|Year : 2017 | Volume
| Issue : 2 | Page : 324-328
Prognostic significance of tumor volume as determined on 3D ultrasound scan in uterine cervix cancer treated by radiotherapy
Shelly Srivastava1, Surendra Kumar Saini1, Awadhesh Kumar Dixit1, Deepti Dwivedi2
1 Department of Radiotherapy and Oncology, J. K. Cancer Institute, Kanpur, Uttar Pradesh, India
2 Department of Radiodiagnosis, J. K. Cancer Institute, Kanpur, Uttar Pradesh, India
|Date of Web Publication||23-Jun-2017|
Surendra Kumar Saini
Department of Radiotherapy and Oncology, M. P. Shah Government Medical College, Jamnagar - 361 008, Gujarat
Source of Support: None, Conflict of Interest: None
Aims: The aim of this prospective study is to evaluate prognostic significance of tumor volume determined by three-dimensional (3D) ultrasound scan in uterine cervix cancer patients treated by radiotherapy.
Patients and Methods: A total of 67 patients of Stage IB2-IIIB were studied and analyzed. Cervical tumor volume was determined by 3D ultrasound scan. Two groups were made on the basis of volume on ultrasound scan (Group 1 <40 cc = 36 and Group 2 >40 cc = 31). Both groups received external beam radiotherapy (EBRT) and intracavitary radiation therapy (ICRT). Cisplatin 40 mg/m 2 every week was given concurrently with external irradiation. Tumor volumes were taken by 3D USG every week during EBRT, after each fraction of ICRT, and after 8 weeks of completion of treatment. Primary end point was disease-free survival (DFS), and secondary endpoints were 5-year survival and toxicities.
Results: After 2 months of completion of treatment, 1 out of 36 patients of Group A was having residual and 7 out of 31 of Group B were having residual diseases (P = 0.034). DFS and 5-year survival were significantly different in the groups (log rank test P = 0.0014, hazard ratio (HR) =2.3622 95% confidence interval (CI) 1.3090–4.2625 and P = 0.0421, HR = 1.9274 95% CI 0.9998–3.7156, respectively).
Conclusions: Ultrasound is a cheap, simple, and useful in predicting the outcome of treatment and DFS based on the tumor volume.
Keywords: Cancer cervix, cervix volume, radiotherapy, three-dimensional ultrasound
|How to cite this article:|
Srivastava S, Saini SK, Dixit AK, Dwivedi D. Prognostic significance of tumor volume as determined on 3D ultrasound scan in uterine cervix cancer treated by radiotherapy. J Can Res Ther 2017;13:324-8
|How to cite this URL:|
Srivastava S, Saini SK, Dixit AK, Dwivedi D. Prognostic significance of tumor volume as determined on 3D ultrasound scan in uterine cervix cancer treated by radiotherapy. J Can Res Ther [serial online] 2017 [cited 2019 Nov 13];13:324-8. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/324/183201
| > Introduction|| |
In India, carcinoma cervix is most common cancer among the rural population and in some metro cities., Worldwide, cervical cancer is the second most common cancer in women, and the most common cancer in women in developing countries. In developed countries, cervical cancer accounts for 1.7% of all cancers, whereas in developing countries, this figure is 7%. In 2008, the World Health Organization estimated that there were 529,828 newly diagnosed cases of cervical cancer and this disease was associated with 275128 deaths annually, 80% of these deaths occur in developing countries. Due to the absence of any effective screening program and awareness in developing country like India, patients usually present in late stage despite prominent clinical features that present early in the course of disease.
Surgery and radiotherapy are two main modalities of treatment of cervical cancer. Chemotherapy recently incorporated concurrently with radiotherapy in management to improve local control in the late stage disease. Although survival and control of pelvic disease in cervical cancer patients are correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, prognosis is also influenced by a number of tumor characteristics that are not included in the staging system. Clinical tumor diameter is strongly correlated with prognosis for patients treated with radiation. For this reason, in 1994 FIGO modified the Stage I category to subdivide these tumors according to clinical tumor diameter.,,,,,,,, Various methods of tumor volume determination by imaging are available but expensive and not easily available everywhere, especially in developing countries where disease has maximum bulk. Three-dimensional (3D) ultrasound is an effective, fast, and relatively inexpensive alternative diagnostic tool in the assessment of tumor in cervical cancer. Cervical tumor volume measured by magnetic resonance imaging was positively correlated with the tumor volume measured by 3D ultrasonography (r = 0.91, P< 0.0001).
The purpose of this study was to evaluate prognostic relevance of tumor volume determined by ultrasound scan in uterine cervix cancer patients treated by radiotherapy.
| > Patients and Methods|| |
Cases were selected from patients registered in J. K. Cancer Institute. Treatment-naive carcinoma cervix (FIGO Stage IB2–IIIB) cases with age between 20 and 70 years and Eastern Cooperative Oncology Group performance status ≤1 were included in the study. Patients with any comorbid illnesses where radiotherapy and/or chemotherapy becomes contraindication was not included in the study. Patients also had to have normal organ functions as defined by hemoglobin ≥11, an absolute neutrophil count ≥1,500 cells/μL, platelet count ≥100,000 cells/μL, total bilirubin <1.25× the laboratory upper limit of normal, and a calculated creatinine clearance of more than 50 mL/min. Computed tomography (CT) scan of abdomen and pelvis was done during initial evaluation only in each patient. Volume of cervix was measured by transabdominal ultrasound with 5–7.5 MHz radiofrequency probe before definitive radiotherapy, every week during radiotherapy and 8 weeks after completion of radiotherapy. The volume was measured using the formula π/6 × (R1 × R2 × R3), where R1, R2, and R3 were the maximal transverse, anteroposterior, and longitudinal length of tumor, respectively. Total of sixty-seven patients enrolled were divided into two groups according to tumor volume (Group 1 - cervix vol <40 cc = 36, Group 2 - cervix vol >40 cc = 31). Definitive treatment of chemoradiotherapy was given to both groups. Fifty gray was prescribed to pelvis by external beam radiotherapy (EBRT) in 2 Gy per fraction. For stage IB–IIA, total dose to point A (tumor surrogate point) was 80 Gy low dose rate (LDR) equivalent (50 Gy EBRT + 3 fractions, each of 6 Gy by high dose rate [HDR]), and for Stage IIB–IIIB, it was 85 Gy LDR equivalent (50 Gy EBRT + 3 fractions, each of 7 Gy by HDR). Brachytherapy was delivered by 192 Ir HDR. Cisplatin 40 mg/m 2 every week was given concurrently with external irradiation. All patients completed treatment in 8 weeks. Evaluation of response was done after 8 weeks of completion of radiotherapy. Evaluation of response was done according to response evaluation criteria in solid tumors. For acute and late radiation reactions, the toxicity grading system developed by radiation therapy oncology group was used.
Planning for EBRT was done to cover whole of the disease and draining lymph nodes by four field box techniques. Upper border of anteroposterior/posteroanterior (AP/PA) portal was taken between L4 and L5 vertebrae and lower border below pubic symphysis. In patients with large tumors, the inferior border was extended to the ischial tuberosities and in patients where lower one-third of vagina was involved, lower border was extended to involve introitus. To identify the distal extension of the tumor at the time of simulation, a radiopaque clip or bead was put on the vaginal wall at distal end of disease. Laterally, borders were taken 2 cm lateral from pelvic brim. Superficial inguinal nodes were irradiated where lower third of vagina was involved. For the lateral field borders, posterior margin was taken at S2–S3 junction and anterior margin as vertical line to anterior edge of pubic symphysis to cover external iliac lymph nodes. Posterior margin was extended to sacral hollow in advanced disease to cover uterosacral ligaments, cardinal ligament, and presacral lymph node. Appropriate shielding was employed in AP/PA portal to exclude small bowel. Femoral head was also shielded but not in patients where lower one-third of vagina was involved. Appropriate shielding was also employed in lateral portals.
Clinical examination and ultrasound scan were performed 8 weeks after completion of treatment. If the clinical examination and ultrasound scan demonstrated residual tumors, then a biopsy was performed to confirm histopathologically before further treatment was offered. Surgery and chemotherapy were options provided for patients with recurrences. Eight patients out of 22 patients who had recurrence on follow-up were offered operative intervention and rest chemotherapy or best supportive care in Group 1. Four were disease-free after surgery till the last follow-up and rest four again developed disease and offered chemotherapy or best supportive care. In Group 2, seven patients out of 27 patients who developed recurrence were suitable for surgical intervention but only two patients were disease-free till the last follow-up. None of the patient was re-irradiated on recurrence.
Patients, those had not shown evidence of residual tumor, were kept on regular follow-up every 1 month for 6 months and then every 3 months thereafter. Every follow-up visit included a specific medical history and clinical examination. Routine blood counts, serum chemistries, ultrasound scan of pelvis, and X-ray chest were done once a year or when indicated.
Distributions of patients in two groups were compared by Z-test. Graphs were plotted by help of Microsoft word excel for a gradual reduction in volume in the percentage of initial volume, with time during radiation treatment. Data collected were tabulated showing volume shrinkage against the corresponding week of radiation. Chi-square test was used to detect a difference in response rates in two groups on completion of treatment. P<0.05 was considered statistically significant and <0.01 as highly significant. Kaplan–Meier curve was plotted to show disease-free survival (DFS) and 5-year survival. The difference in survival was determined by log-rank test.
| > Results|| |
In Group 1, median age was 43 (range 32–67), whereas it was 46 (range 34–69) in Group 2. Age of presentation is not statistically different in two group (P = 0.2345). Patients were also stratified according to age in both group and in each stratum numbers of patients were comparable. Distribution of stages in both groups was also statistically not significant [Table 1].
|Table 1: Characteristics of patient population and response with treatment|
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Squamous cell carcinoma was most common (91.04%) histopathology and large cell nonkeratinizing variant was 80.60% of total cases, whereas large cell keratinizing was 10.45%. Adenocarcinoma was 8.96% of total cases. Carcinoma cervix is highly responsive to radiotherapy and shrinkage in volume is observed early in the 1st week of treatment. Maximum reduction (70–80%) of the volume was before 4th and 5th week of radiations. Thirty-five patients were having no evidence of disease after 8 weeks of completion of treatment in <40 cc volume group, whereas in group of more 40 cc, seven patient out of total 31 were having disease. This difference was statistically significant (P = 0.034) [Table 1]. This magnitude of response ultimately translated to reducing in recurrence and survival benefit on long-term follow-up. Median time for recurrence was 27 months for Group 1, whereas it was only 10 months for Group 2 (P = 0.0014, hazard ratio (HR) 2.3622, 95% confidence interval (CI) 1.3090–4.2625) [Figure 1]. The 1 and 2 years DFS were 72.2% and 52.8% for Group 1, whereas they were 41.9% and 24.5% for Group 2. Five years survival was significantly reduced in group with volume more than 40 cc (P = 0.0421 (HR 1.9274, 95% CI 0.9998–3.7156) [Figure 2]. The 1 and 2-year survival was 83.3% and 66.7% for Group I and 71.4% and 50.7% for Group 2. Reduction of magnitude of in 5 years survival may be due to effect of adjuvant treatment. Grade 1 and 2 diarrhea was most commonly encountered radiotherapy-related toxicity and occurred in 80.60% of study population. Grade 1 and 2 vomiting and skin reactions were observed in 17.91% and 29.85% of patients, respectively [Table 2]. Bladder and rectal complication were most common late morbidities. Grade 3 and 4 bladder and rectal reactions were observed in 2.98% and 7.46% cases, respectively [Table 2].
|Figure 1: Disease-free survival. Determined by Kaplan–Meier method (P = 0.0014)|
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|Figure 2: Five years survival. Determined by Kaplan–Meier method (P = 0.0421)|
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| > Discussion|| |
Being the common malignancy of half of the population of the country, research has to be directed toward increasing cure rates as well as finding prognostic markers that can add in quest of finding cure. Majority of studies mentioned were with magnetic resonance imaging (MRI) but based on positive correlation in detecting volume, we used 3D ultrasound that is comparatively cheap and easily available in countries such as India.
Piver and Chung demonstrated in 1975 in surgical series that tumor size is clearly a prognostic factor in carcinoma of the cervix, both in terms of controlling the primary tumor and in predicting the likelihood of pelvic nodal involvement. Magee et al. reported tumor size determined by transrectal ultrasound as marker of relapse despite small patient size and short follow-up of 18 months only. He also found a significant correlation between size and stage (P = 0.001). Cancer cervix is highly responsive to radiation and irrespective of initial volume almost 70–80% of tumor volume regressed by the 4th week of irradiation in our study. This is an interesting finding and makes patient suitable for subsequent intracavitary application. Flueckiger et al. observed in a study with MRI that eighty percent of patient responded promptly to radiation therapy with a volume reduction and significant decrease of signal intensity in the early posttreatment phase (1–3 months) and with total tumor regression at 1–6 months. Although large tumor in his study showed delayed response. Hricak, et al. mentioned that FIGO stage had a significant correlation with patient outcome, but it correlated poorly with complete tumor regression and tumor local control. In contrast, MRI stage showed a significant correlation with complete tumor regression, tumor local control, and DFS at 12 months. In this study, the multivariate analysis demonstrated that the most related variables in order of significance were the presence of juxtaregional and paraaortic lymph nodes, patient age, tumor size, and MRI tumor stage. However, the study was focused on tumor response with relatively short period of follow-up. Retrospective analysis of recurrence by Kovalic et al. mentioned that stage (P = 0.0001) and central bulkiness of tumor (P = 0.026), both were independently predictive of DFS. With local control as the endpoint, only Stage (IIB vs. IIIB) was significant (P = 0.008). Perez et al. one mentioned that size of cervix uteri evaluated by CT has no prognostic significance in cervical cancer patients treated with radiotherapy. The prognostic value of FIGO stage of cervical cancer is influenced by other factors, analyzed in this study and is not an independent prognostic factor.
Many other studies determining volume by other imaging modalities found volume of tumor, an important prognostic marker for response and survival.,,,,,, Mayr et al. reveal that tumor regression rate (rapid versus slow) was more precise than the initial tumor size in the prediction of outcome. We did not study the correlation of tumor regression with the disease control. Mayr's study compared MR finding with pelvic examination in prediction of local control and MR provided a more accurate and earlier prediction of local control than pelvic.,, Narayan et al. reported that in patients with advanced cervical cancer, tumor volume, and corpus invasion provide important prognostic information over and above that provided by FIGO stage, clinical tumor diameter, histology, and age. Possible explanation of poor outcome with increase in tumor volume is, increase in tumor mass leads to hypoxic environment making tumor cells less vulnerable to radiation damage. These hypoxic cells are still clonogenic and capable of providing a focus for tumor regrowth and metastases.
Our overall patient numbers are not high enough in this study to allow assessment of tumor volume parameter with respect to other prognostic variables. Our data will need further evaluation with a larger number of patients.
| > Conclusions|| |
Ultrasound is a cheap, simple, and useful tool in predicting the outcome of treatment and DFS based on the tumor volume and similar to other publication that has used MRI in a similar way.
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Nandakumar A, Ramnath T, Meesha C. The magnitude of cancer cervix in India. Indian J Med Res 2009;130:219-21.
] [Full text]
National Cancer Registry Programme (NCRP, ICMR). Consolidated Report of Population Based Cancer Registries 2004-2005. Bangalore: National Cancer Registry Programme; 2008.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 1975;46:507-10.
Magee BJ, Logue JP, Swindell R, McHugh D. Tumour size as a prognostic factor in carcinoma of the cervix: Assessment by transrectal ultrasound. Br J Radiol 1991;64:812-5.
Flueckiger F, Ebner F, Poschauko H, Tamussino K, Einspieler R, Ranner G. Cervical cancer: Serial MR imaging before and after primary radiation therapy – A 2-year follow-up study. Radiology 1992;184:89-93.
Hricak H, Quivey JM, Campos Z, Gildengorin V, Hindmarsh T, Bis KG, et al.
Carcinoma of the cervix: Predictive value of clinical and magnetic resonance (MR) imaging assessment of prognostic factors. Int J Radiat Oncol Biol Phys 1993;27:791-801.
Eifel PJ, Morris M, Wharton JT, Oswald MJ. The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1994;29:9-16.
Kovalic JJ, Perez CA, Grigsby PW, Lockett MA. The effect of volume of disease in patients with carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1991;21:905-10.
Perez CA, Grigsby PW, Nene SM, Camel HM, Galakatos A, Kao MS, et al.
Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 1992;69:2796-806.
Alvarez RD, Potter ME, Soong SJ, Gay FL, Hatch KD, Partridge EE, et al.
Rationale for using pathologic tumor dimensions and nodal status to subclassify surgically treated stage IB cervical cancer patients. Gynecol Oncol 1991;43:108-12.
Delgado G, Bundy BN, Fowler WC Jr., Stehman FB, Sevin B, Creasman WT, et al.
A prospective surgical pathological study of stage I squamous carcinoma of the cervix: A Gynecologic Oncology Group Study. Gynecol Oncol 1989;35:314-20.
Tanaka K, Umesaki N. Impact of three-dimensional (3D) ultrasonography and power Doppler angiography in the management of cervical cancer. Eur J Gynaecol Oncol 2010;31:10-7.
Mayr NA, Yuh WT, Zheng J, Ehrhardt JC, Sorosky JI, Magnotta VA, 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;39:395-404.
Mayr NA, Taoka T, Yuh WT, Denning LM, Zhen WK, Paulino AC, et al.
Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2002;52:14-22.
Mayr NA, Yuh WT, Taoka T, Wang JZ, Wu DH, Montebello JF, et al.
Serial therapy-induced changes in tumor shape in cervical cancer and their impact on assessing tumor volume and treatment response. AJR Am J Roentgenol 2006;187:65-72.
Soutter WP, Hanoch J, D'Arcy T, Dina R, McIndoe GA, DeSouza NM. Pretreatment tumour volume measurement on high-resolution magnetic resonance imaging as a predictor of survival in cervical cancer. BJOG 2004;111:741-7.
Narayan K, Fisher R, Bernshaw D. Significance of tumor volume and corpus uteri invasion in cervical cancer patients treated by radiotherapy. Int J Gynecol Cancer 2006;16:623-30.
Chen AC, Sung WH, Wang PH, Sheu MH, Doong JL, Yuan CC. Correlation of three-dimensional tumor volumetry with cervical cancer prognostic parameters. Eur J Gynaecol Oncol 2002;23:401-4.
Kim HJ, Kim W. Method of tumor volume evaluation using magnetic resonance imaging for outcome prediction in cervical cancer treated with concurrent chemotherapy and radiotherapy. Radiat Oncol J 2012;30:70-7.
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