Aim: To analyse and assess the effect of dose rate of 192ir-source strength on late complications and local control rate during treatment of carcinoma cervix. Materials and Methods: One hundred and two cases of carcinoma cervix were included in the study. All patients were treated with a curative intent with radical dose of radiation as per the department protocol. All patients were treated with both EBRT plus Brachytherapy with Inj. Cisplatin 40 mg/m 2 weekly. Patients were divided into 2 groups based on activity i.e. group A (10-6Ci) and group B (5-2Ci). After brachytherapy, point doses were analysed based on ICRU 38 recommendations. During follow up, morbidities were evaluated using RTOG grading system. Results: There was no difference in local control and distant metastasis in both groups after six months of follow up. Late Complications were comparable in both groups irrespective of source strength. Bladder complications were minimal with no significant difference in both study groups. Further Patients were divided into four groups i.e. BED of ICRU rectal point (<100 Gy 3 and ≥100 Gy 3) and source strength (10-6Ci and 5-2Ci), when BED was >100 Gy 3 resulted in higher late rectal complication rate (P < 0.05) compared to BED < 100 Gy 3. Conclusion: This study suggests that change in source activity did not make a difference in local control, late rectal and bladder morbidities at 6 months of follow up. Longer follow up is required to assess long term results and morbidities.
Some components, such as multi-leveled equations, graphics, and tables are not prescribed, although the various table text styles are Cancer of the cervix is the most common cancer in India [
While there are four decades of published literature on the efficacy of HDR brachytherapy over LDR brachytherapy, variation in fractionation schedules and its effect of change in dose rate on treatment outcome and normal tissue complications is well reported but very few reports on the effect of source strength of HDR brachytherapy on local control and late rectal and bladder morbidity is available. The probable reason for such under reporting is due to variation in the fractionation schedules between various institutions.192Ir Radioisotope which is commonly used as HDR Brachytherapy source and has very short half-life of 78.3 days. In India, source is being utilized even when the activity is less than 2Ci mainly to economize the source cost. At the same time efficacy of low source activity in relation to disease control is still remain unanswered in clinical settings. Hence this study was undertaken to compare and understand the radiobiological relationships of Iridium source activity on local control and late rectal, bladder morbidities.
For EBRT treatment was delivered using 6-MV linear accelerator. For all the patients, simulation of the pelvic treatment fields was done on Acuity Varian simulator machine. Total dose of external beam radiation therapy (EBRT) to the whole pelvis was 46 Gy in 23 fractions over 5 weeks. Dose delivered to pelvis by two field technique (anterior-posterior fields) and patients with wider separation were considered for four cross field technique. Midline shielding was used up to 50 Gy. All patients received concurrent weekly I.V Cisplatin dose of 40 mg/m2.
Intracavitary application was done on outpatient basis under I.V sedation. Applicator insertion followed by place- ment of posterior vaginal wall retractor to displace the rectum. Finally, vaginal packing was done to stabilize the applicator and displace the bladder. Radiopaque rectal tube and dye was used to identify rectum and bladder. Then orthogonal X-rays antero-posterior and lateral X-rays taken with the dummy source in the applicator. Dosimetric computations was done in the treatment planning system using the orthogonal films and dose was calculated to point A, Point B, ICRU rectal and bladder points. Ir-192 Microselectron HDR remote control brachytherapy machine (
Figures 1(a)-(d): Brief description of brachytherapy steps: (Department of radiation oncology, jipmer, pudu- cherry, India). a) Ring and tandem applicator; b) orthogonal X-ray with dwell positions; c) isodose curves showing pear shaped dose distribution; and d) micro selectron brachytherapy equipment.
Ca cervix IIA-IIIB
(N = 102)
Whole Pelvis External Beam Radiotherapy (EBRT)
46 Gy/23# @ 200 cGy/#, 5days/week
+
Concurrent weekly chemotherapy with I/V Cisplatin 40 mg/m2
Followed by
Parametrial EBRT boost 4 Gy/2# @ 200 cGy/# with central shielding
7 days gap
Intracavitary High Dose Rate Brachytherapy using Ir-192 source
(9 Gy/# ×2 sessions, at weekly interval)
Group A: 50 patients were recruited in whom source had activity of 10-6Ci (Air Kerma Strength −2.857 cGy∙m2∙h−1 to 4.082 cGy∙m2∙h−1).
Group B: 52 patients were recruited in whom source had activity of 5 to 2Ci (Air Kerma Strength −0.8164 cGy∙m2∙h−1 - 2.041 cGy∙m2∙h−1).
Study design:
· Inclusion Criteria:
· Histological proven squamous cell carcinoma cervix patients, FIGO stage IIB to IIIB with less than upper 1/3rd of vagina involvement, who are suitable for radical radiotherapy by EBRT to pelvis followed by HDR Intracavitary brachytherapy.
· Age < 55 years.
· ECOG (0 - 2).
· Normal Haemogram, kidney function and liver function.
· No evidence of distant metastasis.
· No prior treatment for carcinoma cervix in form of radiation, surgery or chemotherapy.
· Clinical and dosimetric Parameters Studied.
· Local control of the disease.
· Distant metastasis.
· Bladder and rectal complications.
· Mean BED Bladder dose/maximum bladder dose.
· Mean BED Rectal dose/maximum rectal dose.
· Average dose at Point A.
· Average dose at Point B.
Strength calculated by using the formula:
where
BED
Biological effective dose
n—Number of fractions;
d—Dose per fraction;
Variables were expressed as mean and standard deviation. Chi square test, Man Whitney test was used for analysis of parameters P value of <0.05 was considered significant. SPSS software was utilized to complete the statistical analysis.
Total of 102 patients enrolled in this study. In group A, 3 patients had residual disease and in group B, 4 patients had residual disease at 6 months of follow up. We analyzed the incidence distant metastasis between both groups; remarkably we observed significant incidence of distant metastasis after 6 months of follow up.
When ICRU rectal point BED was analysed in 50 patients in group A, BED ranged from 85 Gy - 154 Gy3 and majority of patients BED was between 100 - 130 Gy3.. In group B, ICRU rectal point BED ranged from 83 Gy - 164 Gy3 and majority of patients BED is between 110 - 130 Gy3. When ICRU bladder point BED was analysed in group A, BED ranged from 85 Gy3 - 175 Gy3 and majority of patients BED was between 100 - 140 Gy3. One patient had received Dose > 170 Gy3. In group B, Doses were ranged from 86 Gy3 - 169 Gy3 and majority of Patients BED between 90 - 150 Gy3. Three patients had received Dose >160 Gy3. We found there was no significant difference between BED between two groups.
The Mean BED of rectum in group A and B were 115 Gy3 and 121 Gy3 (P < 0.05) respectively with EBRT plus brachytherapy. It was observed that rectal BED was received by patients in group B which was statistically significant (P < 0.05) (
Group | Residual Disease | SCF | Bone | Liver | P-A Node |
---|---|---|---|---|---|
A (10-6Ci) | 3 | 1 | 2 | 0 | 3 |
B (5-2Ci) | 4 | 0 | 0 | 1 | 4 |
R.T.O.G. Late Toxicity | No. of Patients | Mean ICRU Rectum BED | Std. Deviation | Statistical Significance | ||
---|---|---|---|---|---|---|
BED Rectum A | Grade I | 11 | 108.1 | 11.6 | P < 0.05* | |
Grade II | 20 | 126.8 | 12.5 | |||
Grade III | 5 | 132.6 | 14.9 | |||
Total | 36 | 115.1 | 18.2 | |||
BED Rectum B | Grade I | 15 | 106.3 | 11.1 | P < 0.05* | |
Grade II | 14 | 134.0 | 6.0 | |||
Grade III | 6 | 143.0 | 20.6 | |||
Total | 35 | 121.8 | 16.2 |
On further sub group analysis in (rectal BED i.e. ≤100 Gy3 and ≥100 Gy3) 32 patient had received ≤100 Gy3 and 70 patients had received dose ≥ 100 Gy3. It was also observed that stage IIIB (63) patients had received high
rectal BED ≥ 100 Gy3 dose in comparison of other stage of presentation. This implies that there was increase in probability of late rectal complications as the disease advances (
The incidence of rectal complications and occurrence of different grades of toxicity with respect to the BED Twenty nine patients (28.4%) had no complications. No grade IV complications were observed in both groups. Twenty seven cases (26.4%), 35 cases (34.3%), and 11 cases (10.7%) had Grade I, II and III late rectal complications respectively (
Manning et al. postulated a model showing that cell killing was dependent on source activity, especially in cells with a short repair time. There are several factors that affect local control or complications in HDR-ICBT for cervical cancer such as stage, fractionation scheme, biological dose, and optimization strategy and insertion technique, are extremely complex. The dose-rate effect of an HDR 192Ir source is a strange factor which is currently being investigated [
Shang-Wen Chen et al., reported 5-year overall survival was 75% for all patients. The pelvic relapse-free survival was 88% for all patients, 90% for stage IIB, and 79% for stage III. They stated that there was no apparent dose-rate effect on pelvic control for stage IIB and stage III tumors when source activity was stratified with activity of 2.4 cGy∙m2∙h−1 [
Das D. et al. from India reported the incidence of distant metastasis in cancer cervix. In their study 6 patients developed distant metastasis after 2 years follow up. Nelson et al. reported on 104 patients with stage II and III cancer cervix, who underwent exploratory laparotomy and Para-aortic lymph node biopsies. They observed
Number of Patients by T-Stage, Rectal BED, Source Activity | |||||
---|---|---|---|---|---|
Rectal BED (Gy3) | |||||
<100 Gy3 | >100 Gy3 | ||||
T-Stage | Total | Activity (10-6Ci) | Activity (5-2Ci) | Activity (10-6Ci) | Activity (5-2Ci) |
IIA | 1 | 1 | - | 0 | - |
IIB | 38 | 7 | 8 | 19 | 4 |
IIIB | 63 | 8 | 8 | 15 | 32 |
Total | 102 | 16 | 16 | 34 | 36 |
Source Strength | Grade 0 | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Total | Percentage |
---|---|---|---|---|---|---|---|
Group A (<100 Gy3) | 7 | 4 | 5 | 0 | 0 | 16 | 18% |
Group B (<100 Gy3) | 1O | 4 | 2 | 0 | 0 | 16 | 12% |
Group A (>100 Gy3) | 5 | 8 | 16 | 5 | 0 | 34 | 58% |
Group B (>100 Gy3) | 7 | 11 | 12 | 6 | 0 | 36 | 55% |
Total | 29 | 27 | 35 | 11 | 0 | 102 | |
Percentage | 28.4% | 26.49% | 34.3% | 10.7% | 0 |
12.5% of patients with stage IIA disease, 14.9% with stage IIB, and 38.4% with stage III disease had Para-aortic lymph node metastases. [
para-aortic lymph nodes treated with external irradiation to the pelvis and para-aortic regions (45 to 50 Gy) combined with brachytherapy. They found tumor recurrence occurred in 20 patients (3 pelvis, 9 pelvis and distant metastasis, and 8 distant metastasis only) [
Suzuki and Isohashi et al. calculated rectal dose based on ICRU recommendations and GECESTRO, DVH parameters. They observed that rectal BED range was 37.5 Gy3 - 195.5 Gy3 and majority was within the range 85 - 125 Gy3 in majority of cases [
Suzuki et al., analyzed rectal complications based on ICRU recommendations in 132 patients, 39 patients (30%) developed rectal complications, including 25 patients (19%) with Grade 1 toxicity, 9 (7%) with Grade 2, 3 (2%) with Grade 3, and 2 (2%) with Grade 4. They concluded that there was definitive correlation between the source strength and rectal complications. Shang-Wen Chen et al. reported rectal complications in 42 patients developed grade 1 to 4 late rectal complications (13 grade 1, 23 grade 2, 4 grade 3, 2 grade 4). The cumulative rate of rectal complications was 19.8% for grade 1% - 4%, 13.7% for grade 2% - 4% and 2.8% for grade 3% - 4%. The median time for the development of rectal complications was 12 months (range, 3 - 35 months) [
Ogino, et al. found that the rectal BED was significantly correlated with the incidence of late rectal complications. They reported 50% of complications and the calculated incidence of grade 3 - 4 complications ranged from 5% to 10% at a BED of 119 to 146 Gy. There was no correlation of complications with source activity, and the calculated incidence of grade 3 - 4complications ranged from 5% to 10% at BED of 119 to 146 Gy [
Present study as well as several other studies described rectal bleeding rate was greater in cases where rectal BED exceeds >100 Gy3. The BED were compared with late rectal and bladder complications in both group A and group B. it was observed that with the BED increase, the incidence of late rectal complications increased [
This study demonstrated no obvious dose-rate effect of the 192Ir source in HDR ICBT for cervical cancer in terms of pelvic control or radiation morbidity. However, longer study group with longer follow up is required to substantiate the results. Thus, there was no evidence that the practice of HDR should be modified when considering the dose rate effect. Careful monitoring of the biological doses i.e. BED for both the rectum and bladder is required, since it act as a good predictor for development of late sequelae. Further research and clinical trials should be focusing on the impact of source strength on the clinical outcome and a common consensus has to be developed based on evidence.