Pretreatment tumour volume measurement on high-resolution magnetic resonance imaging as a predictor of survival in cervical cancer

Transcription

1 BJOG: an International Journal of Obstetrics and Gynaecology July 2004, Vol. 111, pp DOI: /j x Pretreatment tumour volume measurement on high-resolution magnetic resonance imaging as a predictor of survival in cervical cancer W. Patrick Soutter, a Joseph Hanoch, a Tom D Arcy, a Roberto Dina, b G. Angus McIndoe, a Nandita M. desouza c,d Objective To evaluate pretreatment tumour volume as a predictor of survival in patients with cervical cancer using both endovaginal and external coil magnetic resonance imaging in order to achieve high spatial resolution and delineate small volume disease. Design A retrosfection case series. Setting A tertiary referral centre for gynaecological oncology. Population/Sample One hundred and six consecutive women with invasive carcinoma of the cervix underwent endovaginal and external coil magnetic resonance imaging on a 0.5-T or 1.5-T scanner. Methods T2-W FSE images, sagittal and transverse to the cervix, were obtained and tumour volume was calculated on the sagittal images by the standard technique of multiplying the sum of the areas by the slice thickness. Patients were treated in accordance with normal clinical practice and their subsequent outcome was recorded. The relationships between clinical or imaging parameters and survival were assessed with Cox s proportional hazard method. Main outcome measures Disease-free survival. Results In 89 of these women, the tumour was Stage I and 88 of the 106 were treated principally by surgery. The median tumour volume was 4.75 cm 3 (upper and lower quartiles 22 and 0.6). The median length of follow up of surviving patients was 223 weeks (quartiles 158 and 274 weeks). Stage, treatment type, lymphovascular space involvement, invasion of the parametrium, closeness of the excision margin, lymph node metastases, and magnetic resonance imaging measurements of tumour volume, parametrial invasion and lymph node disease were all significantly associated with survival in univariate analysis. Only magnetic resonance imaging measurement of tumour volume remained consistently and strongly associated with survival after multivariate analysis of parameters available prior to treatment (P ¼ 0.001, Wald statistic 10.74). A receiver operating characteristic curve of tumour volume and disease-free survival confirmed the utility of this investigation and suggested that a cutoff around 13.0 cm 3 would predict survival with a positive predictive value of 0.93 and a negative predictive value of Conclusion Magnetic resonance imaging assessment of tumour volume using both an endovaginal and an external coil approach provides an accurate prediction of prognosis in cervical cancer and defines a population of women at high risk of recurrence and death. The predictive value of this investigation is superior to the clinical and histological parameters previously used. Use of this technique permits a more accurate choice of treatment options. These results suggest that it is the size of tumour burden that determines the outcome rather than invasion beyond the anatomical margins of the uterus. a Department of Gynaecological Oncology, Hammersmith Hospital, London, UK b Department of Histopathology, Hammersmith Hospital, London, UK c Robert Steiner Magnetic Resonance Unit, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, UK d Department of Imaging, Hammersmith Hospital, London, UK Correspondence: Mr W. P. Soutter, Department of Gynaecological Oncology, Queen Charlotte s and Chelsea Hospital for Women, Du Cane Road, London, W12 0HS, UK. D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology INTRODUCTION Cervical cancer is a major cause of death worldwide, with almost half a million cases diagnosed each year. The prognostic factor used most widely is the Federation Internationale Gynecological Oncology (FIGO) Stage which determines the extent of disease with an examination under anaesthesia, cystoscopy, a chest X-ray and an intravenous urogram. Our experience of clinical staging and that of others has shown that this form of assessment is inaccurate. 1 3 Also, although increasing stage is associated with a rising risk of death, early stage disease contains large subgroups of women whose prognosis is far better or far

2 742 W.P. SOUTTER ET AL. worse than the average for the stage as a whole. Therefore, there has been considerable interest in developing other methods of defining the prognosis with greater accuracy. A clinical estimate of the diameter of the tumour is usually used as a measure of tumour size to predict prognosis. 4 At first, studies that measured tumour volume could use only post-operative, histological data. The largest of these included 1028 women treated by surgery, in whom the tumour volume measured in the specimen removed correlated more closely with survival than did tumour stage. 5 Women with a tumour volume smaller than 2.5 cm 3 had a five-year survival of 91%, while those with larger tumours (10 50 cm 3 ) had a five-year survival rate of 70%. More recently, Trattner et al. 6 also measured tumour volume histopathologically in a study of 113 women with a median volume of 21 cm 3. They found that increasing volume was associated with more frequent lymph node metastases and with a significant deterioration in survival rate. However, in multivariate analysis, only lymph node metastases and histopathological staging remained independent prognostic factors in their study. Magnetic resonance imaging has excellent soft tissue contrast for delineating cervical tumours. 7,8 In a recently published study from Holland, tumour diameter and volume were measured with magnetic resonance imaging using an external body coil in 126 patients. 9 The median tumour volume of these tumours was 30 cm 3. Women with tumours 35 cm 3 or less in volume appeared to have a better prognosis initially than those with larger tumours, although it is not clear if this difference was significant. Nor was multivariate analysis undertaken. The conventional external coil techniques employed in this study have insufficient resolution to delineate small tumours, so that accurate measurement in patients with tumours <10 cm 3 would have been difficult. 10 We have previously shown that use of an endovaginal coil magnetic resonance technique provides high spatial resolution imaging allowing accurate pre-operative assessment of tumour volume in patients with small cervical tumours. 11,12 We have also suggested in a preliminary study of 39 women that a tumour volume greater than 10 cm 3 indicated a poor prognosis. 12 The purpose of this study was to extend these preliminary observations in order to more fully evaluate tumour volume as a predictor of survival in patients with cervical cancer using both endovaginal and external coil magnetic resonance imaging in order to achieve high spatial resolution and delineate small volume disease. Thirty-nine of these women were included in our earlier publication. 12 All patients underwent combined endovaginal and external coil magnetic resonance imaging prior to treatment. Clinical data noted were: age, presenting symptoms, date of diagnosis, whether a cone biopsy had been performed and clinical stage. The histopathological type of tumour, grade and the presence of lymphovascular space invasion were determined from the diagnostic biopsy. The treatment administered, any surgical findings, the histopathological report on any surgical specimen, details of any adjuvant treatment and subsequent progress were recorded. The ring-design endovaginal receiver coil was of solenoid geometry, 37 mm in diameter. Details of the endovaginal coil have been described previously. 11,12 The coil was inserted into the vagina and positioned around the cervix by manipulation of the handle and immobilised by an external clamp. Despite the cervical mass and recent cervical biopsies in 17 cases, all patients were able to tolerate the coil for the length of the examination (30 40 minutes). In no case was the examination terminated because of patient discomfort. Imaging was performed either at 0.5 or 1.5 T (Apollo or Eclipse, Marconi Medical Systems, Highland Heights, Ohio, USA) using transverse to the cervix T1-weighted spin-echo (SE /20 [TR/TE] ms), and sagittal T2- weighted fast spin-echo (FSE 2500/80 [TR/TE] ms) sequences. Contiguous slices 2 3 mm thick were acquired with a matrix, two to four signal averages and a 12-cm field of view. On completion of the endovaginal imaging, the coil was removed. An external four-channel pelvic phased array coil (Picker International, Highland Heights, Ohio) was then used to acquire transverse to the cervix T1-weighted spin-echo and sagittal T2-weighted FSE images with 6 mm contiguous slices, a matrix, two to four signal averages and a cm field of view at 0.5 T. Additional short tau inversion recovery (STIR) sequences were done for assessment of pelvic lymphadenopathy. Survival was calculated by the product limit method of Kaplan and Meier (Statistica version 5.0, Statsoft, Tulsa, USA). Cox logistic regression analysis was used to assess the effect of relevant parameters on survival (Statistica version 5.0, Statsoft). The receiver operating characteristic curve was used to demonstrate the power of magnetic resonance imaging determined tumour volume as a predictor of survival and to ascertain the optimum cutoff value to identify women with a poor prognosis (StatsDirect, Ashwell, UK). METHODS We studied 106 consecutive cervical cancer patients who were scanned between 1 September 1993 and 31 August Thirty-nine women were scanned in the first three years and 67 were scanned in the second three-year period. RESULTS Pretreatment tumour volumes in the 106 patients measured by magnetic resonance imaging ranged from 0 to 125 cm 3 (median 4.75 cm 3, lower and upper quartiles 0.6 and 22 cm 3, respectively; Fig. 1). Sixty-three patients

3 TUMOUR VOLUME MEASUREMENT AS SURVIVAL PREDICTOR IN CERVICAL CANCER 743 Fig. 1. Transverse T2-weighted (fast spin-echo 2500/88 ms [TR/effective TE]) A, and transverse whole mount histological section through the cervix B, showing a 3.7 cm 3 tumour (arrows) replacing the anterior cervix. A polypoid extension of tumour into the endocervical canal (arrowheads) is noted. (59.4%) had tumour volumes <10 cm 3 (Fig. 2). The smallest tumours identified were 0.1 cm 3 in volume. The average age was 44.2 years (SD F11.6). The FIGO stage distribution and median tumour volumes (lower and upper quartiles) were: Ia1 1, 0.7 cm 3 ; Ib1 68, 1.1 cm 3 ( ); Ib2 20, 25.6 cm 3 ( ); IIa 6, 13.5 cm 3 ( ); IIb 5, 28.8 cm 3 ( ); IIIb 3, 43.0 cm 3 ( ); IV 3, 57.5 cm 3 ( ). A diagnostic cone biopsy or loop diathermy biopsy had been performed on 48 (45.3%) of these women. The histological type of tumour was squamous in 77; adenocarcinoma in 21; adenosquamous in 4; and neuroendocrine in 3. This information could not be obtained in one case. Thirty-four percent were Grade 3 tumours and 38.7% had lymphovascular space involvement. A radical hysterectomy and pelvic lymph node dissection was performed on 85 women. Two others underwent trachylectomy and one a simple hysterectomy. Five women had a retroperitoneal lymph node dissection followed by radiotherapy or chemoradiotherapy. Only 2 of the 92 Fig. 2. Histogram of the distribution of tumour volumes as measured by magnetic resonance imaging.

4 744 W.P. SOUTTER ET AL. Table 1. Univariate analyses of all parameters with potential value for predicting death (Cox proportional hazard). Parameter Beta t Wald statistic P Age Stage Surgery Treatment date Radiotherapy Chemotherapy Chemoradiotherapy Histological type Histological grade Lymphovascular space involvement Histological invasion of parametetrium Histological involvement of margins No. of nodes removed Histologically positive nodes No. of positive nodes MRI volume MRI invasion of parametrium MRI detection of involved nodes women who underwent lymphadenectomy had fewer than 10 nodes identified and both had 9 nodes removed (median, upper and lower quartiles of number of nodes removed were 27, 34 and 21). Pre-operative chemotherapy was given to 19 women. Post-operative radiotherapy or chemoradiotherapy was given to 20 women. Eighteen women were treated only with radiotherapy or chemoradiotherapy. Parametrial invasion was detected histologically in 9 of the 85 radical hysterectomy specimens. This was not detected by magnetic resonance imaging in two patients (sensitivity 77.8%). Parametrial invasion was suggested by magnetic resonance imaging in 9 of the 76 women in whom parametrial invasion was not detected histologically (specificity 88.2%). The margins of the specimen were more than 4 mm clear of disease in 67 of the 85 radical hysterectomy specimens and tumour was seen within 4 mm of the margin but not involving it in 13. The margins were involved with tumour in five (5.9%). Lymph node metastases were confirmed histologically in 26 (28.3%) of the 92 women who underwent lymphadenectomy. Nodal disease was predicted by magnetic resonance imaging in 19 of these women (sensitivity 73%). Magnetic resonance imaging correctly predicted the nodal disease status in 61 of the 66 women whose nodes were free of metastases (specificity 93.8%). The median length of follow up of surviving patients was 223 weeks (lower and upper quartiles 158 and 274 weeks, respectively) and 24 women died. The overall fiveyear survival calculated for the 104 women with the Kaplan Meier method was 75.0% (Statistica, Statsoft). The five-year survival rates for all 88 Stage Ib cases and for the 81 women treated with surgery for Stage Ib disease were 79.2% and 83.7%, respectively. A univariate analysis of all potentially useful parameters for predicting survival was undertaken using Cox s proportional hazard model (Table 1, Statistica, Statsoft). The magnetic resonance imaging measurement of volume; the number of nodes with histologically confirmed metastases; magnetic resonance imaging detection of nodal disease or parametrial invasion; histological confirmation of invasion of the parametrium or of nodal metastases; and the use of radiotherapy or chemotherapy were most strongly associated with survival. Multivariate analysis of all of the parameters that would be available before treatment, together with all the treatment parameters, showed that only the magnetic resonance imaging measurement of volume was significantly associated with survival (Table 2). The post-operative findings of the histological examination of the radical hysterectomy specimen and the pelvic lymph nodes parametrial invasion, margin status and both the presence of nodal metastases and the number of affected nodes were added to the analysis of survival in the 85 women treated by radical hysterectomy and pelvic lymph node dissection (Table 3). The magnetic resonance imaging measurement of volume remained by far the strongest Table 2. Multivariate analysis of all parameters known before treatment and all treatment parameters with respect to survival. Parameter Beta t Wald statistic Stage Surgery Radiotherapy Chemotherapy Chemoradiotherapy Lymphovascular space involvement MRI volume MRI invasion of parametrium MRI detection of involved nodes P

5 TUMOUR VOLUME MEASUREMENT AS SURVIVAL PREDICTOR IN CERVICAL CANCER 745 Table 3. Mutivariate analysis with respect to survival of all parameters known before treatment and the post-operative findings of the histological examination of the radical hysterectomy specimen and the pelvic lymph nodes in the 83 women treated by radical hysterectomy and pelvic lymph node dissection. Parameter Beta t Wald statistic Stage Lymphovascular space involvement Parametrial invasion on histology Margin status Lymph node metastasis on histology No. of positive nodes on histology MRI volume MRI invasion of parametrium MRI detection of involved nodes predictor of survival ( Wald statistic 10.74, P ¼ 0.001). Lymphovascular space involvement status was weakly associated with survival ( Wald statistic 4.14, P ¼ 0.042). Removing the magnetic resonance imaging detection of parametrial invasion and nodal disease made the histological detection of parametrial disease a marginally significant prognostic factor ( Wald statistic 3.98, P ¼ 0.05). Magnetic resonance imaging measurement of volume remained the strongest predictor ( Wald statistic 12.95, P ¼ ). A receiver operating characteristic analysis of the relation between the magnetic resonance imaging estimation of volume and disease-free survival of the 89 women who had been free of disease for at least three years or had developed recurrence or had died confirmed the high predictive value of this measurement with an area under the curve of P 0.91 (95% CI , Wilcoxon estimates, StatsDirect) (Fig. 3). With a cutoff value of 13.0 cm 3, 93.0% of those with a tumour volume equal to or less than this value were alive and disease-free; whereas only 25.0% of those with tumours larger than this were free of disease (sensitivity ¼ 0.869, specificity ¼ 0.857, positive predictive value ¼ 0.930, negative predictive value ¼ 0.750). DISCUSSION This study shows that magnetic resonance imaging determined tumour volume is the most valuable prognostic factor for survival in this disease. We have previously shown that endovaginal magnetic resonance imaging is more sensitive than external coil techniques for identifying small volume disease 10 and in this study we were able to determine the pretreatment tumour volume of cervical cancers as small as 0.1 cm 3, It should therefore enable more accurate counselling and indicate the most appropriate treatment strategy. Other recent studies using histopathological measurement 6 and magnetic resonance imaging with an external body coil 9 did not show a clear prognostic value for tumour volume. These studies included mainly women with larger tumours. The median volumes of the tumours in these studies were 21 and 30 cm 3, respectively compared with the median volume of 4.75 cm 3 in the present study. Inspection of the receiver operating characteristic curve derived from the current data (Fig. 3) shows that the discriminatory value of volume among tumours greater than 13 cm 3 will be poor. Fig. 3. Receiver operator characteristic curve of the magnetic resonance imaging estimation of volume and disease-free survival. An optimum cutoff value of 13.0 is suggested.

6 746 W.P. SOUTTER ET AL. Others have shown that parametrial invasion by tumour has little predictive value in node negative women. 13 This and the poor performance of FIGO stage as a prognostic value suggest that it is the size of tumour burden that determines the outcome rather than invasion beyond the anatomical margins of the uterus. Baltzer and Koepcke 14 reported many years ago that blood vessel invasion and, to a lesser extent, lymphatic invasion, significantly influenced survival in patients with squamous cell carcinoma of the cervix. Nevertheless, this factor has not been consistently found to be an independent risk factor in cervical cancer because the rate at which it is reported is dependent upon the assiduousness with which it is sought. In common with many others, this study showed only a weak association between lymphovascular space invasion and survival. In recent years, the number of patients presenting in the early stages of cervical cancer has increased. This trend reflects the effectiveness of the screening programme, which detects premalignant lesions or asymptomatic, small volume invasive disease. These small invasive lesions can be assessed reliably only by an endovaginal technique that improves signal-to-noise by placing the receiver coil immediately adjacent to the tissue of interest and allows an in-plane resolution of 0.5 mm. Other magnetic resonance imaging techniques such as dynamic contrast enhancement 15,16 and even vaginal opacification with contrast media 17 have failed to provide improved resolution. There is evidence that young women with small volume invasive disease that does not invade deeply into the cervix might be treated successfully by radical removal of the cervix, thereby conserving their fertility. 18 Preliminary reports from other centres describe investigation with conventional magnetic resonance imaging to assess a patient s suitability for trachelectomy. 19 This conservative surgery is limited to ectocervical tumours because hitherto it has been impossible to accurately determine the extent of small endocervical lesions and because their recurrence rate increases with size and is greater when conservative treatment is performed. 20,21 Endovaginal magnetic resonance imaging allows a precise definition of the size and location of the tumour and lends greater confidence to the selection of women for whom such conservative surgical treatment might be appropriate. In the future, it may also permit an extension of the indications for conservative surgery to include those with small volume endocervical tumours. In a recent prospective Gynaecology Oncology Group (GOG) study 22 evaluating the frequency with which intended radical hysterectomy for cervical cancer is abandoned, 98 out of 992 patients did not have the proposed radical operation completed. The only required imaging studies were chest X-ray and intravenous urography. No pre-operative characteristics clearly identified patients whose surgery was abandoned. Our experience suggests that pre-operative magnetic resonance imaging would have improved surgical planning in these cases. Following cone biopsy, distortion of the cervix, local haematoma or granulation tissue make image interpretation difficult. Such appearances may result in false positive reports. Nevertheless, magnetic resonance imaging is useful in excluding the presence of gross tumour but small lesions less than 0.2 cm 3 continue to present a diagnostic challenge. In such cases, magnetic resonance proton spectroscopy used in conjunction with magnetic resonance imaging may prove valuable. 23,24 With an endovaginal technique, the parametrium is seen clearly up to 6 cm from the coil surface. Some caution must be exercised in diagnosing parametrial invasion as peritumoural inflammatory tissue can mimic the appearance of parametrial invasion on magnetic resonance imaging. 25 Involvement of the iliac and obturator nodes should be routinely assessed with conventional external pelvic phased array or body coil techniques. Magnetic resonance imaging, particularly using both an endovaginal and external coil approach, is an invaluable technique in the assessment of invasive cervical cancer and should now be the modality of choice for tumour evaluation. The predictive value of this investigation is superior to the clinical and histological parameters previously used. Armed with accurate information about the volume and extent of cervical disease, the clinician can plan treatment with greater confidence. Acknowledgements The authors would like to thank Graeme Bydder, Professor of Magnetic Resonance Imaging and Director of the Robert Steiner Unit, for his constant support. Contributors Pat Soutter, Nandita desouza and Angus McIndoe thought of the study idea. Nandita desouza conducted the magnetic resonance imaging evaluation and quantification. Roberto Dina performed the histopathological evaluation. Joseph Hanoch and Tom D Arcy collated the clinical and magnetic resonance imaging data and the follow up information. Pat Soutter and Joseph Hanoch wrote the preliminary drafts and all authors contributed to the final version. Pat Soutter undertook the statistical analysis and acts as guarantor for the paper. Conflict of interest There are no conflicts of interest. References 1. Mayr NA, Yuh WT, Zheng J, et al. Tumor size evaluated by pelvic examination compared with 3-D quantitative analysis in the prediction of outcome for cervical cancer. Int J Radiat Oncol Biol Phys 1997;39: Lagasse LD, Creasman WT, Shingleton HM, Ford JH, Blessing JA.

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