Clinical Investigation
Translating Response During Therapy into Ultimate Treatment Outcome: A Personalized 4-Dimensional MRI Tumor Volumetric Regression Approach in Cervical Cancer

https://doi.org/10.1016/j.ijrobp.2009.02.036Get rights and content

Purpose

To assess individual volumetric tumor regression pattern in cervical cancer during therapy using serial four-dimensional MRI and to define the regression parameters' prognostic value validated with local control and survival correlation.

Methods and Materials

One hundred and fifteen patients with Stage IB2–IVA cervical cancer treated with radiation therapy (RT) underwent serial MRI before (MRI 1) and during RT, at 2–2.5 weeks (MRI 2, at 20–25 Gy), and at 4–5 weeks (MRI 3, at 40–50 Gy). Eighty patients had a fourth MRI 1–2 months post-RT. Mean follow-up was 5.3 years. Tumor volume was measured by MRI-based three-dimensional volumetry, and plotted as dose(time)/volume regression curves. Volume regression parameters were correlated with local control, disease-specific, and overall survival.

Results

Residual tumor volume, slope, and area under the regression curve correlated significantly with local control and survival. Residual volumes ≥20% at 40–50 Gy were independently associated with inferior 5-year local control (53% vs. 97%, p <0.001) and disease-specific survival rates (50% vs. 72%, p = 0.009) than smaller volumes. Patients with post-RT residual volumes ≥10% had 0% local control and 17% disease-specific survival, compared with 91% and 72% for <10% volume (p <0.001).

Conclusion

Using more accurate four-dimensional volumetric regression analysis, tumor response can now be directly translated into individual patients' outcome for clinical application. Our results define two temporal thresholds critically influencing local control and survival. In patients with ≥20% residual volume at 40–50 Gy and ≥10% post-RT, the risk for local failure and death are so high that aggressive intervention may be warranted.

Introduction

Despite advances in the therapy approach, the treatment of advanced cervical cancer remains a challenge, and approximately one third of patients with Stage IB2–IVA tumors die of the disease (1). Once tumor recurrence is found after definitive radiation (RT) and chemotherapy, salvage options and outlook are poor (2).

Early-response assessment during the treatment course, while adjustments in therapy can still be made, has been a challenge because of the difficulty in accurately measuring the volume of irregular tumor shapes and nonlinear tumor shrinkage during treatment. Evaluation of tumor response and therapy success have generally relied on clinical palpation of the tumor by pelvic examination. However, clinical palpation is known to be relatively insensitive in accurately assessing tumor size and volume, particularly during the ongoing course of RT 3, 4, 5.

Magnetic resonance imaging (MRI) provides highly precise assessment of tumor volume and extent in cervical cancer, compared with clinical palpation and other imaging modalities 6, 7, 8. Three-dimensional (3D) MRI-based volumetry is established as the most accurate tumor measurement in cervical cancer on the basis of histopathologic volume correlation (9). Because MRI is noninvasive and can be performed serially during RT and after treatment 10, 11, such high-precision tumor measurement can encounter the challenges of irregular shape and nonlinear tumor shrinkage and improve accuracy for assessing subtle volume changes. This serial quantitative volumetry provides a new glimpse into the “fourth dimension of tumor volume”: the longitudinal volumetric tumor changes during and after the course of RT in cervical cancer.

Tumor response assessments are commonly performed in daily practice and for clinical trials. However, response alone does not readily translate into the reality of ultimate therapy outcome with respect to local control and survival. Even with quantitative response measurements using one- or two-dimensional measurements, size criteria with prognostic value for local control and survival have not been clearly defined in cervical cancer. In the limited experience with studies of serial MRI during RT, the timing of imaging has been variable, and correlation with ultimate tumor control is sparse 12, 13. Therefore, the significance of MRI-based longitudinal tumor volume change during RT is unclear, and there are no well-defined criteria that judge true therapy responsiveness and that can be employed in clinical practice to optimize the therapy strategies.

The purpose of this study was to define and validate four-dimensional (4D) volumetric tumor regression parameters in cervical cancer that are significant for ultimate therapy outcome and potentially applicable to adapt therapy strategy.

The specific aims were as follows: (1) to measure 3D tumor volume with MRI before, during, and after the RT course; (2) to develop dose–tumor volume regression curves and assess velocity of tumor shrinkage, and (3) to derive volume regression parameters and evaluate their correlation with local tumor control, disease-specific, and overall survival.

Section snippets

Patient population and treatment

One hundred and fifteen patients with biopsy-proven advanced cervical cancer who were treated with RT, were studied prospectively with serial MRI. Sixty-five patients had had Fédération Internationale de Gynécologie Obstétrique (FIGO) stage IB2-II, and 50 had Stage III–IV disease. Median age at diagnosis was 50 (range, 25–89) years. Detailed patient characteristics are presented in Table 1.

Pretreatment evaluations were performed following FIGO guidelines (14) and included history and physical

Results

In the 115 patients, the regression slopes derived from the plots of the proportional tumor volumes at MRI 2 and MRI 3 during RT showed wide variability among patients, ranging from 0.3–3.6%/Gy (mean,1.8; median, 1.8; SD, 0.5). Similarly, AUCs were highly variable, ranging from 11.3% to 49.8% (mean, 26.1; median, 25.2; SD, 7.2). There was no significant difference in slope or AUC between patients receiving chemotherapy vs. those with RT alone, nor between patients with squamous vs. non–squamous

Discussion

The critical influence of tumor volume on treatment outcome in cervical cancer is well established. Both local control and survival can profoundly change within the same stage category based on tumor size 15, 16. MRI is now increasingly used in cervical cancer 6, 7, 8, 17, 18, 19, 20 and has greatly refined our ability to delineate and measure cervical tumors (9) over the semiqualitative approach and inaccuracies of clinical palpation 3, 4, 5. Tumor measurement is no longer limited to uni- or

Conclusion

MRI-based 4D volumetric tumor regression pattern reflects the inherent radioresponsiveness of cervical cancers. The temporal threshold criteria of proportional tumor volume at 40–50 Gy and 1–2 months post-therapy independently correlate with local control and survival and may be useful for the adaptation of treatment within the time frame of the RT course or shortly thereafter.

References (26)

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This research was supported by the National Institutes of Health (Contract Grant No. RO1 CA 71906).

Conflict of interest: none.

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