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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2167-2171 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.035 Posttherapy [18F] Fluorodeoxyglucose Positron Emission Tomography in Carcinoma of the Cervix: Response and OutcomeFrom the Department of Radiation Oncology and Division of Nuclear Medicine, Mallinckrodt Institute of Radiology; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; and Alvin J. Siteman Cancer Center Cancer Center; Washington University School of Medicine, St Louis, MO. Address reprint requests to Perry W. Grigsby, MD, Department of Radiation Oncology, Box 8224, Washington University School of Medicine, 4921 Parkview Pl, Lower Level, St Louis, MO 63110; e-mail: pgrigsby{at}wustl.edu
PURPOSE: The aim of this study was to evaluate response to therapy using posttherapy molecular imaging with [18F] fluorodeoxyglucose (FDG), and to compare the response with patient outcome. PATIENTS AND METHODS: This was a retrospective medical record review of 152 patients with carcinoma of the cervix. All patients underwent a pre- and posttreatment whole-body positron emission tomography (PET) imaging scan with FDG. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy whole-body FDG-PET was performed 1 to 12 months (mean, 3 months) after completion of treatment. RESULTS: The posttherapy PET did not show any abnormal FDG uptake in 114 patients, and their 5-year cause-specific survival estimate was 80%. There was persistent (in the irradiated region) abnormal FDG uptake in the cervix or lymph nodes in 20 patients. Their 5-year cause-specific survival estimate was 32%. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were present in 18 patients, and none were alive at 5 years. A Cox proportional hazards model of survival outcome indicated that any abnormal posttherapy FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from cervical cancer when compared with pretreatment- and treatment-related prognostic factors (P < .0001). CONCLUSION: Posttherapy abnormal FDG uptake (persistent or new) as detected by whole-body PET measures tumor response and might be predictive of tumor recurrence and death from cervical cancer. Prospective validation of these results is warranted.
Invasive cervical cancer provides a clinical model for the evaluation of therapeutic response by use of positron emission tomography (PET) with the glucose analog [18F] fluorodeoxyglucose (FDG) to assess posttherapy glucose metabolism in the primary tumor and metastases. FDG-PET has been shown to be highly sensitive and specific for detecting primary and recurrent cervical cancer.1-5 A feature of cervical cancer is that the tumor predictably metastasizes from the cervix first to the pelvic lymph nodes, then to the para-aortic lymph nodes, then to the supraclavicular lymph nodes, and then to distant sites such as lung, liver, and bone. Recurrent disease, however, does not follow a specific anatomic pattern and may recur at sites of initial disease, at distant sites, or both. FDG-PET molecular imaging of tumor response to chemotherapy and irradiation has been evaluated for patients with a variety of cancers, including lymphoma, and breast, lung, and colorectal carcinoma.6 We have previously reported our initial experience with 76 patients with cervical cancer monitored by FDG-PET.7 In the current study, we have expanded on our previous investigation and have evaluated posttherapy response, sites of failure, and survival outcome in a larger patient population.
We retrospectively reviewed the medical records of 152 patients who were diagnosed between March 1998 and December 2002 with invasive cervical cancer. The institutional Human Studies Committee approved this retrospective record review. All patients in this review were seen and treated at Washington University Medical Center. Patients selected for this review underwent posttherapy FDG-PET as part of their routine clinical evaluation at the discretion of the attending physician. Patients with symptoms or suspicious clinical findings were excluded from this review. Patients were evaluated by a medical history review and a physical examination. Routine CBCs and chemistry profiles were performed. All patients had a pelvic examination under anesthesia. Patients with urinary and gastrointestinal symptoms had a cystoscopy and a proctosigmoidoscopy performed with biopsies when indicated. Cervical biopsies were obtained in all patients. Pretreatment imaging studies in all patients included chest radiography, computed tomography (CT) scan of the abdomen and pelvis, and whole-body FDG-PET. Posttherapy FDG-PET was performed 1 to 12 months (mean, 3 months; standard deviation, 2.5 months) after completion of treatment for response evaluation. FDG-PET was performed and interpreted in routine clinical fashion with use of the techniques we have previously described.7 Patient age ranged from 23 to 88 years (mean, 49 years). There were 51 women with stage Ib, 55 with stage II, 42 with stage III, and four with stage IV disease. The histology of the tumor was squamous cell carcinoma in 141 patients, adenosquamous cell carcinoma in six, adenocarcinoma in four, and small-cell carcinoma in one. The duration of follow-up ranged from 2 to 62 months (mean, 28 months) for the patients alive at the time of last follow-up. The patient status at last follow-up was no evidence of disease in 109, alive with disease in 10, dead of disease in 30, and dead of intercurrent disease in three. Radiotherapy of the cervical cancer was performed in all patients and consisted of external irradiation and intracavitary brachytherapy. The mean total dose to point A was 83.8 Gy. Concurrent chemotherapy consisting of six weekly cycles of cisplatin (40 mg/m2) was given to 132 patients. Clinical follow-up of patients was performed 6 weeks after completion of therapy, and periodically as follows: monthly for 3 months; every 3 months until 12 months; every 4 months during the second year; and every 6 months during years 3, 4, and 5. Abnormal foci of FDG uptake on posttherapy studies, overall survival, cause-specific survival, and patterns of relapse were the major end points of this study. Survival and relapse were measured from the completion of treatment. The Kaplan-Meier (product-limit) method was used to derive estimates of survival.8 The tests of equivalence of the estimates of survival were performed by the generalized Wilcoxon log-rank test.9 Multivariate analysis of variables was performed using the Cox proportional hazard regression model.10
Posttherapy PET did not show any abnormal sites of FDG uptake in 114 patients. There was persistent abnormal FDG uptake (in the irradiated region) in the cervix or lymph nodes in 20. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were noted in 18 patients (with or without sites of persistent uptake). The status of the posttherapy response and the ultimate sites of biopsy-proven disease recurrence are predicted in Table 1 (P < .0001). The sites of ultimate disease recurrence among the 20 patients with persistent abnormal posttherapy FDG uptake (in the cervix or lymph nodes) are presented in Table 2 (P = .1710).
The overall survival rates as a function of the posttherapy FDG response pattern are shown in Figure 1. The 5-year overall survival rates were 92% for those with no abnormal FDG uptake and 46% for those with persistent FDG uptake, whereas there were no survivors for those with new FDG uptake (P < .001). The corresponding 5-year cause-specific survival rates were 80%, 32%, and 0%, respectively (P < .001; Fig 2). Figure 3 shows the cumulative hazard for disease recurrence by posttherapy FDG response.
A Cox proportional hazards model of survival outcome evaluating pretreatment FDG-PET lymph node status (by region of involvement), clinical stage (I, II, III, or IV), total irradiation dose (continuous), overall treatment time (continuous), use of concurrent chemotherapy (yes v no), and posttherapy FDG response (persistent or new v negative) demonstrated that any abnormal posttherapy FDG uptake was the most significant predictor of death from cervical cancer (P < .00021; Table 3).
Molecular imaging with FDG-PET is now a standard, pretreatment imaging study used for staging of many different cancers. The utility of posttherapy FDG-PET to monitor tumor response also has been evaluated in several tumors. Response to therapy is a significant prognostic factor for all cancer types. This finding is relevant for the primary tumor, metastatic disease, and recurrent disease. The evaluation of tumor response may be by physical examination, serum tumor markers, or by imaging studies. The monitoring of cervical cancer tumor response to curative therapy with irradiation has been nonspecific. There are no reliable serum tumor markers for cervical cancer. Squamous cell carcinoma antigen has been evaluated in this setting for patients with cervical cancer, but has been found to have a low sensitivity and specificity for evaluating response and for detecting recurrent disease.11 During the course of curative irradiation, the cervical tumor mass regresses in size as determined by pelvic examination. At the completion of irradiation, most patients will have had complete tumor regression. Persistent tumor of the cervix, during the first 3 months after irradiation, can be detected by pelvic examination. Persistent cervical cancer at 3 months is predictive of a poor survival outcome.12 Of course, physical examination does not evaluate the response of pelvic and para-aortic lymph node metastases. Evaluation of the tumor response in these lymph node sites is essentially nonexistent at present. CT and magnetic resonance imaging are nonspecific tests for evaluating tumor response in the primary tumor and in irradiated lymph nodes and are informative only if they demonstrate an increase in size, which implies tumor growth. Lymph nodes that are unchanged in size, as determined by CT and magnetic resonance imaging, do not reliably indicate whether tumor is present or absent.13 Papanicolaou tests and cervical biopsies have not been performed routinely within the first few months after completing irradiation because the abnormal pathologic features that are seen are often due to radiation effect and are, therefore, nonspecific.14 However, there is pathologic evidence that persistent tumor present in the cervix after irradiation is a predictor of a poor survival outcome. Keys et al15 performed a prospective phase III clinical trial testing the role of adjuvant hysterectomy after standardized irradiation in patients with stage Ib2 cervical cancer. Histologic evaluation of the cervical specimens for the 123 patients who underwent hysterectomy (median time to surgery from study entry was 3.0 months) showed no cancer in 48% (59 patients), microscopically positive cervical specimens in 40% (49 patients), and grossly positive specimens in 12% (15 patients). There was a statistically significant decrease in the progression-free and overall survival rates of patients with positive specimens compared to those with negative specimens. However, these data do not address the issue of lymph node response or the development of distant metastases. FDG-PET has been found to be useful in the detection of cervical cancer recurrence. However, the only data addressing therapeutic response is from our preliminary study.7 This current study updates our initial study with longer patient follow-up and additional patients. There are three findings in this current study: (1) a complete metabolic response on PET was predictive of a good survival outcome (92% 5-year survival); (2) a partial metabolic response (persistent, abnormal FDG uptake in the irradiated cervix or lymph nodes) was predictive of a poor survival outcome (46% 5-year survival); and (3) progressive disease (new sites of abnormal FDG uptake outside of the irradiated volume) was predictive of death from cervical cancer in 17 of 18 patients. A limitation of this study was that it was retrospective, and the posttherapy FDG response evaluations were performed at times varying from 1 to 12 months (mean, 3 months) after completion of irradiation. The optimal timing for the posttherapy PET cannot be ascertained from our data. Our current practice is to perform the posttherapy total-body FDG-PET imaging at 3 months after completion of irradiation because our prior clinical data demonstrated that persistent tumor in the cervix after 3 months was predictive of a poor outcome.12 Despite these limitations, there are two implications from our study: (1) patients with an incomplete response to therapy and (2) patients with new sites of metastases, as evaluated by FDG-PET, might be appropriate for clinical trials exploring novel treatment approaches for new and persistent disease, assuming the prognostic significance of PET in this patient group is prospectively validated.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Rose PG, Adler LP, Rodriguez M, et al: Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: A surgicopathologic study. J Clin Oncol 17:41–45, 1999 2. Narayan K, Hicks RJ, Jobling T, et al: A comparison of MRI and PET scanning in surgically staged loco-regional advanced cervical cancer: Potential impact on treatment. Int J Gynecol Cancer 11:263–271, 2001[CrossRef][Medline]
3. Grigsby PW, Siegel BA, Dehdashti F: Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19:3745–3749, 2001
4. Ryu SY, Kim MH, Choi SC, et al: Detection of early recurrence with 18F-FDG PET in patients with cervical cancer. J Nucl Med 44:347–352, 2003 5. Havrilesky LJ, Wong TZ, Secord AA, et al: The role of PET scanning in the detection of recurrent cervical cancer. Gynecol Oncol 90:186–190, 2003[CrossRef][Medline]
6. Kostakoglu L, Goldsmith SJ: 18F-FDG PET: evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma. J Nucl Med 44:224–239, 2003 7. Grigsby PW, Siegel BA, Dehdashti F, et al: Posttherapy surveillance monitoring of cervical cancer by FDG-PET. Int J Radiat Oncol Biol Phys 55:907–913, 2003[CrossRef][Medline] 8. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]
9. Breslow N: A generalized Kruskal-Wallis test for comparing K samples subject to unequal patterns of censorship. Biometrika 57:579–594, 1970 10. Cox DR: Regression models and life tables. J R Stat Soc 34:187–220, 1972 11. 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 65:89–93, 2003[CrossRef][Medline] 12. 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 57:944–950, 1986[CrossRef][Medline] 13. Bodurka-Bevers D, Morris M, Eifel P, et al: Posttherapy surveillance of women with cervical cancer: An outcomes analysis. Gynecol Oncol 78:187–193, 2000[CrossRef][Medline] 14. Ansink A, De Barros-Lopes A, Monaghan JM: Recurrent stage IB cervcial carcinoma: Evaluation of the effectiveness of routine follow-up surviellance. Br J Obstet Gynaecol 103:1156–1158, 1996[Medline] 15. Keys HM, Bundy BN, Stehman FB, et al: Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: A randomized trial of the Gynecologic Oncology Group. Gynecol Oncol 89:343–353, 2003[CrossRef][Medline] Submitted September 9, 2003; accepted March 2, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
