Assessment of the early predictive power of quantitative magnetic resonance imaging parameters during neoadjuvant chemotherapy for uterine cervical cancer.

ORIGINAL STUDY

Assessment of the Early Predictive Power of Quantitative Magnetic Resonance Imaging Parameters During Neoadjuvant Chemotherapy for Uterine Cervical Cancer Yuki Himoto, MD,* Koji Fujimoto, MD, PhD,* Aki Kido, MD, PhD,* Noriomi Matsumura, MD, PhD,Þ Tsukasa Baba, MD, PhD,Þ Sayaka Daido, MD,* Kayo Kiguchi, MD,* Fuki Shitano, MD,* Ikuo Konishi, MD, PhD,Þ and Kaori Togashi, MD, PhD*

Objectives: The purpose of this study was to quantitatively evaluate 3 types of magnetic resonance imaging (MRI) parameters in parallel for the early prediction of neoadjuvant chemotherapy (NACT) effectiveness in cervical cancerVtumor volume parameters, diffusion parameters, and perfusion parameters. Materials and Methods: We prospectively evaluated 13 patients with International Federation of Gynecology and Obstetrics stage IB to IIB cervical squamous cell carcinoma who underwent 3 serial MRI studies, that is, pretreatment, postYfirst course NACT, and postYsecond course NACT followed by radical hysterectomy. We obtained tumor volume parameters, diffusion parameters, and dynamic contrast materialYenhanced perfusion parameters quantitatively from pretreatment MRI and postYfirst course MRI. The correlation of these parameters and the eventual tumor volume regression rate (TVRR) obtained from pretreatment MRI and postYsecond course MRI before surgery were investigated, statistically based on the Pearson correlation coefficient. Results: Thirteen patients had a total of 39 scans. Early TVRR (r = 0.844; P G 0.001), the fractional volume of the tissue extracellular extravascular space (Ve, r = 0.648; P G 0.05), and the change of Ve during the first course of NACT (r = j0.638; P G 0.05) correlated with eventual TVRR. Conclusions: Early TVRR, Ve, and the change of Ve could be useful predictors for the treatment effectiveness of NACT. These parameters could help to modify strategy in the early stage of NACT and to choose individualized treatment to avoid the delay of radical treatment, even when NACT is ineffective. Key Words: Uterine cervical cancer, Neoadjuvant chemotherapy, Magnetic resonance imaging, Diffusion-weighted imaging, Perfusion-weighted imaging, Tumor volume Received October 16, 2013, and in revised form February 12, 2014. Accepted for publication February 18, 2014. (Int J Gynecol Cancer 2014;24: 751Y757)

Departments of *Diagnostic Imaging and Nuclear Medicine, and †Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Address correspondence and reprint requests to Koji Fujimoto, MD, PhD, Department of Diagnostic Imaging and Nuclear Medicine, Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000124 International Journal of Gynecological Cancer

Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net). The authors declare no conflicts of interest.

& Volume 24, Number 4, May 2014

Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

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International Journal of Gynecological Cancer

cervical cancer is the third most commonly diagU terine nosed cancer and the fourth leading cause of cancer death

in women worldwide.1 By International Federation of Gynecology and Obstetrics staging, the prognosis of cervical cancers in stage IB2 to IIB is relatively poor.2 For cervical cancers in these stages, concurrent chemoradiation (CCRT) is now considered the standard of care worldwide. Neoadjuvant chemotherapy (NACT) followed by radical surgery is another treatment of choice in these stages.3Y5 The purpose of NACT for cervical cancer is to reduce the tumor volume before radical surgery and to eliminate latent/micro lymph node metastases.6 A randomized phase 3 study of NACT followed by surgery versus CCRT in patients with stage IB2 to IIB uterine cervical cancer is under investigation by the European Organisation for Research and Treatment of Cancer (EORTC 55994). The NACT for squamous cell carcinoma of the uterine cervix consists of several courses of chemotherapy that include a platinum-containing agent.7 The most important problem with NACT is the delay of definitive treatment when NACT is found to be ineffective. When this occurs, modifying the treatment strategy has to be considered, including earlier surgery or radiation therapy (RT).5 Thus, robust early predictors of NACT effectiveness would be helpful. We evaluated the quantitative magnetic resonance imaging (MRI) performed before and during NACT to see if any measurable parameters can serve as predictive biomarkers. Recent advances in MRI have made possible precise morphological imaging and various types of functional imaging that reflect the microenvironment of tumors.8,9 Various surrogate imaging parameters extracted from these techniques, such as tumor volume, water diffusion, and perfusion within tumor tissue, are reported to be useful for predicting cancer treatment effectiveness. For cervical cancer, the utility of quantitative MRI has been shown for RT and CCRT.10Y14 However, to our knowledge, there are a limited number of reports investigating multiple parameters simultaneously.14 Reports investigating the utility of quantitative MRI for NACT are also limited.15 The purpose of this study was to prospectively evaluate the predictive power of MRI tumor volume parameters, diffusion parameters, and perfusion parameters obtained at baseline and midtreatment for the effectiveness of NACT in cases of cervical cancer.

MATERIALS AND METHODS Ethics approval for this prospective study was granted by the institutional review board, and written informed consent was obtained from all the patients. Inclusion criteria for this study were as follows: (1) diagnosis of squamous cell carcinoma of the uterine cervix in clinical stages IB2 to IIB and (2) planned treatment with NACT followed by radical surgery. Between October 2010 and October 2012, 13 patients (mean age, 52.3 years; range, 30Y64 years) were enrolled. All patients had undergone biopsy, and their conditions were diagnosed with squamous cell carcinoma by an experienced gynecological pathologist and clinically staged by an experienced gynecological oncologist. Four patients were in stage IB2, 9 patients were in stage IIB, and no patients were in stage

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IIA. For this preliminary study, MRI parameters obtained were not used to modify the treatment strategy. Based on the consensus review by gynecologists and radiologists, if tumor progression was not observed compared with pretreatment evaluations, patients received NACT after radical hysterectomy. None of the patients had progressive disease during NACT. Consequently, all patients were treated with 2 courses of NACT, composed of nedaplatin (NDP) and irinotecan (CPT-11). The chemotherapy regimen was as follows: intravenous infusion of NDP (80 mg/m2) on day 1 and of CPT-11 (60 mg/m2) on days 1 and 8. In 1 patient, the dose for the second chemotherapy cycle was reduced (NDP 70 mg/m2 and CPT-11 50 mg/m2) on days 1 and 8 because of elevated liver enzyme levels. After the 2 cycles, all patients underwent a radical hysterectomy. All patients had a baseline MRI (study 1) of the pelvis with dynamic contrast enhancement (DCE), followed by a second scan after the first course of NACT (study 2) and a third scan after the second course (study 3) just before the surgery. The interval between study 1 and study 2, day 1 of NACT and study 2, and study 1 and study 3 ranged from 25 to 45 days (mean, 32.3 days), from 13 to 38 days (mean, 18.2 days), and from 49 to 67 days (mean, 57.4 days), respectively. A total of 39 MRI data sets were obtained.

Imaging Protocol For all examinations, patients were placed in the supine position and had a partially filled bladder. Before the examinations, 20 mg of hyoscine butyl bromide (Buscopan; Boehringer Ingelheim, Ingelheim am Rhein, Germany) was administered to reduce bowel motion, unless there was a contraindication. All baseline scans (study 1) and 10 midtreatment scans (study 2) with DCE MRI for perfusion imaging were performed using a 3.0-T MR scanner (Skyra; Siemens, Erlangen, Germany). For 3 subjects, study 2 was performed without DCE on a 1.5-T scanner (Avanto; Siemens, n = 1) or on a 3.0-T MR scanner (Skyra or Trio; Siemens, n = 2). The posttreatment scans (study 3) were performed without DCE for all subjects (Skyra, n = 12; Trio, n = 1). All images used in this study were in the sagittal plane. Fast-spin echo T2weighted images (T2WIs), diffusion-weighted images (DWIs), and T1-weighted 3-dimensional (3D) gradient echo images for DCE MRI were obtained. Acquisition parameters for each sequence are summarized in the table, Supplemental Digital Content 1, available at http://links.lww.com/IGC/A215.

Data Analysis The overall study is summarized in Figure 1. The quantitative MRI parameters evaluated in this study are summarized in Table 1. All volumes of interest (VOIs) in this study were drawn by 1 radiologist (YH). Tumor volume was measured for study 1 (pretreatment tumor volume [Vol_pre]), study 2 (tumor volume after the first course of NACT [Vol_NACT1]), and study 3 (tumor volume after the second course of NACT [Vol_NACT2]). By using an offline workstation, regions of interest (ROIs) were drawn for each slice on T2WI, and the tumor volume was calculated by a summation of all of the * 2014 IGCS and ESGO




MRI Predictive Parameters of NACT

FIGURE 1. The outline of the study.

voxels of ROIs and multiplied by the voxel size. The final tumor volume reduction rate (TVRR) was calculated with the following equation:

MRI parameters, Vol_pre, Vol_NACT1, and the early TVRR were calculated with the following equation:

ðVolCprejVolCNACT2Þ=Vol Cpre

For DWI, tumor ROI was drawn on each slice of the apparent diffusion coefficient (ADC) map by referencing the DWI, T2WI, and DCE images, and by avoiding the cystic or necrotic areas, and tumor VOI included all these tumor ROIs. From tumor VOI, the mean ADC values and minimum ADC values were measured for study 1 and study 2

ð1Þ

In addition, it was considered as the criterion standard for the effectiveness of NACT. Correlation coefficients of all of the quantitative (volumetric and functional) MRI parameters with the final TVRR were evaluated. For the volumetric

ðVolCprejVolCNACT1Þ=Vol Cpre

ð2Þ

TABLE 1. Quantitative MRI parameters obtained from pretreatment MRI (study 1), after the first course of MRI (study 2), and both studies Pretreatment MRI Study PostYFirst Course MRI Study Parameters Obtained From Both Studies Tumor volume parameters Diffusion parameters

Perfusion parameters

Vol_pre

Vol_NACT1

Early TVRR

n = 13 Mean ADC_pre

n = 13 Mean ADC_NACT1

n = 13 Mean ADC_$[NACT1-pre]

Minimum ADC_pre n = 13 Ktrans_pre

Minimum ADC_NACT1 n = 13 Ktrans_NACT1

Minimum ADC_$[NACT1-pre] n = 13 Ktrans_$[NACT1-pre]

Ve_pre kep_pre AUC_pre n = 13

Ve_NACT1 kep_NACT1 AUC_NACT1 n = 10

Ve_$[NACT1-pre] kep_$[NACT1-pre] AUC_$[NACT1-pre] n = 10

The number (n) of patients is also shown. _NACT1, obtained after the first course of chemotherapy; _pre, obtained before the treatment; $[NACT1-pre], changes before and after the first course of NACT; Vol, tumor volume.

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(mean ADC_pre, mean ADC_NACT1, minimum ADC_pre, minimum ADC_NACT1). The minimum ADC value was defined as the lowest mean ADC value of at least 5 circular ROIs that encompassed 5 voxels (approximately 25 mm3) placed manually by 1 radiologist (xxx, blinded for review) on the whole VOI of the tumor.16 The change of ADC before and after the first course (mean ADC_$[NACT1-pre]; minimum ADC_$[NACT1-pre]) was also obtained as follows: ð ADC after the first course of chemotheraphyÞ ð ADC of the pretreatment MRIÞ

ð3Þ

From DCE MRI data sets, Ktrans (the transfer constant of contrast from the plasma to the tissue extracellular extravascular space [EES]), Ve (the fractional volume of the tissue EES), kep (the rate constant between the plasma and the EES), and AUC60 (area under the gadolinium concentration time curve during the 60 seconds after bolus arrival) were obtained during study 1 and, when available, study 2. The VOI for perfusion parameters was summed from ROIs drawn on sagittal contrast-enhanced T1-weighted images by referencing sagittal T2WIs. The data were analyzed based on the Tofts model using Tissue 4D application (Siemens).17,18 From study 1 and study 2 data sets, Ktrans, Ve, kep, and AUC60 of tumors for each study (Ktrans_pre, Ktrans_NACT1, Ve_pre, Ve_NACT1, kep_pre, kep _NACT1, AUC_pre, and AUC_NACT1), the change of each parameter after the first course were obtained and were evaluated as perfusion parameters; these are as follows: ðK transC $½NACT1j pre;

ð4Þ

ðVeC $½NACT1j pre;

ð5Þ

k ep C $½NACT1j pre;

ð6Þ

AUCC $½NACT1j pre;

ð7Þ

Statistical Analysis The Pearson correlation coefficient r was calculated for each parameter with the final TVRR. A P value of less than 0.05 was considered to show statistical significance.

RESULTS Radical hysterectomy after NACT was performed in all 13 patients, and all specimens were pathologically examined. Surgical complications included a bladder injury repaired by urologists in 1 patient due to firm vesicouterine adhesion. Postoperative complications included a lymphorrhea in 1 patient and mild infection in 3 patients, resolved with conservative management. Four patients succeeded in down staging, from clinical stage IB2 to pathological stage IB1 in 3 patients and from clinical stage IIB to pathological stage IB1 in 1 patient. Eleven patients were treated with 3 to 4 cycles of adjuvant chemotherapy with the same regimen as NACT. One patient refused to have additional treatment. One patient with pathological high-risk factors, positive parametrial lymph nodes, and bilateral parametrial invasion was treated with postoperative CCRT. The mean, the range, the Pearson correlation coefficient (r), and the P value for each quantitative MRI measurement

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are summarized in Table 2. The Vol_pre ranged from 13.52 to 67.87 cm3 (mean, 34.21 cm3). The Vol_NACT1 ranged from 1.17 to 22.63 cm3 (mean, 11.19 cm3). The Vol_NACT2 ranged from 0.17 to 15.16 cm3 (mean, 6.26 cm3). The final TVRR, which was the criterion standard of effectiveness for this study, ranged from 0.51 to 0.99 (mean, 0.79). For tumor volumetric measurements, early TVRR showed significant correlation with the final TVRR (r = 0.844; P G 0.001; Fig. 2A) and ranged from 0.41 to 0.96 (mean, 0.64). The Vol_pre and the Vol_NACT1 did not show a correlation (r = 0.42, P G 0.15; r = j0.50, P = 0.07, respectively). For diffusion parameters, the mean values of mean ADC and of minimum ADC showed slight increases after the first course of NACT (from 0.842 to 0.901 for mean ADC, from 0.610 to 0.691 for minimum ADC). There was no significant correlation for any of the following diffusionrelated parameters: mean ADC_pre, mean ADC_NACT1, mean ADC_$[NACT1-pre], minimum ADC_pre, minimum ADC_NACT1, and minimum ADC_$[NACT1-pre]. For perfusion parameters, Ve_pre and Ve_$[NACT1pre] showed significant negative and positive correlation (mean, 0.261; r = j0.64; P G 0.05 and mean, 0.072; r = 0.63; P G 0.05, respectively, Figs. 2B, C), respectively. No significant correlation was found for other parameters (Ve_NACT1 and parameters for Ktrans, kep, and AUC60).

DISCUSSION For early prediction of the effectiveness of RT and CCRT for cervical cancers, some parameters have been reported to be useful, such as tumor volume reduction during therapy,13,19 ADC,11 and perfusion-related parameters.12,14,20 To the best of our knowledge, there has been only 1 report evaluating the prediction of the NACT outcome by MRI using ADC values.15 We prospectively collected data for 13 patients with International Federation of Gynecology and Obstetrics stage IB to IIB squamous cell carcinoma of the cervix and evaluated the predictive value of various quantitative MRI parameters for the effectiveness of NACT. In our study, early TVRR significantly correlated with the effectiveness of NACT, as was reported for RT and CCRT,13,19 whereas the baseline tumor volume was not significant. Early TVRR has an important advantage as a biomarker because it can be obtained noninvasively using clinical MRI without contrast agents or special technique. For CCRT, some researchers have reported that the TVRR also provides information about 5-year local control and diseasefree survival in addition to short-term treatment effectiveness.13,19 In the future, this study should be extended to evaluate the significance of TVRR for the prediction of longterm outcome for NACT. For predicting the outcome of CCRTusing TVRR, Mayr et al19 compared different methods of tumor volume measurement during RT and concluded that 3D volumetry by tracing the contour of the tumor, similar to our method, was the most predictive. Despite its accuracy, a disadvantage of contour tracing 3D volumetry is the time required for measurement. Comparison of different methods of volumetry should be investigated further to overcome this issue. * 2014 IGCS and ESGO





TABLE 2. The mean, range, Pearson correlation coefficient (r), and P value for each quantitative MRI measurement r

P

34.21 (13.52Y67.87) 11.19 (1.17Y22.63) 0.64 (0.41Y0.96)

0.42 j0.50 0.84

0.15 0.07 G0.001*

0.842 0.901 0.059 0.61 0.691 0.080

(0.761Y0.976) (0.766Y1.056) (j0.042 to 0.221) (0.463Y0.825) (0.597Y0.813) (j0.031 to 0.233)

j0.14 j0.22 j0.17 0.04 j0.33 j0.36

0.64 0.46 0.56 0.88 0.26 0.22

0.092 0.103 0.012 0.261 0.318 0.072 0.391 0.43 0.029 15.13 16.42 1.36

(0.038Y0.162) (0.037Y0.152) (j0.032 to 0.076) (0.121Y0.512) (0.213Y0.492) (j0.065 to 0.232) (0.272Y0.572) (0.249Y0.661) (j0.204 to 0.307) (7.38Y25.19) (11.11Y21.82) (j8.90 to 7.33)

0.35 0.19 j0.17 j0.64 0.29 0.63 0.55 0.57 0.22 j0.12 j0.19 j0.02

0.23 0.58 0.62 G0.05* 0.41 G0.05* 0.05 0.08 0.54 0.68 0.59 0.93

Mean (Range) Final TVRR Tumor volume parameters Vol_pre, cm3 Vol_NACT1, cm3 Early TVRR Diffusion parameters Mean ADC_pre Mean ADC_NACT1 Mean ADC_$[NACT1-pre] Minimum ADC_pre Minimum ADC_NACT1 Minimum ADC_$[NACT1-pre] Perfusion parameters Ktrans_pre Ktrans_NACT1 Ktrans_$[NACT1-pre] Ve_pre Ve_NACT1 Ve_$[NACT1-pre] kep_pre kep_NACT1 kep_$[NACT1-pre] AUC_pre AUC_NACT1 AUC_$[NACT1-pre]

0.79 (0.51Y0.99)

The mean and range of the final TVRR are shown. *Significant correlation.

Among perfusion parameters investigated in this study, pretreatment Ve showed negative correlation, and the difference in Ve before and after the first course of NACT showed positive correlation with treatment effectiveness, whereas other perfusion parameters did not correlate significantly. In previous reports about the perfusion of cervical cancer,

Zahra et al21 reported that higher Ktrans and kep of primary tumors showed significant correlation with tumor reduction by CCRT. This study was based on the Kety model; Ve, which was found to have a significant correlation in our study, was not evaluated.21 The meaning of the correlation of pretreatment Ve and the change of Ve after the first course of

FIGURE 2. Correlation of (A) early TVRR, (B) pretreatment Ve, and (C) the change of Ve after the first course of NACT with final TVRR. * 2014 IGCS and ESGO


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NACT with the effectiveness of NACT are uncertain. However, Ve is defined as the fraction of EES, which should represent the space into which fluid can leak from a capillary. A low pretreatment Ve might reflect rich vascular supply to the tumor and heightened chemotherapy sensitivity. For ovarian cancer, Sala et al22 reported a significant increase of ADC and Ve after chemotherapy, especially in responders. They speculated that the increase of ADC and Ve reflected the reduction in cell density and an associated increase in the extracellular space as a response to chemotherapy. In our study, ADC did not correlate with treatment effectiveness, as is mentioned later. The increase of Ve during early chemotherapy in our study might reflect chemotherapy-related microenvironmental alterations such as decrease of cellularity and an associated increase in the extracellular space from fibrosis, which could be difficult for ADC to depict. Diffusion parameters could not predict the effectiveness of NACT in this study. Our results were different from the article by Fu et al15 that showed a correlation between treatment effectiveness and the change of mean ADC during the first course of chemotherapy. This might be due to the differences in the method of comparison. They analyzed data using a nonparametric approach, classifying subjects into the effective group and the ineffective group using the Response Evaluation Criteria in Solid Tumors. We took a parametric approach and evaluated quantitative parameters by defining the final TVRR as the criterion standard for effectiveness. In our study, ADC values, Ktrans, kep of primary tumors, and the changes in these parameters during treatment did not correlate with the treatment effectiveness. For the prediction of the effectiveness of CCRT for cervical cancer, both positive and negative results for pretreatment ADC values were reported.11,20 Harry et al11 reported that a change in ADC values correlated with the final effectiveness of CCRT. For perfusion parameters for CCRT, in contrast to our results, Zahra et al21 reported that the Ktrans and kep of pretreatment primary tumors correlated with treatment response whereas those measured in midtreatment did not. These disparate findings may be due to the difference between chemotherapy and chemotherapy with RT. We speculate that another reason for the contradictory findings would be the difference in the timing of the midtreatment MRI study. In reports about RT and CCRT, midtreatment MRIs were generally performed 2 weeks after treatment initiation. In our study, MRI was performed a few days later (mean, 18 days from the start of NACT). Because microenvironmental changes precede morphological changes, MRI after the first course of NACT might be too late to observe initial changes in ADC or other perfusion-related parameters that might have predictive value. The time delay might work to the advantage of early TVRR. This consideration requires further investigation. There are several limitations in this study. First, the number of subjects was relatively small. It would have been more informative to recruit a larger cohort of patients. In this study, NACT was effective to a degree that radical hysterectomy was successfully accomplished in all patients. No patients showed progressive disease during the first course of NACT nor showed tumor regrowth after the first course of chemotherapy. If patients included had shown progressive

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course, the results should have been clinically more useful. We acquired some quantitative parameters that are statistically significant. This preliminary analysis would be helpful in further studies with increased numbers of subjects and with long-term outcome assessment. Second, our results are applicable only to squamous cell carcinoma in clinical stages IB2 to IIB; our results may not be applicable to large tumors in higher clinical stages, which would be treated with chemotherapy. This is because (1) our study population included only cervical cancers in stage IB2 to IIB and (2) modification by necrosis might seem more significantly in large tumors. Third, we used 3 different MRI scanners in study 2 and study 3 with different field strengths, 3.0 T and 1.5 T. Perfusion parameters were all obtained from the same 3.0-T scanner (Skyra; Siemens). For ADC values, using the same scanner with the same field strength would be the best for reproducibility, although it was difficult in our institution to use the same scanner for all of the studies within a restricted time frame in the clinical situation. Theoretically, ADC value is independent of the strength of the static magnetic field23,24 although reproducibility of MRI parameters between 1.5 T and 3.0 T has not been fully validated. Fourth, to evaluate the precise extent of the tumor, the measurement by the final histological specimen is the most accurate. Nevertheless, we determined to use TVRR, which can only be obtained by MRI, as a criterion standard because we aimed to correlate quantitative MRI parameters with treatment effectiveness (ie, responsiveness to therapy). This also enables comparison of our study to other previous reports evaluating CCRT.21

CONCLUSIONS This study revealed that early tumor volume reduction, pretreatment Ve, and change of Ve after the first course of NACT have significant correlations with the final effectiveness of NACT for cervical squamous cell carcinoma. These parameters might help to determine and individualize treatment strategy. By accumulating these data over a long duration in a large number, further investigation to correlate other outcome measures, such as relapse or survival after NACT, and evaluation for reproducibility should be carried out.

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Simultaneous changes of magnetic resonance diffusion-weighted imaging and pathological microstructure in locally advanced cervical cancer caused by neoadjuvant chemotherapy.

UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer.

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