Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics: ■ Follow-up and survivorship of patients with resected colorectal cancer■ Indications for liver metastasectomy■ Treatment of oligometastases by stereotactic body radiation therapy■ Treatment of borderline resectable and unresectable pancreatic cancer■ Transarterial chemoembolization in hepatocellular carcinoma■ Infectious complications of antineoplastic agents.

Eastern Canadian Colorectal Cancer Consensus Conference 2013: emerging therapies in the treatment of pancreatic, rectal, and colorectal cancers.

The annual Eastern Canadian Colorectal Cancer Consensus Conference held in Montreal, Quebec, 17-19 October 2013, marked the 10-year anniversary of this meeting that is attended by leaders in medical, radiation, and surgical oncology. The goal of the attendees is to improve the care of patients affected by gastrointestinal malignancies. Topics discussed during the conference included pancreatic cancer, rectal cancer, and metastatic colorectal cancer.

Metabolic syndrome-related hepatocellular carcinoma treated by volumetric modulated arc therapy.

Hepatocellular carcinoma (hcc) is a leading cause of cancer mortality, and its incidence is increasing in developed countries. Risk factors include cirrhosis from viral hepatitis or alcohol abuse. Metabolic syndrome is a newly recognized, but important, risk factor that is likely contributing to the increased incidence of hcc. Surgery is the therapy of choice for hcc, but local therapies are often contraindicated, usually because of advanced disease or comorbid conditions such as cardiac disease (which is associated with metabolic syndrome). Current radiation therapy techniques such as stereotactic body radiotherapy allow for treatment plans that highly conform to the target and provide excellent sparing of normal structures. Radiation therapy is emerging as a viable option in patients not eligible for surgery or other locoregional therapies. Here, we report a case of a large hcc presenting in a patient with metabolic syndrome without significant alcohol history or biochemical liver dysfunction. The patient was not a candidate for locoregional therapies because of cardiac and renal comorbidities typical of patients experiencing the long-term sequelae of metabolic syndrome. Treatment using an arc-based volumetric-modulated arc therapy technique allowed for the highest dose of radiation to be delivered to the tumour while the peripheral radiation dose was minimized. A complete local response was confirmed by computed tomography imaging 21 months after treatment completion.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Adapting liver motion models using a navigator channel technique.

Deformable registration can improve the accuracy of tumor targeting; however for online applications, efficiency as well as accuracy is important. A navigator channel technique has been developed to combine a biomechanical model-based deformable registration algorithm with a population motion model and patient specific motion information to perform fast deformable registration for application in image-guided radiation therapy. A respiratory population-based liver motion model was generated from breath-hold CT data sets of ten patients using a finite element model as a framework. The population model provides a biomechanical reference template of the average liver motions, which were found to be (absolute mean +/-SD) 0.12 +/- 0.10, 0.84 +/- 0.13, and 1.24 +/- 0.18 cm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The population motion model was then adapted to the specific liver motion of 13 patients based on their exhale and inhale CT images. The patient motion was calculated using a navigator channel (a narrow region of interest window) on liver boundaries in the images. The absolute average accuracy of the navigator channel to predict the 1D SI and AP motions of the liver was less than 0.11, which is less than the out-of-plane image voxel size, 0.25 cm. This 1D information was then used to adapt the 4D population motion model in the SI and AP directions to predict the patient specific liver motion. The absolute average residual error of the navigator channel technique to adapt the population motion to the patients' specific motion was verified using three verification methods: (1) vessel bifurcation, (2) tumor center of mass, and (3) MORFEUS deformable algorithm. All three verification methods showed statistically similar results where the technique's accuracy was approximately on the order of the voxel image sizes. This method has potential applications in online assessment of motion at the time of treatment to improve image-guided radiotherapy and monitoring of intrafraction motion.

Contrasting Some Differences in Managing Advanced Unresectable Hepatocellular Carcinoma Between the East and the West.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, although its aetiologies vary significantly between the East and the West. About a half of HCC cases present with advanced unresectable HCC at the time of diagnosis, leading to a worse prognosis. Over the past 20 years, the treatment paradigm for advanced unresectable HCC has shifted from an entirely palliative approach to a multidisciplinary treatment, with continuous reassessment and possible repeat treatment attributed to the advent of novel and improved local, regional and systemic therapeutic options, contributed by both the East and the West. An individualised treatment plan should be determined for each patient, as there can be substantial differences in the decision-making and treatment response to the same treatment for different patients and different patient populations. This review provides a summary of the recent advances in management and compares Eastern and Western strategies for HCC.

Conformal radiotherapy for hepatocellular carcinoma.

Technical advancements in radiation therapy (RT) have facilitated the safe delivery of conformal, dose-escalated radiation to a wide spectrum of hepatocellular carcinoma (HCC) patients. A variety of doses and RT fractionation schemes have been used, and RT has been used in combination with transarterial chemoembolization (TACE). Compared to untreated historical controls or those treated with TACE alone, outcomes following RT alone or TACE and RT are better. Despite advances in RT delivery, liver toxicity following RT remains a dose-limiting factor, and investigations to better understand the pathophysiology of RT-induced liver toxicity are warranted. For most tumors, RT can provide sustained local control. However, HCC tends to recur within the liver away from the irradiated volume, providing rationale for combining RT with systemic or regional therapies. There is a particular interest in combining RT with anti-VEGF-targeted agents for their independent activity in HCC as well as their radiation sensitization properties. Randomized trials of RT are warranted.

Microbial DNA profiling by multiplex terminal restriction fragment length polymorphism for forensic comparison of soil and the influence of sample condition.

AIMS: To evaluate: (i) the impact of air-drying on bacterial, archaeal and fungal soil DNA profiles and (ii) the potential use of multiplex-terminal restriction fragment length polymorphism (M-TRFLP) as a tool for forensic comparison of soil. METHODS AND RESULTS: An M-TRFLP approach was used to profile bacterial, archaeal and fungal DNA profiles from five different soil sites. Air-drying soil significantly reduced the quantity of DNA but the number of operational taxanomic units (OTU) was unaffected. The impact of air-drying on soil DNA profiles was dependent on soil site and microbial primers. Fungal profiles were altered the least by air-drying. For prokaryotic profiles, air-drying altered the relative similarity/dissimilarity between soil sites. The M-TRFLP approach was more discriminatory compared with soil colour and single-taxa profiling, but did not significantly improve resolution between two similar soils. CONCLUSIONS: Of those tested, soil fungi were potentially the more robust target for application to soil forensic studies as they were altered less by air-drying and provided clear discrimination of soils from different sites. The M-TRFLP method demonstrated potential to achieve greater resolution, discriminating the soil sites based on both bacterial and fungal components. SIGNIFICANCE AND IMPACT OF THE STUDY: Soil DNA profiling has potential as a forensic tool, but sample condition and the appropriate selection of microbial target taxa must be considered.

The evolving role of radiation therapy in hepatocellular carcinoma.

Technical advancements in imaging, in radiation therapy (RT) planning and RT delivery, have facilitated the safe delivery of conformal radiation therapy to patients with unresectable hepatocellular carcinoma (HCC). Although experience in liver cancer RT is limited, the RT technologies and tools to deliver RT safely are being disseminated rapidly. A variety of doses and RT fractionations have been used to treat HCC, and RT has been used in combination with other therapies including transarterial hepatic chemoembolization (TACE). Outcomes following RT alone or RT and TACE appear better than outcomes following similar historical controls of TACE alone, however, randomized trials of RT are needed. The first site of recurrence following RT is most often within the liver, away from the high dose volume, providing rationale for combining RT with regional or systemic therapies. Given the vascular properties of HCC, the combination of RT with anti-VEGF targeted agents may improve outcomes further.

The discrimination of geoforensic trace material from close proximity locations by organic profiling using HPLC and plant wax marker analysis by GC.

There is a need to develop a wider empirical research base to expand the scope for utilising the organic fraction of soil in forensic geoscience, and to demonstrate the capability of the analytical techniques used in forensic geoscience to discriminate samples at close proximity locations. The determination of wax markers from soil samples by GC analysis has been used extensively in court and is known to be effective in discriminating samples from different land use types. A new HPLC method for the analysis of the organic fraction of forensic sediment samples has also been shown recently to add value in conjunction with existing inorganic techniques for the discrimination of samples derived from close proximity locations. This study compares the ability of these two organic techniques to discriminate samples derived from close proximity locations and finds the GC technique to provide good discrimination at this scale, providing quantification of known compounds, whilst the HPLC technique offered a shorter and simpler sample preparation method and provided very good discrimination between groups of samples of different provenance in most cases. The use of both data sets together gave further improved accuracy rates in some cases, suggesting that a combined organic approach can provide added benefits in certain case scenarios and crime reconstruction contexts.

The identification of markers for Geoforensic HPLC profiling at close proximity sites.

Soil is a highly transferable source of trace physical material that is both persistent in the environment and varied in composition. This inherent variability can provide useful information to determine the geographical origin of a questioned sample or when comparing and excluding samples, since the composition of soil is dependent on geographical factors such as climate, bedrock geology and land use. Previous studies have limited forensic relevance due to the requirement for large sample amounts and unrealistic differences between the land use and geographical location of the sample sites. In addition the philosophical differences between the disciplines of earth sciences, for which most analytical techniques have been designed, and forensic sciences, particularly with regard to sample preparation and data interpretation have not been fully considered. This study presents an enhanced technique for the analysis of organic components of geoforensic samples by improving the sample preparation and data analysis strategies used in previous research into the analysis of soil samples by high performance liquid chromatography (HPLC). This study provides two alternative sets of marker peaks to generate HPLC profiles which allow both easy visual comparison of samples and the correct assignment of 100% of the samples to their location of origin when discriminating between locations of interest in multivariate statistical analyses. This technique thereby offers an independent form of analysis that is complementary to inorganic geoforensic techniques and offers an easily accessible method for discriminating between close proximity forensically relevant locations.

Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies.

PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003). CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Accuracy of finite element model-based multi-organ deformable image registration.

As more pretreatment imaging becomes integrated into the treatment planning process and full three-dimensional image-guidance becomes part of the treatment delivery the need for a deformable image registration technique becomes more apparent. A novel finite element model-based multiorgan deformable image registration method, MORFEUS, has been developed. The basis of this method is twofold: first, individual organ deformation can be accurately modeled by deforming the surface of the organ at one instance into the surface of the organ at another instance and assigning the material properties that allow the internal structures to be accurately deformed into the secondary position and second, multi-organ deformable alignment can be achieved by explicitly defining the deformation of a subset of organs and assigning surface interfaces between organs. The feasibility and accuracy of the method was tested on MR thoracic and abdominal images of healthy volunteers at inhale and exhale. For the thoracic cases, the lungs and external surface were explicitly deformed and the breasts were implicitly deformed based on its relation to the lung and external surface. For the abdominal cases, the liver, spleen, and external surface were explicitly deformed and the stomach and kidneys were implicitly deformed. The average accuracy (average absolute error) of the lung and liver deformation, determined by tracking visible bifurcations, was 0.19 (s.d.: 0.09), 0.28 (s.d.: 0.12) and 0.17 (s.d.: 0.07) cm, in the LR, AP, and IS directions, respectively. The average accuracy of implicitly deformed organs was 0.11 (s.d.: 0.11), 0.13 (s.d.: 0.12), and 0.08 (s.d.: 0.09) cm, in the LR, AP, and IS directions, respectively. The average vector magnitude of the accuracy was 0.44 (s.d.: 0.20) cm for the lung and liver deformation and 0.24 (s.d.: 0.18) cm for the implicitly deformed organs. The two main processes, explicit deformation of the selected organs and finite element analysis calculations, require less than 120 and 495 s, respectively. This platform can facilitate the integration of deformable image registration into online image guidance procedures, dose calculations, and tissue response monitoring as well as performing multi-modality image registration for purposes of treatment planning.

Partial irradiation of the liver.

The use of three-dimensional radiotherapy (RT) and the prospective follow-up of patients for radiation-induced liver disease (RILD) have led to a more quantitative understanding of the partial organ tolerance of the liver compared with previous estimates based on clinical judgment alone. Parameters of both the Lyman normal tissue complication probability (NTCP) model and a local damage-organ injury (D-I) NTCP model have been fit to clinical data from patients who have received hepatic radiation. Based on analyses of over 180 patients, the liver exhibits a large volume effect and a low threshold volume for RILD. Mean liver dose is associated with RILD, and no cases of RILD have been reported in patients with a mean liver dose of less than 31 Gy. Most recent estimates of the partial liver tolerance to RT suggest that if less than 25% of the normal liver is treated with RT, then there may be no upper limit on dose associated with RILD. Estimates of the liver doses associated with a 5% risk of RILD for uniform irradiation of one third, two thirds, and the whole liver are 90 Gy, 47 Gy, and 31 Gy, respectively.

The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease.

The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5-HT1A agents and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.

Evolving perspectives in contralateral breast cancer.

Despite extensive publications reviewing contralateral breast cancer (CBC), the role of screening and preventative measures for contralateral tumours is controversial and optimal clinical management remains undefined. This paper addresses the incidence, the predisposing factors, the prevention and the treatment of bilateral breast cancer based on a review of the literature. Risk factors for CBC include young age at primary breast cancer diagnosis, hereditary breast cancer (due to a germline mutation), familial breast cancer (one or more affected relatives), radiation exposure at a young age, lobular carcinoma in situ (LCIS), lobular invasive carcinoma and multicentricity. Retrospective studies suggest that contralateral mammographic surveillance results in the early detection of breast cancer, but no clear survival benefit has been demonstrated. Trials of adjuvant tamoxifen in breast cancer patients have shown a reduction in the incidence of CBC in both pre- and postmenopausal women. In addition, breast cancer patients treated with ovarian ablation and prednisone have significantly reduced CBC versus controls. In patients with primary breast cancer there is no evidence that contralateral breast biopsies or contralateral prophylactic mastectomy reduce mortality. Randomised, prospective trials to determine optimal surveillance, prevention and treatment strategies for the contralateral breast in breast cancer patients have not been conducted. Based on the published literature, contralateral breast surveillance in breast cancer patients reasonably includes breast self-examination, regular physical examinations and annual mammography. In women who have no evidence of distant metastasis at the time of CBC diagnosis, we recommend that the CBC be treated in the same manner as a first breast cancer, taking into account prior local and systemic therapy.

The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus.

Preclinical evidence has suggested a possible role for the 5-HT(6) receptor in the treatment of cognitive dysfunction. However, currently there is little neurochemical evidence suggesting the mechanism(s) which may be involved. Using the selective 5-HT(6) antagonist SB-271046 and in vivo microdialysis, we have evaluated the effects of this compound on the modulation of basal neurotransmitter release within multiple brain regions of the freely moving rat. SB-271046 produced no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly, this compound had no effect on excitatory neurotransmission in the striatum or nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus, respectively. These effects were completely attenuated by infusion of tetrodotoxin but unaffected by the muscarinic antagonist, atropine. Here we demonstrate for the first time the selective enhancement of excitatory neurotransmission by SB-271046 in those brain regions implicated in cognitive and memory function, and provide mechanistic evidence in support of a possible therapeutic role for 5-HT(6) receptor antagonists in the treatment of cognitive and memory dysfunction.

Target position variability throughout prostate radiotherapy.

PURPOSE: To quantify the variability in prostate and seminal vesicle position during a course of external beam radiotherapy, and to measure the proportion of target variability due to setup error. METHODS AND MATERIALS: Forty-four weekly planning computerized tomography (CT) studies were obtained on six patients undergoing radiotherapy for prostate cancer. All patients were scanned in the radiotherapy treatment position, supine with an empty bladder, with no immobilization device. All organs were outlined on 3-mm-thick axial CT images. Anterior and lateral beam's eye view digitally reconstructed radiographs and multiplanar reformatted images were generated. The position of the prostate and seminal vesicles relative to the isocenter location as set that day was recorded for each CT study. Target position relative to a bony landmark was measured to determine the relative contribution of setup error to the target position variability. RESULTS: The seminal vesicle and prostate position variability was most significant in the anterior-posterior (AP) direction, followed by cranial-caudal (CC) and mediolateral (ML) directions. Setup error contributed significantly to the total target position variability. Rectal filling was associated with a trend to anterior movement of the prostate, whereas bladder filling was not associated with any trends. Although most deviations from the target position determined at the initial planning CT scan were within 10 mm, deviations as large as 15 mm and 19 mm were seen in the prostate and seminal vesicles respectively. Target position variations were evenly distributed around the initial target position for some patient studies, but unpredictable patterns were also seen. From a simulation based on the observed variability in target position, the AP, CC, and ML planning target volume (PTV) borders around the clinical target volume (CTV) required for target coverage with 95% certainty are 12.4 mm, 10.3 mm, and 5.6 mm respectively for the prostate and 13.8 mm, 8.6 mm, and 3.9 mm respectively for the seminal vesicles. CONCLUSION: Target position variability is significant during prostate radiotherapy, requiring large PTV borders around the CTV. This target position variability may be potentially reduced by improving the setup accuracy.

Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.

PURPOSE: To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. PATIENTS AND METHODS: From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ ("oral cavity") were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. RESULTS: The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. CONCLUSION: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the uninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.