|Year : 2004 | Volume
| Issue : 1 | Page : 18-24
Tumor regression dynamics with external radiotherapy in cancer cervix and its implications
NR Datta, A Rajkumar, R Basu
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
N R Datta
Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow
Source of Support: None, Conflict of Interest: None
BACKGROUND : To study the external radiotherapy (EXTRT) regression patterns in cancer of the cervix. AIMS : Evaluate EXTRT tumor regression doses (TRD) for 50% (TRD50), 80% response (TRD80), normalized dose response gradient (γ50) and slope (slope50) with clinical outcome. SETTINGS AND DESIGN : Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. MATERIAL AND METHODS : Seventy-seven patients received 50Gy of EXTRT at 2 Gy/fraction followed by 18Gy of high-dose rate intracavitary brachytherapy at 6 Gy/fraction. Loco-regional regressions were assessed clinically at weekly intervals during EXTRT to generate EXTRT dose-response curves. STATISTICAL ANALYSIS USED : Student's t test, logistic regression, Kaplan Meier and Cox's proportional hazard model. Scatter plots were fitted using cubic fit. RESULTS : Age (P=0.052) and absence or presence of gross residual tumor (AGRT and PGRT respectively) following EXTRT (P<0.001) were the only determinants for complete response (CR) at 1 month following completion of radiotherapy. EXTRT tumor regression sigmoid curves obtained for various patient characteristics differed only for those with AGRT and PGRT with differences in TRD50, (P<0.001); TRD80 (P<0.001) and slope50 (P=0.001). Response status to EXTRT was a prognosticator for loco-regional disease free survival (LDFS) (AGRT vs. PGRT; P=0.046). On multivariate analysis, both TRD50 and TRD80 emerged as significant predictors for tumor status at end of EXTRT while TRD80 was the sole determinant of LDFS. CONCLUSION : Extent of tumor regression to EXTRT is an important predictor for treatment outcome in cancer cervix as evident from TRD50 and TRD80 values of EXTRT tumor regression curves.
Keywords: Dose-response curve, Radiotherapy, Cervical cancer
|How to cite this article:|
Datta N R, Rajkumar A, Basu R. Tumor regression dynamics with external radiotherapy in cancer cervix and its implications. Indian J Cancer 2004;41:18-24
| » Introduction|| |
External radiotherapy (EXTRT) forms an important component of management of cancer cervix. The dynamics of radiation induced tumor regression can be best evaluated using “S” shaped sigmoid dose-response curve.,, Although, there has been unanimity in accepting this relation to be sigmoid, difference of opinion exists about the best possible parameter to quantify this curve to carry an inter-comparison between the various studies.,,,,,
A major concern has revolved primarily around quantifying the position and slope of this sigmoid curve. The parameter widely accepted for defining the steepness is normalized dose gradient - g, proposed by Brahme. However, recently an alternative estimate of steepness has been proposed - slope50 and q50 (defined later)., Bentzen and Tucker reviewed and highlighted the ambiguities that are associated with estimation of these parameters.
A true sigmoid dose-response curve can be generated only if the various data points on clinical outcome are available for the entire range of the radiation dose, starting from a minimum to a maximum tolerable dose. It is ethically difficult to subject patients to such a wide range of doses in clinical situations, for constructing a dose-response relation over this entire range. Thus, majority of the data, which are available, are near maximum clinically acceptable doses for a given tumor.,
Perhaps one of the ways that could be explored to get a dose-response curve over a wide range of doses would be to look at the regression pattern of the gross tumor during a course of EXTRT. The present study has been carried out to establish the dose-response relation of primary tumor regression during the course of EXTRT in a group of patients of carcinoma of the cervix treated with an identical teletherapy and brachytherapy protocol. Outcomes were correlated with various demographic and dose-response parameters to identify the most relevant parameter of the sigmoid curve and recognize its implication in management of carcinoma of the cervix.
| » Material and methods|| |
Seventy-seven patients of carcinoma of the cervix were selected from the database of all patients of cervical cancer treated at our institution from January 1996 to June 2001. Before the start of therapy, all patients were subjected to routine clinical, hematological, biochemical and radiological investigations and staged clinically as per FIGO staging guidelines. The inclusion criteria were - (a) patients who had received a planned EXTRT of 50 Gy at 2 Gy per fraction with 5 fractions per week followed by (b) high-dose-rate intracavitary brachytherapy (ICBT) of 18 Gy in 3 fractions at weekly intervals to Point A, started one to two weeks following the completion of EXTRT and (c) in those where periodic tumor responses at corresponding doses were available during the course of the radiotherapy. EXTRT was delivered by either telecobalt (Theratron 780C, AECL, Canada) or 6 MV / 10MV photons (ML 20DX, Mitsubishi Corporation, Japan). This was followed one to two weeks later by high dose rate ICBT (Microselectron HDR, Nucletron, The Netherlands or Ralstron 20B, Shimadzu Corporation, Japan).
Loco-regional response at the primary and parametria were recorded as percentage regression from the pretreatment size. These were based on clinical evaluation namely, per speculum, per vaginum and rectovaginal examinations carried out during weekly monitoring of patients during the course of treatment. Even though, this forms a retrospective collection of cases, these patients had been part of other prospective studies, where weekly recording of tumor regression was mandatory.
At the end of EXTRT, tumor responses were graded based on the criteria defined by Hong et al. and Chen et al. This includes (a) absence of any gross residual tumor (AGRT): complete or near complete regression of pelvic tumor, nonspecific, fibrosis, or granulation over cervix and (b) presence of gross residual tumor (PGRT): presence of gross residual tumor or palpable nodularity on cervix and / or palpable nodularity on the parametrium. At 1 month following completion of EXTRT and ICBT, all patients who had complete regression of the primary tumor at cervix along with smoothening of both parametrium were considered as complete response (CR) while all others were taken as partial response (PR). Patients who continued to have no evidence of any loco-regional disease and on follow-up were considered as censored for the purpose of survival analysis. Toxicity scoring was done as per RTOG/ EORTC criteria.
Dose-regression curves were plotted individually for each of the 77 patients taking into account the percentage responses achieved at the corresponding EXTRT dose while on treatment. The scatter plots were fitted (cubic fit) and various parameters for the curve - TRD50, TRD80, γ50, slope50 and θ50 were estimated directly from the curve. TRD50 and TRD80 represent the tumor control doses (TRD) (in Gy) for a 50% and 80% response respectively. The normalized dose gradient- γ50, expressed as %/%, was the increment in response, in percentage points for a 1% increase in dose, defined at the 50% response level., Slope50, was estimated from the relation, Slope50 (%/Gy) = 100 (γ50/ TRD50). The other proposed measure of the slope of the dose-response curve - θ50, was calculated using the relation, θ50 (%/Gy) = γ50 / TRD50. Off the 77 patients included in this study, in 3 patients, the above parameters could not be quantified since the total gross response at end of EXTRT failed to reach 50%.
Response status at completion of EXTRT and ICBT were assessed for demographic parameters using either a chi-square or student's “t test”. The impact of various individual dose-response curve parameters - TRD50, TRD80, γ50, slope50 and θ50 for the patient and treatment related variables were evaluated. The normality tests for these variables were tested using Kolmogorov - Smirnov test. The means of these values for patient and treatment variables were tested using “t test” for univariate analysis. For gross features these were tested using one way ANOVA. Kaplan-Meier estimates were computed for patients with AGRT for loco-regional disease free survival (LDFS). Survival analysis was based on worst case scenario. Multivariate analysis using Cox's proportional hazard model was also performed to look for the dose-response variables likely to significantly influence the LDFS. For both logistic regression and Cox's proportional hazard model, various dose-response variables were entered using a forward step wise regression with probability of F to enter being <0.05 and removal at ≥ 1.0. The factors entered into regression model were - TRD50, TRD80, γ50, slope50 and θ50. The exponent of coefficient β and its 95% confidence intervals were computed. All the statistical calculations were performed using SPSS software package for windows, version 9.0 (SPSS Inc. Chicago, IL, USA).
| » Results|| |
For maintaining a uniform cohort of patients for this study, all the 77 patients evaluated had received an identical dose and fractionation schedule of EXTRT and ICRT. Age ranged from 27 to 77 years (median: 50 years) and except 2 patients, all had squamous cell carcinoma. Most of them were either in FIGO stages II or III and had ulceroproliferative tumors. Pretreatment hemoglobin at presentation, ranged from 6.4 gm% to 14 gm%. Every effort was made to ensure that before start of radiotherapy, hemoglobin was at least 10 gm% or more by blood transfusions and iron supplementations. Although all the patients had received 50 Gy of EXTRT at 2 Gy per fraction, overall treatment time for EXTRT ranged from 33 to 52 days. The detail demographic features are listed in [Table - 1].
Fifty-three patients (68.8%) had achieved a CR at one month following the end of EXTRT and ICBT. Of these, 40 (51.9%) had AGRT at completion of EXTRT alone. Significantly severe (> grade 3) acute bladder and rectal toxicity was experienced by 1 and 3 patients respectively. Only two patients reported with grade III late bladder morbidity, while none had similar late rectal toxicity.
Univariate analysis revealed that younger patients (< 50 years) were more likely to have residual disease at one month from completion of radiotherapy (P=0.052). No other factors like gross features, FIGO stages, pre-treatment hemoglobin, histology or overall EXTRT treatment time within the range in which this was delivered had any significant impact on the likelihood of a CR at end of radiotherapy [Table - 2]. The maximum follow up period was 71 months and the cumulative probability of LDFS at 5 years was estimated at 36% (median: 34 months). There was strong evidence that patients who had an absence of gross residual tumor at completion of EXTRT had a greater probability of achieving a better LDFS (P=0.046, [Figure - 1]. Additional quantum of response to brachytherapy was not found to be different between those with CR and PR at end of the entire course of radiotherapy, median being 10% and 12.5% respectively. Apart from tumor response at completion of EXTRT (AGRT or PGRT) and at 1 month of completion of radiotherapy (CR or PR), none of the patient demographical parameters nor duration of treatment was found to have an impact on LDFS [Table - 3].
The various parameters for quantifying the position and slope of the dose response curves were directly read from curve fits of individual patients. TRD50, TRD80, γ50 values were normally distributed while slope50 and θ50 had a significance value which was at the lower bound of significance. The interquartile range for slope50 and θ50 are 0.819 and 0.008 respectively. The fitted dose-response curve for all the 77 patients during EXTRT was sigmoid. Addition of ICBT did not change the shape or position of this curve, except stretching the terminal plateau segment. Curve fits were generated from the scatter plots of dose-response separately between patients based on known prognostic factors, which could have an impact on the outcome. These include - age, FIGO stage, gross features, pretreatment hemoglobin, EXTRT treatment time and response with EXTRT [Figure - 2]. Of these, the curves for age groups, FIGO stage groups and responders with EXTRT were different in terms of the slope and their positions. These were also evident from the significant differences in the estimated parameters of the tumor regression parameters namely - TRD50 (P=0.049) and TRD80 (P=0.049) for age groups; TRD80 (P=0.050) and slope50 (P=0.008) for FIGO stage group and TRD50 (P<0.001), TRD80 (P<0.001), and slope50 (P=0.001) for responders to EXTRT [Table - 4]. The curve was shifted to the right for the poor prognostic groups, while in all other cases; curves almost superimposed or crossed over at some points.
On logistic regression for AGRT versus PGRT at end of EXTRT, only TRD50 (P=0.017) and TRD80 (P=0.004) retained their significance [Table - 5]. However, of all the EXTRT dose-regression parameters evaluated, only TRD80 was found to influence LDFS on multivariate analysis [Table - 5].
| » Discussion|| |
The present study attempted to identify the prognostic variables for different endpoints and correlate them with radiation dose-response characteristics. With a uniform dose of radiotherapy to all patients, age and quantum of regression achieved during EXTRT were found to impact the loco-regional control and LDFS. Similar observations have been reported by others.,,
Dose-response relationship has been previously studied for a wide range of tumors where loco-regional controls at completion of various dose schedules have been presented.,, In the present study, responses occurring over the entire range of dose delivered have been considered. The responses recorded could have an element of subjectivity since these were based on clinical examination alone. However, even radiological assessment and estimation of volumes of the primary tumor during EXTRT at the cervix and parametrium, could be ambiguious. Moreover, it would not be practically possible to undertake weekly radiological assessments in the routine set up of a department and also not financially feasible for patients to pay for weekly radiological studies involving either computed tomography or magnetic resonance imaging. Nevertheless, the relation obtained by clinical examination was a sigmoid curve, which is widely accepted to represent the radiation dose-response relationship.
Different authors have argued and tried to justify the various parameters that would give a true representation of the “S” shaped curve in terms of its position and steepness.,,, In view of such uncertainties; the estimates of the various parameters in this study were made directly from the graphs based on their definitions. Okunieff et al. had estimated the TRD50, g50, and slope50 of carcinoma of the cervix from the literature and reported to vary from 24.27 to 64.38 Gy, 0.64 to 20.93 %/% and 1.08 to 61.27%/Gy respectively. On excluding the outliers from the estimates of stages IIB and III (from Perez et al. and Perez and Kao values for TRD50, γ50 and slope50 in carcinoma of the cervix ranged between 24 - 34Gy, 0.64 - 0.71 %/% and 2.52 - 2.77 %/Gy respectively. The mean TRD50, γ50, and slope50 values for the entire group of our patients has been 34.68 Gy, 0.77 %/% and 2.24 %/Gy respectively. These are in close agreement with those estimated by Okunieff et al. These values were different for different subgroups and between the responders and nonresponders as listed in [Table - 4]. Thus, of all the parameters evaluated in this study, position and steepness of the dose-response curves are best represented by TRD80 which is also reflected in multivariate analysis for LDFS [Table - 5].
Since TRD80 has been observed to be the most significant parameter in this study, other variables have been compared with TRD80. A closer perusal indicates that patients with AGRT following EXTRT had a less scatter of various parameters compared to those with PGRT [Figure - 3]. This could indicate a greater degree of heterogeneity in partial responders in terms of their biological behavior and could contribute to a relatively inherent radioresistance to conventional radiation therapy. For all patients, TRD50 and TRD80 show a linear positive correlation, with patients having AGRT clustered at the lower values of TRD80 [Figure - 3]a). γ50 did not follow an expected pattern of fall with increasing TRD80 [Figure - 3]b). This could be explained by the non significant difference in γ50 values between AGRT and PGRT patients [Table - 4]. Slope50 and γ50 demonstrated a gradual decline with increase in TRD80 [Figure - 3]c and [Figure - 3]d. The parameters of slope50 and θ50 differ only by a factor of 100 and hence have a perfect linear relation between them [Figure - 3]e. The slope50 and γ50, both of which indicate the steepness of the dose-response curve, also exhibit a linear relation. However, patients with AGRT have a higher slope50 value compared to those with PGRT for any g50 value [Figure - 3]f.
It thus appears that there could be certain subsets of patients who might fail to conventional radiotherapy and might be benefited by concomitant chemoradiotherapy. These could be patients younger than 50 years and those with tumors which are inherently radioresistant.,, These could be identified by various tumor cytokinetic studies and radiobiological parameters.,,
Thus, even with the gradual acceptance of chemotherapy as a part of treatment protocol for cancer cervix, it could be important to identify certain subsets of patients who would be benefited with the addition of chemotherapy.,,, With a planned combination of EXTRT and ICBT, a 5 year survival ranging from 62% to 78% in stages I and II and 43% to 50% in stages III have been reported even from developing countries, like India. Moreover, as the recent phase III trial between radiotherapy alone versus chemoradiotherapy in cancer cervix has failed to show any benefit with chemotherapy, therapeutic options should be carefully weighed. Till results from further large sample stratified randomized trials based on the possible prognosticators are available, acute and long term toxicities that could result following chemoradiotherapy should influence therapeutic decisons. This could be of importance in developing countries where loco-regional advanced cancer cervix is a major cancer problem, especially for the weaker socio-economic class of population.
| » References|| |
|1.||Bentzen SM. Steepness of the clinical dose-control curve and variation in the in vitro radiosensitivity of head and neck squamous cell carcinoma. Int J Radiat Biol 1992;61:417-23. |
|2.||Bentzen SM. Radiobiological considerations in the design of clinical trials. Radiother Oncol 1994;32:1-11. |
|3.||Okunieff P, Morgan D, Niemierko A, Suit HD. Radiation dose-response of human tumors. Int J Radiat Oncol Biol Phys 1995;32:1227-37. |
|4.||Bentzen SM, Tucker SL. Quantifying the position and steepness of radiation dose-response curves. Int J Radiat Biol 1997;71:531-42. |
|5.||Brahme A. Dosimetric precision requirements in radiation therapy. Acta Radiol Oncol 1984;23:379-91. |
|6.||Brahme A, Lind BK. Quantification of the steepness of the dose-response relation. Int J Radiat Oncol Biol Phys 1999;45:243-5. |
|7.||Suwiniski R, Withers HR. Why the utility of a normalized dose-response gradient (?-factor) should be redefined. Int J Radiat Oncol Biol Phys 1998;42:463. |
|8.||Yaes, RJ. The slope of the sigmoid dose response curve for tumor control. Int J Radiat Oncol Biol Phys 1999;44:470-1. |
|9.||Bataini P, Brugere J, Bernier J, Jaulerry CH, Picot C, Ghossein NA. Results of radical radiotherapeutic treatment of carcinoma of the pyriform sinus. Experience of the Institut Curie. Int J Radiat Oncol Biol Phys 1982;8:1277-86. |
|10.||Hong JH, Chen MS, Lin FJ, Tang SG. Prognostic assessment of tumor regression after external irradiation for cervical cancer. Int J Radiat Oncol Biol Phys 1992;22:913-7. |
|11.||Chen SW, Liang JA, Yang SN, Ko HL, Lin FJ. The adverse effect of treatment prolongation in cervical cancer by high-dose-rate intracavitary brachytherapy. Radiother Oncol 2003;67:69-76. |
|12.||Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6. |
|13.||Armitage P, Berry G, Matthews JNS. Modeling continuous data. In: Statistical Methods in Medical Research. 4th edn. Oxford: Blackwell Science Ltd; 2002. pp.312-77. |
|14.||Kaplan ES, Meier PJ. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. |
|15.||Cox DR. Regression models and life tables. J Royal Stat Soc 1972;34:187-202. |
|16.||Gasinska A, Urbanski K, Jakubowicz J, Klimek M, Biesaga B, Wilson GD. Tumour cell kinetics as a prognostic factor in squamous cell carcinoma of the cervix treated with radiotherapy. Radiother Oncol 1999;50:77-84. |
|17.||Hricak H, Yu KK. Radiology in invasive cervical cancer. Am J Roentgenol 1996;167:1101-8. |
|18.||Perez CA, Breaux S, Madoc-Jones H, Bedwinek JM, Camel HM, Purdy JA et al. Radiation therapy alone in the treatment of carcinoma of uterine cervix I. Analysis of tumor recurrence. Cancer 1983;51:1393-402. |
|19.||Perez CA, Kao MS. Radiation therapy alone or combined with surgery in the treatment of barrel-shaped carcinoma of the uterine cervix (stages IB, IIA, IIB). Int J Radiat Oncol Biol Phys 1985;11:1903-9. |
|20.||Mackay RI, Hendry JH. The modelled benefits of individualizing radiotherapy patients' dose using cellular radiosensitivity assays with inherent variability. Radiother Oncol 1999;50:67-75. |
|21.||Suwiniski R, Taylor JM, Withers HR. The effect of heterogeneity in tumor cell kinetics on radiation dose-response. An exploratory investigation of a plateau effect. Radiother Oncol 1999;50:57-66. |
|22.||Peters L, McKay M. Predictive assays: will they ever have a role in the clinic? Int J Radiat Oncol Biol Phys 2001;49:501-4. |
|23.||Tsang RW, Fyles AW, Li Y, Rajaraman MM, Chapman W, Pintilie M, et al. Tumor proliferation and apoptosis in human uterine cervix carcinoma I: correlations between variables. Radiother Oncol 1999;50:85-92. |
|24.||Tsang RW, Wong CS, Fyles AW, Levin W, Manchul LA, Milosevic M, et al. Tumor proliferation and apoptosis in human cervix carcinoma II: correlations with clinical outcome. Radiother Oncol 1999;50:93-101. |
|25.||West CML, Davidson SE, Roberts SA, Hunter RD. The independence of intrinsic radiosensitivity as a prognostic factor for patient response to radiotherapy of carcinoma of the cervix. Br J Cancer 1997;76:1184-90. |
|26.||Duẹas-Gonzalez A, Cetina L, Mariscal I, de la Garza J. Modern management of locally advanced cervical carcinoma. Cancer Treat Rev 2003;29:389-99. |
|27.||Engleman MA, Small W Jr. Combined modality therapy in the treatment of gynecologic malignancies. Semin Oncol 2003;30:80-94. |
|28.||Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. The Lancet 2001;358:781-6. |
|29.||Kumar L, Bhargava VL. Chemotherapy in recurrent and advanced cervical cancer. Gynecol Oncol 1991;40:107-11. |
|30.||Patel FD, Sharma SC, Negi PS, Ghoshal S, Gupta BD. Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 1994;28:335-41. |
|31.||Pearcey R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966-72. |
|32.||Maduro JH, Pras E, Willemse PHB, de Vries EGE. Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer. Cancer Treat Rev 2003;29:471-88. |
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]
|This article has been cited by|
||Variations in clinical estimates of tumor volume regression parameters and time factor during external radiotherapy in cancer cervix: Does it mimic the linear-quadratic model of cell survival
| ||Datta, N.R., Rajkumar, A., Basu, R. |
| ||Indian Journal of Cancer. 2005; 42(2): 70-77 |