Making a case for high-volume robotic surgery centers: A cost-effectiveness analysis of transoral robotic surgery.

OBJECTIVE: To evaluate the cost-effectiveness of transoral robotic surgery (TORS) compared to intensity-modulated radiotherapy (IMRT) for early stage (T1-2, N0, M0) oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: A Markov decision tree model with a 5-year time horizon was developed. Comparative groups were: i) TORS with concurrent ipsilateral neck dissection +/- adjunctive IMRT, and ii) primary IMRT. Primary outcome was cost/quality adjusted life year (QALY). Perspective was the United States third party payer. Costs and effects were discounted at a rate of 3.5%. A threshold and probabilistic sensitivity analysis were performed. RESULTS: TORS strategy cost $30,992 and provided 4.81 QALYs/patient. The IMRT strategy cost $26,033 and provided a total of 4.78 QALYs/patient. The incremental cost effectiveness ratio for TORS vs. IMRT in the reference case was $165,300/QALY. The probability that TORS is cost-effective compared to IMRT at a maximum willingness-to-pay threshold of $50,000/QALY is 42%. CONCLUSION: An IMRT strategy for management of early stage OPSCC is more likely to be cost-effective compared to TORS. To improve the value of TORS for early stage OPSCC, consolidating TORS procedures to create high-volume centers of excellence may be a potential strategy to increase incremental effectiveness and reduce incremental costs. J. Surg. Oncol. 2015 111:155-163. © 2015 Wiley Periodicals, Inc.

Quantifying the severity of sarcopenia in patients with cancer of the head and neck.

BACKGROUND & AIMS: Existing skeletal muscle index (SMI) thresholds for sarcopenia are inconsistent, and do not reflect severity of depletion. In this study we aimed to define criterion values for moderate and severe skeletal muscle depletion based on the risk of mortality in a population of patients with head and neck cancer (HNC). Additionally, we aimed to identify clinical and demographic predictors of skeletal muscle depletion, evaluate the survival impact of skeletal muscle depletion in patients with minimal nutritional risk or good performance status, and finally, benchmarking SMI values of patients with HNC against healthy young adults. METHODS: Population cohort of 1231 consecutive patients and external validation cohorts with HNC had lumbar SMI measured by cross-sectional imaging. Optimal stratification determined sex-specific thresholds for 2-levels of SMI depletion (Class I and II) based on overall survival (OS). Adjusted multivariable regression analyses (tumor site, stage, performance status, age, sex, dietary intake, weight loss) determined relationships between 2-levels of SMI depletion and OS. RESULTS: Mean SMI (cm2/m2) was 51.7 ± 9.9 (males) and 39.8 ± 7.1 (females). The overall and sex-specific population demonstrated an increased risk of mortality associated with decreasing SMI. Sex-specific SMI (cm2/m2) depletion thresholds for 2-levels of muscle depletion determined by optimal stratification for males and females, respectively (male: 45.2-37.5, and <37.5; female: 40.9-34.2, and <34.2). In the overall population, Normal SMI, Class I and II SMI depletion occurred in 65.0%, 24.0%, and 11.0%, respectively. Median OS was: Normal SMI (114 months, 95% CI, 97.1-130.8); Class I SMI Depletion (42 months, 95% CI, 28.5-55.4), and Class II SMI Depletion (15 months, 95% CI, 9.8-20.1). Adjusted multivariable analysis compared with Normal SMI (reference), Class I SMI Depletion (HR, 1.49; 95% CI, 1.18-1.88; P < .001), Class II SMI Depletion (HR, 1.91; 95% CI, 1.42-2.58; P < .001). CONCLUSIONS: Moderate and severe SMI depletion demonstrate discrimination in OS in patients with HNC. Moderate and severe SMI depletion is prevalent in patients with minimal nutrition risk and good performance status. Benchmarking SMI values against healthy young adults exemplifies the magnitude of SMI depletion in patients with HNC and may be a useful method in standardizing SMI assessment.

Identification of a new microRNA expression profile as a potential cancer screening tool.

PURPOSE: Small non-coding microRNAs (miRNAs) are key components of cancer development and are considered as potential biomarkers for cancer diagnosis and treatment monitoring. This study investigated miRNA expression profiles of human cancer cells in order to develop a screening method for lung cancer. METHODS: A series of lung cancer related miRNAs (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, let-7a) were selected as candidates for miRNA expression profiles of human lung cancer cell lines (A549, SK-mes-1). MicroRNA u6 was the endogenous control. Cancer cell lines for positive controls; breast MCF-7, prostate Du-145, and glioblastoma U118. The negative control was normal lung fibroblast cell line MRC-5. RT-PCR was performed on StepOnePlus (Applied Biosystem, USA). MiRNA expressions of malignant cells were compared with normal fibroblast cells as well as endogenous control (u6) using the thermal cycle at threshold. Assessment of miRNA expression profiles were then performed using agglomerative hierarchical cluster analysis software (SPSS13, USA). RESULTS: We demonstrated that miR-21, miR-182 and let7-5a were over-expressed, and miR-145 and miR-155 were under-expressed in all cancer cell lines. Combined with the cluster analysis we were able to clearly distinguish cell lines for normal fibroblasts, breast cancer, prostate cancer, glioblastoma, and lung cancer. CONCLUSION: There is potential utility of screening for lung cancer with miRNA expression profiles. Future work will focus on the sensitivity of such miRNA expression profiles in screening sputum for lung cancer, which can be performed in real time.

Prevalence and prognostic significance of malnutrition in patients with cancers of the head and neck.

BACKGROUND & AIMS: Head and neck cancer (HNC) are at high nutritional risk; however the prevalence and severity of malnutrition in contemporary patients with HNC are unclear. Diagnostic criteria for cancer-associated weight loss grading (WLG) (Grades 0 to 4) [1] have been validated and are recommended in oncology nutrition clinical practice guidelines [2-3]. The aim was to determine the prevalence using WLG in HNC patients and determine the extent to which reduced dietary intake (DI) explained variation of WLG. METHODS: A population-based cohort of HNC patients (N = 1756) in northern Alberta, Canada included consecutive new patients, 2004-2016. At referral to the regional cancer center weight history and DI categories were collected. Multinomial logistic regression (MLR) identified predictors of weight loss (WL) severity. Overall survival (OS) in relation to WL Grade and DI was determined by multivariable Cox proportional hazard. RESULTS: WL was absent in 42.9% and the remainder had Grade 1 (18%), Grade 2 (14.7%), Grade 3 (15.9%) and Grade 4 (8.5%) WL. Independent predictors of WLG in adjusted MLR model, included stage (P < 0.000), performance status (PS) (P < 0.000) and DI categories (P < 0.000); sex, age and disease site were not significant. Compared to "normal food in normal amount" adjusted Odds Ratio for WL Grade 4 was 4.0 (2.1-7.5) "normal food, but less than normal amount"; 25.2 (10.7-59.1) "little solid food"; 51.8 (10.5-255.3) "very little of anything"; 42.4 (11.0-163.0) "only liquids"; 25.9 (7.1-94.3) "only nutritional supplements". In the Cox model controlled for age, sex, cancer stage and site and PS, both WLG ((P < 0.000) and DI categories (P = 0.003) independently predicted OS. CONCLUSION: Data from this population cohort provide a benchmark for prevalence of cancer associated WL severity at diagnosis. Patient reported DI categories are strong predictors of WL and prognostic for OS.

Should Stereotactic Radiosurgery Be Considered for Salvage of Intracranial Recurrence after Prophylactic Cranial Irradiation or Whole Brain Radiotherapy in Small Cell Lung Cancer? A Population-Based Analysis and Literature Review.

BACKGROUND: Prophylactic cranial irradiation (PCI) improves survival and prevents intracranial recurrence (IR) in limited stage (LS) and extensive stage (ES) small cell lung cancer (SCLC). However, despite PCI, IR affects 12%-45%, and limited data exist regarding salvage brain reirradiation (ReRT). We performed a population-based review of IR in SCLC. METHODS: Demographic, treatment, and outcome data of consecutive patients (N = 371) with SCLC assessed at a tertiary cancer centre (01/2013-12/2015) were abstracted, and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed. RESULTS: Median age was 66.1 years, and 59.8% were Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Median survival was 24 months (95% CI 18.3-29.7 months) for LS (N = 103) and 7 months (95% CI 6.1-7.9 months) for ES (N = 268). 72 of 103 patients with LS and 97 of 214 of those with ES received PCI. 54 of 268 ES presented with brain metastases (BM) of whom 46 of 54 received whole brain RT (WBRT). 18.9% (32/169) recurred post-PCI (13 LS; 19 ES) and 30.4% (14/46) recurred after WBRT. Of those who recurred/progressed after cranial RT, 56.5% (26/46) had <5 BM, 39.1% had no extracranial disease, and 50% were ECOG 0-2. In retrospect, 17 of 46 would have been candidates for salvage stereotactic radiosurgery: 13 post-PCI and 4 post-WBRT. CONCLUSIONS: This cohort challenges commonly held beliefs that IR is always diffuse, associated with clinical deterioration, and synchronous with systemic failure. Approximately 1 in 3 SCLC patients with IR after PCI or WBRT appear clinically appropriate for salvage stereotactic radiosurgery.

Functional outcomes of the modified submandibular gland transfer procedure.

OBJECTIVES: Treatment for advanced head and neck cancers typically includes surgery followed by radiation therapy (RT). Radiation-induced xerostomia is a common sequela of these treatments. The modified submandibular gland transfer (M-SGT) procedure was developed to decrease xerostomia in the treatment of oral cavity cancer by sparing one submandibular gland (SMG) from radiation. This study's objectives were to: 1) elucidate the radiation-sparing capacity of the M-SGT, and 2) study the xerostomia-reducing potential of the M-SGT based on the University of Washington Quality-of-Life Questionnaire (UW-QOL). METHODS: Radiation therapy treatment plans were reviewed for all patients treated with surgery and RT who had a M-SGT at the University of Alberta Hospital during the study period. Outcomes included: 1) radiation dose received by the transferred SMG within the periparotid area compared to the submandibular triangle (ST), and 2) patient-reported saliva scores on the UW-QOL compared to historical controls without a gland transfer. RESULTS: Twenty-two patients were included. The mean radiation dose received by the transferred SMG was 29.00 grays (Gy) (standard deviation 14.59 Gy), thus reducing the mean radiation dose to the SMG by a statistically significant 18.34 Gy (confidence interval 95% (13.37, 23.32), P < 0.01) compared to the ST and below the D50 of the SMG (34 Gy). Sixty-five percent of patients rated their saliva as normal or mildly reduced on the UW-QOL as compared to 16% of controls (P = 0.01). CONCLUSION: The M-SGT technique is successful at reducing the radiation dose sustained by the SMG during adjuvant treatment and provides a significant improvement in xerostomia-related functional outcomes as compared to historical controls not receiving a gland transfer. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:925-929, 2020.

Combination of submandibular salivary gland transfer and intensity-modulated radiotherapy to reduce dryness of mouth (xerostomia) in patients with head and neck cancer.

BACKGROUND: Xerostomia is a debilitating side effect of radiotherapy for head and neck cancer. Combining surgical submandibular-gland transfer (SMGT) with intensity-modulated radiotherapy (IMRT) may provide greater protection of salivary function. METHODS: This was a single-institution, prospective phase II feasibility trial. Patients with head and neck cancer or unknown primary with neck node metastases received primary surgery with SMGT and postoperative radiotherapy with tomotherapy (60 Gy in 30 fractions). Toxicity and quality of life (QOL) were assessed before surgery, before RT, and after RT. RESULTS: Forty patients received SMGT and IMRT. Only 1 patient experienced grade 3 salivary gland toxicity. At 12 months post-RT, the rate of absent or only mild xerostomia was 89%, and salivary flow rates were approximately 75% of pre-RT levels. CONCLUSIONS: The combination of IMRT with SMGT is feasible and with improved dose constraints may maximally spare the parotid and submandibular glands, leading to decreased xerostomia and improved patient QOL.

Sparing the parotid glands and surgically transferred submandibular gland with helical tomotherapy in post-operative radiation of head and neck cancer: a planning study.

BACKGROUND AND PURPOSE: To evaluate the feasibility of sparing the parotid glands and surgically transferred submandibular gland (SMG) by intensity modulated radiotherapy (IMRT) in post-operative cases of head and neck cancer (HNC). MATERIALS AND METHODS: Ten patients (larynx-2, base of tongue-4, tonsil-3, and unknown primary-1; pathologic stages III-IV) who underwent SMG transfers on the side of N0 neck along with definitive surgery were selected for this study. IMRT planning was done retrospectively using helical tomotherapy approach. Planning objective was to deliver 60 Gy to PTV1 and 54 Gy to PTV2 while maintaining the mean dose to the total parotid volume (TPV) and SMG less than 26 Gy. RESULTS: The mean dose (+/-SD) to the TPV and SMG were 25+/-0.6 Gy and 23+/-1.9 Gy, respectively. The D(95) for PTV1 and PTV2 were 59.9+/-0.1 Gy and 54.9+/-0.3 Gy, respectively, satisfying our planning goal for PTV coverage. The D(99) for PTV1 and PTV2 were 58.2+/-0.7 Gy and 49.5+/-2.2 Gy, respectively, showing that sparing the salivary glands did not result in underdosing of the PTVs. CONCLUSIONS: By combining the gland transfer and IMRT, the mean dose to TPV and transferred SMG could be reduced to less than 26 Gy in post-operative patients of HNC.

Free thyroid transfer: Short-term results of a novel procedure to prevent post-radiation hypothyroidism.

BACKGROUND: The incidence of radiation-induced hypothyroidism (RIH) in patients with head and neck cancer is >50%. The purpose of this study was to assess the long-term efficacy of free thyroid transfer (FTT) for prevention of RIH in patients with head and neck cancer. METHODS: Hemithyroid dissection was completed in 10 patients with advanced head and neck cancer undergoing ablation, radial forearm free flap (RFFF) reconstruction, and postoperative radiotherapy (RT). The hemithyroid was anastomosed to the donor site vessels in the forearm. Thyroid laboratory testing and technetium (Tc) scans were performed 6 weeks and 12 months postoperatively to establish functional integrity. RESULTS: FTT was successfully performed in 9 of 10 recruited patients. Postoperative Tc scans demonstrated strong Tc uptake in the forearm donor site at 6 weeks and 12 months in all patients who underwent transplantations. CONCLUSION: FTT is feasible with maintenance of function, and may represent a novel strategy for prevention of RIH. © 2016 Elsevier Head & Neck Published by Wiley Periodicals, Inc. Head Neck 39: 1234-1238, 2017.

Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer.

PURPOSE: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. METHODS AND MATERIALS: Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). RESULTS: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. CONCLUSIONS: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

Free Thyroid Transfer: A Novel Procedure to Prevent Radiation-induced Hypothyroidism.

PURPOSE: The incidence of hypothyroidism after radiation therapy for head and neck cancer (HNC) has been found to be ≤53%. Medical treatment of hypothyroidism can be costly and difficult to titrate. The aim of the present study was to assess the feasibility of free thyroid transfer as a strategy for the prevention of radiation-induced damage to the thyroid gland during radiation therapy for HNC. METHODS AND MATERIALS: A prospective feasibility study was performed involving 10 patients with a new diagnosis of advanced HNC undergoing ablative surgery, radial forearm free-tissue transfer reconstruction, and postoperative adjuvant radiation therapy. During the neck dissection, hemithyroid dissection was completed with preservation of the thyroid arterial and venous supply for implantation into the donor forearm site. All patients underwent a diagnostic thyroid technetium scan 6 weeks and 12 months postoperatively to examine the functional integrity of the transferred thyroid tissue. RESULTS: Free thyroid transfer was executed in 9 of the 10 recruited patients with advanced HNC. The postoperative technetium scans demonstrated strong uptake of technetium at the forearm donor site at 6 weeks and 12 months for all 9 of the transplanted patients. CONCLUSIONS: The thyroid gland can be transferred as a microvascular free transfer with maintenance of function. This technique could represent a novel strategy for maintenance of thyroid function after head and neck irradiation.

Survival Outcomes and Patterns of Recurrence in Patients with Stage III or IV Oropharyngeal Cancer Treated with Primary Surgery or Radiotherapy.

PURPOSE: To compare and contrast the patterns of failure in patients with locally advanced squamous cell oropharyngeal cancers undergoing curative-intent treatment with primary surgery or radiotherapy +/- chemotherapy. METHODS AND MATERIALS: Two hundred and thirty-three patients with stage III or IV oropharyngeal squamous cell carcinoma who underwent curative-intent treatment from 2006-2012, were reviewed. The median length of follow-up for patients still alive at the time of analysis was 4.4 years. Data was collected retrospectively from a chart review. RESULTS: One hundred and thirty-nine patients underwent primary surgery +/- adjuvant therapy, and 94 patients underwent primary radiotherapy +/- chemotherapy (CRT). Demographics were similar between the two groups, except primary radiotherapy patients had a higher age-adjusted Charleston co-morbidity score (CCI). Twenty-nine patients from the surgery group recurred; 15 failed distantly only, seven failed locoregionally, and seven failed both distantly and locoregionally. Twelve patients recurred who underwent chemoradiotherapy; ten distantly alone, and two locoregionally. One patient who underwent radiotherapy (RT) alone failed distantly. Two and five-year recurrence-free survival rates for patients undergoing primary RT were 86.6% and 84.9% respectively. Two and five-year recurrence-free survival rates for primary surgery was 80.9% and 76.3% respectively (p=0.21). There was no significant difference in either treatment when they were stratified by p16 status or smoking status. CONCLUSIONS: Our analysis does not show any difference in outcomes for patients treated with primary surgery or radiotherapy. Although the primary pattern of failure in both groups was distant metastatic disease, some local failures may be preventable with careful delineation of target volumes, especially near the base of skull region.

Modification of the submandibular gland transfer procedure.

OBJECTIVES/HYPOTHESIS: The treatment for most advanced head and neck cancers (stage III and IV) usually includes radiation, and the most common side effect of this treatment modality is a permanent decrease in salivary production. Xerostomia is a devastating complication that significantly affects patients' quality of life by interfering with functions of taste, mastication, deglutition, and speech production. Treatment of xerostomia is varied, but one of the strategies developed by our group was to preserve one submandibular gland by surgically transferring it to the submental space and shielding it from the full dose of radiation. This procedure is proven to reduce the rate of radiation-induced xerostomia, but its main disadvantage is that it is contraindicated in oral cavity cancer. This study describes and evaluates a modification of the submandibular gland transfer (SGT) procedure, where the submandibular gland contralateral to the disease process is relocated to the parotid region. This modification has the potential of expanding the benefits of submandibular gland transfer procedures to patients with oral cavity cancers. STUDY DESIGN: Prospective feasibility study. METHODS: This study involved nine patients with a new diagnosis of advanced head and neck cancer undergoing major head and neck cancer resection with postoperative adjuvant radiation therapy. The new modified salivary gland transfer procedure was performed on all nine patients, and the glands total dose received with radiation therapy was assessed. RESULTS: All the modified SGT procedures were successful with no post-operative complications. The radiation oncology team has been able to successfully localize the transferred submandibular glands and shield them from the radiation beam postoperatively. CONCLUSIONS: We have successfully demonstrated that surgical transfer of a submandibular salivary gland to the parotid region is feasible, surgically viable, oncologically sound, and does not interfere with radiation therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2492-2496, 2016.

Comparing step-and-shoot IMRT with dynamic helical tomotherapy IMRT plans for head-and-neck cancer.

PURPOSE: The goal of this planning study was to compare step-and-shoot intensity-modulated radiotherapy (IMRT) plans with helical dynamic IMRT plans for oropharynx patients on the basis of dose distribution. METHODS AND MATERIALS: Five patients with oropharynx cancer had been previously treated by step-and-shoot IMRT at the University Medical Centre Utrecht, The Netherlands, applying five fields and approximately 60-90 segments. Inverse planning was carried out using Plato, version 2.6.2. For each patient, an inverse IMRT plan was also made using Tomotherapy Hi-Art System, version 2.0, and using the same targets and optimization goals. Statistical analysis was performed by a paired t test. RESULTS: All tomotherapy plans compared favorably with the step-and-shoot plans regarding sparing of the organs at risk and keeping an equivalent target dose homogeneity. Tomotherapy plans in particular realized sharper dose gradients compared with the step-and-shoot plans. The mean dose to all parotid glands (n = 10) decreased on average 6.5 Gy (range, -4 to 14; p = 0.002). The theoretical reduction in normal tissue complication probabilities in favor of the tomotherapy plans depended on the parotid normal tissue complication probability model used (range, -3% to 32%). CONCLUSION: Helical tomotherapy IMRT plans realized sharper dose gradients compared with the clinically applied step-and shoot plans. They are expected to be able to reduce the parotid normal tissue complication probability further, keeping a similar target dose homogeneity.

A planning comparison of 3-dimensional conformal multiple static field, conformal arc, and volumetric modulated arc therapy for the delivery of stereotactic body radiotherapy for early stage lung cancer.

The primary objective of this study was to compare dosimetric variables as well as treatment times of multiple static fields (MSFs), conformal arcs (CAs), and volumetric modulated arc therapy (VMAT) techniques for the treatment of early stage lung cancer using stereotactic body radiotherapy (SBRT). Treatments of 23 patients previously treated with MSF of 48Gy to 95% of the planning target volume (PTV) in 4 fractions were replanned using CA and VMAT techniques. Dosimetric parameters of the Radiation Therapy Oncology Group (RTOG) 0915 trial were evaluated, along with the van׳t Riet conformation number (CN), monitor units (MUs), and actual and calculated treatment times. Paired t-tests for noninferiority were used to compare the 3 techniques. CA had significant dosimetric improvements over MSF for the ratio of the prescription isodose volume to PTV (R100%, p < 0.0001), the maximum dose 2cm away from the PTV (D2cm, p = 0.005), and van׳t Riet CN (p < 0.0001). CA was not statistically inferior to MSF for the 50% prescription isodose volume to PTV (R50%, p = 0.05). VMAT was significantly better than CA for R100% (p < 0.0001), R50% (p < 0.0001), D2cm (p = 0.006), and CN (p < 0.0001). CA plans had significantly shorter treatment times than those of VMAT (p < 0.0001). Both CA and VMAT planning showed significant dosimetric improvements and shorter treatment times over those of MSF. VMAT showed the most favorable dosimetry of all 3 techniques; however, the dosimetric effect of tumor motion was not evaluated. CA plans were significantly faster to treat, and minimize the interplay of tumor motion and dynamic multileaf collimator (MLC) motion effects. Given these results, CA has become the treatment technique of choice at our facility.

Phenomenologic model describing flow reduction for parotid gland irradiation with intensity-modulated radiotherapy: evidence of significant recovery effect.

OBJECTIVE: To develop a model describing the relationship between the parotid gland radiation dose and salivary flow reduction. Salivary function was described by the "relative flow reduction" (RFR)-a continuous variable in contrast to the traditional binary response used in normal tissue complication probability estimations. METHODS AND MATERIALS: Twenty-three patients with squamous cell carcinoma of the head and neck who were treated with intensity-modulated radiotherapy (RT) were the subject of this study. Of these patients, 19 had sufficiently long follow-up to be eligible for analysis. All were treated with curative intent, most (14 of 19) in the postoperative setting. The planning objectives were to deliver a mean dose of 50, 60, or 70 Gy, respectively, to low-risk microscopic, high-risk microscopic, and gross disease areas, while maintaining a mean dose of < or =20 Gy to the spared portion of one or both parotid glands. The mean dose to all parotid glands (right and left) was 30.2 Gy. All submandibular glands received >50 Gy when not surgically removed. Whole-mouth saliva collections, including both stimulated and unstimulated saliva flow, were obtained before treatment and at regular intervals after RT. These measurements were converted to the RFR by comparing the posttreatment and pretreatment flow rates. Any follow-up flow rates greater than baseline were scored as 0 relative reduction. We used Lyman's model to relate the equivalent uniform dose to RFR at various points for each patient. The equivalent uniform dose was calculated using the linear quadratic model, with an assumed alpha/beta ratio of 3 Gy for the parotid gland. Measurements were modeled 1-3 months after RT (early) and >6 months after RT (late), and using the best and worst measurements, regardless of when measured. RESULTS: Fitting the Lyman model to RFR data of unstimulated flow revealed a statistically significant dose-complication relationship. We observed a stepwise reduction in flow, with the threshold dose D(50) at 2 Gy per fraction (D(50)) increasing from 12.4 Gy (early) to 43.9 Gy (late). For the worst and best flow measurements, the corresponding D(50) (2 Gy/fr) was 13.0 Gy and 40.1 Gy, respectively. For most stimulated flow measurements, a weak relationship was found between the RFR and equivalent uniform dose. In those cases, the model did not yield a statistically significant description of the data. However, in the case of late measurements, the relationship was statistically significant and similar to that seen in the unstimulated cases, with a D(50) (2 Gy/fr) of 47.5 Gy. CONCLUSION: We observed a strong relationship between the generalized mean parotid gland dose and RFR. The threshold dose increased markedly between the early and late measurements, indicating a statistically significant recovery effect in this tissue. Compared with unstimulated flow, the RFR for stimulated flow was not described as well by the model, because the effect of the stimulant was not included in the model.

Preservation of oral health-related quality of life and salivary flow rates after inverse-planned intensity- modulated radiotherapy (IMRT) for head-and-neck cancer.

PURPOSE: To assess whether comprehensive bilateral neck intensity-modulated radiotherapy (IMRT) for head-and-neck cancer results in preserving of oral health-related quality of life and sparing of salivary flow in the first year after therapy. METHODS AND MATERIALS: Twenty-three patients with head-and-neck cancer (primary sites: nasopharynx [5], oral cavity [12], oropharynx [3], and all others [3]) were accrued to a Phase I-II trial. Inverse planning was carried out with the following treatment goals: at least 1 spared parotid gland (defined as the volume of parotid gland outside the planning target volume [PTV]) to receive a median dose of less than 20 Gy; spinal cord, maximum 45 Gy; PTV(1) to receive a median dose of 50 Gy; PTV(2) to receive a median dose of 60 Gy (postoperative setting, n = 15) or 66-70 Gy (definitive radiotherapy setting, n = 8). Treatment was delivered with 6 and 15 MV photons using a "step-and-shoot" technique on a Varian 2300 EX linac with 120-leaf Millenium MLC. Unstimulated and stimulated whole-mouth salivary flow rates were measured, and patients completed the University of Washington instrument (UWQOL) and a separate xerostomia questionnaire (XQOL) in follow-up. RESULTS: Early functional outcome end point data are available at the 1-, 3-, and 12-month follow-up time points for 22, 22, and 18 patients, respectively. The combined mean parotid dose was 30.0 Gy (95% confidence interval: 26.9-33.1). The differences from baseline in mean overall UWQOL scores at 1, 3, and 12 months postradiotherapy were -0.24, 0.32, and 4.28, not significantly different from zero (p = 0.89, p = 0.87, p = 0.13). None of the UWQOL individual domain scores related to oral health (pain, eating-chewing, eating-swallowing, and speech) at 1, 3, or 12 months were significantly different from baseline. Both unstimulated and stimulated whole-mouth flow was variably preserved. Unstimulated salivary flow at 1 and 12 months was inversely correlated with combined mean parotid dose (p = 0.014, p = 0.0007), whereas stimulated salivary flow rates at 3 and 12 months were also correlated with combined mean parotid dose (p = 0.025, p = 0.0016). Combined maximum parotid dose was correlated with unstimulated flow rate at 12 months (p = 0.02, r = -0.56) and stimulated flow rate at 1 and 12 months (p = 0.036, r = -0.45; p = 0.0042, r = -0.66). The proportion of patients reporting total XQOL scores of 0 or 1 (no or mild xerostomia) did not diminish significantly from baseline at 1, 3, or 12 months (p = 0.72, p = 0.51, p = 1.0). Unstimulated and stimulated flow at 1 month was inversely correlated with total XQOL score at 12 months (p = 0.025, p = 0.029). CONCLUSIONS: Oral health-related quality of life (HRQOL) was highly preserved in the initial 12 months after IMRT, as assessed with separate, validated instruments for xerostomia-specific quality of life and oral HRQOL. In general, patients with better-preserved unstimulated salivary flow rates tended to report lower xerostomia scores. Whole-mouth salivary flow rates post IMRT were inversely correlated with combined mean parotid doses. Longer follow-up is required to assess to what extent HRQOL is favorably maintained.

Reduction in radiation dose to lung and other normal tissues using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements.

The purpose of this study was to determine whether the use of tomotherapy in the treatment of non-small-cell lung cancer (NSCLC) has the potential to reduce radiation dose to normal tissues, in particular, the lungs, esophagus, and spinal cord, as compared with standard radiotherapy. Five patients with anatomically or physiologically inoperable stage III NSCLC were studied, representing a variety of tumor sizes and locations. For each patient, two treatment plans were generated. One was developed using conventional field arrangements (CFA), and the other for tomotherapy. Using dose-volume histogram reduction techniques, including mean normalized dose (NTDmean), V20, and effective uniform dose (EUD), the normal tissue doses for CFA and tomotherapy plans for a given fixed tumor dose were compared. In addition, the maximum tumor doses possible for a given level of mean normalized lung dose were computed and compared for the CFA and tomotherapy plans. The gross tumor volumes in the five patients studied ranged from 13.5 to 87.1 cm. The tumor dose distributions, determined by EUD and minimum dose, were similar for both CFA and tomotherapy plans, as intended. In all cases, the NTDmean of both lungs was significantly reduced using tomotherapy planning (range: 10-53% reduction, mean: 31%). The volume of lung receiving more than 20 Gy was also reduced in all cases using tomotherapy (range: 17-37% reduction, mean: 22%). For a constant lung NTDmean, it is shown that it should be possible to increase tumor dose to up to 160 Gy in certain patients with tomotherapy. The dose to the spinal cord and esophagus was also reduced in all cases with tomotherapy planning, compared with plans generated using conventional field arrangements. Both tomotherapy, and to a lesser extent conventional three-dimensional conformal radiotherapy, have the potential to significantly decrease radiation dose to lung and other normal structures in the treatment of NSCLC. This has important implications for dose escalation strategies in the future.