Effect of induction chemotherapy on estimated risk of radiation pneumonitis in bulky non–small cell lung cancer

Patients with bulky non–small cell lung cancer (NSCLC) may be at a high risk for radiation pneumonitis (RP) if treated with up-front concurrent chemoradiation. There is limited information about the effect of induction chemotherapy on the volume of normal lung subsequently irradiated. This study aims to estimate the reduction in risk of RP in patients with NSCLC after receiving induction chemotherapy. Between 2004 and 2009, 25 patients with Stage IV NSCLC were treated with chemotherapy alone (no surgery or radiation therapy [RT]) and had computed tomography (CT) scans before and after 2 cycles of chemotherapy. Simulated RT plans were created for the prechemotherapy and postchemotherapy scans so as to deliver 60 Gy to the thoracic disease in patients who had either a >20% volumetric increase or decrease in gross tumor volume (GTV) from chemotherapy. The prechemotherapy and postchemotherapy scans were analyzed to compare the percentage of lung volume receiving≥20 Gy (V20), mean lung dose (MLD), and normal tissue complication probability (NTCP). Eight patients (32%) had a GTV reduction >20%, 2 (8%) had GTV increase >20%, and 15 (60%) had stable GTV. In the 8 responders, there was an absolute median GTV decrease of 88.1 cc (7.3 to 351.6 cc) or a 48% (20% to 62%) relative reduction in tumor burden. One had >20% tumor progression during chemotherapy, yet had an improvement in dosimetric parameters postchemotherapy. Among these 9 patients, the median decrease in V20, MLD, and NTCP was 2.6% (p<0.01), 2.1 Gy (p<0.01), and 5.6% (p<0.01), respectively. Less than one-third of patients with NSCLC obtain >20% volumetric tumor reduction from chemotherapy alone. Even with that amount of volumetric reduction, the 5% reduced risk of RP was only modest and did not convert previously ineligible patients to safely receive definitive thoracic RT.     

Can tumor contrast enhancement be used as a criterion for differentiating tumor grades of oligodendrogliomas?

BACKGROUND AND PURPOSE: The association of high-grade oligodendrogliomas with tumor contrast material enhancement on MR images has been reported. Some authors have even used contrast enhancement as a criterion for their oligodendroglioma grading system. The purpose of our study was to evaluate if tumor contrast enhancement is a specific finding for anaplastic oligodendroglioma. METHODS: Pretreatment MR images of 24 oligodendrogliomas were reviewed retrospectively, and findings were compared with the histologic grade. The presence or absence and the pattern of tumor contrast enhancement were evaluated qualitatively. A contrast enhancement ratio (CER), a quantitative criterion, was calculated to assess the difference in degree of enhancement between the low-grade and anaplastic tumors. Tumor grade was diagnosed at pathologic examination according to the World Health Organization classification system. RESULTS: Contrast enhancement was noted in nine (56%) of 16 low-grade tumors and in five (62%) of eight anaplastic tumors. A characteristic enhancement pattern, nodular-like enhancement, was found in eight tumors. The CERs were 2.12-40.88 (mean, 20.08) in low-grade tumors and were 3.20-62.52 (mean, 28.73) in anaplastic tumors (P > .05). CONCLUSION: Tumor contrast enhancement was not statistically significantly different between the tumor groups. We believe that the presence or absence of tumor contrast enhancement is not a specific finding for simply discriminating low-grade from anaplastic oligodendrogliomas. Histologic confirmation is necessary even in tumors without contrast enhancement.     

Can pretreatment CT perfusion predict response of advanced squamous cell carcinoma of the upper aerodigestive tract treated with induction chemotherapy?

BACKGROUND AND PURPOSE: Treatment of advanced stage squamous cell carcinoma of the upper aerodigestive tract with nonsurgical organ preservation protocols demonstrates improved cure rates with fewer comorbidities compared with surgery and radiation. The purpose of this study was to prospectively assess whether pretreatment evaluation of the primary site with quantitative CT perfusion measurements predicted response to induction chemotherapy and to create a prediction model to predict the response to induction chemotherapy in future patients. METHODS: Seventeen patients who were enrolled in a prospective trial assessing surgical intervention versus a nonsurgical protocol underwent a pretreatment CT perfusion followed by direct laryngoscopy. After induction chemotherapy, tumor response was determined by the surgeon's estimate of tumor volume. The CT perfusion parameters were correlated with the clinical response using a Wilcoxon rank-sum analysis. A logistic regression model was used to create a prediction based on the most significant CT perfusion parameter. RESULTS: Elevated values of blood volume (P = .004) and blood flow (P = .03) were significantly correlated with >50% reduction in tumor volume after chemotherapy. A prediction model based on tumor blood volume demonstrated 91.7% sensitivity and 80.0% specificity, with an area under the receiver operating characteristic curve of 0.95. CONCLUSION: Our preliminary data imply that tumors with elevated blood volume and blood flow were statistically associated with response to induction chemotherapy. These results suggest that pretreatment CT perfusion may be able to identify patients who will successfully respond to induction chemotherapy, which could potentially eliminate this step for subsequent patients when deciding on the appropriate treatment regimen.     

Lack of effect of small high-dose volumes on the dose–response relationship for the development of fibrosis in distant parts of the ipsilateral lung in mini-pigs

Purpose : Multi-field radiation therapy for intrathoracic tumours results in a heterogeneous dose distribution in lung tissue. This study investigated whether irradiation of small lung volumes with high fibrogenic doses affects the dose–response relationship for development of fibrosis in distant parts of the ipsilateral lung of mini-pigs. Materials and methods : The whole right lung of 26 ’Mini-Lewe? pigs was irradiated with homogeneous doses of between 25 Gy and 40 Gy given in five equal fractions using opposing anterior–posterior portals and a linear accelerator. Another 32 animals were irradiated with a constant dose of 35 Gy to a small house-shaped high-dose field (base 3.0 cm, height 4 cm) located 3 cm caudolateral to the right hilus, while the surrounding right lung received either no irradiation or homogeneous doses of between 20 Gy and 30 Gy. The radiation fields were simulated and port films were obtained for each of the 10 fields in all pigs. Fibrosis was quantified 9 months after irradiation by determination of the hydroxyproline (HP) content of the 32 high-dose volumes and in the lung apex and the basolateral lung of all 58 pigs. Based on the reference value for the HP-ratio, i.e. the HP-concentration of the right lung over the left lung, obtained in 12 unirradiated control animals, the experimental results were converted into quantal data for probit analysis, a responder being an animal with an HP-ratio > 1.33. Results : A dose–response relationship for the HP-ratio was obtained in the different lung sites and irradiation groups. For a given dose level the mean HP-ratios and response rates did not differ systematically between the lung apex and the basolateral lung. Probit analysis of the pooled data produced ED 50 values of 21.8 Gy (95% CI 12–37) for irradiation without a high-dose volume and 25.9 Gy (24–28) for irradiation with a high-dose volume. These values are not significantly different. The results from both irradiation groups could be well fitted by a common dose–response curve with an ED 50 value of 26.1 Gy. Unexpectedly, the response rates in the high-dose volume increased with increasing dose to the surrounding right lung. Analysis of the port films provided an explanation for this finding: inaccuracies in daily field positioning. When this error was corrected for by use of the mean dose to the high-dose volume, a dose–response curve with an ED 50 of 25.2 Gy (22–29) was determined for the high-dose volume. Conclusions : The results of the study indicate that the irradiation of a small lung volume with high fibrogenic doses does not affect the dose–response relationship for development of fibrosis in distant parts of the ipsilateral lung.     

Does the pretreatment tumor sampling location correspond with metabolic activity on 18F-FDG PET/CT in breast cancer patients scheduled for neoadjuvant chemotherapy?

Purpose

To define the correlation between the core biopsy location and the area with highest metabolic activity on 18F-FDG PET/CT in stage II–III breast cancer patients before neoadjuvant chemotherapy. Also, we would like to select a subgroup of patients in which PET/CT information may optimize tumor sampling.

Methods

A PET/CT in prone position was acquired in 199 patients with 203 tumors. The distance and relative difference in standardized uptake value (SUV) between core biopsy localization (indicated by a marker) and area with highest degree of FDG uptake were evaluated. A distance ≥2 cm and a relative difference in SUV ≥25% were considered clinically relevant and a combination of both was defined as non-correspondence. Non-correspondence for different tumor characteristics (TNM stage, lesion morphology on MRI and PET/CT, histology, subtype, grade, and Ki-67) was assessed.

Results

Non-correspondence was found in 28 (14%) of 203 tumors. Non-correspondence was significantly associated with T-stage, lesion morphology on MRI and PET/CT, tumor diameter, and histologic type. It was more often seen in tumors with a higher T-stage (p = 0.028), diffuse (non-mass) and multifocal tumors on MRI (p = 0.001), diffuse and multifocal tumors on PET/CT (p < 0.001), tumors >3 cm (p < 0.001), and lobular carcinomas (p < 0.001). No association was found with other features.

Conclusion

Non-correspondence between the core biopsy location and area with highest FDG uptake is regularly seen in stage II–III breast cancer patients. PET/CT information and possibly FDG-guided biopsies are most likely to improve pretreatment tumor sampling in tumors >3 cm, lobular carcinomas, and diffuse and multifocal tumors.     

The potential for increased tumor control probability in non–small cell lung cancer with a hypofractionated integrated boost to the gross tumor volume

Treatment outcomes in locally advanced non–small cell lung cancer (NSCLC) to date have been poor, with normal tissue toxicity often limiting the dose that can be delivered to the tumor. Treatment intensification in NSCLC via targeted dose escalation with modern delivery techniques may offer the potential for a significant increase in tumor control probability (TCP) without a clinically significant increase in organ-at-risk (OAR) toxicity. In this planning study, 20 patients were re-planned with a volumetric modulated arc therapy (VMAT) and an inhomogeneous dose distribution with iteratively escalated doses to the gross tumor volume (iGTV) (composite GTV across multiple 4-dimensional computed tomography [4DCT] phases) in a series of 20 fraction regimes. For each plan OAR doses, target coverage and predicted TCPs were collected and compared with homogenous 3-dimensional (3D) and VMAT plans, as well as with each other. In 70% of patients, it was possible to escalate to 75?Gy in 20 fractions within OAR tolerances, opening the possibility of treating these patients to a biological effective dose (BED) of 103.1?Gy₁₀. This planning study forms the basis of a clinical trial INTENSE (Inhomogeneous Targeted Dose Escalation in Non-Small CEll Lung Cancer), CTRIAL 15-47.     

Does chemotherapy influence the quantification of SUV when contrast-enhanced CT is used in PET/CT in lymphoma?

Purpose In patients with lymphoma, we investigated the impact of contrast-enhanced CT on PET attenuation correction in lesions and normal tissues, particularly when PET/CT was performed after chemotherapy. Methods Fifty patients (51±18 years) with Hodgkin’s disease (n=17) or non-Hodgkin lymphomas (n=33) were studied before and after chemotherapy. PET/CT scans were performed 60 min after injection of FDG. Iopamiron 300 (iopamidol, 1.5 cc/kg) was injected immediately afterwards, followed 50 s later by a second craniocaudal CT (CT+). PET images were successively reconstructed using the unenhanced CT (PET−) and the CT+ (PET+) for attenuation correction, using iterative reconstruction (4 iterations, 8 subsets, 5 mm post-filtering). HU_mean, SUV_max and SUV_mean were measured before and after chemotherapy in ten non-tumoural ROIs [aorta, femur, kidney, lung, iliopsoas muscle, occipital cortex, T12 vertebra, liver, spleen and inferior vena cava (IVC)] and in tumoural lymphadenopathies or malignant tissues (n=397 and 51 VOIs respectively before and after chemotherapy) using a 3D-thresholding method (identical threshold for PET− and PET+). ROIs were defined on the PET− and automatically applied on the unenhanced CT (CT−), the CT+ and the PET+. Results In the non-tumoural tissues, HU_mean increased significantly in the CT+ compared with the CT− in the vessels and the highly vascularised organs, and slight increases were observed in the occipital cortex (+11%), the iliopsoas muscle (+6%) and the femur (+3%). SUV_max increased significantly in the PET+ compared with the PET− in the aorta (+14%), the liver (+10%), the spleen (+10%) and the IVC (+12%). SUV_mean increased significantly in the PET+ compared with the PET− in the aorta (+15%), the kidney (+13%), the liver (+11%), the spleen (10%) and the IVC (+12%). In the lesions, HU_mean was not significantly different before and after chemotherapy, whatever the normal region considered. SUV_max increased significantly after treatment in the T12 vertebra (+12%). SUV_mean increased significantly after treatment in the T12 vertebra (+13%) and in the liver (+12%). HU_mean increased significantly in the CT+ compared with the CT− in the lesions (+55%) before chemotherapy. SUV_max and SUV_mean increased significantly in the PET+ compared with the PET− in the lesions (+4%) only before chemotherapy. No significant difference was seen in measurements (HU_mean, SUV_max and SUV_mean) after chemotherapy. Conclusion Our study demonstrates that use of enhanced CT for attenuation correction has a negligible effect on quantification at staging and after chemotherapy. A “single-shot” enhanced PET/CT may thus be performed in the evaluation of patients with lymphoma at staging, during treatment and at follow-up.     

Extrapulmonary small cell carcinoma: An indication for prophylactic cranial irradiation?

Background

Information about extrapulmonary small cell carcinoma (EPSCC) is limited and the role of prophylactic cranial irradiation (PCI) is unknown.

Patients and Methods

Disease presentation and outcome of all EPSCC at our hospital between 1990 and 2009 were retrospectively analyzed.

Results

Of 30 EPSCC, the male:female ratio was 58%:42%; 83% had a performance status of 0?C2. Median age was 71 years (32?C80). Seventeen (57%) had limited stage (LS), 13 (43%) extensive stage (ES). The location of the primary tumor was gastrointestinal (n = 8), unknown (6), gynecological (6), urogenital (5), and ear nose throat (5). Four (13%) developed brain metastases (2 ES, 2 LS). In ES, first line chemotherapy (CT) was given in 85%, mostly platinum?Cetoposide (64%). Response rate was 90%. In LS, CT and radiotherapy (RT) ± resection resulted in persistent remissions in 67% of patients. Median survival was 16 months (1?C107 months), 18 months (1?C107 months), and 9 months (0.4?C25 months) for LS + ES, LS, and ES, respectively. Weight loss ??5 % and ECOG performance status 3 + 4 were associated with poorer survival (p < 0.001 and p < 0.01, respectively).

Conclusion

The incidence of brain metastases was relatively low (13%). More studies are necessary, before routinely offering PCI to patients with EPSCC. Best survival outcomes in LS were achieved with multimodality treatment including CT and RT. Prognosis was poor in patients with ES.     

Spiral CT of the neck: When do neck malignancies delineate best during contrast enhancement?

The aim of this study was to determine the time of best contrast of neck malignancies in contrast-enhanced CT. The CT was done in 20 patients with squamous cell carcinoma using a standard protocol (100 ml contrast agent at 2 ml/s). Dynamic series of the tumors were performed (scan interval 6 s). In all relevant structures of the neck, densities were measured to obtain time-density curves. The best tumor contrast was measured > or =50 s after the start of the injection, and the best contrast of lymph nodes < or =75 s. For staging and volume measurements of neck primaries the best achievable contrast is necessary. Using the examined single-bolus technique, spiral CT allows a combination of perfect tumor contrast with a good contrast between lymph nodes and neck vessels between 50 and 75 s after starting the injection.     

On the possible benefits of a hybrid VMAT technique in the treatment of non–small cell lung cancer

To assess, using clinical cases, the potential of a hybrid technique for the treatment of non–small cell lung cancer (NSCLC)-blending volumetric-modulated arc therapy (VMAT) and conformal radiation therapy (CRT) fields, and to consider potential issues with implementation of such a technique. Eight clinical cases already treated with CRT were used for a planning study comparing target coverage and organs at risk (OAR) sparing between CRT and hybrid VMAT (VMATh). Quality assurance (QA) implications of the resultant hybrid plans are discussed. The hybrid technique resulted in superior target conformity or improved sparing of OAR or both. The hybrid technique shows promise, but the QA implications of motion at treatment need careful consideration.     

Does background parenchymal enhancement on MRI affect the rate of positive resection margin in breast cancer patients?

Objective:

The purpose of our study was to evaluate whether strong background parenchymal enhancement (BPE) would be a significant independent factor associated with positive resection margin in patients treated initially with breast-conserving surgery (BCS).

Methods:

Retrospective evaluation of breast MRI examinations of 314 patients with breast cancer was carried out. Breast cancer was histologically confirmed in all patients who underwent BCS from January 2008 to December 2010. BPE was dichotomized into weak (minimal or mild) and strong (moderate or marked) enhancement for statistical analysis. Histopathological features of attained specimens were evaluated by an experienced pathologist and were also dichotomized for statistical analysis.

Results:

On univariate analysis, positive extensive intraductal component (p < 0.001), strong BPE (p = 0.001) and human epidermal growth factor receptor 2 (HER2) positivity (p = 0.08) had significant association with positive surgical margin. Tumour size, axillary lymph node metastasis, nuclear grade, histological grade, lymphovascular invasion, oestrogen receptor and progesterone receptor did not show significant correlation with positive surgical margin. On multivariate analysis, the significant independent predictors were extensive intraductal component [odds ratio, 5.68; 95% confidence interval (CI), 2.72–11.82] and strong BPE (odds ratio, 2.39; 95% CI, 1.20–4.78).

Conclusion:

Strong BPE is a significant independent factor for positive resection margin along with positive extensive intraductal component, and performing MRI during the period of lower parenchymal enhancement is needed in patients with strong BPE.

Advances in knowledge:

As far as we know, this is the first study to reveal that BPE is a significant independent factor associated with positive resection margin.Overall survival after breast-conserving surgery (BCS) followed by adjuvant radiation therapy has been shown to be equivalent to that after mastectomy for early stage breast cancer.^1–4 Nowadays, BCS has become the standard treatment for early stage breast cancer. However, the rate of local recurrence is higher in patients with BCS than in those with mastectomy,² and the most important predictor of local recurrence is margin status.⁵ In a meta-analysis reporting local recurrence relative to margin status, odds ratio for local recurrence was 2.42 (p < 0.001) with a positive margin.⁶ There are many known risk factors associated with positive resection margin, including younger age, less than 45 years of age, mammographic density of Category 4, larger tumour size, positive lymph nodes, tumour multifocality, the presence of microcalcification in mammography, lobular histology, higher grade, the presence of extensive intraductal component and the presence of lymphovascular invasion.^7–11Accurate pre-operative assessment of tumour extent is essential for surgical planning and for reducing positive surgical margin. Breast MRI has been widely used for pre-operative evaluation of tumour extent and could substantially decrease the rate of positive resection margins and reoperations in patients with breast cancer who underwent BCS.¹² However, the common problem in MRI interpretation is that there are some difficulties in lesion detection and cancer extent evaluation owing to strong background parenchymal enhancement (BPE) in pre-menopausal patients. Breast tissue is well known to be hormonally sensitive, especially to oestrogen, which is believed to cause increased vascularization of breast parenchyma during actively secreting phase. There are many studies reporting that BPE in pre-menopausal females is higher than that of postmenopausal females, which is thought to be associated with differences in hormone level.^13,14Our hypothesis was that additional cancer foci around the index cancer could be masked by strong BPE, and therefore, positive resection margin would be more frequent in patients who had strong BPE on pre-operative MRI than in patients with weak BPE. The purpose of our study was to evaluate whether the strong BPE would be a significant independent factor associated with positive resection margin.     

Should mediastinoscopy actually be incorporated into the FDG PET strategy for patients with non-small cell lung carcinoma?

BACKGROUND: Incorporating mediastinoscopy (MS) into the PET-based strategy for non-small cell lung carcinoma (NSCLC) patients might be cost-effective because MS can allow unnecessary thoracotomies to be avoided. The objective of our study was to assess the cost-effectiveness of incorporating MS into a PET strategy for NSCLC patients. METHODS: To determine life expectancy (LE), quality adjusted life years (QALY), and the incremental cost-effectiveness ratio (ICER), a decision-tree sensitivity analysis was designed for histopathologically confirmed NSCLC patients with M0 disease, based on the three competing strategies of chest CT only vs. PET + CT vs. PET + CT + MS. A simulation of 1000 NSCLC patients was created using baselines of other relevant variables in regard to sensitivity, specificity, mortality, LE, utilities and cost from published data. One-way sensitivity analyses were performed to determine the influences of mediastinal metastasis prevalence on LE, QALY and ICER. RESULTS: The LE and QALY per patient in the CT only strategy, PET + CT strategy and PET + CT + MS strategy were 4.79 and 4.35, 5.33 and 4.93 and 5.68 and 5.33 years, respectively, with a 20% prevalence of mediastinal metastasis. The ICERs were 906.6 yen x 10(3) (7555 US dollars)/QALY/patient at a 20% mediastinal metastasis prevalence, and 2194 yen x 10(3) (18,282 US dollars)/QALY/patient at a 50% prevalence, but exceeded 5280 yen x 10(3) (44,000 US dollars)/QALY/ patient at 80%. CONCLUSIONS: Our study quantitatively showed the CT + PET + MS strategy in place of the PET + CT strategy in managing NSCLC patients to be cost-effective. MS should be incorporated into the PET + CT strategy for NSCLC patients except in those highly suspected of having mediastinal disease on chest CT or PET.     

Does pregnancy affect vascular enhancement in patients undergoing CT pulmonary angiography?

The aim of this study was to evaluate whether pregnancy affects contrast enhancement within the pulmonary arteries during computed tomography pulmonary angiography (CTPA). This was a retrospective analysis of the CTPA examinations of 16 pregnant and 16 non-pregnant female patients, suspected of having an acute pulmonary embolus (PE), during the same time period. Pulmonary vascular enhancement was evaluated by measuring the CT density within the pulmonary arteries. In a blinded evaluation, subjective grading of contrast enhancement within the pulmonary arteries was also performed. There was a significant difference in arterial enhancement between the two groups, with pregnant patients having a mean pulmonary arterial density 112 HU less than patients in the control group [mean attenuation of 259.79 ± 59.31 HU in pregnant patients versus 371.88 ± 60.63 HU in non-pregnant patients (p < 0.001)]. The mean subjective pulmonary arterial enhancement score in the pregnant group was 8.19 ± 2.51 versus 13.69 ± 3.07 in the control group (p < 0.001). Pregnant women undergoing CTPA have significantly decreased pulmonary arterial enhancement compared to non-pregnant patients, probably due to the increase in cardiac output in pregnancy. We may need to reconsider how we perform CTPA in this group in order to ensure adequate opacification for diagnosis.     

Does the degree of background enhancement in breast MRI affect the detection and staging of breast cancer?

Objective  

The purpose of this study was to assess the influence of background enhancement on the detection and staging of breast cancer using MRI as an adjunct to mammography or ultrasound.