Submandibular gland sparing in intensity-modulated radiotherapy for N0-stage nasopharyngeal carcinoma

Objective:

This study evaluated and quantified the feasibility of submandibular gland (SMG) sparing in intensity-modulated radiotherapy (IMRT) for N0-stage nasopharyngeal carcinoma (NPC).

Methods:

Ten patients with N0-stage NPC were enrolled in the study. Four IMRT plans were produced for each, with different limiting conditions. In plan A, SMG sparing was ignored; in plans B, C and D, the mean dose to SMGs was restricted to 39 Gy. In addition, at least 95% of planning target volume (PTV)-IIa (PTV of clinical target volume involving level IIa lymph node) in plan C and 90% of PTV-IIa in plan D were required to have a 60 Gy covering.

Results:

The average mean dose to SMGs was 54.6 ± 3.6 Gy in plan A and was lower 39.3 ± 0.3, 49.3 ± 1.9 and 46.7 ± 2.8 Gy in plans B, C and D, respectively. The volume of PTV-IIa covered by 60 Gy was 98.9%, 81.6%, 95.2% and 90.8% in plans A, B, C and D, respectively, and showed a parallel association between dose reduction to SMGs and the covering deficit of PTV-IIa.

Conclusion:

Reducing the mean dose received by SMG to 39 Gy or less in IMRT for N0-stage NPC is feasible.Xerostomia is the most prevalent sequela following radiotherapy of nasopharyngeal carcinoma (NPC),¹ but can be reduced by parotid gland sparing using intensity-modulated radiotherapy (IMRT) techniques. In recent years, the submandibular gland (SMG) was found to play an important role in the secretion of saliva,^2,3 contributing up to 90% of unstimulated salivary output as well as contributing to a patient''s subjective sense of moisture. Therefore, sparing the SMGs from high-dose irradiation would be useful in reducing the symptoms of xerostomia.SMGs are located inside the area of neck node level Ib and anterior to the level II region. Level II neck nodes are generally elected to receive prophylactic irradiation. It has been reported that with three-dimensional conformal radiotherapy for head and neck cancers,⁴ the SMGs would receive an unplanned dose of 62 Gy on average. Preservation of SMG function was reported for head and neck cancer treated with IMRT.^5–7 However, data from our institution showed that the average unplanned dose received by SMGs was 58 Gy in IMRT of N0-stage NPC, although level I neck nodes were omitted for selected irradiations.To our knowledge, the abovementioned studies focused only on the contralateral SMG (cSMG).^5–7 However, is it possible to spare the bilateral SMGs in N0-stage NPC patients but what will be the subsequent trade-off of dose distribution to planning target volume 1 (PTV1) around the SMG area? This study was designed to address this question, and the results will be a valuable reference in planning the IMRT of NPC.     

Simultaneously modulated accelerated radiation therapy reduces severe oesophageal toxicity in concomitant chemoradiotherapy of locally advanced non-small-cell lung cancer

Objective:

The aim of this study was to evaluate the potential of simultaneously modulated accelerated radiation therapy (SMART) to reduce the incidence of severe acute oesophagitis in the treatment of unresectable locally advanced non-small-cell lung cancer (LANSCLC).

Methods:

21 patients were treated with SMART and concomitant platinum-based chemotherapy. The prescribed doses were limited to 54 Gy at 1.8 Gy per day to the zones of presumed microscopic extent while simultaneously maintaining doses of 66 Gy at 2.2 Gy per day to the macroscopic disease. The whole treatment was delivered over 30 fractions and 6 weeks. Dosimetric parameters of SMART and the standard technique of irradiation [intensity-modulated radiation therapy (IMRT)] were compared. Acute toxicity was prospectively recorded.

Results:

The highest grade of oesophagitis was 62% (13 patients) grade 1, 33% (7 patients) grade 2 and 5% (1 patient) grade 3. Three (14%) patients experienced acute grade 2 pneumonitis. There was no grade 4 oesophageal or pulmonary toxicity. Doses to the organs at risk were significantly reduced in SMART compared with IMRT [oesophagus: V_50Gy, 28.5 Gy vs 39.9 Gy (p = 0.003); V_60Gy, 7.1 Gy vs 30.7 Gy (p = 0.003); lung: V_20Gy, 27.4 Gy vs 30.1 Gy (p = 0,002); heart: V_40Gy, 7.3 Gy vs 10.7 Gy (p = 0.006); spine: D_max, 42.4 Gy vs 46.4 Gy (p = 0.003)]. With a median follow-up of 18 months (6–33 months), the 1-year local control rate was 70% and the disease-free survival rate was 47%.

Conclusion:

SMART reduces the incidence of severe oesophagitis and improves the whole dosimetric predictors of toxicity for the lung, heart and spine.

Advances in knowledge:

Our study shows that SMART optimizes the therapeutic ratio in the treatment of LANSCLC, opening a window for dose intensification.     

Vaginal displacement during course of adjuvant radiation for cervical cancer: results from a prospective IG-IMRT study

Objective:

To compare internal target volume (ITV) generated using population-based displacements (ITV_study) with empty and full bladder scan fusion (ITV_EBFB) for organ-at-risk (OAR) doses during adjuvant intensity-modulated radiation therapy (IMRT) for cervical cancer.

Methods:

From January 2011 to October 2012, patients undergoing IMRT were included. CT simulation was carried out after inserting vault markers. Planning target volume (PTV)_EBFB received 50 Gy per 25 fractions. Pre-treatment megavoltage CT (MVCT) was performed. MVCTs were registered using bony landmarks with Day 1 MVCT. Displacement of the centre of mass of markers was measured along each axis. Directional ITV was calculated using mean ± 2 standard deviations (SDs) (ITV_study). Replanning was performed using PTV study, and OAR doses were compared with PTV_EBFB using Wilcoxon test.

Results:

A total of 348/386 data sets were evaluable for 16 patients. The median vaginal displacement was 1.2 mm (SD, 1.3 mm), 4.0 mm (SD, 3.5 mm) and 2.8 mm (SD, 3.3 mm) in the mediolateral, superoinferior and anteroposterior directions, respectively. The ITV margins were 4.1, 10.3 and 10.6 mm. ITV_study and ITV_EBFB were 115.2 cm³ (87.7–152.2 cm³) and 151 cm³ (95.7–277.1 cm³) (p < 0.0001), respectively. PTV_study and PTV_EBFB were 814 and 881 cm³ (p < 0.0001), respectively. Median doses to the bladder were lower with the PTV_study (46.2 Gy vs 43.2 Gy; p = 0.0001), and a similar trend was observed in the volume of the small bowel receiving 40 Gy (68.2 vs 60.1 cm³; p = 0.09).

Conclusion:

Population-based PTV margins can lead to reduction in OAR doses.

Advances in knowledge:

Population-based ITV may reduce OAR doses while executing adjuvant IMRT for cervical cancer.Adjuvant pelvic radiation for cervical and endometrial cancers is recommended in patients with adverse histopathological features following surgery.^1,2 Although it improves outcomes, it is associated with increased acute and late bowel morbidity.^1,2 Recently published results of the Radiation Therapy Oncology Group (RTOG) Phase II study demonstrate that the use of pelvic intensity-modulated radiation therapy (IMRT) is associated with reduced treatment-related acute and short-term gastrointestinal (GI) toxicity, and this can be achieved without worsening disease control.³ However, implementing IMRT may be challenging owing to the unpredictable nature of vaginal displacements during the course of external radiation. Therefore, the RTOG recommends that for planning IMRT, both empty and full bladder (EBFB) scans should be obtained for localizing residual vagina and for generating the internal target volume (ITV).⁴ These recommendations are being followed by two ongoing Phase III randomized controlled trials that aim at reducing acute and late bowel toxicity of adjuvant pelvic radiation.^5,6 Although this strategy may ensure that all extreme displacements arising out of variations in bladder filling are accounted for, this may result in increased planning target volume (PTV) and thereby increased dose to adjacent organs at risk (OAR). Strong correlation has been reported between the dose received by the bowel and late bowel morbidity after adjuvant pelvic radiation for cervical cancer.⁷ The present study was initiated with an aim of evaluating vaginal displacement for the post-hysterectomy cohort and to investigate if population-based ITV could reduce dose to OARs.     

Parametrized rectal dose and associations with late toxicity in prostate cancer radiotherapy

Objective:

We investigated possible associations between planned dose–volume parameters and rectal late toxicity in 170 patients having radical prostate cancer radiotherapy.

Methods:

For each patient, the rectum was outlined from anorectal junction to sigmoid colon, and rectal dose was parametrized using dose–volume (DVH), dose–surface (DSH) and dose–line (DLH) histograms. Generation of DLHs differed from previous studies in that the rectal dose was parametrized without first unwrapping onto 2-dimensional dose–surface maps. Patient-reported outcomes were collected using a validated Later Effects in Normal Tissues Subjective, Objective, Management and Analytic questionnaire. Associations between dose and toxicity were assessed using a one-sided Mann–Whitney U test.

Results:

Associations (p < 0.05) were found between equieffective dose (EQD2₃) and late toxicity as follows: overall toxicity with DVH and DSH at 13–24 Gy; proctitis with DVH and DSH at 25–36 Gy and with DVH, DSH and DLH at 61–67 Gy; bowel urgency with DVH and DSH at 10–20 Gy. None of these associations met statistical significance following the application of a Bonferroni correction.

Conclusion:

Independently confirmed associations between rectal dose and late toxicity remain elusive. Future work to increase the accuracy of the knowledge of the rectal dose, either by accounting for interfraction and intrafraction rectal motion or via stabilization of the rectum during treatment, may be necessary to allow for improved dose–toxicity comparisons.

Advances in knowledge:

This study is the first to use parametrized DLHs to study associations with patient-reported toxicity for prostate radiotherapy showing that it is feasible to model rectal dose mapping in three dimensions.     

Intensity-modulated radiotherapy increases dose to the brachial plexus compared with conventional radiotherapy for head and neck cancer

Objective

The preferential use of intensity-modulated radiotherapy (IMRT) over conventional radiotherapy (CRT) in the treatment of head and neck cancer has raised concerns regarding dose to non-target tissue. The purpose of this study was to compare dose-volume characteristics with the brachial plexus between treatment plans generated by IMRT and CRT using several common treatment scenarios.

Method

The brachial plexus was delineated on radiation treatment planning CT scans from 10 patients undergoing IMRT for locally advanced head and neck cancer using a Radiation Therapy Oncology Group-endorsed atlas. No brachial plexus constraint was used. For each patient, a conventional three-g0ield shrinking-g0ield plan was generated and the dose-volume histogram (DVH) for the brachial plexus was compared with that of the IMRT plan.

Results

The mean irradiated volumes of the brachial plexus using the IMRT vs the CRT plan, respectively, were as follows: V50 (18±5 ml) vs (11±6 ml), p = 0.01; V60 (6±4 ml) vs (3±3 ml), p = 0.02; V66 (3±1 ml) vs (1±1 ml), p = 0.04, V70 (0±1 ml) vs (0±1 ml), p = 0.68. The maximum point dose to the brachial plexus was 68.9 Gy (range 62.3–78.7 Gy) and 66.1 Gy (range 60.2–75.6 Gy) for the IMRT and CRT plans, respectively (p = 0.01).

Conclusion

Dose to the brachial plexus is significantly increased among patients undergoing IMRT compared with CRT for head and neck cancer. Preliminary studies on brachial plexus-sparing IMRT are in progress.Although intensity-modulated radiotherapy (IMRT) is widely considered the current standard in the radiotherapeutic management of head and neck cancer, investigators are increasingly recognising that this technology is associated with significant beam path doses to non-target structures that previously received little dose using previous, less conformal techniques [1]. Indeed, since the clinical implementation of IMRT at our institution, we have observed a striking number of patients returning for follow-up with symptoms thought to be related to radiation-induced brachial plexopathy. The purpose of this study was to compare dose-volume characteristics to the brachial plexus between treatment plans generated by IMRT and conventional radiotherapy (CRT) using several common head and neck cancer treatment scenarios.     

Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI

Objective:

Pelvic radiation therapy (RT) can influence fertility in female rectal cancer survivors. Data regarding its effects on the adult uterus are scant. This study aims to evaluate the uterus before and after RT, using dynamic contrast-enhanced MRI.

Methods:

Eligible patients (n=10) received RT for rectal cancer, had an intact uterus and underwent dynamic contrast-enhanced MRI before and after RT. Seven patients were pre-menopausal.

Results:

Patients received pelvic RT (median, 50.2 Gy) with concurrent 5-fluorouracil. Five patients were treated with intensity modulated RT (IMRT) and five with a three-field technique. The median D95 of the uterus was 30 Gy; D05 was 48 Gy; and V95 was 97%. The median cervical D95 was 45 Gy; D05, 50 Gy; and V95, 100%. Cervical dose was higher with IMRT than with three-field plans (p≤0.038). On T₂ MRI, the junctional zone was visible in nine patients before and in one after RT (p=0.001). Median cervical length (2.3 vs 3.0 cm) and endometrial thickness (2.6 vs 5.9 mm) were reduced after RT (p≤0.008). In pre-menopausal patients, the volume transfer constant, K_trans, (0.069 vs 0.195, p=0.006) and the extracellular extravascular volume fraction, V_e, (0.217 vs 0.520, p=0.053) decreased.

Conclusion:

Pelvic RT significantly affected uterine anatomy and perfusion. Cervical dose was higher with IMRT than three-field plans, but no attempt was made to constrain the dose.

Advances in knowledge:

Pelvic RT significantly affects the adult uterus. These findings are crucial to understand the potential consequences of RT on fertility, and they lay the groundwork for further prospective studies.As the cure rate in locally advanced rectal cancer continues to improve, understanding the long-term sequelae of therapy is gaining importance. Research has shown that young cancer survivors are concerned about treatment-related effects on fertility, pregnancy and neonatal outcomes [1,2]. Previously, pelvic irradiation, standard in the management of locally advanced rectal cancer, invariably caused sterility in females as a result of acute ovarian failure. Currently, however, the risk of ovarian dysfunction may be greatly reduced by transposing the ovaries to the paracolic gutters before radiation therapy (RT) [3]. Additionally, an increasing number of females undergo embryo or oocyte cryopreservation before receiving RT [4]. These advances prompt the question: if a young female has undergone pelvic RT, can she carry a pregnancy to term?Answering this question requires an understanding of the effects of the pelvic RT on the uterus. Ultrasounds of paediatric cancer survivors suggest that pelvic RT alters uterine volume, distensibility and vasculature, with patients who are younger at the time of RT being the most vulnerable to these effects [5–7]. Additionally, population-based studies of paediatric cancer survivors have demonstrated an association between abdominal and/or pelvic RT and adverse pregnancy and neonatal outcomes, including placental abnormalities, pre-term delivery, low birth weight infants and perinatal mortality [8–11]. However, only sparse data exist regarding the effects of pelvic RT on the adult uterus, which may be more radioresistant.The aim of this study was to use dynamic contrast-enhanced (DCE) MRI to assess the acute effects of RT on the uterus in females treated for locally advanced rectal cancer. A second aim was to compare dosimetric parameters of conventional three-field RT and intensity modulated RT (IMRT) treatment plans.     

SmartArc-based volumetric modulated arc therapy can improve the middle ear,vestibule and cochlea sparing for locoregionally advanced nasopharyngeal carcinoma: a dosimetric comparison with step-and-shoot intensity-modulated radiotherapy

Objective:

Radiation-induced sensorineural hearing loss is a common complication after radiotherapy in patients with nasopharyngeal carcinoma (NPC) that significantly affects their quality of life. The goal of this study was to compare SmartArc-based volumetric modulated arc therapy (VMAT-S) with step-and-shoot intensity-modulated radiation therapy (IMRT) for patients with locoregionally advanced NPC with regard to the sparing effect on middle ear, vestibule and cochlea.

Methods:

20 patients with non-metastatic Stage III or IV NPC were selected to have planning with VMAT-S and IMRT [using Philips Pinnacle Planning System (Philips, Fitchburg, WI) for Varian accelerator] for dosimetric comparison. Mean middle ears, vestibule and cochlea doses for the two planning techniques were compared using a paired t-test. Target coverage and dose homogeneity were evaluated by calculating conformity index (CI) and homogeneity index (HI) values.

Results:

VMAT-S had significantly improved homogeneity and conformity compared with IMRT. Mean HI of planning target volume of gross tumour volume (PGTV) was better with VMAT-S (1.05 ± 0.02) than IMRT (1.09 ± 0.03) (p < 0.001). Mean CI of PGTV is also better with VMAT-S (0.59 ± 0.12) than IMRT (0.54 ± 0.12) (p < 0.001). Mean doses to the left cochleas were 43.8 ± 3.6 and 47.8 ± 4.0 (p < 0.001) for VMAT-S and IMRT plans, respectively. Mean doses to the right cochleas were 42.7 ± 4.7 and 47.6 ± 5.4 (p < 0.001) for VMAT-S and IMRT plans, respectively. VMAT-S also significantly reduced the mean doses to middle ears (p < 0.001 for both) and vestibule (p < 0.001 for both).

Conclusion:

Our results indicate that VMAT-S provides better sparing of hearing apparatus in locoregionally advanced NPC.

Advances in knowledge:

VMAT-S can improve the middle ear, vestibule and cochlea sparing in patients with locoregionally advanced NPC.     

Effect on therapeutic ratio of planning a boosted radiotherapy dose to the dominant intraprostatic tumour lesion within the prostate based on multifunctional MR parameters

Objective:

To demonstrate the feasibility of an 8-Gy focal radiation boost to a dominant intraprostatic lesion (DIL), identified using multiparametric MRI (mpMRI), and to assess the potential outcome compared with a uniform 74-Gy prostate dose.

Methods:

The DIL location was predicted in 23 patients using a histopathologically verified model combining diffusion-weighted imaging, dynamic contrast-enhanced imaging, T₂ maps and three-dimensional MR spectroscopic imaging. The DIL defined prior to neoadjuvant hormone downregulation was firstly registered to MRI-acquired post-hormone therapy and subsequently to CT radiotherapy scans. Intensity-modulated radiotherapy (IMRT) treatment was planned for an 8-Gy focal boost with 74-Gy dose to the remaining prostate. Areas under the dose–volume histograms (DVHs) for prostate, bladder and rectum, the tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) were compared with those of the uniform 74-Gy IMRT plan.

Results:

Deliverable IMRT plans were feasible for all patients with identifiable DILs (20/23). Areas under the DVHs were increased for the prostate (75.1 ± 0.6 vs 72.7 ± 0.3 Gy; p < 0.001) and decreased for the rectum (38.2 ± 2.5 vs 43.5 ± 2.5 Gy; p < 0.001) and the bladder (29.1 ± 9.0 vs 36.9 ± 9.3 Gy; p < 0.001) for the boosted plan. The prostate TCP was increased (80.1 ± 1.3 vs 75.3 ± 0.9 Gy; p < 0.001) and rectal NTCP lowered (3.84 ± 3.65 vs 9.70 ± 5.68 Gy; p = 0.04) in the boosted plan. The bladder NTCP was negligible for both plans.

Conclusion:

Delivery of a focal boost to an mpMRI-defined DIL is feasible, and significant increases in TCP and therapeutic ratio were found.

Advances in knowledge:

The delivery of a focal boost to an mpMRI-defined DIL demonstrates statistically significant increases in TCP and therapeutic ratio.Phase III trials using conformal external beam radiotherapy have shown that a dose escalation improves biochemical progression-free survival in patients with prostate cancer;^1–5 however, increases in late rectal and urinary morbidity are associated with the dose distributions used to achieve these gains.With the advent of intensity-modulated radiotherapy (IMRT), complex three-dimensional (3D) dose distributions can be delivered to areas of disease whilst reducing the dose to the surrounding tissues and also potentially boosting the dose to encompassed small volumes such as the dominant intraprostatic lesions (DILs). This is potentially advantageous, as local recurrence has been shown to originate within the initial tumour volume.⁶This approach requires reliable and reproducible imaging to identify the DIL. Conventional MR using high spatial resolution T₂ weighted (T2W) contrast has insufficient sensitivity and specificity for defining the tumour within the prostate gland, especially if the lesions are <1 cm in diameter.⁷ A combination of MRI methods whose contrast is determined by tissue physiology and biochemistry rather than anatomy offers improved sensitivity and specificity for delineation of prostate cancers. Functional methods include diffusion-weighted imaging, MR spectroscopic imaging (MRSI) and dynamic contrast-enhanced MRI (DCE-MRI) and together present a multiparametric MRI (mpMRI) data set. We have previously validated a multiparametric model to identify prostate cancer and the location of DILs with histology from prostatectomy specimens.⁸mpMRI data are reliable only if acquired before androgen deprivation (hormone) therapy, as there is profound functional signal degradation after hormone therapy.^9–11 Our standard institutional practice for intermediate- and high-risk localized prostate cancer uses hormone therapy for 3–6 months prior to external beam radiotherapy,^12–14 so modelling a radiation boost to mpMRI-defined tumour nodules requires acquisition of functional data before hormone therapy to be registered with anatomical images obtained post hormone treatment and immediately prior to radiotherapy¹⁵ in order to translate the tumour location to radiotherapy planning CT images. The aim of this planning study therefore was to demonstrate the use of a mpMRI-defined DIL to create a radiotherapy boost volume. IMRT treatment plans were optimized to deliver either a uniform 74 Gy to the whole prostate or to add an 8-Gy simultaneous integrated boost to the DIL, and the potential clinical outcomes compared using dose–volume histograms (DVHs) and radiobiological models for tumour control probability (TCP) and normal tissue complication probabilities (NTCPs).     

Stereotactic body radiation therapy for a new lung cancer arising after pneumonectomy: dosimetric evaluation and pulmonary toxicity

Objective:

To evaluate the tolerance of stereotactic body radiation therapy (SBRT) for the treatment of secondary lung tumours in patients who underwent previous pneumonectomy.

Methods:

12 patients were retrospectively analysed. The median maximum tumour diameter was 2.1 cm (1–4.5 cm). The median planning target volume was 20.7 cm³ (2.4–101.2 cm³). Five patients were treated with a single fraction of 26 Gy and seven patients with fractionated schemes (3 × 10 Gy, 4 × 10 Gy, 4 × 12 Gy). Lung toxicity, correlated with volume (V) of lung receiving >5, >10 and >20 Gy, local control and survival rate were assessed. Median follow-up was 28 months.

Results:

None of the patients experienced pulmonary toxicity > grade 2 at the median dosimetric lung parameters of V₅, V₁₀ and V₂₀ of 23.1% (range 10.7–56.7%), 7.3% (2.2–27.2%) and 2.7% (0.7–10.9%), respectively. No patients required oxygen or had deterioration of the performance status during follow-up if not as a result of clinical progression of disease. The local control probability at 2 years was 64.5%, and the overall survival at 2 years was 80%.

Conclusion:

SBRT appears to be a safe and effective modality for treating patients with a second lung tumour after pneumonectomy.

Advances in knowledge:

Our results and similar literature results show that when keeping V₅, V₁₀ V₂₀ <50%, <20% and <7%, respectively, the risk of significant lung toxicity is acceptable. Our experience also shows that biologically effective dose 10 >100 Gy, necessary for high local control rate, can be reached while complying with the dose constraints for most patients.     

Intensity-modulated extended-field chemoradiation plus simultaneous integrated boost in the pre-operative treatment of locally advanced cervical cancer: a dose-escalation study

Objective:

To investigate the feasibility and determine the recommended pre-operative intensity-modulated radiotherapy (IMRT) dose of extended-field chemoradiation along with simultaneous integrated boost (SIB) dose escalation.

Methods:

A radiation dose of 40 Gy over 4 weeks, 2 Gy/fraction, was delivered to the tumour and the lymphatic drainage (planning target volume, PTV3), which encompassed a volume larger than standard (common iliac lymphatic area up to its apex, in front of the L3 vertebra), concurrently with chemotherapy (cisplatin and 5-fluorouracil). Radiation dose was escalated to the pelvis (PTV2) and to the macroscopic disease (PTV1) with the SIB-IMRT strategy. Three dose levels were planned: Level 1 (PTV3: 40/2 Gy; PTV2: 40/2 Gy; PTV1: 45/2.25 Gy), Level 2 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 45/2.25 Gy) and Level 3 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 50/2.5 Gy). All treatments were delivered in 20 fractions. Patients were treated in cohorts of between three and six per group using a Phase I study design. The recommended dose was exceeded if two of the six patients in a cohort experienced dose-limiting toxicity within 3 months from treatment.

Results:

19 patients [median age: 46 years; The International Federation of Gynecology and Obstetrics (FIGO) stage IB2: 3, IIB: 10, IIIA–IIIB: 6] were enrolled. Median follow-up was 24 months (9–60 months). The most common grade 3/4 toxicity was gastrointestinal (GI) (diarrhoea, mucous discharge, rectal/abdominal pain). At Levels 1 and 2, only one grade 3 GI toxicity per level was recorded, whereas at Level 3, two grade 3 GI toxicities (diarrhoea, emesis and nausea) were recorded.

Conclusion:

The SIB-IMRT technique was found to be feasible and safe at the recommended doses of 45 Gy to PTV1 and PTV2 and 40 Gy to PTV3 in the pre-operative treatment of patients with locally advanced cervical cancer. Unfortunately, this complex technique was unable to safely escalate dose beyond levels already achieved with three-dimensional conformal radiotherapy technique given acute GI toxicity.

Advances in knowledge:

A Phase I radiotherapy dose-escalation trial with SIB-IMRT technique is proposed in cervical cancer. This complex technique is feasible and safe at the recommended doses.     

Clinical-dosimetric relationship between lacrimal gland dose and ocular toxicity after intensity-modulated radiotherapy for sinonasal tumours

Objective:

To characterise the relationship between lacrimal gland dose and ocular toxicity among patients treated by intensity-modulated radiotherapy (IMRT) for sinonasal tumours.

Methods:

40 patients with cancers involving the nasal cavity and paranasal sinuses were treated with IMRT to a median dose of 66.0 Gy. Toxicity was scored using the Radiation Therapy Oncology Group morbidity criteria based on conjunctivitis, corneal ulceration and keratitis. The paired lacrimal glands were contoured as organs at risk, and the mean dose, maximum dose, V₁₀, V₂₀ and V₃₀ were determined. Statistical analysis was performed using logistic regression and the Akaike information criterion (AIC).

Results:

The maximum and mean dose to the ipsilateral lacrimal gland were 19.2 Gy (range, 1.4–75.4 Gy) and 14.5 Gy (range, 11.1–67.8 Gy), respectively. The mean V₁₀, V₂₀ and V₃₀ values were 50%, 25% and 17%, respectively. The incidence of acute and late Grade 3+ toxicities was 23% and 19%, respectively. Based on logistic regression and AIC, the maximum dose to the ipsilateral lacrimal gland was identified as a more significant predictor of acute toxicity (AIC, 53.89) and late toxicity (AIC, 32.94) than the mean dose (AIC, 56.13 and 33.83, respectively). The V₂₀ was identified as the most significant predictor of late toxicity (AIC, 26.81).

Conclusion:

A dose–response relationship between maximum dose to the lacrimal gland and ocular toxicity was established. Our data suggesting a threshold relationship may be useful in establishing dosimetric guidelines for IMRT planning that may decrease the risk of acute and late lacrimal toxicities in the future.

Advances in knowledge:

A threshold relationship between radiation dose to the lacrimal gland and ocular toxicity was demonstrated, which may aid in treatment planning and reducing the morbidity of radiotherapy for sinonasal tumours.The majority of tear fluid is produced by the paired lacrimal glands, which are located in the superior temporal quadrants of the orbits. Each bilobed lacrimal gland is anatomically divided into the larger orbital and smaller palpebral parts, both of which contain excretory components consisting of ductal cells that mechanically assist in the secretion of tears on to the ocular surface by modifying the fluid secreted by acinar and myoepithelial cells [1]. The glands of Krause and Wolfring are smaller accessory lacrimal glands located in the superior fornix that secrete additional tear fluid. Functionally, the lacrimal gland is responsible for the secretion of fluid that continually moistens, lubricates and protects the surface of the eye.An increasingly recognised complication of radiotherapy to the periorbital region is dry eye syndrome, defined by the International Dry Eye WorkShop as a “multi-factorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface accompanied by increased osmolarity of the tear film and inflammation of the ocular surface” [2]. Although previous research has suggested a variable association between radiation dose to the lacrimal gland and incidence of dry eye syndrome [3–11], the exact nature of this dose–response relationship remains undetermined. This is particularly relevant given the ability of intensity-modulated radiotherapy (IMRT) to limit dose to normal structures designated as organs at risk (OARs). The aim of the present study was to characterise this relationship between various dosimetric parameters related to the lacrimal gland and ocular toxicity in patients treated with IMRT for sinonasal tumours.     

A quantitative analysis of 1H-MR spectroscopy at 3.0?T of three brain regions from childhood to middle age

Objective:

To study age-related metabolic changes in different brain regions.

Methods:

Point-resolved spectroscopy (repetition time/echo time = 2000 ms/30 ms) was performed in the left and right hippocampus, the left thalamus and the left centrum semiovale of 80 healthy subjects (37 females and 43 males aged 7–64 years). Analysis of covariance and linear regression were used for statistical analysis. Both metabolite concentration ratios with respect to total creatine (tCr) and absolute metabolite concentrations were included for analysis.

Results:

Ins (myo-inositol)/tCr (p < 0.001) and absolute Ins concentration (p = 0.031) were significantly increased with age after adolescence. NAA (N-acetylaspartic acid)/tCr (p < 0.001) and absolute NAA concentration (p = 0.010) significantly declined with age after adolescence.

Conclusion:

Age-related increase of Ins and decline of NAA are found in all three regions, especially at the hippocampus, indicating possible gliosis in the ageing brain.

Advances in knowledge:

We could use NAA/tCr and Ins/tCr as an indicator to estimate the neurons-to-glial cells ratio at the thalamus. This may be an index to distinguish normal tissues from gliosis.     

Helical tomotherapy with simultaneous integrated boost dose painting for the treatment of synchronous primary cancers involving the head and neck

Objective:

To demonstrate the feasibility of helical tomotherapy (HT)-based intensity-modulated radiotherapy (IMRT) for the treatment of synchronous primary cancers arising from the head and neck.

Methods:

14 consecutive patients with histologically proven squamous cell carcinoma of the head and neck were determined to have a second primary cancer in the upper aerodigestive tract on further evaluation and were treated with HT using simultaneous integrated boost IMRT. Megavoltage CT scans were acquired daily as part of an image-guided registration protocol. Concurrent platinum-based systemic therapy was given to nine patients (64%).

Results:

HT resulted in durable local control in 21 of the 28 primary disease sites irradiated, including a complete clinical and radiographic response initially observed at 17 of the 20 sites with gross tumour. The mean displacements to account for interfraction motion were 2.44 ± 1.25, 2.92 ± 1.09 and 2.31 ± 1.70 mm for the medial–lateral (ML), superior–inferior (SI) and anteroposterior (AP) directions, respectively. Table shifts of >3 mm occurred in 19%, 20% and 22% of the ML, SI and AP directions, respectively. The 2-year estimates of overall survival, local-regional control and progression-free survival were 58%, 73% and 60%, respectively.

Conclusion:

The effectiveness of HT for the treatment of synchronous primary cancers of the head and neck was demonstrated.

Advances in knowledge:

HT is a feasible option for synchronous primary cancers of the head and neck and can result in long-term disease control with acceptable toxicity in appropriately selected patients.The proportion of patients with newly diagnosed head and neck cancer who are found to have a synchronous second primary tumour has been estimated to range from 5% to 15%.^1–3 Slaughter et al⁴ described the concept of field cancerization as the most logical explanation for the development of multiple cancers in the upper aerodigestive tract. With the routine adoption of panendoscopy and the widespread utilization of positron emission tomography (PET) as a component of the initial staging evaluation, the number of patients diagnosed with synchronous cancers involving the head and neck appears to be increasing.⁵ Despite the increased prevalence, uncertainty exists regarding the optimal manner in which patients with synchronous primary cancers of the head and neck should be managed. For patients receiving radiotherapy, the large areas at risk for tumour recurrence make treatment delivery a therapeutic and technical challenge.Intensity-modulated radiotherapy (IMRT) reduces radiation to critical structures while maintaining desired doses to user-defined targets through a computer-derived optimization process (i.e. inverse planning) and non-uniform beam intensities. Because of its ability to achieve conformal dose distributions to convex and concave targets, IMRT represents the standard in the radiotherapeutic management of head and neck cancer. Helical tomotherapy (HT) is a specialized form of IMRT, which is also based on inverse planning but relies on a rotational gantry and a binary multileaf collimator system rather than a fixed number of beam angles for radiation delivery. We report here our experience with HT for the treatment of synchronous primary cancers involving the head and neck.     

CT and MRI findings of radiation-induced external auditory canal carcinoma in patients with nasopharyngeal carcinoma after radiotherapy

Objective:

To summarize the radiological and clinical features of radiation-induced external auditory canal carcinomas (RIEACCs) in patients with nasopharyngeal carcinomas (NPCs) after radiation therapy.

Methods:

CT, MRI and clinical features in 16 patients with histologically proven RIEACCs were retrospectively reviewed. There were 2 females and 14 males, with a median age of 52.5 years at the time of diagnosis of RIEACC. Imaging parameters including lesion extent, size, margin, shape, bone destruction, adjacent structure invasion, density/signal intensity, and pattern and degree of enhancement were assessed. Clinical features including clinical staging, histological type, treatment and radiation dose (RD) of primary NPC as well as the histological type, staging of radiation-induced tumour and the latent period between NPC and RIT were recorded.

Results:

All patients had a single RIEACC. The lesions had a size of 3.5 ± 1.4 cm and were localized (n = 7) or extensive (n = 9). Most of the lesions were partially or ill defined with an irregular shape and had an intermediate density/signal pattern and moderate homogeneous enhancement. The latent period of RIEACCs ranged from 10 to 20 years in nine patients with a RD of 68–70 Gy; from 2 to 10 years in five patients with a RD of 68–74 Gy; and more than 20 years in two patients with a RD of 70 or 72 Gy.

Conclusion:

An external auditory canal (EAC) mass with homogeneous, intermediate CT density or signal intensity in patients with NPC after radiotherapy is highly suggestive of RIEACC, which should be included in the routine surveillance for patients with NPC after radiotherapy.

Advances in knowledge:

RIEACCs could occur as short as 2 years after radiotherapy in patients with NPC and have distinct features from otitis media and sarcomas. This EAC malignancy should be included in routine surveillance for patients with NPC after radiotherapy.Radiotherapy is the conventional and main treatment method in patients with nasopharyngeal carcinoma (NPC). As one of the most common carcinogenic agents, ionization radiation can induce many complications such as radiation encephalopathy and radiation-induced tumours (RITs) in the irradiation field. The reported incidence of RITs ranges from 0.04% to 7% in post-radiation NPC.¹ Among them, radiation-induced sarcomas (RISs) such as fibrosarcoma and osteosarcoma arising in the paranasal sinuses and the nasal cavity are the most common tumours.^1–3 Their imaging features have been well documented previously.^1–3Radiation-induced external auditory canal carcinomas (RIEACCs) are rare, but are another clinically challenging problem of RITs in patients previously irradiated for nasopharyngeal neoplasm.⁴ Previously, MRI findings of only four cases of radiation-inducted squamous-cell carcinomas (SCCs) in the external auditory canal (EAC) had been described.¹ To date, there are few reports describing radiological features of RIEACCs. The CT and MRI features of RIEACC are far from well described. In this study, CT, MRI and clinical data in 16 cases of pathologically proven RIEACCs in patients with irradiated NPCs were retrospectively reviewed, and their main CT and MRI findings and clinical features were summarized.     

Correlation between anthropometric parameters and acute skin toxicity in breast cancer radiotherapy patients: a pilot assessment study

Objective:

The objective of the present study was to identify acute skin toxicity risk factors linked to the anthropometric characteristics of patients with breast cancer treated with radiation therapy.

Methods:

Consecutive patients with breast cancer were enrolled after breast-conserving surgery and before radiotherapy course. Acute skin toxicity was assessed weekly during the 7 weeks of radiotherapy with the International Classification from National Cancer Institute. Grade 2 defined acute skin toxicity. Patient characteristics and anthropometric measurements were collected.

Results:

54 patients were enrolled in 2013. Eight patients (14.8%) had grade ≥2 toxicity. The average weight and chest size were 65.5 kg and 93.6 cm, respectively. Bra cup size is significantly associated with a risk of grade 2 dermatitis [odds ratio (OR) 3.46, 95% confidence interval (CI) (1.29–11.92), p = 0.02]. Anthropometric breast fat mass measurements, such as thickness of left [OR 2.72, 95% CI (1.08–8.26), p = 0.04] and right [OR 2.45, 95% CI (0.99–7.27), p = 0.05] axillary fat, are correlated with an increased risk. Distance between the pectoral muscle and nipple is a reproducible measurement of breast size and is associated with acute skin toxicity with significant tendency (OR = 2.21, 95% CI (0.97–5.98), p = 0.07).

Conclusion:

Breast size and its different anthropometric measurements (thickness of left and right axillary fat, nipple-to-pectoral muscle distance) are correlated with the risk of skin toxicity.

Advances in knowledge:

The present article analyses several characteristics and anthropomorphic measurements of breast in order to assess breast size. A standardized and reproducible protocol to measure breast volume is described.     

Dose–volume-related dysphagia after constrictor muscles definition in head and neck cancer intensity-modulated radiation treatment

Objective:

Dysphagia remains a side effect influencing the quality of life of patients with head and neck cancer (HNC) after radiotherapy. We evaluated the relationship between planned dose involvement and acute and late dysphagia in patients with HNC treated with intensity-modulated radiation therapy (IMRT), after a recontouring of constrictor muscles (PCs) and the cricopharyngeal muscle (CM).

Methods:

Between December 2011 and December 2013, 56 patients with histologically proven HNC were treated with IMRT or volumetric-modulated arc therapy. The PCs and CM were recontoured. Correlations between acute and late toxicity and dosimetric parameters were evaluated. End points were analysed using univariate logistic regression.

Results:

An increasing risk to develop acute dysphagia was observed when constraints to the middle PCs were not respected [mean dose (D_mean) ≥50 Gy, maximum dose (D_max) >60 Gy, V50 >70% with a p = 0.05]. The superior PC was not correlated with acute toxicity but only with late dysphagia. The inferior PC was not correlated with dysphagia; for the CM only, D_max >60 Gy was correlated with acute dysphagia ≥ grade 2.

Conclusion:

According to our analysis, the superior PC has a major role, being correlated with dysphagia at 3 and 6 months after treatments; the middle PC maintains this correlation only at 3 months from the beginning of radiotherapy, but it does not have influence on late dysphagia. The inferior PC and CM have a minimum impact on swallowing symptoms.

Advances in knowledge:

We used recent guidelines to define dose constraints of the PCs and CM. Two results emerge in the present analysis: the superior PC influences late dysphagia, while the middle PC influences acute dysphagia.In the past decade, substantial progress has been made in the treatment of head and neck cancer (HNC). Several reports show that radiotherapy (RT) with concomitant chemotherapy or altered fractionation schedules improve tumour control and survival rate.^1,2However, xerostomia and dysphagia often remain relevant side effects for patients with HNC, compromising their quality of life (QoL), as a consequence of radiation damage to the parotid glands and to the organ at risk (OAR) involved in the swallowing process (SWOARs).³Intensity-modulated radiation therapy (IMRT) and rotational intensity-modulated techniques, including volumetric-modulated arc therapy (VMAT), allow for a better dose conformation to target structures while reducing the dose.^4–8 In comparison with three-dimensional-conformal radiation therapy, several studies have shown that IMRT in HNC treatment reduces overall adverse effects such as xerostomia and dysphagia and thus improves QoL, even when chemotherapy is added.^9–13Regarding tolerance of the parotid glands, several studies have suggested significant recovery when the mean dose is inferior to 26 Gy. Open questions remain for SWOARs, especially with reference to the delineation modalities of the involved structures to the volumes or the dose constraints to be applied.^14–18 More authors hypothesized that sparing a portion of the constrictor muscles (PCs), not involved by tumour and not at risk of subclinical disease, might reduce dysphagia.^19–21 These studies obtained different results, maybe, owing to a number of methodological issues and to the ambiguous contouring of the PCs. For this purpose, Christianen et al²² recently defined guidelines for SWOARs contouring.Based on these findings, the aim of this retrospective analysis is to evaluate potential relationships between planned dose–volume parameters and observed incidence of acute and late dysphagia in patients with HNC treated with IMRT or VMAT, after a recontouring of the PCs according to these recently published guidelines.     

The Prognostic Value of the Metabolic Tumor Volume in FIGO stage IA to IIB Cervical Cancer for Tumor Recurrence: Measured by F-18 FDG PET/CT

Purpose

The purpose of this study was to evaluate the prognostic value of the metabolic tumor volume (MTV), in FIGO stage IA–IIB cervical cancer patients, measured by F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging.

Methods

Forty-five patients with invasive cervical cancer who underwent FDG-PET imaging were recruited. Metabolically active tumor regions were delineated on the pretreatment FDG-PET scans by encompassing regions equal to or greater than an standardized uptake value (SUV) of 40% of the peak tumor intensity. The relationship of the metabolic tumor volume (MTV) to the disease-free survival was analyzed. The MTV of the cervical cancer was compared with pathological and clinical prognostic factors, including lymph node metastasis, parametrial invasion, the depth of invasion, resection margins, tumor differentiation and FIGO stages.

Results

Cox proportional hazard regression analysis showed that the MTV was a significant independent predictor of recurrence of cervical cancer (p = 0.027). Patients with an MTV of >20 cm³ had a significantly reduced disease-free survival compared with patients with an MTV ≤ 20 cm³ (p = 0.029). The correlation of the MTV with traditional prognostic factors showed significantly higher values in patients that were lymph node (LN) metastasis positive (p = 0.028) and parametrial invasion positive (p = 0.022). The MTV significantly differed among the groups according to tumor differentiation (p = 0.0319) and FIGO stage (p = 0.001).

Conclusion

The MTV measured by FDG-PET was an independent prognostic factor for tumor recurrence in patients with stage IA–IIB cervical cancer. These findings must be confirmed by large population based prospective studies.     

Simultaneous integrated boost intensity-modulated radiotherapy for treatment of locally advanced non-small-cell lung cancer: a retrospective clinical study

Objective:

To evaluate the clinical efficacy and safety of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with locally advanced non-small-cell lung cancer (LANSCLC).

Methods:

48 patients with LANSCLC treated with SIB-IMRT from January 2010 to April 2012 were retrospectively analysed. A radiation dose of 45–63 Gy (median dose, 51.58 Gy) was delivered to the planning target volume (1.8–2.0 Gy daily fractions) simultaneously with 55.0–74.2 Gy (median dose, 63 Gy) to the planning gross tumour volume (2.00–2.25 Gy daily fractions). 45 patients received concurrent/sequential chemotherapy. The overall survival (OS), locoregional recurrence-free survival (LRFS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Treatment-related pneumonitis and oesophagitis were graded according to the Common Terminology Criteria for Adverse Events v. 4.0.

Results:

By 1 July 2013, 29 of the 48 patients were dead. The median follow-up time for the survivors was 28 months (19–44 months). The median OS and PFS were 21 and 14 months, respectively. The median LRFS time was not reached. The 2-year LRFS, OS and PFS were 62.5%, 45.1% and 28.0%, respectively. Two patients experienced Grade 3 treatment-related pneumonitis, two patients experienced Grade 5 treatment-related pneumonitis and two patients had ≥Grade 3 oesophagitis.

Conclusion:

SIB-IMRT appears to be an effective therapeutic option in patients with LANSCLC and warrants further evaluation with increased number of patients in prospective clinical trials.

Advances in knowledge:

This study explores the feasibility of delivering tumoricidal doses of radiation to primary lesions in non-small-cell lung cancer.The true value of radiotherapy confined to the thorax is indisputable in the treatment of locally advanced non-small-cell lung cancer (LANSCLC). However, even with standard chemoradiation, it is difficult to achieve durable local control, and this contributes to the high morbidity and mortality of patients with non-small-cell lung cancer (NSCLC).¹ Despite a demonstrated positive association between the radiation dose and tumour control,² results of the Radiation Therapy Oncology Group (RTOG) 0617 clinical (Phase III) trial showed that the overall survival (OS) of Stage III NSCLC patients given high-dose (74 Gy) conformal radiation therapy with concurrent chemotherapy was no better than that of patients given the standard dose (60 Gy).³The unpublished data showed that the higher dose had no further effects on improving the OS during the RTOG 0617 trial, and the reason still remained unclear, the radiation-induced decline in quality of life may be responsible for this.⁴ Thus, researchers turned their attention to focus on better ways of delivering radiation to tumours, while sparing surrounding normal structures. Initially, the radiation dose applied to the gross tumour was identical to that directed at targeted nodal areas, but logic suggests that the dose required to control subclinical lesions should be lower than that of the primary disease.Simultaneous integrated boost (SIB) is a recent modality applied in conjunction with intensity-modulated radiotherapy (IMRT) in the treatment of malignancies.^5,6 Simultaneous integrated boost–intensity-modulated radiotherapy (SIB-IMRT) simultaneously delivers a higher dose to the primary disease and a relatively lower dose to the subclinical disease or selected other regions. However, outcomes for SIB-IMRT in LANSCLC remain to be determined.Herein, we retrospectively analysed clinical outcomes of patients with LANSCLC treated with SIB-IMRT to evaluate the feasibility of this technology and to provide evidence in support of future clinical study.