Evaluation of T2-W MR imaging and diffusion-weighted imaging for the early post-treatment local response assessment of patients treated conservatively for cervical cancer: a multicentre study

Cervical cancer represents a major health burden, with for instance around 12,000 newly diagnosed patients in the USA each year (US Cancer Statistics Working Group 2016). The standard treatment for locally advanced cervical cancer is external beam radiotherapy with image-guided adaptive brachytherapy [1, 2] and concurrent chemotherapy [3, 4] or hyperthermia [5]. More than 90% of patients show complete local response after such treatment [6‐8].

To detect local residual tumour at an early time point (2–3 months after treatment) and allow potentially curative salvage therapy, response assessment after radiotherapy is uniformly recommended [9‐11]. Although the effect of salvage surgery on survival is not well studied, retrospective studies suggest that early detection of local residual disease in asymptomatic women may offer survival benefit [12, 13]. Moreover, salvage hysterectomy for local disease at a later, i.e. symptomatic, stage has high complication rates or is not feasible because of irresectable disease [14]. Therefore, a well-founded diagnosis of local residual tumour shortly after completing radiotherapy would be helpful in the timely selection of women for salvage surgery, and might contribute to enhanced survival. Secondly, the patient with residual disease not suitable for salvage surgery might be quickly informed about her unfortunate prognosis in a timely manner.

In most centres, response assessment is performed via clinical response examination (CRE) at 2–3 months after radiotherapy [1, 2]. This pelvic exam can be unsatisfactory because of the altered anatomy after radiotherapy (no cervix, stricture of the vagina, fibrosis) and the discomfort and pain experienced by patients. Subsequently an examination under anaesthesia may be necessary.

A seemingly attractive alternative after completing radiotherapy therefore is imaging, either with PET CT scanning or magnetic resonance (MR) imaging.

The use of PET-CT has recently been advised for response evaluation according to the National Comprehensive Cancer Network (NCCN 2017). In the earlier European Society of Medical Oncology guideline PET-CT is not incorporated for response evaluation [15]. As far as we know, no data exists on its diagnostic value in the first response evaluation. For this reason we do not use PET-CT in our departments. Further prospective studies are needed to ensure its diagnostic value.

MR imaging has so far been unable to fulfil the need to detect residual disease after radiation because of a false positive rate of up to 45% [16, 17] that is mainly attributable to difficulties in differentiating residual tumour from local oedema. The development of MR imaging with diffusion-weighted imaging (DWI) has led to investigations of its potential in differentiating high cellular matrix (as seen in tumour) from low cellular matrix (as seen in oedema). Several studies have shown promising results in identifying local residual tumour after radiotherapy, for instance in rectal cancer and breast cancer [18‐21]. In 2015, a systematic review described the additional value of DWI in monitoring treatment response in patients undergoing chemoradiotherapy for locally advanced uterine cervical cancer [21]. A greater increase of the apparent diffusion coefficient (ADC) was seen after treatment versus before treatment if response was complete. However, data were not externally validated. Moreover, reference standard was mostly based on MR imaging findings. To the best of our knowledge, only two recent studies have evaluated the accuracy of MR imaging with DWI [22, 23]. The first study was a single-centre study of retrospective design, while the second study involved retrospective analysis without standard use of pathologic evidence as a reference standard, instead also using radiological follow-up.

The primary aim of our study was to perform a multicentre study of the incremental value of MR imaging with DWI compared to standard MR imaging in the first response evaluation after radiotherapy for cervical cancer. A secondary aim was to evaluate the additional value of MR imaging with or without DWI in comparison to CRE. Histopathology or a minimal follow-up of 1 year was used as reference standard.

In this prospective multicentre study, we found that DWI significantly increases the specificity of MR imaging in the detection of residual local tumour compared to T2W imaging alone during response evaluation of cervical carcinoma following radiotherapy. MR imaging with DWI also showed significant incremental value over CRE.

In a situation where MR imaging is appended to the treatment response evaluation, DWI information should always be added to reduce the chance of incorrectly declaring an unfavourable outcome, i.e. presumed residual tumour in cases with a complete response. This is in line with our hypothesis, since the presence of oedema hampers T2-WI, resulting in misdiagnoses of residual disease. Oedema is typically seen in the first months after radiation therapy, at the time when response evaluation is performed to decide on complementary surgery in case of residual disease. Our finding is also in line with a previous study showing that T2-WI alone resulted in up to 50% false positives [16].

Our findings are in accordance with a recent retrospective study, where a high specificity (84 %) was found using a combination of high intensity on T2-WI and high intensity on DWI [22]. However, that study differed from ours since their inclusion consisted mainly of lower stages of cervical carcinomas in a neoadjuvant setting.

To the best of our knowledge, our study is the first to compare CRE with combined T2-WI and DWI for early response assessment after radiation for cervical carcinoma. One study evaluating CRE versus conventional MR imaging in the response assessment after radiation therapy reported that MRI scored significantly worse than CRE, mainly in terms of specificity [16]. However, as that study did not incorporate DWI, it is difficult to compare their results with ours. With the current protocol, we found that MR imaging with DWI significantly improves work-up compared to CRE. It is unlikely that there was bias from the same clinician doing the clinical assessment as doing the CRE, as these assessments were done a year apart.

One could argue that as a result of current optimised radiation therapy schemes, including MR imaging or CT-guided brachytherapy, the percentage of patients with local residual tumour after radiotherapy treatment for cervical cancer is too low to justify further protocols such as MR imaging. Distant recurrence probably has more impact on survival. However, it remains a fact that only local residual tumour can potentially be cured, for instance with salvage surgery. Despite the low prevalence of local residual tumour without distant metastases, it is therefore imperative that the patient with residual tumour is recognised soon after treatment while salvage is still an option.

Logistic regression analysis showed that if both CRE and MR imaging with DWI are used, only the latter has a significant impact on identifying local residual tumour. A first option would be to replace all CRE by MR imaging with DWI. Although theoretically our data suggest that this would be an acceptable alternative, in clinical practice clinicians would still prefer to examine the patient during the first response evaluation, since it is inexpensive. Moreover, very small superficial and mucosal based residual tumours will probably remain undetected with MR imaging. A second option could be to use MR imaging with DWI in case CRE is difficult to perform or when the patient is uncooperative. A third option is to perform both CRE and MR imaging during the first response evaluation in all cases. The last two options have four clear advantages. First, the MR images can be reviewed at a later time point and can be discussed with colleagues, which is impossible with CRE. CRE also depends on the experience of the physician. A second advantage is that these initial MRI data are available during follow-up, particularly in cases in which new (clinical) problems and queries arise. The third advantage of using MR imaging is to guide eventual biopsy more precisely in the deeper cervical regions that are more difficult to evaluate with CRE. Finally, in the case of proven local residual tumour, MR imaging is usually better than CRE in identifying local parametrial or pelvic wall invasion, which could make salvage hysterectomy unfeasible, as was shown in an earlier meta-analysis by our study group [24].

A final option is to add MR imaging depending on the probability of local residual tumour and distal tumour recurrence. Higher stages of cervical carcinoma, especially those with possible lymphadenopathy outside the radiation field, would have less benefit of salvage surgery, making MRI with DWI less useful.

Quantitative evaluation of the ADC post-therapy versus pre-therapy was less helpful in our study, in contrast to findings reported in an earlier systematic review [21]. The overall absolute cut-offs found for residual tumour versus absence thereof were not reproduced in our multicentre setting. The use of different MR systems may have possibly played a role in our varied results. Indeed, a previous study has shown that absolute ADC values can be vendor-specific, depending on the region scanned in the upper abdomen [25]. As far as we know, the reproducibility of ADC values in the cervical regions across different scanners has not been fully studied. However, in terms of our findings, it is debatable whether the use of different vendors explains the differences, since only two protocols were used, with very similar sequence details and b values. On the basis of our findings, we conclude that measurement of ADC differences is time-consuming and is not particularly helpful, even more so because our logistic regression model showed no influence of these data on the final diagnosis of local residual tumour for either radiologist reader.

There are some drawbacks to our study. The inter-reader agreement was only moderate to fair for MR imaging evaluation, which might suggest that the results are not fully reproducible. This could be an important obstacle to further implementation of this technique. However, the readers took different approaches to image evaluation despite having received the same predetermined interpretation criteria as mentioned earlier. Reader 1 was more cautious and evaluated indeterminate lesions more often as residual tumour, thereby increasing sensitivity, while reader 2 used more strict criteria for diagnosing residual tumour, i.e. he evaluated indeterminate lesions more often as a complete response. Furthermore, reader 1 had more experience with DWI in the pelvis (10 years versus 6 years), which could also explain his higher sensitivity (although not significantly higher). Further studies should be performed to establish the reproducibility of DWI for identifying residual cervical cancer post radiotherapy.

The results concerning sensitivity were not significantly different across protocols. As a result of the low prevalence of residual disease, our study would have required over 240 patients to allow conclusions about sensitivity. For reasons of feasibility we powered the study to demonstrate an increase in specificity by adding DWI to the T2-weighted imaging.

According to the most recent guidelines, treatment evaluation should be done around 3 months after the end of treatment [15]. We decided to perform the MRI some weeks earlier, mainly because we wanted to diagnose residual tumour as soon as possible, in order to enhance the possibilities of local salvage. Too soon after treatment though, the interpretation could be hampered by oedema. However, we prioritised early detection, as the use of DWI for identifying tumour is not compromised by local oedema.

In conclusion, the addition of DWI to the standard MRI protocol significantly improves the value of MR imaging. Furthermore, MR imaging with DWI has significant incremental value relative to CRE in finding residual cervical tumour after radiation therapy, and could possibly replace the latter in situations where CRE is less practical. ADC has no incremental diagnostic value.