Journal of Nuclear Medicine Radiology & Radiation Therapy Category: Medical Type: Opinion
Pre-therapeutic (18) F-fluoro-2-deoxyglucose ((18) F-FDG) Positron Emission Tomography (PET) in Cervix Cancer: Is it a Reliable and Independent Prognostic Factor for Survival?
- Ming Yin Lin1*, Kailash Narayan2
- 1 Department Of Radiation Oncology And Cancer Imaging, Peter MacCallum Cancer Centre, Australia
- 2 Department Of Obstetrics And Gynaecology, Peter MacCallum Cancer Centre, University Of Melbourne, Melbourne, Australia
*Corresponding Author:Ming Yin Lin
Department Of Radiation Oncology And Cancer Imaging, Peter MacCallum Cancer Centre, Australia
Received Date: Aug 24, 2015 Accepted Date: Aug 31, 2015 Published Date: Sep 15, 2015
There has been an ongoing quest to identify new prognostic factors in cervix cancer patients in addition to FIGO stage, tumour volume and nodal involvement in order to tailor individualized patient management and improve survival.
Positron Emission Tomography (PET) - Computer Tomography (CT) with 18-F-2-fluoro-2-deoxygluglose (FDG) has been shown to be invaluable in the diagnosis and staging of cervix cancers as well as many other malignancies. PET has demonstrated the ability to detect neoplastic involvement in lymph nodes of normal or borderline size and the advent of hybrid PET-CT has further improved its anatomic localisation of lesions of interest . Several studies have demonstrated that FDG-PET is superior to conventional imaging methods for detecting metastatic disease especially those in the lymph nodes and is helpful in staging, restaging and treatment planning of patients with cervix cancer [2-4].
In addition to its efficacy in assessing nodal and metastatic disease, FDG-PET/CT is thought to have a potential role as a prognostic factor .
STANDARDIZED UPTAKE VALUE (SUV)
FDG uptake is dependent on glucose utilization by cells and may correlate with tumour proliferation, inflammation and arguably tumour aggressiveness . SUVmax of the primary tumour has been suggested to be predictive of Lymph Node (LN) involvement, treatment response and overall survival . Differential behavior to SUV has been investigated in many types of cancer, including lymphoma, Non-Small Cell Lung Cancer (NSCLC), esophageal cancer, and head and neck cancer [7,8]. For NSCLC in particular, FDG uptake has been shown to be significantly different for adenocarcinoma versus squamous cell carcinoma and for well-differentiated versus poorly differentiated tumors . On the other hand, some types of aggressive cancer such as clear cell or certain subtypes of sarcomas may show relatively low FDG uptake.
The exact mechanism of differential FDG uptake by tumour is unclear. There appears to be a correlation between FDG uptake and Glut-1 expression, which has led to research into glucose transporter gene expression . In breast cancer patients, Bos et al.,  found a correlation between FDG uptake and Glut-1 expression, mitotic index, amount of necrosis, tumor cell volume, and micro vessel density. In NSCLC patients, increased FDG uptake correlated with expression of Hypoxia-inducible Factor 1-alpha (HIF-1a) and Glut-1 expression . Similar correlation between higher SUV and Glut-1 expression  as well as Glut-1 overexpression and tumour grade  was found in cervix cancers patients. In contrast, no correlation was found between Glut-1 and Glut-3 expression and tumour differentiation or indeed SUVmax in oral Squamous Cell Carcinoma (SCC) .
THE ROLE OF SUV IN PROGNOSTICATING CERVIX CANCER
CURRENTLY KNOWN PROGNOSTIC FACTORS IN CERVIX CANCER
However, in advanced stage disease or in patients with a large volume disease the prognostication based of compartmental spread of tumour remain inadequate. Realizing the importance of tumour volume FIGO stage 1 and 2A was again modified to subdivide stage 1B into 1B1, 1B2 and 2A in to 2A1 and 2A2 using 4 cm clinical tumour diameter as a cutoff point.
Clinical estimation of tumour size and hence volume was highly subjective and correlated very poorly with histological findings. CT scanning was only marginally better in estimation of tumour volume, although it could easily detect enlarged metastatic lymph nodes. MRI provided a more accurate measure of tumour volume that co-related with histological measurements well . Subsequently, tumour volume was used as a dichotomized value (13 cc) in selecting treatment modalities in small operable tumours  or in prognostication of treatment outcome in larger (50 cc) tumours . MRI obtained tumour volume was assessed for prognostic significance in a multivariable analysis in 179 patients treated with curative intent, and it was found to be a continuous variable further influenced by tumour infiltrating in the uterine corpus  or the presence of nodal metastasis .
In advanced cervix cancer patients where surgery is inappropriate and the in order to assess the known prognostic factors by non-invasive methods, MRI to assess the local spread of tumour as well as volume and PET scans to assess the metastatic lymph nodes and their station were invaluable. It has been shown that five year survival rates in patients with corpus non-invasive tumour was 77% and those with corpus invasion was 41% . Those without the lymph node metastasis and with lymph node metastasis the 5 year survival was 70% and 48% respectively . Those with lymph node metastasis limited to pelvis was 57% and where it extended to involve para-aortic nodes the survival declined to 32-26% [26,27].
Based on the current knowledge of prognostic markers in cervix cancer, there is no one all-encompassing prognostic marker that can put a single numerical value or a series of discrete values predicting an outcome better than the combination of MRI volume, (analyzed as a continuous variable) and nodal status on PET-CT imaging as a dichotomized value such as lymph node metastasis present / not present and if present, the echelon lymph node level which is involved.
WHERE DOES THE SUVMAX FIT IN THIS PROGNOSTIC MATRIX?
In order to survive and metastasize, it is hypothesized that tumour cells from the primary site would be required to come in contact with the terminal lymphatics, survive in the lymphatic space, invade lymph nodes where they would need to evade the host immune response, continue to proliferate and be selected for clonal expansion to replace lymph nodes with metastases. These cells also need to come in contact with intertissular lymphatic-venous anastomoses , pass in to circulation, survive and find a suitable tissue to colonize and form distant metastases.
When a matrix of invasiveness and local growth is observed by MRI and the distribution of viable tumour colonies is detected by PET imaging, a complete snap shot of tumour and host interaction is assessable and accurate prediction of prognosis becomes possible. A single value, (or a range of values simply based on metabolic capacity of the primary tumour devoid of any host interaction parameters), such as SUVmax alone, would only enable one to know the potential of the tumour to exhibit a more or less aggressive behavior, rather than actually predicting the likelihood of recurrence. For example, in uterine cancers, it is known that serous and clear cell histologies have a poorer prognosis compared to endometerioid histologies. However, the overall prognosis is further modified by other prognostic factors, such as the presence or absence of Lymphovascular Space Invasion (LVSI) or lymph node metastasis. In fact, patients with clear cell and endometrioid histologies that are lymph node negative and do not have LVSI, were both found to have <8% recurrence rates . However LVSI positive endometrioid histology will still have worse prognosis than LVSI and node negative clear cell or serous cancers of uterus.
Therefore, just as “bad” histology on its own is not sufficient to predict prognosis, we believe that an increased SUVmax (a sign of increased metabolic activity) in isolation is likewise insufficient as a reliable predictor of treatment outcome.
In a study by Kidd et al.,  a PET-based nomogram was used which included tumour volume, SUVmax of primary tumour and presence of and level of nodal involvement. The authors found that the most significant poor prognostic factor was the detection of lymph node metastasis by PET imaging and the level of nodes, rather than their SUVmax. SUVmax value was only marginally better than tumour volume for predicting Relapse Free Survival (RFS). The HR for OS in locally advance cervix cancer was 0.6, 1.12, 1.40 and 3.24 in node negative, pelvic, common iliac and para-aortic node positive patients respectively , in comparison, HR for OS was of 1.009 for SUVmax of >14 for primary tumour . Perhaps the prognostic significance of SUVmax of the primary tumour could be better explored in PET node negative patients for it to have a practical application.
We believe several aspects related to SUVmax need to be explored before it could become a practical and reproducible prognostic parameter useful in the management of cervix cancer patients.
- Is SUVmax a continuous variable or it can be subdivided in quartiles or even dichotomized?
- What is the best way of integrating the SUVmax of Lymph Nodes (SUVLN) in the presence of nodal metastases in the overall matrix of a SUVmax based prognostic tool?
- Are there different implications on the interpretation of the prognostic potential of SUVmax (primary tumour) in node negative and node positive patients? Should there be separate SUVmax based prognostic tools?
- Since SUVmax is measured in relation to background uptake, for example, in liver, where this background uptake could vary from patient to patient, is there a need for a universal correction factor?
We have more than 300 patients of cervix cancer treated with curative intent between 2002 and 2010 who underwent pretreatment PET and MRI studies. The details of the pretreatment assessment, histopathological data, treatment and follow-up have been prospectively collected and recorded in our institutional database. We are currently testing the hypothesis that there would be a trend of higher SUVmax with the lymph node metastases but survival will relate the level of nodal metastases and only in node negative patients SUVmax may have a significant prognostic role in stratifying patients over tumour volume and the FIGO stage of the disease.
As a pilot study to test this hypothesis, we randomly selected cervix cancer patients from 4 different categories thought to increasingly have poor prognosis. (n=16)
- Small primary and negative nodes
- Small primary with positive nodes
- Large primary with negative nodes
- Large primary with positive nodes
|Patient||FIGO||SUV||MRIVol||No + nodes||Highest Involved node||SUV Max||Relapse & Follow up|
|11$||1B||14.5||100||0||PA, D||Dead (tumour)||513|
|12@||3B||26.7||84||2||Pelvic||15.5||PA, SC, D||Dead (Tumour)||1079|
PA= Para Aortic; Inf = Inferior; SC = Supraclavicular; D = Distant; P = Primary; N = Node
* = small primary, node negative; #= small primary, node positive; $ = large primary, node negative; @ = large primary, node positive
To our knowledge, most of previously published studies have attempted to relate the SUVmax of primary tumour with survival by utilizing various methods of obtaining a cutoff value that may fit their data. However, in addition to the limitation of small sample sizes and variable tumour types, no uniform value has emerged. The independent and clinically useful prognostic potential of SUVmax still remains undecided.
- Rockall AG, Cross S, Flanagan S, Moore E, Avril N (2012) The role of FDG-PET/CT in gynaecological cancers. Cancer Imaging 12: 49-65.
- Maffione AM, Piva M, Tsamita CS, Nanni C, Castellucci P, et al. (2009) Positron-emission tomography in gynaecologic malignancies. Arch Gynecol Obstet 280: 521-528.
- Beddy P, O'Neill AC, Yamamoto AK, Addley HC, Reinhold C, et al. (2012) FIGO staging system for endometrial cancer: added benefits of MR imaging. Radiographics 32: 241-254.
- Narayan K, Lin MY (2015) Staging for cervix cancer: Role of radiology, surgery and clinical assessment. Best Pract Res Clin Obstet Gynaecol 29: 833-844.
- Kidd EA, Siegel BA, Dehdashti F, Grigsby PW (2007) The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer 110: 1738-1744.
- Long NM, Smith CS (2011) Causes and imaging features of false positives and false negatives on F-PET/CT in oncologic imaging. Insights Imaging 2: 679-698.
- Facey K, Bradbury I, Laking G, Payne E (2007) Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers. Health Technol Assess 11: 267.
- Wood KA, Hoskin PJ, Saunders MI (2007) Positron emission tomography in oncology: a review. Clin Oncol (R Coll Radiol) 19: 237-255.
- Meijer TW, Schuurbiers OC, Kaanders JH, Looijen-Salamon MG, de Geus-Oei LF, et al. (2012) Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4. Lung cancer 76: 316-323.
- Schuurbiers OC, Meijer TW, Kaanders JH, Looijen-Salamon MG, de Geus-Oei LF, et al. (2014) Glucose metabolism in NSCLC is histology-specific and diverges the prognostic potential of 18FDG-PET for adenocarcinoma and squamous cell carcinoma. J Thorac Oncol 9: 1485-1493.
- Bos R, van Der Hoeven JJ, van Der Wall E, van Der Groep P, van Diest PJ, et al. (2002) Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 20: 379-387.
- van Baardwijk A, Dooms C, van Suylen RJ, Verbeken E, Hochstenbag M, et al. (2007) The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1 alpha and GLUT-1 in non-small cell lung cancer. Eur J Cancer 43: 1392-1398.
- Yen TC, See LC, Lai CH, Tsai CS, Chao A, et al. (2008) Standardized uptake value in para-aortic lymph nodes is a significant prognostic factor in patients with primary advanced squamous cervical cancer. Eur J Nucl Med Mol Imaging 35: 493-501.
- Mendez LE, Manci N, Cantuaria G, Gomez-Marin O, Penalver M, et al. (2002) Expression of glucose transporter-1 in cervical cancer and its precursors. Gynecol Oncol 86: 138-143.
- Tian M, Zhang H, Nakasone Y, Mogi K, Endo K (2004) Expression of Glut-1 and Glut-3 in untreated oral squamous cell carcinoma compared with FDG accumulation in a PET study. Eur J Nucl Med Mol Imaging 31: 5-12.
- Xue F, Lin LL, Dehdashti F, Miller TR, Siegel BA, et al. (2006) F-18 fluorodeoxyglucose uptake in primary cervical cancer as an indicator of prognosis after radiation therapy. Gynecol Oncol 101: 147-151.
- Cho SH, Lim JY, Kim SN, Hong S, Chung HW, et al. (2015) The prognostic significance of pretreatment [18F]FDG-PET/CT imaging in patients with uterine cervical cancer: preliminary results. Eur J Gynaecol Oncol 36: 30-35.
- Onal C, Reyhan M, Parlak C, Guler OC, Oymak E (2013) Prognostic value of pretreatment 18F-fluorodeoxyglucose uptake in patients with cervical cancer treated with definitive chemoradiotherapy. Int J Gynecol Cancer 23: 1104-1110.
- Kidd EA, Siegel BA, Dehdashti F, Grigsby PW (2010) Pelvic lymph node F-18 fluorodeoxyglucose uptake as a prognostic biomarker in newly diagnosed patients with locally advanced cervical cancer. Cancer 116: 1469-1475.
- Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, et al. (1999) A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 73: 177-83.
- Narayan K, McKenzie AF, Hicks RJ, Fisher R, Bernshaw D, et al. (2003) Relation between FIGO stage, primary tumor volume, and presence of lymph node metastases in cervical cancer patients referred for radiotherapy. Int J Gynecol Cancer 13: 657-663.
- Soutter WP, Hanoch J, D'Arcy T, Dina R, McIndoe GA, et al. (2004) Pretreatment tumour volume measurement on high-resolution magnetic resonance imaging as a predictor of survival in cervical cancer. BJOG 111: 741-747.
- Kodaira T, Fuwa N, Toita T, Nomoto Y, Kuzuya K, et al. (2003) Comparison of prognostic value of MRI and FIGO stage among patients with cervical carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 56: 769-777.
- Narayan K, Fisher R, Bernshaw D (2006) Significance of tumor volume and corpus uteri invasion in cervical cancer patients treated by radiotherapy. Int J Gynecol Cancer 16: 623-630.
- Narayan K, Fisher RJ, Bernshaw D, Shakher R, Hicks RJ (2009) Patterns of failure and prognostic factor analyses in locally advanced cervical cancer patients staged by positron emission tomography and treated with curative intent. Int J Gynecol Cancer 19: 912-918.
- Grigsby PW, Siegel BA, Dehdashti F (2001) Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19: 3745-3749.
- Rajasooriyar C, Van Dyk S, Bernshaw D, Kondalsamy-Chennakesavan S, Barkati M, et al. (2011) Patterns of failure and treatment-related toxicity in advanced cervical cancer patients treated using extended field radiotherapy with curative intent. Int J Radiat Oncol Biol Phys 80: 422-428.
- Haymans O, Fallais C, Hustinx R (2006) Intratissular Lymphaticovenous Anastomoses Demonstrated by Perioperative Intramuscular Injection of 99mTc-Colloids. Lymphat Res Biol 4: 29-33.
- Narayan K, Khaw P, Bernshaw D, Mileshkin L, Kondalsamy-Chennakesavan S (2012) Prognostic significance of lymphovascular space invasion and nodal involvement in intermediate- and high-risk endometrial cancer patients treated with curative intent using surgery and adjuvant radiotherapy. Int J Gynecol Cancer 22: 260-266.
- Kidd EA, El Naqa I, Siegel BA, Dehdashti F, Grigsby PW (2012) FDG-PET-based prognostic nomograms for locally advanced cervical cancer. Gynecol Oncol 127: 136-140.
Citation:Lin MY, Narayan K (2015) Pre-therapeutic (18) F-fluoro-2-deoxyglucose ((18) F-FDG) Positron Emission Tomography (PET) in Cervix Cancer: Is it a Reliable and Independent Prognostic Factor for Survival? J Nucl Med Radiol Radiat Ther 1: 001.
Copyright: © 2015 Ming Yin Lin, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.