Keywords
Cervical cancer - concurrent chemoradiation - Cisplatin - external-beam radiotherapy
- International Federation of Gynecology and Obstetrics - high dose rate intracavitary
brachytherapy
Introduction
Cervical cancer is the second most common cancer diagnosed in women in India.[1] About 122,844 new cervical cancer cases are diagnosed annually in India.[2] At our center, carcinoma cervix is the most common cancer among females. Patients
usually present to us with International federation of Gynecology and Obstetrics (FIGO)
stage IIB, III and IV; in which Concurrent Chemo-Radiotherapy (CCRT) plays a major
role in the management.[3]
[4]
Subjects and Methods
The present prospective study was carried out at Sawai Man Singh Medical College and
attached group of Hospitals, Jaipur, Rajasthan from January 2014 to June 2015 with
a median follow up of 33 months. 110 histopathologically confirmed newly diagnosed
cases of squamous cell carcinoma of cervix FIGO stage IIB to IVA with ECOG performance
status 0–2 were randomised into study and control groups, with 55 patients in both
groups. All patients were younger than 70 but older than 18 years with hemoglobin
≤9 g%, absolute neutrophil count >1500/uL, platelet count >1,00,000/uL, serum creatinine
level <1.4 mg/dl and serum bilirubin <2 times the normal upper unit. Patients with
other than squamous pathology, history of previous radiotherapy or surgery for the
same malignancy, second malignancy, distant metastasis, other uncontrolled comorbidities,
and pregnancy were excluded from the study.
Chemotherapy
All patients who were enrolled in the study group were planned to receive injection
cisplatin with dose of 75 mg/m2 intravenously on day 1, 22, and 43 of radiotherapy,
for a total of three courses. Those who were enrolled in the control arm were planned
to receive injection cisplatin with dose of 40 mg/m2 intravenously on day 1, 8, 15,
22, 29, and 36 of radiotherapy, for a total of six courses.
Radiotherapy
Combined external-beam radiotherapy (EBRT) and high dose rate intracavitary brachytherapy
(HDR ICBT) was used for the treatment of patients. The primary tumor and regional
lymphatics were treated with 45–50.4 Gy in conventional fractionation at 1.8 Gy per
fraction over Seimens Oncor Expression Linear Accelerator using three-dimensional
conformal radiotherapy technique with 15 MV beam energy. The first HDR ICBT was performed
toward the latter part of EBRT when sufficient tumor regression was noted to permit
satisfactory applicator geometry. This was usually after the 3rd week of EBRT and
additional EBRT was delivered with a central shield. On the day of ICBT, neither EBRT
nor chemotherapy was prescribed. The recommended total point A dose combining EBRT
with ICBT was 80 Gy for small volume cervical tumors and 85–90 Gy for large volume
tumors. To avoid the negative impact of treatment prolongation, the overall treatment
time was intended to be kept <8 weeks.[5]
[6]
Evaluation of patients
All patients were clinically examined weekly during the treatment for any complaints.
Hemogram and biochemical investigations were performed and noted before giving chemotherapy.
The clinical appearance of the primary tumor at the initiation of treatment was noted.
The regression of primary tumor during the treatment was assessed and noted biweekly.
Any delay causing treatment interruption was also noted and necessary gap correction
for radiotherapy was done. Chemotherapy was withheld during radiotherapy interruptions,
but radiotherapy was continued in spite of chemotherapy being discontinued due to
hematological toxicities. At the completion of treatment and subsequent follow up,
the disease response was assessed. The results of study group were analyzed and compared
with control group in terms of compliance, toxicities, and tumor response. Response
was assessed as per the WHO Criteria. Acute toxicities were assessed as per the Radiation
Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring criteria. Chemotherapy
induced toxicities such as nausea, vomiting, renal and hematological toxicities were
assessed as per the CommonTerminology Criteria for Adverse Events (v4.03), National
Cancer Institute (USA). Patients were evaluated every month on follow up with detailed
clinical examination to assess local disease response and to note any bladder/bowel
symptom. Hematological tests and imaging studies were done wherever indicated.
Statistical analysis
This was an open-label, randomized trial with 1:1 allocation. The randomized assignment
was done using a chit in box method with replacement. The categorical clinical characteristics
between the two treatments were compared using Chi-square (χ2) test. Data were analyzed
using Statistical Package for Social Sciences (SPSS) software trial version 20.0 (IBM
Corp., Armonk, New York, USA).
Results
In the present study, the patient and tumor characteristics were identical in the
two groups [Table 1]. In both the groups, patients were in the age group of 30–70 and majority of them
were in their 4th and 5th decade of life. Mean age of presentation was 49.36 and 49.43
years for study and control group, respectively. More than two-third of the patients
belonged to the rural background in both the groups. All the patients included in
the study were having ECOG performance status score up to 2. The hemoglobin of all
patients included in the study was equal or above 9.0 g%, mean hemoglobin at presentation
was 10.56 g% and 10.60 g% for study and control group, respectively. Only histopathologically
proven squamous cell carcinoma patients were included in this study. The distribution
of patients according to the histological differentiation of primary tumor revealed
moderately differentiation as the most common pattern of differentiation. Among the
study group, 78.2% and in the control group, 81.8% had moderately differentiated tumor.
The most common stage of presentation was FIGO stage IIB with 54.5% in the study group
and 50.9% in control group.
Table 1
Patient, tumour and treatment characteristics
|
Study group, n (%)
|
Control group, n (%)
|
P value
|
|
ECOG – Eastern cooperative oncology group; FIGO – International federation of gynecology
and obstetrics
|
|
Age (years)
|
|
|
|
|
≤40
|
9
|
13
|
0.15
|
|
41-50
|
25
|
18
|
|
|
51-60
|
16
|
12
|
|
|
61-70
|
5
|
12
|
|
|
Geographic distribution
|
|
|
|
|
Rural
|
38 (69)
|
37 (67.3)
|
0.84
|
|
Urban
|
17 (31)
|
18 (32.7)
|
|
|
ECOG performance status
|
|
|
|
|
0
|
0
|
0
|
0.54
|
|
1
|
50 (91)
|
48 (87.3)
|
|
|
2
|
5 (9)
|
7 (12.7)
|
|
|
FIGO stage
|
|
|
|
|
IIB
|
30 (54.5)
|
28 (50.9)
|
0.70
|
|
IIIA
|
2 (3.6)
|
1 (1.9)
|
|
|
IIIB
|
22 (40)
|
23 (41.8)
|
|
|
IVA
|
1 (1.9)
|
3 (5.4)
|
|
|
Differentiation of squamous cell carcinoma
|
|
|
|
|
Well differentiated
|
10 (18.2)
|
7 (12.7)
|
0.68
|
|
Moderately differentiated
|
43 (78.2)
|
45 (81.8)
|
|
|
Poorly differentiated
|
2 (3.6)
|
3 (5.5)
|
|
|
Duration of radiotherapy (weeks)
|
|
|
|
|
≤8
|
48
|
52
|
0.18
|
|
>8
|
7
|
3
|
|
Treatment related toxicities are shown in [Table 2] and [Figure 1]. In the study group, 10 patients (18.2%) had grade 1 skin reactions as compared
to 20 (36.4%) in the control group. 34 (61.8%) and 11 (20%) patients in the study
group and 26 (42.8%) and 7 (12.7%) in the control group had grade 2 and grade 3 skin
reaction, respectively (P = 0.06). For nausea, in the study group 17 (30.9%) of the patients had grade 1 reactions
as compared to 23 (41.8%) in the control group. 31 (56.4%) in the study group and
25 (45.5%) in the control group had grade 2 reaction. The incidence of grade 3 was
7 (12.7%) and 7 (12.7%) in the study group and control group, respectively (P = 0.46). The vomiting during the treatment was more in the study group which was
statistically significantly P < 0.001. In the control group, 30 (54.5%), 21 (38.18%) and 4 (7.27%) patients had
grade 1, 2, and 3 vomiting, respectively, as compared to 5 (9.09%), 27 (49.09%), and
23 (41.8%) patients in the study group. The incidence of acute diarrhea during treatment
was seen more in study group; 31 (56.4%), 12 (21.8%), and 0 (0%) had grade 1, 2, and
3, respectively compared to control group having 23 (41.8%), 12 (21.8%), and 4 (7.2%)
grade 1, 2, and 3 diarrhea, respectively. There is no statistical difference in incidence
of acute diarrhea between the study and control groups (P = 0.12).
Table 2
Worst acute toxicity during treatment
|
Toxicity
|
Study group
|
Control group
|
Statistics
|
|
Grade 0
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
Grade 0
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
P Value
|
|
TLC – Total leukocyte counts; ANC – Absolute neutrophil counts
|
|
Acute skin reaction
|
0
|
10
|
34
|
11
|
0
|
2
|
20
|
26
|
7
|
0
|
0.06
|
|
Nausea during treatment
|
0
|
17
|
31
|
7
|
0
|
0
|
23
|
25
|
7
|
0
|
0.46
|
|
Vomitting during treatment
|
0
|
5
|
27
|
23
|
0
|
7
|
23
|
21
|
4
|
0
|
<0.001
|
|
Acute diarrhea
|
12
|
31
|
12
|
0
|
0
|
16
|
23
|
12
|
4
|
0
|
0.12
|
|
Heamoglobin
|
0
|
21
|
34
|
0
|
0
|
0
|
20
|
35
|
0
|
0
|
0.84
|
|
TLC
|
29
|
14
|
10
|
2
|
0
|
37
|
16
|
2
|
0
|
0
|
0.04
|
|
ANC
|
36
|
8
|
9
|
2
|
0
|
48
|
5
|
2
|
0
|
0
|
0.03
|
|
Nephrotoxicity
|
45
|
10
|
0
|
0
|
0
|
48
|
7
|
0
|
0
|
0
|
0.43
|
Figure 1: Worst Acute Toxicity During Treatment
As far as hematological toxicities are concerned, in the study group 21 (38.2%) had
grade 1 and 34 (61.8%) had grade 2 anemia, whereas in control group, 20 (36.4%) had
grade 1 and 35 (63.6%) had grade 2 anemia (P = 0.84). For total leukocyte counts, study group had more grade 2 (10 [18.2%]) and
grade 3 toxicity (2 [3.6%]) compared to control group having only 2 (3.6%) grade 2
toxicity. 14 (25.5%) and 16 (29.09%) had grade 1 toxicity in study and control group,
respectively. This difference is statistically significant, showing more toxicity
in the study group compared to control group, P = 0.04. Similar to total leucocyte count, absolute neutrophil count showed the same
pattern of toxicity profile. 36 (65.5%) and 48 (87.3%) had no toxicity, 8 (14.5%)
and 5 (9.09%) had grade 1, 9 (16.4%) and 2 (3.6%) had grade 2 and 2 (3.6%) and none
(0%) had grade 3 toxicity in the study and control group, respectively. This difference
was statistically significant, more in the study group compared to control group (P = 0.03). No nephrotoxicity was found in 45 (81.8%) in the study group and 48 (87.3%)
in the control group, whereas 10 (18.2%) and 7 (12.7%) were found to have grade 1
toxicity in the study and control group, respectively (P = 0.43). The audiometry report of all the patients was comparable to their pretreatment
and post treatment reports, i.e., there was no increased hearing loss or ototoxicity
found among all the patients in both study and control group.
Compliance of the treatment was defined in terms of completeness of chemotherapy and
radiotherapy within the prescribed time limits. The American Brachytherapy Society
recommends keeping the total treatment duration to <8 weeks, i.e., 56 days.[7] In the study group, the average time of completion of radiotherapy was 54.63 days,
(range = 48–81 days), 48 (87.27%) patients completed their radiotherapy within 56
days (8 weeks) of starting treatment. Whereas in the control group, the average time
was 51.34 days, (range = 48–60 days), 52 (94.54%) patients completed within the prescribed
time of 56 days (8 weeks). This difference did not reach statistical significance
(P = 0.18).
Treatment response of disease of patients was done using the WHO criteria while on
treatment and subsequent follow up. At the end of treatment, 46 (83.63%) of study
group and 44 (80%) of control group had complete response (CR), 9 (16.37%) patients
of study group and 11 (20%) patients of control group had partial response (PR) (P = 0.62). At 6 months after completion of CCRT, both the study and control group had
50 (90.9%) CR and 5 (9.1%) PR rates (P = 1). At last follow up, the disease-free survival was same for both the study and
control group [Table 3].
Table 3
Follow-up status
|
Treatment response
|
Study group (n)
|
Control group (n)
|
Statistics
|
|
Complete response
|
Partial response
|
No change
|
Progressive disease
|
Complete response
|
Partial response
|
No change
|
Progressive disease
|
P value
|
|
End of treatment
|
46
|
9
|
0
|
0
|
44
|
11
|
0
|
0
|
0.63
|
|
6 month follow up
|
50
|
5
|
0
|
0
|
50
|
5
|
0
|
0
|
1.00
|
Discussion
In 1999, five large prospective randomized trials performed by the Gynecologic Oncology
Group (GOG), RTOG, and the South-West Oncology Group demonstrated significant survival
advantage and superiority in reducing risk of death by 30%–50% in cisplatin-based
chemotherapy given concurrently with pelvic radiotherapy when compared to either radiotherapy
alone or radiotherapy with concurrent nonplatinum containing chemotherapy. It was
stated that cisplatin-based CCRT also decreased the relative risk of recurrence and
the mortality. Among the previous five randomized clinical trials, two trials performed
by the GOG used weekly cisplatin 40 mg/m2, whereas the other three trials used tri-weekly
cisplatin at a dosage range of 50–75 mg/m2 combined with 5-fluorouracil. Although
recently reported meta-analysis studies also demonstrated 6% improvement in 5-year
survival with cisplatin-based CCRT, the optimal cisplatin dose and dosing schedule
are still undetermined. Hence, in this study, we tried to investigate the response,
compliance and toxicity of weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2
administration concurrent with radiotherapy.[4]
[8]
[9]
[10]
The results of five randomized studies which included nearly 2000 patients were published
in 1999, demonstrating that survival rate with CCRT based on cisplatin was superior
to that obtained with radiation alone. Afterward, a meta-analysis based on 19 trials
(17 published and two unpublished) including 4580 patients corroborated these findings,
confirming that chemoradiation offers an absolute survival benefit of 12% at 5 years.[11] Thus, cisplatin-based CCRT was largely accepted as the standard of care for patients
with locally advanced cervical cancer with FIGO stage IB2-IVA, except for patients
with comorbidities who are radiated for stage IB1 or less. CCRT also showed significant
benefit for local recurrence and the suggestion of a benefit for distant recurrence.
Acute hematological and gastrointestinal toxicity was significantly higher in the
CCRT group.[12] After years of studying multi-modality treatments as an alternative to radiation
alone in randomized phase III trials, the standard treatment has changed to CCRT based
on cisplatin.[13] Despite these encouraging results, there remains room for improvement as the 5-year
survival of patients treated with CCRT ranges from nearly 80% in bulky IB tumors to
only 25% in stage IVA disease.
Kato et al.[14] studied CCRT with weekly cisplatin in locally advanced cervical carcinoma and observed
acute grade 3 leukopenia in 21% of the patients, and grade 3 gastrointestinal toxicity
in 6%. No patient failed to complete the radiotherapy course because of toxicity.
The 2-year local control and overall survival rate for all patients were 87.1% and
79.6%, respectively. In this study, they had more toxicity, may be due to less number
of patients enrolled in the present study. Ryu et al.[15] in 2010 compared weekly versus tri-weekly cisplatin administered concurrently with
radiotherapy in 104 locally advance ca cervix patients. He found that all patients
tolerated both treatments very well, with a high completion rate of scheduled chemotherapy
cycles. There was no statistically significant difference in compliance between the
two arms (86.3% in the weekly arm, 92.5% in the tri-weekly arm, P > 0.05). Grade 3–4 neutropenia was more frequent in the weekly arm (39.2%) than in
the tri-weekly arm (22.6%) (P = 0.03). The overall 5-year survival rate was significantly higher in the tri-weekly
arm (88.7%) than in the weekly arm (66.5%) (Hazard ratio 0.375; 95% confidence interval
0.154–0.914; P = 0.03). So, they concluded that tri-weekly cisplatin 75 mg/m2 chemotherapy concurrent
with radiotherapy is more effective and feasible than the conventional weekly cisplatin
40-mg/m2 regimen. Chumworathayi et al.[16] 2005 studied compliance of weekly versus 3-weekly cisplatin as an adjunct to radiotherapy
in high-risk early stage cervical carcinoma after surgery using 40 mg/m2 as weekly
cisplatin dose for 6 cycles and 75 mg/m2 tri-weekly cisplatin for 4 cycles and found
statistically significant difference in neutropenia and hearing loss. In the present
study, none of the patients had hearing loss, whereas the neutropenia was consistent
with the findings. Ikushima et al.[17] in 2006 found severe hematological toxicity in 86% patients, grade 3 in 81% patients
and grade 4 in 4.8% patients. Moderate or severe gastrointestinal toxicity occurred
in 11 patients (52%), grade 2 in 10 patients (48%), and grade 3 in one patient (4.8%).
All patients completed RT without interruption. This study had higher toxicity as
compared to the present study, reason being lesser number of patients enrolled in
the study done by them.
In the study, Chumworathayi et al.[16] have found 100% completion of chemotherapy but with delay in 30.3% cycles in the
3 weekly group and 12.9% cycles delay in the weekly group, which is statistically
not significant. In their study, they have found that all patients completed their
radiotherapy within time, the time frame in their study to complete radiotherapy was
10 weeks. This finding of chemotherapy completion was not consistent with the study.
Although their study showed better compliance in the weekly group, it was not statistically
significant. Moreover, their time period of completion of radiotherapy was 10 weeks
which is different from the recommended duration of 8 weeks.
In a study by Kim et al.[18], full planned CCRT was delivered to 55 (71%) patients. The incidence of acute grade
3/4 hematologic toxicity was 26%. The CR rate was 91%. Four-year overall and progression-free
survival rates were 67% and 66%, respectively, these results are consistent with results
of the present study. Toita et al.[19] reported grade 3/4 leukopenia as the most common acute side effect (83%). The actuarial
3-year pelvic control rate, disease-free survival rate, and overall survival rate
were 91%, 67%, and 79%, respectively; these results are consistent with the result
of the present study.
Conclusion
The present study shows that weekly cisplatin concurrent with radiotherapy is feasible
and has same compliance and response rates as compared with tri-weekly cisplatin in
patients with locally advanced cervical cancer. Despite the small number of patients
in this single institutional study, there were statistically significant differences
in vomiting and grade 3-4 leucopenia and neutropenia, associated more with tri-weekly
cisplatin compared to weekly cisplatin.
