|Year : 2012 | Volume
| Issue : 1 | Page : 23-27
Positron emission tomography scan for predicting clinical outcome of patients with recurrent cervical carcinoma following radiation therapy
Daya Nand Sharma1, Goura Kisor Rath1, Rakesh Kumar2, Arun Malhotra2, Sunesh Kumar3, Jagadesan Pandjatcharam1, Sagar Maharjan2
1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi 110029, India
2 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
3 Department of Gynecology and Obstetrics, All India Institute of Medical Sciences, New Delhi 110029, India
|Date of Web Publication||19-Apr-2012|
Daya Nand Sharma
F-39, Ansari Nagar, New Delhi 110029
Source of Support: None, Conflict of Interest: None
Purpose: To evaluate the role of positron emission tomography (PET) for predicting the clinical outcome of patients with recurrent cervical carcinoma following definitive radiation therapy (RT).
Materials and Methods: Twenty two patients of post irradiated recurrent cervical carcinoma (PIRCC) were enrolled in this prospective study. 18-fluorodeoxyglucose (FDG) PET imaging was performed in each patient before the salvage therapy. The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) were measured and correlated with cumulative progression free survival (PFS).
Results: Median age of patients was 42 years. Majority of patients had stage III disease at the initial presentation and all 22 patients had received prior definitive RT. The median recurrence free period was 11 months. Salvage therapy consisted of surgical resection or re-irradiation depending upon the various clinical and radiological factors. Median SUVmax was 5.8 (range 1.8-50.6) and median MTV was 43 cm 3 (range 5.8-243). The cumulative PFS for all patients was 20% at 30 months. The one-year PFS was 28% for patients with SUVmax value of >5.8 versus 42% for those with SUVmax value of <5.8 (P value 0.01). The one-year PFS was 43% for patients with MTV value of >43 cm 3 versus 45% for those with MTV value of <43 cm 3 (P value 0.8).
Conclusion: Our preliminary experience has suggested that FDG uptake on PET scan can predict the clinical outcome of PIRCC patients. Further randomized studies may be conducted with large sample size and longer follow up to establish its definite predictive value.
Keywords: Cervical carcinoma, positron emission tomography scan, predictive value, recurrence
|How to cite this article:|
Sharma DN, Rath GK, Kumar R, Malhotra A, Kumar S, Pandjatcharam J, Maharjan S. Positron emission tomography scan for predicting clinical outcome of patients with recurrent cervical carcinoma following radiation therapy. J Can Res Ther 2012;8:23-7
|How to cite this URL:|
Sharma DN, Rath GK, Kumar R, Malhotra A, Kumar S, Pandjatcharam J, Maharjan S. Positron emission tomography scan for predicting clinical outcome of patients with recurrent cervical carcinoma following radiation therapy. J Can Res Ther [serial online] 2012 [cited 2020 May 29];8:23-7. Available from: http://www.cancerjournal.net/text.asp?2012/8/1/23/95169
| > Introduction|| |
Radiation therapy is a major treatment modality for cervical carcinoma. Up to 70% of patients with cervical cancer receive RT at some point in their treatment.  Though cure rates in early stage disease are good, yet 30-50% of patients with advanced stage disease will ultimately develop recurrence. , The prognosis of recurrent cervical carcinoma is very dismal and treatment of such patients remains a challenge. , Re-irradiation may be offered to highly selected cases; however, the rate of severe complications, especially fistulas, is significantly high. , Chemotherapy provides very poor results and is used for palliation.  Salvage surgery as pelvic exenteration has been reported to provide five-year survival rates ranging from 30 to 60% but associated with significant operative mortality (about 10%) and severe morbidity (27-54%). ,, Therefore, careful selection of patients, on the basis of various prognostic factors, for salvage treatment is very important since unnecessary over or under treatment will enhance the risk of debilitating toxicity or compromised survival respectively. The various prognostic factors that have been identified, so far, include disease-free interval, size of recurrence, and lateral side wall fixation. The prognosis is better for patients with a disease-free interval greater than six months, recurrence less than 3 cm in diameter, and no side wall fixation. ,, Despite careful selection, it is difficult to reliably predict the outcome. Identification of novel pretreatment factors that potentially predict outcome is thus of great interest.
It has been suggested that FDG uptake by tumor on PET imaging may have prognostic significance. In newly diagnosed primary cervical cancer (PCC) patients, role of FDG-PET has been demonstrated to be useful in staging, assessment of response, post therapy surveillance and prognostication. ,,,,,, Patients with high FDG uptake generally have poor outcome. It is not known whether the predictive value of FDG uptake pertains to the response to specific therapies, or rather might reflect the biologic aggressiveness of the disease. For recurrent cervical cancer, there are few reports ,, regarding the use of FDG-PET for detection and staging; but its role has not been studied so far, to the best of our knowledge, for predicting the therapeutic outcome.
We conducted a prospective trial to study the predictive value of pretreatment FDG-PET in patients with post irradiation recurrent cervical cancer (PIRCC) by correlating the PET imaging parameters, like maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) with survival outcome.
| > Materials and Methods|| |
Between January 2008 and June 2009, 22 patients with pelvic recurrence from cervical carcinoma following definitive radiotherapy (or chemo-radiotherapy) were enrolled into this prospective study. Informed consent was obtained from all patients. Inclusion criteria were: 1) Patients who developed pelvic recurrence after declared to be cured following definitive radiotherapy/chemo-radiotherapy for histopathologically proven carcinoma of cervix. 2) They had diagnosis of recurrent cervical cancer established by histopathology (biopsy or cytology) or clinically evident recurrent disease. 3) Minimum of three months gap between the completion of the definitive RT and presentation with recurrence. Exclusion criteria included: 1) Patients who developed recurrence within three months of completion of definitive RT. 2) Patients showing persistent residual disease after the completion of the primary treatment. 3). Patients who had previously received salvage therapy for recurrence. 4) Patients with distant metastasis detected on conventional imaging (CT scan, chest X-ray). Due to our institution's traditional practice, spread of disease to para-aortic nodes was not taken as metastatic disease.
Pretreatment (pre-salvage therapy) work up of patients included abdomino-pelvic CECT or MRI scan, sigmoidoscopy, cystoscopy, chest X-ray. FDG PET-CT imaging, performed for the study protocol, did not alter staging and the salvage treatment modality. The treatment modality for each individual patient was decided by the gynecologic oncology team based on the extent of disease, disease free period, and performance status/comorbidity and patient's opinion. The surgical treatment comprised of radical hysterectomy/pelvic exenteration. The RT practice usually consisted of external beam radiotherapy (EBRT) and/or intracavitory/interstitial brachytherapy depending upon the previous radiotherapy treatment. Adjuvant chemotherapy was given to suitable patients with regime containing carboplatin and paclitaxel. Patients not suitable for salvage surgery or RT were taken up for palliative RT or best supportive care.
The scans were done with a dedicated PET/CT scanner present in our institute (SIEMENS, BIOGRAPH 64). The patients were fasted for at least 4 h; blood glucose level was kept below 140 mg/dl. For minimizing the physiologically excreted contrast in the urinary tract, Foley's catheter was inserted in the urinary bladder before injecting 10 mCi of 18-FDG intravenously. Intravenous fluids were administered for hydration and i.v. furosemide 20 mg was given for the dieresis. The patients were rested in a quiet room. After 45-60 min uptake period, patients were placed into the scanner. In the PET-CT system, CT scan acquisition was performed on spiral dual slice CT with slice thickness of 4 mm and a pitch of 1. Images were acquired using a matrix of 512 × 512 pixels and pixel size of about 1 mm. After transmission-scan, 3D PET acquisition was taken for 3-5 min per bed position for one-two bed position. PET data was acquired using matrix of 128 × 128 pixels with a slice thickness of 1.5 mm.
After image reconstruction, a region of intrest (ROI) was carefully drawn around the site of abnormal FDG uptake on lesions in consequent 4-6 PET/CT slices. The slice with maximal FDG uptake in the ROI was choosen for quantitative measurement of metabolic activity of the lesion (SUV). From these ROIs, the SUV was calculated according to the formula described below.
Mean ROI activity(MBq/g)/Injected dose(MBq)/Body weight(g)t
Where , MBq= mega-Becquerel, and g=grams
The MTV was calculated as 60% of the volume covered by the SUVmax. The SUVmax and MTV of the pelvic recurrent lesion were recorded for every patient for the analysis.
Patients were followed up every month till six months, then every two months till one year and then subsequently every three to six months. At every visit, clinical and gynecological examination was performed and, if necessary, CT/MRI scans, to assess the disease status. PET scan was not mandatory to assess disease status.
The endpoint of the study was progression free survival. The PFS was defined as period from the date of completion of treatment to the date of progression. The criteria for disease progression were appearance of a new lesion or more than 25% increase in the maximum diameter of the pelvic recurrent disease. Using the statistical software SPSS, version 11.5, the PFS was calculated by Kaplan-Meier survival method.  Each patient, who lost follow up after a certain period was censored at that point of time for survival analysis. PFS was also determined with respect to SUV max, MTV. Log rank test was used to find out the P value and a value of <0.05 was considered as significant.
| > Results|| |
Clinical characteristics are given in [Table 1]. Median age of the patients was 42 years. Majority of patients had stage III disease at the initial presentation and all 22 patients had received prior definitive RT. The median recurrence free period (initial treatment to development of recurrence) was 11 months. All patients had central recurrence; 9 had lateral extension till pelvic wall. Pelvic and PA node metastases were noticed in 6 and 4 patients respectively. Only 2 patients could undergo salvage surgery (1 radical hysterectomy, 1 total pelvic exenteration); rest were either unsuitable for or declined surgery after counseling. Fifteen patients received re-irradiation with a combination of pelvic EBRT (median dose 30Gy, range 26-45 Gy) and HDR IBT (10Gy in 2 fractions). Palliative RT was given to 3 patients with dose ranging from 5 to 20 Gy. Five patients received adjuvant chemotherapy (1 after surgery and 4 after re-irradiation) with a median of 3 cycles.
PET imaging characteristics are given in [Table 2]. Median SUVmax was 5.8 (range 1.8-50.6) and median MTV was 43 cm 3 (range 5.8-243). The correlation between FDG uptake PFS was evaluated using median SUVmax as cutoff value (<5.8 vs >5.8). Similarly a cutoff value of 43 cm 3 (<43 cm 3 vs >43 cm 3 ) was used for correlating the MTV and PFS.
Median follow up period was 9 months (range 2-31). The cumulative PFS for all patients was 20% at 30 months [Figure 1]. As shown in [Figure 2], the one-year PFS was 28% for patients with SUVmax value of >5.8 versus 42% for those with SUVmax value of <5.8 and this difference was statistically significant (P value 0.01). The MTV had no correlation with PFS. The one-year PFS was 43% for patients with MTV value of >43 cm 3 versus 45% for those with MTV value of <43 cm 3 (P value 0.8) [Figure 3]. Majority of recurrences took place within one year period.
|Figure 2: The progression-free survival of patients with SUVmax value of <5.8 vs >5.8.|
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|Figure 3: The progression-free survival of patients with MTV of <43 cm3 vs >43 cm3|
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| > Discussion|| |
Generally, prognosis of PIRCC is poor. Both patients and treating oncologists are in a quandary whether to combat or surrender. Reliable predictive factors for the success of salvage treatment can help in decision making. PET imaging, which has proved its value as a predictive factor for PCC, can potentially predict the clinical outcome of PIRCC patients.
We conducted this trial in post RT patients since most patients in developing countries initially present in advanced stages and are treated mainly by RT. , Therefore post RT recurrence is a much more commoner situation than post surgery recurrence. The results of our study will be a useful addition to the literature for better understanding of the PET imaging utility for predicting the outcome of PIRCC. We have taken a small sample size since there is very limited experience in the literature with an anticipation that this preliminary experience will help us in designing a larger prospective study.
We have observed a median SUVmax value of 5.8 in our study. This seems to be lower than the SUVmax observed in PCC. Most series ,, have reported a median SUVmax of higher than 10 in PCC. Two recent studies by Kidd et al, and Lee et al,  have reported median SUV max of 11.4 and 12.3 respectively. The lower SUVmax value in PIRCC could be due to the fact that RT induces fibrosis of pelvic tissues, including blood vessels, which might result into hypoxic environment in the pelvis. 
The overall clinical outcome in our series (20% PFS at 30 months) was relatively poorer than the literature. , This was because of several factors: shorter disease free period before recurrence (11 months), advanced disease at the time of recurrence [Table 1], and fewer patients eligible for salvage surgery (9%). We have chosen PFS as the end point in our study since the clinical and radiological methods for ascertaining the disease regression in re-irradiated patients are not very reliable because of the prominent RT-induced fibrotic changes in the pelvic structures.
SUVmax has been a consistent prognostic factor in PCC in most studies. ,,, The results of our study have shown that the FDG uptake is a predictive marker for the survival outcome in PIRCC. The patients having SUVmax value of >5.8 had significantly poorer PFS in our study [Figure 2]. Therefore, PIRCC patients with SUVmax of <5.8 along and other known favorable prognostic clinical factors may preferably be considered for aggressive salvage therapy. On the other hand, patients with SUVmax >5.8 and other poor clinical prognostic factors may be cautiously considered for aggressive therapy.
Though correlation of MTV and response prediction in PCC has been studied in some trials, ,, but no significant association has been established. This could be due to the difference in the method of calculating the MTV in different trials. Some authors , suggest an absolute cutoff value of SUVmax (like 2.0-2.5) while others  suggest a definite percentage of SUVmax (40-60% of SUVmax). We have taken 60% of SUVmax for calculating the MTV. We tried to correlate MTV with PFS, but it failed to predict the outcome.
Lin et al, have studied the role of FDG PET in 26 patients of re-recurrent (recurrence after salvage therapy) cervical carcinoma. Though they have not studied the predictive value of PET scan, they evaluated the clinical impact of PET scan by determining the sensitivity, specificity and accuracy of diagnosing and staging the disease. They concluded that PET scan had a positive impact in 46% of patients.
| > Conclusion|| |
Our study had certain lacunae in the form of small sample size and short duration of follow up. Therefore it is difficult to draw meaningful conclusions; but following are the noticeable findings of our study. (1) SUVmax of the PIRCC is lower than the PCC. (2). FDG uptake is a significant predictive factor and SUVmax value of <5.8 is associated with better survival. (3) The MTV does not predict the clinical outcome of PIRCC patients. Based on our experience through this small study, we therefore suggest that role of PET imaging may further be studied in PIRCC patients to establish its predictive value.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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