Cervical cancer is the second most common cancer among women in the world, trailing only breast cancer in incidence and prevalence. It is also one of the leading causes of cancer death among women worldwide.1 The cure rate of cervical cancer is quite high if detected early, but approximately 30% of patients with cervical cancer will ultimately fail after definitive treatment. The recurrence rate of cervical cancer is between 10% and 20% for International Federation of Gynecology and Obstetrics (FIGO) stages IB to IIA and 50% to 70% in locally advanced cases (stages IIB–IVA).2 The prognosis of recurrent cervical cancer is poor, except for those with isolated vaginal or cervical relapse, with a reported 5-year survival rate of 3.2% to 13%.3,4 Regardless of treatment modalities, the median time to recurrence is usually short, with more than 75% of recurrences occurring within 3 years from diagnosis.5 Therefore, surveillance during this period is essential for early detection of recurrence and to assess treatment outcome. Clinical history, physical and pelvic examination, and Papanicolaou test are usually performed on every visit. Computed tomography (CT) and magnetic resonance imaging (MRI) may be performed yearly for first 3 consecutive years for high-risk groups, in those with elevated tumor markers, and those with symptoms suspicious for recurrence.6,7 These modalities, however, have limited accuracy in posttherapy setting.8
18F-fluorodeoxyglucose (18F-FDG) positron emission tomography–CT (PET-CT) combines the advantages of the excellent functional information provided by PET and the superb spatial and contrast resolution of CT. It is an important tool for detection of recurrence in a wide range of gynecological malignancies, including cervical carcinoma.9–11 In some previous studies, various quantitative and qualitative 18F-FDG PET-CT parameters were found to be useful predictor of survival in primary and recurrent cervical cancer.12,13 In the cases of recurrent cervical cancer, for treatment response evaluation, anatomic imaging modalities such as CT and MRI have limited roles. Both of them rely on size criteria and morphologic change in the lesions. Therefore, they have limitations in differentiating recurrent tumor from residual mass, scarring, fibrosis, and posttherapy changes, whereas 18F-FDG PET-CT gives functional information of metabolic processes that is up-regulated in the malignant cells and thus useful in those cases.14,15 Therefore, the aim of the present study was to evaluate the role of 18F-FDG PET-CT for response evaluation in recurrent cervical cancer and to assess whether metabolic response on PET-CT can predict survival in these patients.
MATERIALS AND METHODS
This was a prospective study approved by institutional review board (ref no IESC/T-141). Written informed consent was obtained from all patients. Because of lack of prospective studies evaluating 18F-FDG PET-CT for response assessment in recurrent carcinoma cervix, for sample size calculation, we reviewed the available data on the role of 18F-FDG PET/PET-CT in predicting the clinical and survival outcome in patients with recurrent carcinoma cervix.16–18 On the basis of these studies, we assumed that the group with progressive metabolic disease (PMD) is expected to have a 1-year survival of around 40%. Although against it, the group with non-PMD is expected to have a better 1-year survival of around 90%. Therefore, we required a minimum of 18 patients in each group (PMD and non-PMD), total 36 patients, to detect this difference of survival (40% vs 90%) in a 2-sided log-rank test with 5% alpha error and 80% power.
Finally, 36 patients with recurrent carcinoma cervix were enrolled in the present study between October 2010 and November 2012. The inclusion criteria were the following: (1) patients who had been declared cured after definitive therapy for histopathologically proven carcinoma of cervix, (2) patients with recurrent cervical cancer established by histopathology or clinically evident recurrent disease, and (3) at least 3 months gap between the completion of the therapy and presentation with recurrence. The exclusion criteria were as follows: (1) presentation within 3 months of completion of definite therapy, (2) patients showing persistent residual disease after the completion of the primary treatment, and/or (3) patients who had previously received salvage therapy for recurrence.
18FDG PET-CT Acquisition Protocol
The studies were acquired on a dedicated PET-CT scanner at our institute (Biograph 2; Siemens Medical Solutions, Erlangen, Germany). All patients fasted for at least 4 hours. Blood glucose was less than 140 mg/dL. A dose of 370 MBq (10 mCi) of 18F-FDG was injected intravenously. The patients rested in a quiet room, and after a 45- to 60-minute uptake period, the patients were taken for PET-CT. No intravenous contrast agent was administered for the CT part of PET-CT. Oral contrast media were administered as routinely done for opacification of bowel. In the PET-CT system, CT acquisition was performed on spiral dual-slice CT with a slice thickness of 4 mm and a pitch of 1. Image was acquired using a matrix of 512 × 512 pixels and pixel size of 1 mm. After CT, 3-dimensional PET acquisition was done for 2 to 3 minutes per bed position. Positron emission tomography data were acquired using a matrix of 128 × 128 pixels with a slice thickness of 1.5 mm. Computed tomography–based attenuation correction of the emission images was used. Positron emission tomography images were reconstructed by iterative method ordered subset expectation maximization (2 iterations and 8 subsets). After CT acquisition, PET acquisition of the same axial range was done with the patient in the same position. After completion of PET acquisition, the reconstructed attenuation corrected PET images, CT images, and fused images of matching pairs of PET and CT images were available for review in axial, coronal, and sagittal planes, as well as in maximum intensity projections (MIP) and 3-dimensional cine mode.
18F-FDG PET-CT Image Analysis
Two experienced nuclear medicine physicians evaluated the PET-CT images in consensus. Positron emission tomography images were looked for any area of abnormal 18F-FDG uptake. Corresponding areas in CT images and fused PET-CT images were corroborated. The areas with abnormally increased 18F-FDG uptake noted on pretherapy PET-CT were looked carefully in posttherapy scan for treatment response evaluation. In addition, any new area of abnormally increased 18F-FDG uptake was looked for. The maximum standardized uptake value (SUVmax) of the region of interest and extent of disease in the PET/CT were measured on pretherapy and posttherapy PET-CT scan. The SUV calculation was done via the default method by body weight (SUV = mean region of interest [ROI] activity [MBq/g]; injected dose [MBq] per body weight [g]).
Treatment and Follow-up
The treatment modality for each individual patient was decided by the gynecological oncology team. Management of recurrent cervical cancer depended on the extent of disease, primary treatment, and performance status/comorbidity. It comprised of combination chemotherapy (paclitaxel and carboplatin), oral chemotherapy (gefitinib), external beam radiotherapy (EBRT), and/or intracavitary/interstitial brachytherapy. Surgical procedure such as wide local excision of the metastatic deposit was performed if indicated. All patients were followed up every month for a period of 6 months after the completion of the salvage treatment, then after, the patients were followed up every 3 months. Thorough clinical examination was done at each visit, and the appropriate radiologic or cytopathologic procedure was done whenever indicated.
Response Evaluation With 18F-FDG PET-CT (European Organization for Research and Treatment of Cancer Criteria)19
Response evaluation in posttherapy 18F-FDG PET-CT was based on European Organization for Research and Treatment of Cancer (EORTC) criteria. Complete metabolic response (CMR) was defined as the absence of abnormal 18F-FDG uptake at the sites of abnormal 18F-FDG uptake noted on the pretherapy scan. A partial metabolic response (PMR) was defined as the reduction of minimum 18F-FDG SUV in tumor from 15% to 25% after 1 cycle of chemotherapy and more than 25% after more than 1 treatment cycle. A PMD was defined as the increase in 18F-FDG tumor SUV of more than 25% within tumor region defined on pretherapy scan; visible increase in extent of 18F-FDG tumor uptake (20% in longest dimension) or appearance of new 18F-FDG uptake in metastatic lesions. All other responses were classified as stable metabolic disease (SMD) and if neither progressive nor partial response was present.
Measurement of Outcome
The following treatment outcome measures were examined as per standard criteria.
For assessment of PFS based on PET-CT response, survival was measured from the date of posttherapy 18F-FDG PET-CT study to the first documentation of progression of disease. Patients who were alive without progression were censored at date last known to be alive.
For assessment of overall survival (OS) based on PET-CT response, survival was measured from the date of posttherapy 18F-FDG PET-CT study to the date of death from any cause. Surviving patients were censored at date last known to be alive.
Descriptive statistics such as mean, median, SD, and range were used to describe baseline demographic and clinical profile of all patients. The OS and PFS according to 18F-FDG PET-CT results were depicted using Kaplan-Meier plots. Proportional survival at specific times was determined using Kaplan-Meier statistics. The P value of less than 0.05 was considered as significant. All the data analyses were performed using Statistical Package for the Social Sciences (SPSS) 11.5 (SPSS Inc, Chicago, IL).
Thirty-six patients meeting the inclusion criteria were included for final analysis. The demographic and clinical characteristics of the patients are detailed in Table 1.
Pretherapy 18F-FDG PET-CT Findings
Of the total 36 patients, local recurrent tumor was seen in 26 patients (vaginal vault, 10 patients; cervix, 8 patients; cervix and upper two-third vagina, 5 patients; and cervix and uterine body, 3 patients). In 19 patients, 18F-FDG PET-CT detected lymph node (LN) metastases (pelvic LNs, 15 patients; retroperitoneal LNs, 14 patients; inguinal LNs, 4 patients; mesenteric and supraclavicular LNs, 2 patients each; and axillary, mediastinal, periportal, and intergluteal LNs, 1 patient each). Of these, 10 patients had more than 1 site of LN metastases. In 9 patients, distant metastasis was found (anterior abdominal wall and scar site metastases, 3 patients; omental and serosal deposits, 3 patients; pulmonary metastases, 3 patients; and skeletal metastases, 1 patient). One patient had more than 1 site of distant metastases (scar site recurrence along with bilateral pulmonary metastases).
Twenty-six patients were treated by combination chemotherapy paclitaxel and carboplatin (number of cycles, 3–6; mean [SD], 5.04 [1.09]; and median, 5.0). In addition, 3 patients received 6 cycles of cisplatin chemotherapy along with EBRT and brachytherapy (Fig. 2). A total of 2 patients received EBRT; 1 patient received interstitial brachytherapy and 1 patient received intravaginal brachytherapy. One patient received oral gefitinib. Wide local excision of the anterior abdominal tumor mass followed by chemotherapy was performed in 2 patients (Table 1).
Posttherapy 18F-FDG PET-CT Findings
Of the 36 patients, 18F-FDG PET-CT finding was positive for local recurrent disease in 23 patients (cervix, 7 patients; vaginal vault, 5 patients; cervix and uterine body, 5 patients; cervix and upper two-third vagina, 4 patients; and cervix, vagina, and uterine body, 2 patients). Lymph nodal metastases were detected in 13 patients (pelvic LNs, 8 patients; retroperitoneal, 10 patients; inguinal, 3 patients; mesenteric mediastinal and celiac, 2 patients each; supraclavicular, 3 patients; axillary, periportal, anterior diaphragmatic, internal mammary, pancreatic, and superior mesenteric, 1 patient each). Of these, 7 patients had more than 1 site of LN metastases. Distant metastases were found in 10 patients (anterior abdominal wall, 1 patient; omental/mesenteric and serosal deposits, 4 patients; lung, 5 patients; liver and bone, 1 patient each). Two patients had more than 1 site of distant metastases (sacrum with bilateral pulmonary metastases in 1 patient and bilateral pulmonary with liver metastases in the other; Fig. 3).
Response Assessment With 18F-FDG PET-CT
The local, nodal, and distant disease was classified into CMR, PMR, SMD, and PMD based on EORTC criteria. The final response was decided, taking into consideration all the lesions of each patient, which has been summarized in Table 2.
Metabolic Response on 18F-FDG PET-CT and Survival
The PFS for patients ranged from 0.5 to 26.5 months (median, 4.2 months; mean [SD], 6.7 [6.1] months) from the posttherapy PET-CT. Median PFS for patients who did not show PMD was not reached, whereas the median PFS for patients with PMD was 3.1 months. Patients who did not show progression on posttherapy PET-CT had a significantly better PFS than patients who showed progression (P < 0.0001; HR, 0.14; 95% confidence interval [CI], 0.04-0.46; Fig. 1). The PFS in patients who had LN metastases was lower than those patients who did not have nodal metastases (13.8 vs 18.8 months), but the difference was not statistically significant (P = 0.5228; HR, 1.35; 95% CI, 0.53-3.42). Similarly, the PFS in patients who had distant metastases was lower than those patients who did not have distant metastases (15.7 vs 18.8 months), but the difference was not statistically significant (P = 0.2991; HR, 1.71; 95% CI, 0.51-5.65).
The median OS for patients who did not show PMD was not reached, and the median OS for patients with PMD was 12.2 months. However, the difference was not statistically significant (P = 0.187; HR, 0.39; 95% CI, 0.07–2.30). The difference in the OS in patients who had lymph nodal metastases and those who did not have lymph nodal metastases was not statistically significant (P = 0.9843; HR, 0.98; 95% CI, 0.22–4.40). Similarly, the difference in OS in patients who had distant metastases and those who did not have distant metastases was not statistically significant (P = 0.1942; HR, 0; 95% CI, 0.15–6.53) (Table 3).
Cervical cancer is a public health problem worldwide. The developing countries carry the biggest burden of cervical cancer where it is also the leading cause of cancer-related death in women.20,21 Despite multimodality treatment, approximately 30% of the patients recur. The prognosis of the persistent or recurrent cervical cancer is generally poor, with a 1-year survival rate between 15% and 20%.22 In patients with persistent or recurrent disease after primary treatment, salvage therapy (surgery, radiotherapy with or without chemotherapy, or both) to resectable pelvic or localized extrapelvic metastasis could lead to a secondary cure in selected patients.4
The monitoring of cervical cancer tumor response has been nonspecific. There are no reliable serum tumor markers for cervical cancer. Squamous cell carcinoma antigen has been found to have a low sensitivity and specificity for treatment response evaluation and recurrence detection.23 After irradiation, the persistent tumor of the cervix can be detected by pelvic examination. Persistent tumor at 3 months is predictive of a poor survival outcome.24 However, physical examination does not take into account the response of pelvic and para-aortic LN metastases. Computed tomography and MRI are informative only if they demonstrate an increase in size, based on Response Evaluation Criteria in Solid Tumors (RECIST), which implies tumor growth. They do not reliably indicate whether tumor is present or absent in the LNs that remain unchanged in size after the treatment.25 Moreover, with both CT and MRI, it is difficult to differentiate postradiation changes from residual/recurrent tumor.8
Positron emission tomography has the ability to dem-onstrate abnormal metabolic activity in organs that may seem normal based on morphologic criteria used on CT/MRI.26 18F-fluorodeoxyglucose PET-CT has been shown to be useful for staging, response monitoring, and prognostication of primary cervical cancer. In addition, 18F-FDG PET and PET-CT are also very accurate for demonstrating recurrent disease.27 18F-fluorodeoxyglucose PET-CT can be used for the initial evaluation of cervical carcinoma, which usually shows high–18F-FDG avidity. The degree of 18F-FDG uptake in the primary tumor, as measured by SUVmax, is a predictive biomarker of LN status at diagnosis, persistent disease after treatment, risk of disease recurrence, and OS.28 Positron emission tomography–CT is more accurate than CT for evaluating LN status.29 Positron emission tomography–CT is also superior for the detection of distant metastases in patients with advanced disease.30
In our study, although the PFS in the patients who had LN and distant metastases was lower than those patients who did not have nodal or distant metastases, the difference was not statistically significant. Similarly, the difference in OS in patients who had LN and distant metastases and those who did not have LN and distant metastases was not statistically significant. These findings suggest that the most important prognostic factor on 18F-FDG PET-CT is the aggresiveness of the recurrent tumor, which in turn is measured by SUVmax. These cells, which show high metabolism and hence high aggressiveness, determine the survival. It will be this clonal cell population that may be resistant to treatment and eventually causing disease progression and death.13 Therefore, 18F-FDG PET-CT may be useful for radiotherapy planning in such patients by identifying highly 18F-FDG avid lesions that need to be included in the radiotherapy field.31 Early detection of recurrent disease facilitates potentially curative treatment of local or advanced disease that has been associated with improved survival.23
We classified the metabolic response into the following categories: CMR, PMR, SMD, and PMD based on EORTC criteria. On the basis of metabolic response on posttherapy PET-CT, 31% of the patients had PMD, whereas 69% of the patients did not show PMD (CMR, 17%; PMR, 33%; and SMD, 19%). Patients who did not show progression on posttherapy PET-CT had a significantly better PFS than those patients who showed progression (P < 0.0001; HR, 0.1386). However, there was no statistically significant difference in OS between the 2 groups (P = 0.1876; HR, 0.393). This might be due to the shorter duration of follow-up and other causes of death such as pneumonia.
In a study by Schwarz et al,11 where 18F-FDG-PET was performed on 92 women with cervical cancer after the completion of radiotherapy, the 3-year PFS rates for the patients with complete response, partial response, and progressive disease in the posttherapy 18F-FDG-PET were 78%, 33%, and 0%, respectively (P = 0.001). But to the best of our knowledge, no such study has been performed in those patients with recurrent cervical carcinoma. Therefore, in the group of patients who did not achieve CMR during treatment, changes in treatment could be beneficial, and this should be studied in prospective clinical trials.
There are few limitations in the present study. The number of patients enrolled was small and the duration of follow-up was relatively short. A prospective study with larger sample size and longer follow-up period is warranted. Second, 18F-FDG PET-CT was not performed in every case of recurrent cervical cancer before salvage therapy during the study period. The application of 18F-FDG PET-CT to only selected cases might have introduced selection bias and influenced the study results.
18F-fluorodeoxyglucose PET-CT is an effective tool for monitoring treatment response in recurrent carcinoma cervix. Metabolic response on 18F-FDG PET-CT scan can prognosticate recurrent cervical cancer. Patients with metabolically progressive disease on posttherapy 18F-FDG PET-CT have a significantly shorter PFS.
1. Armstrong EP. Prophylaxis of cervical cancer and related cervical disease: a review of the cost-effectiveness of vaccination against oncogenic HPV types. J Manag Care Pharm. 2010; 16: 217–230.
2. Lai CH. Management of recurrent cervical cancer. Chang Gung Med J. 2004; 27: 711–717.
3. Wang CJ, Lai CH, Huang HJ, et al. Recurrent cervical carcinoma after primary radical surgery. Am J Obstet Gynecol. 1999; 181: 518–524.
4. Hong JH, Tsai CS, Lai CH, et al. Recurrent squamous cell carcinoma of cervix after definitive radiotherapy. Int J Radiat Oncol Biol Phys. 2004; 60: 249–257.
5. Eralp Y, Saip P, Sakar B, et al. Prognostic factors and survival in patients with metastatic or recurrent carcinoma of the uterine cervix. Int J Gynecol Cancer. 2003; 13: 497–504.
6. Bolli JA, Doering DL, Bosscher JR, et al. Squamous cell carcinoma antigen: clinical utility in squamous cell carcinoma of the uterine cervix. Gynecol Oncol. 1994; 55: 169–173.
7. Hatano K, Sekiya Y, Araki H, et al. Evaluation of the therapeutic effect of radiotherapy on cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 1999; 45: 639–644.
8. Patel CN, Nazir SA, Khan Z, et al. 18
F-FDG PET/CT of cervical carcinoma. AJR Am J Roentgenol. 2011; 196: 1225–1233.
9. Sharma P, Kumar R, Singh H, et al. Role of FDG PET-CT in detecting recurrence in patients with uterine sarcoma: comparison with conventional imaging. Nucl Med Commun. 2012; 33: 185–190.
10. Son H, Khan SM, Rahaman J, et al. Role of FDG PET/CT in staging of recurrent ovarian cancer. Radiographics. 2011; 31: 569–583.
11. Schwarz JK, Siegel BA, Dehdashti F, et al. Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma. JAMA. 2007; 298: 2289–2295.
12. Chung HH, Kim JW, Han KH, et al. Prognostic value of metabolic tumor volume measured by FDG-PET/CT in patients with cervical cancer. Gynecol Oncol. 2011; 120: 270–274.
13. Maharjan S, Sharma P, Patel CD, et al. Prospective evaluation of qualitative and quantitative 18
F-FDG PET-CT parameters for predicting survival in recurrent carcinoma of the cervix. Nucl Med Commun. 2013; 34: 741–748.
14. Wagenaar HC, Trimbos JB, Postema S, et al.Tumor diameter and volume assessed by magnetic resonance imaging in the prediction of outcome for invasive cervical cancer. Gynecol Oncol. 2001; 82: 474–482.
15. Subak LL, Hricak H, Powell CB, et al. Cervical carcinoma: computed tomography and magnetic resonance imaging for preoperative staging. Obstet Gynecol. 1995; 86: 43–50.
16. Grigsby PW, Siegel BA, Dehdashti F, et al. Posttherapy [18
F] fluorodeoxyglucose positron emission tomography in carcinoma of the cervix: response and outcome. J Clin Oncol. 2004; 22: 2167–2171.
17. Pallardy A, Bodet-Milin C, Oudoux A, et al. Clinical and survival impact of FDG PET in patients with suspicion of recurrent cervical carcinoma. Eur J Nucl Med Mol Imaging. 2010; 37: 1270–1278.
18. Sharma DN, Rath GK, Kumar R, et al. Positron emission tomography scan for predicting clinical outcome of patients with recurrent cervical carcinoma following radiation therapy. J Cancer Res Ther. 2012; 8: 23–27.
19. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18
F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999; 35: 1773–1782.
20. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001; 94: 153–156.
21. Drain PK, Holmes KK, Hughes JP, et al. Determinants of cervical cancer rates in developing countries. Int J Cancer. 2002; 100: 199–205.
22. Bonomi P, Blessing JA, Stehman FB, et al. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1985; 3: 1079–1085.
23. Machida S, Ohwada M, Saga Y, et al. Abnormal fragile histidine triad expression in advanced cervical cancer and evaluation of its utility as a prognostic factor. Oncology. 2003; 65: 89–93.
24. Jacobs AJ, Faris C, Perez CA, et al. Short-term persistence of carcinoma of the uterine cervix after radiation. An indicator of long-term prognosis. Cancer. 1986; 57: 944–950.
25. Bodurka-Bevers D, Morris M, Eifel PJ, et al. Posttherapy surveillance of women with cervical cancer: an outcomes analysis. Gynecol Oncol. 2000; 78: 187–193.
26. Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics. 2004; 24: 523–543.
27. Elst P, Ahankour F, Tjalma W. Management of recurrent cervical cancer. Review of the literature and case report. Eur J Gynaecol Oncol. 2007; 28: 435–441.
28. Kidd EA, Siegel BA, Dehdashti F, et al. The standardized uptake value for F-18
fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer. 2007; 110: 1738–1744.
29. Kidd EA, Siegel BA, Dehdashti F, et al. Pelvic lymph node F-18
fluorodeoxyglucose uptake as a prognostic biomarker in newly diagnosed patients with locally advanced cervical cancer. Cancer. 2010; 116: 1469–1475.
30. Liu FY, Yen TC, Chen MY, et al. Detection of hematogenous bone metastasis in cervical cancer: 18
F-fluorodeoxyglucose-positron emission tomography versus computed tomography and magnetic resonance imaging. Cancer. 2009; 115: 5470–5480.
31. Esthappan J, Chaudhari S, Santanam L, et al. Prospective clinical trial of positron emission tomography/computed tomography image-guided intensity-modulated radiation therapy for cervical carcinoma with positive para-aortic lymph nodes. Int J Radiat Oncol Biol Phys. 2008; 72: 1134–1139.