International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationTranslating Response During Therapy into Ultimate Treatment Outcome: A Personalized 4-Dimensional MRI Tumor Volumetric Regression Approach in Cervical Cancer
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.
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Cited by (50)
Image-guided Adaptive Radiotherapy in Cervical Cancer
2019, Seminars in Radiation OncologyCitation Excerpt :In principle, such adaptive treatment planning may be used for any clinical scenario which may benefit from differential doses to different volumes at different risk of recurrence (eg, vagina,16,17 ano-rectal,18,19 oesophagus,20 or head and neck [nasopharynx]21), using any form of high-dose boost technique (eg, brachytherapy, stereotactic photon boosts, or protons and other heavy particles) (Fig. 1). The regression of cervical cancer during chemo-radiation has been investigated in several studies.22 The overall reduction in volume is around 80%-90% at the time of brachytherapy.23
Magnetic resonance imaging during definitive chemoradiotherapy can predict tumor recurrence and patient survival in locally advanced cervical cancer: A multi-institutional retrospective analysis of KROG 16-01
2017, Gynecologic OncologyCitation Excerpt :Another aspect to consider in our data is the association of the tumor size and RFS. Despite some limitations of tumor size evaluation described above, tumor size is still a very significant prognostic factor in cervical cancer [22,23]. In our analysis, tumor size (p = 0.028) demonstrated stronger association with RFS than tumor response (p = 0.045).
A volumetric analysis of GTV<inf>D</inf> and CTV<inf>HR</inf> as defined by the GEC ESTRO recommendations in FIGO stage IIB and IIIB cervical cancer patients treated with IGABT in a prospective multicentric trial (EMBRACE)
2016, Radiotherapy and OncologyCitation Excerpt :Additionally, the extent of parametrial disease in both MRI-D and MRI-BT was scored as no involvement, proximal if within the proximal half of the parametrial space, distal if within the distal half of the parametrial space, or extension to the pelvic wall. The classification criteria were selected based on our knowledge of the impact of initial tumor volume and magnitude of response to CRT represented by the volume of residual disease (CTVHR) and extent of residual parametrial on local dose delivery by BT and subsequently on local control and overall disease outcome [4,5,7–9,13–15]. These were quantified by (1) the volume of the GTVD relative to the median volume of the GTVD of the study population (approximately 40 cm3), by which tumors were classified into small tumors if GTVD was ⩽40 cm3 or large if GTVD was > 40 cm3; (2) the ratio of the CTVHR (considered as a surrogate of residual tumor volume at the time of BT) to GTVD (⩽0.9 vs. 0.9–1.1 vs. >1.1); and (3) the extent of residual disease along the parametria at BT (no involvement vs. proximal vs. distal or to pelvic wall).
This research was supported by the National Institutes of Health (Contract Grant No. RO1 CA 71906).
Conflict of interest: none.