Microscopic Disease Extension Research Articles

Clinicopathologic analysis of microscopic tumor extension in glioma for external beam radiotherapy planning

BackgroundThere is no consensus regarding the clinical target volume (CTV) margins in radiotherapy for glioma. In this study, we aimed to perform a complete macropathologic analysis examining microscopic tumor extension (ME) to more accurately define the CTV in glioma.MethodsThirty-eight supra-total resection specimens of glioma patients were examined on histologic sections. The ME distance, defined as the maximum linear distance from the tumor border to the invasive tumor cells, was measured at each section. We defined the CTV based on the relationships between ME distance and clinicopathologic features.ResultsBetween February 2016 and July 2020, a total of 814 slides were examined, corresponding to 162 slides for low-grade glioma (LGG) and 652 slides for high-grade glioma (HGG). The ME value was 0.69 ± 0.43 cm for LGG and 1.29 ± 0.54 cm for HGG (P < 0.001). After multivariate analysis, tumor grade, O6-methylguanine-DNA-methyltransferase promoter methylated status (MGMTm), isocitrate dehydrogenase wild-type status (IDHwt), and 1p/19q non-co-deleted status (non-codel) were positively correlated with ME distance (all P < 0.05). We defined the CTV of glioma based on tumor grade. To take into account approximately 95% of the ME, a margin of 1.00 cm, 1.50 cm, and 2.00 cm were chosen for grade II, grade III, and grade IV glioma, respectively. Paired analysis of molecularly defined patients confirmed that tumors that had all three molecular alterations (i.e., MGMTm/IDHwt/non-codel) were the most aggressive subgroups (all P < 0.05). For these patients, the margin could be up to 1.50 cm, 2.00 cm, and 2.50 cm for grade II, grade III, and grade IV glioma, respectively, to cover the subclinical lesions in 95% of cases.ConclusionsThe ME was different between the grades of gliomas. It may be reasonable to recommend 1.00 cm, 1.50 cm, and 2.00 cm CTV margins for grade II, grade III, and grade IV glioma, respectively. Considering the highly aggressive nature of MGMTm/IDHwt/non-codel tumors, for these patients, the margin could be further expanded by 0.5 cm. These recommendations would encompass microscopic disease extension in 95% of cases.Trial registrationThe trial was registered with Chinese Clinical Trial Registry (ChiCTR2100049376).

Unilateral versus bilateral nodal irradiation: Current evidence in the treatment of squamous cell carcinoma of the head and neck.

Cancers of the head and neck region often present with nodal involvement. There is a long-standing convention within the community of head and neck radiation oncology to irradiate both sides of the neck electively in almost all cases to include both macroscopic and microscopic disease extension (so called elective nodal volume). International guidelines for the selection and delineation of the elective lymph nodes were published in the early 2000s and were updated recently. However, diagnostic imaging techniques have improved the accuracy and reliability of nodal staging and as a result, small metastases that used to remain undetected and were thus in the past included in the elective nodal volume, will now be included in high-dose volumes. Furthermore, the elective nodal areas are situated close to the parotid glands, the submandibular glands and the swallowing muscles. Therefore, irradiation of a smaller, more selected volume of the elective nodes could reduce treatment-related toxicity. Several researchers consider the current bilateral elective neck irradiation strategies an overtreatment and show growing interest in a unilateral nodal irradiation in selected patients. The aim of this article is to give an overview of the current evidence about the indications and benefits of unilateral nodal irradiation and the use of SPECT/CT-guided nodal irradiation in squamous cell carcinomas of the head and neck.

Consensus Contouring Guidelines for Postoperative Completely Resected Cavity Stereotactic Radiosurgery for Brain Metastases

To propose contouring guidelines based on consensus contours generated by 10 international experts for cavity stereotactic radiosurgery (SRS), an emerging treatment option after surgical resection of brain metastases. No guidelines for contouring the surgical cavity volume have been previously reported. Ten postoperative completely resected cases with varying clinical scenarios and locations within the brain were selected. For each case, 10 expertsindependently contoured the surgical cavity clinical target volume (CTV). All the contours were analyzed, and agreement was calculated using the simultaneous truth and performance level estimation (STAPLE) with the kappa statistic. A follow-up survey was also completed by each investigator to summarize their contouring rationale for a number of different clinical scenarios. The results from the survey and theconsensus STAPLE contours were both summarized to establish contouring guidelines. A high level of agreement was found between the expert CTV contours (mean sensitivity 0.75, mean specificity 0.98), and the mean kappa was 0.65. The agreement was statistically significant at P<.001 for all cases. From these results and analyses of the survey answers, the recommendations for CTV include fusion of the preoperative magnetic resonance imaging scan to aid in volume delineation; contouring the entire surgical tract regardless of the preoperative location of the tumor; extension of the CTV 5 to 10 mm along the dura overlying the bone flap to account for microscopic disease extension in cases with preoperative dural contact; and a margin of ≤5 mm into the adjacent sinus when preoperative venous sinus contact was present. Consensus contouring guidelines for postoperative completely resected cavity SRS treatment were established using expert contours and clinical practice. However, in the absence of clinical data supporting these recommendations, these guidelines serve as a baseline for further study and refinement.

Consensus Contouring Guidelines for Postoperative Stereotactic Body Radiation Therapy for Metastatic Solid Tumor Malignancies to the Spine

Todevelop consensus contouring guidelines for postoperative stereotactic body radiation therapy (SBRT) for spinal metastases. Ten spine SBRT specialists representing 10 international centers independently contoured the clinical target volume (CTV), planning target volume (PTV), spinal cord, and spinal cord planning organ at risk volume (PRV)for 10 representative clinical scenarios in postoperative spine SBRT for metastatic solid tumor malignancies. Contours were imported into the Computational Environment for Radiotherapy Research. Agreement between physicians was calculated with an expectation minimization algorithm using simultaneous truth and performance level estimation with κ statistics. Target volume definition guidelines were established by finding optimized confidence level consensus contours using histogram agreement analyses. Nine expert radiation oncologists and 1 neurosurgeon completed contours for all 10 cases. The mean sensitivity and specificity were 0.79 (range, 0.71-0.89) and 0.94 (range, 0.90-0.99) for the CTV and 0.79 (range, 0.70-0.95) and 0.92 (range, 0.87-0.99) for the PTV), respectively. Mean κ agreement, which demonstrates the probability that contours agree by chance alone, was 0.58 (range, 0.43-0.70) for CTV and 0.58 (range, 0.37-0.76) for PTV (P<.001 for all cases). Optimized consensus contours were established for all patients with 80% confidence interval. Recommendations for CTV include treatment of the entire preoperative extent of bony and epidural disease, plus immediately adjacent bony anatomic compartments at risk of microscopic disease extension. In particular, a "donut-shaped" CTV was consistently applied in cases of preoperative circumferential epidural extension, regardless of extent of residual epidural extension. Otherwise more conformal anatomic-based CTVs were determined and described. Spinal instrumentation was consistently excluded from the CTV. We provide consensus contouring guidelines for common scenarios in postoperative SBRT for spinal metastases. These consensus guidelines are subject to clinical validation.

Impact of microscopic disease extension, extra-CTV tumour islets, incidental dose and dose conformity on tumour control probability.

The impact of microscopic disease extension (MDE), extra-CTV tumour islets (TIs), incidental dose and dose conformity on tumour control probability (TCP) is analyzed using insilico simulations in this study. MDE in the region in between GTV and CTV is simulated inclusive of geometric uncertainties (GE) using spherical targets and spherical dose distribution. To study the effect of incidental dose on TIs and the effect of dose-response curve (DRC) on tumour control, islets were randomly distributed and TCP was calculated for various dose levels by rescaling the dose. Further, the impact of dose conformity on required PTV margins is also studied. The required PTV margins are ~2mm lesser than assuming a uniform clonogen density if an exponential clonogen density fall off in the GTV-CTV is assumed. However, margins are almost equal if GE is higher in both cases. This shows that GE has a profound impact on margins. The effect of TIs showed a bi-phasic relation with increasing dose, indicating that patients with islets not in the beam paths do not benefit from dose escalation. Increasing dose conformity is also found to have considerable effect on TCP loss especially for larger GE. Further, smaller margins in IGRT should be used with caution where uncertainty in CTV definition is of concern.

Significance of Microscopic Disease Extension in Regional Control of Lung Cancer

Significance of Microscopic Disease Extension in Regional Control of Lung Cancer

The impact of microscopic disease on the tumor control probability in non-small-cell lung cancer

PurposeTo indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. Methods and materialsOn the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. ResultsThe presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. ConclusionsMDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.

Microscopic Disease Extension in Three Dimensions for Non–Small-Cell Lung Cancer: Development of a Prediction Model Using Pathology-Validated Positron Emission Tomography and Computed Tomography Features

One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high-risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors.

9043 Computer-assisted prediction of microscopic disease extension around non-small cell lung cancer using a pathology-validated PET/CT classifier

9043 Computer-assisted prediction of microscopic disease extension around non-small cell lung cancer using a pathology-validated PET/CT classifier

Using Histopathology Breast Cancer Data to Reduce Clinical Target Volume Margins at Radiotherapy

This study aimed to quantify the incidence and extension of microscopic disease around primary breast tumors in patients undergoing breast-conserving therapy (BCT), focusing on a potential application to reduce radiotherapy boost volumes. An extensive pathology tumor-distribution study was performed using 38 wide local excision specimens of BCT patients. Specimen orientation was recorded and microscopic findings reconstructed to assess the incidence of microscopic disease around the macroscopic tumor. A model of disease spread was built, showing probability of disease extension outside a treated volume (P(out,vol)). The model was applied in 10 new BCT patients. Taking asymmetry of tumor excision into account, new asymmetric margins for the clinical target volume of the boost (CTV(boost)) were evaluated that minimize the volume without increasing P(out,TTV) (TTV being total treated volume: V(surgery) + CTV(boost)). Potential reductions in CTV(boost) and TTV were evaluated. Microscopic disease beyond the tumor boundary occurred isotropically at distances > 1 cm (intended surgical margin) and > 1.5 cm (intended TTV margin) in 53% and 36% of the excision specimens, respectively. In the 10 prospective patients, the average P(out,TTV) was, however, only 16% due to larger surgical margins than intended in some directions. Asymmetric CTV(boost) margins reduced the CTV(boost) and TTV by 27% (20 cc) and 12% (21 cc) on average, without compromising tumor coverage. Microscopic disease extension may occur beyond the current CTV(boost) in approximately one sixth of patients. An asymmetric CTV(boost) that corrects for asymmetry of the surgical excision has the potential to reduce boost volumes while maintaining tumor coverage.

Defining the Clinical Target Volume for Bladder Cancer Radiotherapy Treatment Planning

There are currently no data for the expansion margin required to define the clinical target volume (CTV) around bladder tumors. This information is particularly relevant when perivesical soft tissue changes are seen on the planning scan. While this appearance may reflect extravesical extension (EVE), it may also be an artifact of previous transurethral resection (TUR). Eighty patients with muscle-invasive bladder cancer who had undergone radical cystectomy were studied. All patients underwent preoperative TUR and staging computed tomography (CT) scans. The presence and extent of tumor growth beyond the outer bladder wall was measured radiologically and histopathologically. Forty one (51%) patients had histologically confirmed tumor extension into perivesical fat. The median and mean extensions beyond the outer bladder wall were 1.7 and 3.1 mm, respectively. Thirty five (44%) patients had EVE, as seen on CT scans. The sensitivity and specificity of CT scans for EVE were 56% and 79%, respectively. False-positive results were infrequent and not affected by either the timing or the amount of tissue resected at TUR. CT scans consistently tended to overestimate the extent of EVE. Tumor size and the presence of either lymphovascular invasion or squamoid differentiation predict a greater extent of EVE. In patients with radiological evidence of extravesical disease, the CTV should comprise the outer bladder wall plus a 10-mm margin. In patients with no evidence of extravesical disease on CT scans, the CTV should be restricted to the outer bladder wall plus a 6-mm margin. These recommendations would encompass microscopic disease extension in 90% of cases.

SU‐GG‐J‐112: Integration and Verification of 3T Magnetic Resonance Spectroscopic Imaging in Radiation Therapy Treatment Planning

Purpose: The purpose of this work is to test the feasibility of MRSI integration into brain tumor RT planning using a custom‐built MRSI head phantom as well as a case study. Method and Materials: A special MRSI head phantom was constructed with spatially well‐defined tube inserts. Each tube contains different pre‐determined concentrations of metabolite solutions that mimic different degrees of brain tumor burden and were immersed in a background solution that emulate normal brain metabolite levels. The 3D MRSI data were acquired on a Siemens 3T TRIO TIM scanner using PRESS (point resolved spectroscopy) sequence with TE/TR: 135/1510 ms, 16×16×8 matrix, FOV: 16×16×8 resulting in MRSI voxel size of 10×10×10 mm3. Registration of MRSI (gray scale DICOM) data with planning CT and creation of metabolite‐derived target contours were performed on Pinnacle treatment planning system. Target contours created using MRSI‐derived tumor metabolic abnormalities were compared with those created based on morphological (T2 and T1 contrast weighted) MRI scans. Results: The CT‐MR (T1) registration accuracy was found to be within 1 mm, with no spatial distortion during MRSI. Registration errors were found in the TPS due to field‐of‐view size and origin difference between studies. These were corrected using a simple algorithm to determine the translation. Re‐scaled MRSI pixel values allowed automated segmentation of metabolic ratios and were consistent with those identified on the control console of the MRI scanner. When applied to a clinical case, a 42 cc (or 58%) reduction in the treated volume of the PTV was possible, assuming the CNI ratio of 2.5 included all microscopic extension of disease requiring the boost dose. Conclusion: MRSI derived functional information can be incorporated into RT planning for brain tumors well within the registration tolerance limits of current planning process.

The outcomes of patients with positive margins after excision for intraepithelial Paget's disease of the vulva

Vulvar Paget's disease is a rare neoplasm that usually occurs in postmenopausal women. Treatment with surgical excision can be complicated by extension of microscopic disease in an irregular manner well beyond the visible margins of the lesion. The objective or our study was to analyze the outcomes of patients with primary vulvar intraepithelial Paget's disease who had positive microscopic margins after primary excision. We reviewed the records of all patients with Paget's disease of the vulva treated at our institution from 1/80 to 9/02. Patients whose sample showed stromal invasion or an underlying carcinoma were excluded. Data were collected regarding patient demographics, disease location, treatment, surgical margin status, additional treatment, and clinical outcome. The medical records and histopathologic specimens of 28 women with intraepithelial Paget's disease of the vulva were evaluated. Surgical treatment consisted of radical vulvectomy in 3 patients (11%), simple vulvectomy in 18 patients (64%), and wide local excision in the other 7 patients (25%). Of the 20 patients with microscopically positive margins, 14 (70%) developed recurrent disease and the remaining 6 (30%) are disease free. Of the 8 patients with negative margins, 3 (38%) developed disease recurrence and the remaining 5 (63%) are disease free. With a median follow-up of 49 months (range, 3-186 months), there was no correlation between disease recurrence and margin status (P=0.20). Of the 17 patients who recurred, 14 (82%) underwent additional surgical excision and 1 patient was treated with Retin-A. The remaining 2 patients refused further treatment and were lost to follow-up. In those patients who underwent surgery for recurrence, between 1 and 3 re-excisions were performed. Of the 15 evaluable patients who were treated for recurrent disease, 12 (80%) had no evidence of persistent disease and 3 (20%) had persistent disease at a median follow-up of 63.7 months (range, 18.5-186 months). Microscopically positive margins following surgical excision of vulvar intraepithelial Paget's disease is a frequent finding, and disease recurrence is common regardless of surgical margin status. Long-term monitoring of patients is recommended, and repeat surgical excision is often necessary.

Three dimensional conformal radiation therapy in pediatric parameningeal rhabdomyosarcomas

We evaluated the utility of three dimensional (3D) treatment planning in the management of children with parameningeal head and neck rhabdomyosarcomas. Five children with parameningeal rhabdomyosarcoma were referred for treatment at our radiation oncology center from May 1990 through January 1993. Each patient was evaluated, staged, and treated according to the Intergroup Rhabdomyosarcoma Study. Patients were immobilized and underwent a computed tomography scan with contrast in the treatment position. Tumor and normal tissues were identified with assistance from a diagnostic radiologist and defined in each slice. The patients were then planned and treated with the assistance of a 3D treatment planning system. A second plan was then devised by another physician without the benefit of the 3D volumetric display. The target volumes designed with the 3D system and the two-dimensional (2D) method were then compared. The dosimetric coverage to tumor, tumor plus margin, and normal tissues was also compared with the two methods of treatment planning. The apparent size of the gross tumor volume was underestimated with the conventional 2D planning method relative to the 3D method. When margin was added around the gross tumor to account for microscopic extension of disease in the 2D method, the expected area of coverage improved relative to the 3D method. In each circumstance, the minimum dose that covered the gross tumor was substantially less with the 2D method than with the 3D method. The inadequate dosimetric coverage was especially pronounced when the necessary margin to account for subclinical disease was added. In each case, the 2D plans would have delivered substantial dose to adjacent normal tissues and organs, resulting in a higher incidence of significant complications. 3D conformal radiation therapy has a demonstrated advantage in the treatment of sarcomas of the head and neck. The improved dosimetric coverage of the tumor and its margin for subclinical extensions may result in improvement in local control of these tumors. In addition, lowering of radiation dose to adjacent critical structures may help lower the incidence of adverse late effects in children.

Dosimetric evaluation of two multileaf collimator conformation strategies for irregular fields

Purpose: The ICRU 50 has defined the concept of planning target volume (PTV) to include the combined volumes of gross disease, suspected extension of microscopic disease and the dosimetric uncertainties due to setup error and isodose constriction. Cerrobend block outlines are designed to meet these criteria. Concern exists that multileafcollimator (MLC) conformation strategies may require different margins to meet these criteria. Several MLC geometric blocking strategies are readily accessible and are currently employed. We examined two commonly used strategies for MLC conformation to the PTV. The first conforms the leaves such that the total area of overshoot and undershoot is minimized resulting in least area discrepancy (LAD). The second conforms the MLC such that the areas of overshoot and undershoot are equivalent and has been termed “transecting” (TRN). The goal of this study was to evaluate dosimetrically these MLC conformation schemes for irregular fields using cerrobend block as a comparison.

Adjuvant Radiotherapy Following Radical Prostatectomy: Results and Complications

Between 1954 and 1978, 148 patients underwent radical perineal prostatectomy for adenocarcinoma clinically confined to the prostate gland. This report is based on 45 of these patients with microscopic extension of disease beyond the gland and a minimum 5-year followup. Of the patients 22 received adjuvant external beam radiation therapy and 23 did not. The groups were comparable with regard to significant prognostic variables. Patient selection was by surgeon preference. Local recurrences were seen in 1 of 22 patients (5 per cent) receiving adjuvant radiotherapy and 7 of 23 (30 per cent) undergoing an operation alone (p less than 0.05). Of 8 patients with local recurrence 7 died of the disease. Delayed radiotherapy of a local recurrence generally was not effective in controlling the disease. Of the 11 patients who died of prostatic cancer with a mean followup of 9.2 years 3 received adjuvant radiotherapy and 8 did not. Severe but nonfatal long-term complications were seen in 14 per cent of the irradiated patients and 6 per cent of those treated with an operation alone. Most of the complications occurred in the earlier years of the study in patients who received 60 cobalt radiotherapy. When clinical stage B cancer of the prostate is found to be pathological stage C following radical perineal prostatectomy, adjuvant radiotherapy can decrease the incidence of subsequent local recurrence. The potential risk of adjuvant radiation therapy should be weighed and its use considered, particularly in patients whose tumor extends to the surgical margins or who have seminal vesicle invasion.