Tumor volume: a basic and specific response predictor in radiotherapy

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Abstract

Background and purpose: Predictive assays of the response of tumor and normal tissues in individual patients offer the possibility of individualized prognosis and treatment decisions. For this purpose a variety of assays are currently being explored. The impact of tumor volume on radiotherapy outcome has long been recognized and in this paper its predictive potential is investigated.

Methods: Re-evaluation of clinical data from the literature.

Results: Tumor volume significantly influences radiotherapy outcome and in many sites it is likely a superior prognostic indicator to tumor stage, which reflects tumor size only partially and is mainly correlated to operability. Tumors even of identical stage may vary by factors of more than 100 in volume and neglect of this heterogeneity clearly reduces the power of a study considerably. The precision requirements for the measurement of tumor volume are small; ±50% is sufficient for reasonable results.

Conclusion: The data evaluated here suggest that tumor volume is the most precise and most relevant predictor of radiotherapy outcome. Its determination is achievable with sufficient accuracy in most radiotherapy departments. Individual tumor volume should always be reported in clinical studies and considered in data analyses.

Introduction

The goal of predictive assays is to measure one or more tumor characteristics that would identify patients who are unlikely to be cured by standard radiotherapy so that they can then be considered for alternative therapy. The planning of clinical trials will be confounded by their omission and the same holds true for the analysis of the outcome of treatment.

The hypoxic fraction of tumors, intrinsic radiosensitivity of tumor cells and their doubling times are recognized potential predictors of tumor response. A further consideration is the number of clonogens that have to be sterilized for tumor cure; in general, a small tumor is more easily controlled with a certain radiation dose than a large tumor. There is in fact a mountain of evidence in the clinical literature for a decisive impact of tumor volume on treatment outcome and the evidence continues to accrue.

For stage IB squamous cell carcinoma of the uterine cervix, central and pelvic tumor control and disease-specific survival correlated strongly (P<0.0001) with tumor diameter [8]. Actuarial relapse rates of IB to IIIB cervix carcinoma significantly depended on tumor size [18]. In a study to assess the prognostic value of pre-treatment potential doubling time (Tpot) in carcinoma of the uterine cervix, tumor size was the only significant predictor (P=0.004) for disease-free survival [27]. Tumor volume significantly influenced the likelihood of disease control in pelvis and survival in patients treated with irradiation alone for stages IB and IIA–B carcinoma of the cervix [19]. Ito et al. [14]divided cervical tumors by their mass into three groups of approximately 50, 100 and 150 g. Tumor mass had a statistically significant influence on both response rate after 2 months and survival (actuarial, 10-year follow up).

Tumor size was a significant factor for local control in 463 breast cancer patients treated with radiotherapy alone [1].

In the randomized head and neck cancer trial EORTC 22811, primary tumor volume and total tumor volume were highly significant factors determining locoregional control and survival [28]. The same parameters were predictors of disease-free survival in 51 cases of advanced squamous cell carcinoma of the head and neck [15]. The correlation between local recurrence and tumor size was significant (P<0.001) in 308 stage I–IV laryngeal carcinoma patients 7, 13. Control of positive neck nodes treated with irradiation only depended significantly on node diameter [24]. There was a significant impact of tumor volume on local control of supraglottic larynx carcinoma [9]and T3 glottic carcinoma [22]and in these studies it was shown that patients in the T3 stage grouping could be divided into two groups with significantly different outcome, based only on the volume of primary.

In a study of 204 lesions of malignant melanoma, tumor size was of major importance (P<0.001) in the prediction of local control 5, 21.

The influence of tumor volume has been the subject of a number of recent publications 3, 6. It is often not mentioned that the measurement of tumor volume is not an easy matter in some tumor sites. The purpose of this paper is to consider the matter further, with particular emphasis on the level of accuracy that would be required to make tumor volume a meaningful predictor of clinical outcome.

Section snippets

Impact of tumor volume

Other factors being equal, small tumors are easier to cure than large tumors, on account of there being fewer clonogens to sterilize [26]. Under the assumption that, on average, the number of tumor clonogens is proportional to its volume [6], the control probabilities TCP1 and TCP2 of two tumors of different size are given by (n, density of clonogenic tumor cells; V1, V2, volume; SF, surviving fraction after irradiation)TCP1=e−nV1×SFandTCP2=e−nV2×SFwhich yields [10]TCP2=TCP(V2/V1)1=TCPVrel1

Experimental data

In Fig. 2 we have transposed the curve from Fig. 1 exactly as it stands, lining up the horizontal position of the curve on the logarithmic abscissa to suit the experimental volume data that is given in absolute units. We then overlaid the experimental tumor control rates. The results for local control of the rat rhabdomyosarcoma R1H clearly depend on tumor size.

Clinical data

Clinical studies demonstrating a significant impact of tumor volume on treatment outcome for tumors of different sites and stages are

Discussion of results

The clinical volume response data (Fig. 3A–HFig. 4) agree well with the predicted curve in Fig. 1 but the relationship appears to be less steep than expected. This is likely to be due to a variety of sources of inhomogeneity, including inaccuracies in volume measurement, variations in treatments administered, differences in primary site and biological variability, e.g. in radiosensitivity. In some of the studies tumor diameters were measured using rather crude methods and volume was calculated

Conclusions

Volume appears to be the main factor in determining treatment outcome in radiotherapy. This is in accordance with common sense and it is confirmed by experimental and clinical data. The precision requirements of volume measurement are low (±50% standard deviation) and manageable for many tumor entities in most radiotherapy departments. In many cases tumor size can reasonably be estimated from one or two diameters measured from radiographs or by means of sonography. Acquisition of volume data is

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