 54 Gy in 30 fractions. Incidence of ≥grade 2 subjective xerostomia was the primary end point. Secondary end points included incidences of acute and late toxicities and survival outcomes. RESULTS: Forty-two patients with American Joint Committee on Cancer stages II (12%), III (26%) and IV (62%) (World Health Organization subtype: I [5%]; II [40%]; III [55%]) completed treatment between January 2006 and April 2010 with a median follow-up of 32 months. Incidences of ≥grade 2 acute toxicities were: dysphagia 83%; xerostomia 76%; mucositis 97%; pain 76%; fatigue 99% and ototoxicity 12%. At 12 months, ≥grade 2 subjective xerostomia was observed in 31%, ototoxicitiy in 13% and dysphagia in 4%. Two year locoregional control was 86.2% (95% confidence interval: 70.0-94.0) with 2 year progression-free survival at 78.4% (61.4-88.6) and 2 year overall survival at 85.9% (69.3-93.9). CONCLUSIONS: Chemo-IMRT for LA-NPC is feasible with good survival outcomes. At 1 year, 31% experience ≥grade 2 subjective xerostomia.

Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies.

AIMS: To determine the clinical outcomes of an intensity-modulated radiotherapy technique for total mucosal irradiation (TM-IMRT) in patients with head and neck carcinoma of unknown primary (HNCUP). MATERIALS AND METHODS: A single-centre prospective phase II trial design was used in two sequential studies to evaluate TM-IMRT for HNCUP. Patients were investigated for primary tumour site using examination under anaesthetic and biopsies, computed tomography ± magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Patients received IMRT to the potential primary tumour sites and elective cervical nodes. Concomitant chemotherapy was used in patients who received primary radiotherapy or those with nodal extracapsular extension. RESULTS: Thirty-six patients with HNCUP were recruited; 72% male. Twenty-five patients (69.4%) had p16-positive disease. Two year mucosal and local nodal control rates were 97.1% (95% confidence interval 91.4-100) and 89.8% (78.4-100), respectively. One mucosal primary was detected 7.3 months after TM-IMRT and three patients died from recurrent/metastatic squamous cell carcinoma of the head and neck. Twelve patients (33%) developed grade 3 (Late Effects in Normal Tissue-Subjective, Objective, Management and Analytical; LENT-SOMA) dysphagia with a 1 year enteric tube feeding rate of 2.7%. The high-grade subjective xerostomia rate (LENT-SOMA) at 24 months after IMRT was 15%. CONCLUSIONS: At a median follow-up of 36.1 months, the use of TM-IMRT was associated with good local control. Toxicity was comparable with previously reported TM-IMRT regimens encompassing similar mucosal volumes.

Galanin immunohistochemistry and electron microscopic studies in developing human fetal mammillary bodies.

Development and maturation of nuclear groups in the mammillary complex of second and third trimester human fetal hypothalamus were studied using Nissl stain, galanin immunocytochemistry and transmission electron microscopy. While the identity of the supra and medial mammillary nucleus was established at 24 weeks of gestation (w.g.) in Nissl stained preparation, galanin immunoreactive (Gal-ir) neurons were seen in the supra and medial mammillary nucleus of 27 through 39 w.g. fetuses. Immunoreactive perikarya in the lateral mammillary nucleus appear later at 34 w.g. and show relatively meager population. Gal-ir neurons of the supramammillary nucleus were divisible in dorsal and ventral subgroups. There was a progressive increase in galanin expressing neurons in more and more ventral positions, along the medial margin of either mammillary body so that in term fetal specimens, the ventral subgroup appeared to be continuous with the medial mammillary nucleus. Galanin positive neurons were relatively sparse in the core of the mammillary bodies. Transmission electron micrographs revealed neurons with varying degree of indentation of the nuclear envelope. Vigorous synaptogenesis was seen in the supramammillary region of the mammillary bodies. The height and width of the synaptic complex also showed a progressive increase. Although galanin neurons were reported from the supramammillary nucleus of adult human mammillary complex, no immunoreactivity was detected in the medial and lateral components of the mammillary body. We suggest that expression of galanin in the medial and lateral components may be of transient occurrence and may serve a significant role in the synaptogenesis.

Metastatic breast cancer response after Exemestane withdrawal: a case report.

A forty-three year old female patient with right sided breast cancer was treated with adjuvant radiotherapy and Tamoxifen. She had a relapse in the right supraclavicular fossa after a disease free period of 12 years. She progressed, after a short period of disease stabilization on Idoxifene followed by a further stable period on Anastrazole. At further disease relapse, she was commenced on Exemestane. After a period of disease stabilization and subsequent disease progression in the right supraclavicular fossa, Exemestane was discontinued. Six weeks later there was a marked regression of the right supraclavicular mass. Withdrawal response to Tamoxifen is well documented. To our knowledge a similar response after Exemestane withdrawal has not been reported in the literature.

Current attitudes of head and neck oncologists in the United Kingdom to induction chemotherapy for locally advanced head and neck cancer: a survey of centres participating in a national randomised controlled trial.

OBJECTIVES: Induction chemotherapy (IC) followed by chemoradiation (CRT) for locally advanced squamous cell head and neck cancer (SCCHN) remains controversial in the absence of clear evidence to define its role. As part of a prospective, randomised, multicentre study of CRT for stage III/IV laryngeal/hypopharyngeal cancers (ART DECO, CRUK/10/018), we have examined the attitudes of oncologists in the United Kingdom (UK) to IC. MATERIALS AND METHODS: Head and neck oncologists across the UK who expressed an interest in participating in the ART DECO trial were asked to complete a short written questionnaire designed to identify current UK practice of IC for stage III-IVb SCCHN. Completed questionnaires were returned to the clinical trials office prior to patient recruitment. RESULTS: Clinicians from twenty-five/48 centres (52.1%) responded. Twenty centres (80%) elected to use IC in the trial. For stage III disease, 80% of centres did not prescribe IC for T1N1 disease and 60% did not offer IC for T3N0 disease. Patients with bulky primary tumours or extensive nodal disease were more likely to receive IC. Thirteen prescribing centres (65%) use 3 drugs (docetaxel, cisplatin, and 5-fluorouracil) compared to 7 (35%) using 2 drugs (cisplatin and 5-fluorouracil). Fifteen centres (75%) prescribed 2 cycles of IC, and 5 (25%) prescribed 3 cycles. There was variation in the dosage for both the 2- and 3-drug regimens. CONCLUSION: Results suggest that clinical practice in the UK is currently divided between a 2- versus 3-drug regimen for IC for specific subgroups of patients. A consensus regarding the optimal combinations and dosages is required before further optimization of systemic therapy with other cytotoxics and biological agents is attempted.

Neurocognitive function after (chemo)-radiotherapy for head and neck cancer.

Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo)-radiotherapy for HNC, with a focus on studies of NCF in this patient population.

Equivalence of cisplatin and carboplatin-based chemoradiation for locally advanced squamous cell carcinoma of the head and neck: a matched-pair analysis.

BACKGROUND: Carboplatin can be substituted for cisplatin in concomitant chemoradiation (CRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) when the latter is contraindicated. This matched-pair study aimed to compare the efficacy and acute toxicity of carboplatin and cisplatin. METHODS: Patients treated with 2 cycles of concomitant carboplatin-based CRT were matched to patients treated with 2 cycles of cisplatin. Matching criteria included age, tumour site, stage, smoking status and use of induction chemotherapy. Radiation was delivered using conformal techniques. Data on weekly acute toxicity throughout CRT was compared using the chi-squared test for proportions. Kaplan Meier statistics described time to local relapse, distant relapse and overall survival, the log-rank test was used to compare 3-year survival outcomes. RESULTS: Sixty-five patients who received carboplatin were matched to 65 who received cisplatin. Significant differences in toxicity included increased emesis with cisplatin and more anaemia and thrombocytopenia with carboplatin. There was no significant difference in 3-year locoregional control (87% vs. 79%, p=0.54), freedom from distant metastases (88% vs. 85%, p=0.79) and overall survival (59% vs. 68%, p=0.24) between the carboplatin and cisplatin cohorts, respectively. CONCLUSIONS: When cisplatin is contraindicated, carboplatin-based CRT yields equivalent treatment outcomes in patients with LASCCHN.

The role of intensity modulated radiotherapy in advanced oral cavity carcinoma.

It is increasingly being recognized that oral cavity cancer incidences are rising globally. Furthermore, these tumors represent a high risk group of tumors comparative to other head and neck tumor sub-sites and have a high preponderance of occult nodal metastases. Surgery alone leads to excellent outcomes in early stage disease. Advanced tumors require adjuvant radiotherapy with or without concomitant chemotherapy. Irradiation using 3D conformal radiotherapy results in high incidence of late radiation side-effects. Xersostomia and mandibular osteoradionecrosis result in most significant effects on patients' quality of life. Intensity modulated radiotherapy (IMRT) is an advanced approach to 3-D treatment planning and conformal therapy (3D-CRT). It optimizes the delivery of irradiation to irregularly-shaped volumes and has the ability to produce concavities in radiation treatment volumes and hence enables sparing of normal tissue while delivering adequate doses to the tumor volumes. In this manuscript, we discuss the advantages of IMRT based on review of published peer reviewed literature.