Clinical investigation: lung
Evaluation of microscopic tumor extension in non–small-cell lung cancer for three-dimensional conformal radiotherapy planning

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Abstract

Purpose: One of the most difficult steps of the three-dimensional conformal radiotherapy (3DCRT) is to define the clinical target volume (CTV) according to the degree of local microscopic extension (ME). In this study, we tried to quantify this ME in non–small-cell lung cancer (NSCLC).

Material and Methods: Seventy NSCLC surgical resection specimens for which the border between tumor and adjacent lung parenchyma were examined on routine sections. This border was identified with the naked eye, outlined with a marker pen, and the value of the local ME outside of this border was measured with an eyepiece micrometer. The pattern of histologic spread was also determined.

Results: A total of 354 slides were examined, corresponding to 176 slides for adenocarcinoma (ADC) and 178 slides for squamous cell carcinoma (SCC). The mean value of ME was 2.69 mm for ADC and 1.48 mm for SCC (p = 0.01). The usual 5-mm margin covers 80% of the ME for ADC and 91% for SCC. To take into account 95% of the ME, a margin of 8 mm and 6 mm must be chosen for ADC and SCC, respectively. Aerogenous dissemination was the most frequent pattern observed for all groups, followed by lymphatic invasion for ADC and interstitial extension for SCC.

Conclusion: The ME was different between ADC and SCC. The usual CTV margin of 5 mm appears inadequate to cover the ME for either group, and it must be increased to 8 mm and 6 mm for ADC and SCC, respectively, to cover 95% of the ME. This approach is obviously integrated into the overall 3DCRT procedure and with other margins.

Introduction

Optimization of conformal radiotherapy of intrathoracic tumors is based on an improved definition of target volumes to (1) include all of the macroscopic tumor volume and microscopic extension, and (2) limit exposure of the surrounding healthy lung tissue. The achievement of this goal, practically impossible with classical external beam techniques, is nearly reached with the three-dimensional conformal radiation therapy (3DCRT) introduced in the last decade. But, because of the present inability to define the boundaries between tumor and normal tissues in absolute terms, radiation target volumes have classically included a “safety” margin of surrounding normal tissue. In 1993, the “International Commission on Radiation Units and Measurements” (ICRU) published Report 50, which contained recommendations on how to report a treatment in external photon beam therapy (1). The recent ICRU Report 62 (2), supplement to ICRU 50, revises some of the definitions and concepts especially to differentiate between internal movements and setup inaccuracy. However the initial concepts of gross tumor volume (GTV) and clinical target volume (CTV) are not reconsidered. The GTV corresponds to the tumor volume as delineated from palpation or imaging. The CTV is the volume of tissue including the GTV, associated with a significant probability of containing microscopic tumor extensions (subclinical disease). In addition to these clinicopathologic volumes, defined by the radiotherapist, other margins, such as the planning target volume (PTV) are defined. In the ICRU Report 62, the PTV is specified with more accurate precision, its global concept being not changed. The internal margin (IM) definition is added to take into account geometric uncertainties, such as those due to organ movements during breathing, and the setup margin (SM) is added to take into account all uncertainties in patient–beam positioning 3, 4. Segregating the IM and the SM from the PTV reflects the differences in the source of uncertainties (2).

Modern imaging modalities (CT, MRI, isotope imaging) and three-dimensional (3D) treatment-planning systems give access to better organ delineation, which makes it possible to identify more precisely the tumor and healthy tissues 5, 6. Many uncertainties persist, however, and determination of the CTV is probably one of the most difficult challenges for radiotherapists. They must define the limits of the CTV based exclusively on their own experience, as none of the available imaging techniques allows to detect microscopic extension (ME) directly. This is the most controversial margin, and its delineation, often very vague in published studies, is still considered to be more of an art than a science (7).

The classical attitude in NSCLC consists of adding a margin of 1.5–2 cm around the GTV, but this margin appears to be excessive, especially in dose-intensification studies, in which a 3D addition of the margins considerably increases the volume of healthy lung tissue receiving high doses and consequently the risk of pneumonitis (5). On the other hand, clinical and experimental studies suggest that distant metastases in many patients with local failure are derived from new metastatogenic clonogens generated only secondarily to the regrowth of the primary tumor, and that radiation therapy has a curative potential when the primary tumor is confined to its locoregional site (8).

Therefore improvement of the therapeutic efficiency is strongly dependent on the ability to define precisely the limits of the target volumes and especially the limits of the CTV. The aim of this study was to evaluate the ME of NSCLC quantitatively from histologic investigations to define the CTV as precisely as possible. We also investigated whether or not ME depended on any particular clinical or histologic factors that would allow the CTV to be optimally adapted to individual situations.

Section snippets

Patients

Over a 12-month period (April 1998 to April 1999), 81 NSCLC specimens, treated by lobectomy or pneumonectomy, were sent to the Pathology Department of Hôpital Tenon. Eleven not well-fixed specimens were eliminated. Seventy operative specimens were examined by a systematic macroscopic protocol (see Table 1), according to pathology consensus guidelines concerning the site and number of samples (9). Samples were taken from the specimen after manual injection of 10% formalin, either endobronchially

Patient population

The patient characteristics are presented in Table 1. 176 slides of adenocarcinomas (ADC) derived from 32 tumors and 178 slides of SCC derived from 38 tumors were analyzed. Patients with SCC were more often men (92% vs. 68%, p = 0.02) and were significantly older (67.8 vs. 61.4 years, p = 0.02) than patients with ADC. The distributions according to stage, TNM, and pTNM classification, and tumor site were similar for the 2 histologic groups.

Topographically, SCC were situated proximally in the

Discussion

Based on their clinical experience, radiotherapists know that subclinical invasion is present around the GTV, in the form of isolated tumor cells, small tumor islands, or real microscopic tumor extension. Unfortunately, this subclinical invasion cannot be visualized by any available imaging system, possibly with the exception of positron emission tomography (PET), which is currently under evaluation (15). An additional margin, irradiated at the same dose as the GTV, is therefore added around

Conclusion

In this study, we have measured the microscopic tumor extension of NSCLC used to define the CTV for 3DCRT techniques. The mean microscopic extension for all of the samples examined was much lower than the CTV usually adopted and differed considerably between the two histologic types studied. On good quality samples, ME was equal to 1.48 mm for SCC and 2.69 mm for ADC. In the more practical context of radiotherapy, these results can be expressed in terms of probability, in which ME corresponds

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