Conclusions:
The overall response with the
use of paclitaxel, which is the study arm, are equal to those with
cisplatin. Though not significant, but tumor response was more in
paclitaxel arm compared to cisplatin
arm.
I. Introduction
Cancer is the third biggest killer in India. India recorded 9.8 lakh new cases of cancer
in the year 2010, an increase of about 80,000 new cases as compared to 2009. In India, four lakhs die of cancer
every year. There is data that shows 25 lakh
cancer patients in the country at any point in time. By
2015, the number of new cases in India is expected to cross 15 lakhs.
(1). Among Indian males,
lung, head and neck cancer is the most common and among women,
breast
and
cervical cancer is the most frequent.
Carcinoma of the Uterine Cervix is
the most common malignancy to affect females of developing countries. It ranks second in incidence among females,
after
Breast Cancer. Worldwide, approximately 5 lakh new cases are identified each year and
about 2.33 lakh patients die of the disease .
(2). In developing countries, it accounts for about 3.4 lakh new cases & 1.6 lakh deaths every year (3).In
India about 1.82 lakh new cases & 80,000 deaths every year from this disease .
(4).An estimated 1,82,027 new cases and 77,096 deaths due to cervical cancer occurred in India in 2010,
contributing to 29% and 30% of the global burden of
cervical cancer incidence
and mortality.
(5).
Patients with Cervical Cancer usually present with locally advanced disease that is clinically
confined to the pelvis (FIGO stage IIB, III & IV) in which surgery has higher morbidity. Radiotherapy plays a
major role in management of these patients. The limitation of radiotherapy in controlling pelvic diseases for
locally advanced cervical cancers is that radiation doses required to treat large tumours in the setting
of
poor tumour oxygenation exceeds the limit of toxicity in normal tissue. This was the main
reason for treatment failure supporting by the fact that about 70% of relapses have pelvic failure as the first
sites .
(6). Many strategies have been made trying to improve outcomes in locally advanced diseases such as uses of
hypoxic cell sensitizers, hyperbaric oxygen, neutron therapy, and hyper-fractionation. However,
results of those mentioned were found limited or unsuccessful.
(7). After a 1999
National Cancer Institute (NCI) Clinical alert was issued,
chemoradiotherapy has become widely used in
treating women with cervical cancer .
Cisplatin is considered the
most active cytotoxic agent and the drug of choice for
concurrent chemoradiation. Meta-analysis
studies have also demonstrated improved local control rates and survival with
cisplatin-based
chemotherapy concurrent to radiation therapy (RT). Although many prospective
studies had shown that CTRT with cisplatin-based chemotherapy clearly improve the outcome of patients with
carcinoma of the cervix, many patients treated on these protocols continue to fail in the pelvis and
at distant sites .
[8]. In addition, one intergroup study using weekly concurrent cisplatin with radiotherapy for patients with
carcinoma of the cervix could not demonstrate a beneficial effect of CTRT over standard RT alone
.
[9]. non-superiority finding was attributed to many factors like possible enrollment of
patients
with
paraaortic lymph nodes, and an imbalance among randomization groups for known prognostic
factors
such as anemia.
[10]. These facts have lead many groups to investigate other drugs for
CTRT like
paclitaxel
in an attempt to improve on what can be achieved by concurrent cisplatin [11].Paclitaxel is a taxane
chemotherapy drug that was found to have significant activity in solid tumors especially
epithelial ovarian
cancer, lung, and breast cancer . Preclinical studies have shown a
radiosensitizing effect of
paclitaxel in human cervical cancer cell lines.(12)
At Our Centre, the treatment for locally advanced cervical cancer is
concurrent
chemoradiotherapy;
the protocol is cisplatin 50 mg/m2 once a week for 5 weeks concurrent with pelvic radiation .Radiation is
administered with cobalt-60 and
HDR Brachytherapy.
Paclitaxel is also radiosensitizing
agent ,We conducted study to investigate the efficacy and response of Paclitaxel with concurrent
radiotherapy versus Cisplatin with concurrent radiotherapy.
II. Method and Meterials
Patients coming to the department of radiotherapy & cancer treatment centre, SMS medical
college &hospital jaipur were included in the study.After proper evaluation of the Biochemical and
Hematopoietic profile, 50 patients were randomly divided into study and control group.
III. Inclusion Criteria
1.
Patients with newly
diagnosed cases of Squamous Cell Carcinoma Cervix FIGO stage-III &IV were
taken for study and control group.
2.
Patients with
advanced & inoperable cervix cancer.
3.
Age between 18 to 70 years.
4.
ECOG (eastern cooperetive
oncology group) performance status. 0 to 2.
IV. Exclusion Criteria
1.
Patients previously treated with radiotherapy ,Surgery, Chemotherapy.
2.
Any histology other than
squamous cell carcinoma.
3.
Poor perfomence status ECOG 3 &4.
4.
Any uncontrolled intercurrent illness.
5.
Pt who don�t give consent for the study.
6.
Class III & IV cardiac failure according to
NYHA classification.
7.
Pregnant & lactating women.
In the study and control group , patients were given 5 weeks of
external beam radiotherapy followed
by
brachytherapy. External beam irradiation each of 200cGy/fr, on linear acceleretor
by parallel opposed � anterior and posterior fields was given. External beam irradiation was followed by
Intracavitary brachytherapy 700cGy/week for 3 weeks each with High Dose Rate
Iridium 192 source. Patients received 50 Gy by External beam irradiation (200cGy/fr, total 25 Fr) and 21 Gy by
Intracavitary brachytherapy (7Gy/fr, 3fr) .In control group, patients were treated by concurrent
weekly cisplatin with external beam radiotherapy.In study group patients were treated by concurrent weekly
paclitaxel with external beam radiotherapy .
Response was assessed as per the
RECIST Criteria 1.1(13) .The results of study group were
analyzed & compared with control group in terms of various aspects like side effects, tumor response, &
local disease status. The data thus collected were analyzed by using
Chi-square test for
co-relation.
V. Results
Treatment Response at The end of Study --
Table a shows treatment response of disease of patients using
RECIST version 1.1 criteria while
on
treatment and subsequent follow up .
After 2nd week of initiating treatment, 9 (36%) patients of study group and 8 (32%) patients of control group had
partial response, 16 (64%) patients of study group and 17 (68%) patients of control group had stable disease (?2 =
0.089, p = 0.76).
After 4th week of initiating treatment, 2(8%)patients of study group and 1(4%) patients of control had
complete response, 18 (72%) patients of both study & control group had partial response and 5
(20%) patients of study group and 6 (24%) patients of control group had stable disease (?2 =.42 , p = 0.80).
After 5th week of initiating treatment, 4(16%) of control group and 5(20%) of study group had complete response,
17 (68%) patients of control group and study group had partial response 4(16%) patients of control group and 3
(12%) patients of study group had stable disease (?2 = .25, p = 0.88).
At end of treatment,18(72%) of control & 19(76%) of study group had complete response, 5
(20%) patients of control group and 4(16%) patients of study group had partial response 2 (8%) patients of study
group and control group had stable disease (?2 = .13, p = 0..94).
At 1st month of follow up, 19 (76%) patients of control group and 20 (80%) patients of study group had complete
response 4 (16%) patients of control group and 3(12%) patients of study group had partial response and 2 (8%)
patients of study group and control group had stable
disease (?2 = .16, p = 0..91).
At 3rd month of follow up, 21 (84%) patients of study group and control group had complete response, 3 (12%)
patients of study group and control group had partial response and 1 (4%) patients of study and control group had
stable disease (?2 = 0, p = 1).
At 6th month of follow up, 21 (84%) patients of study group and control group had complete response, 4 (16%)
patients of study group and control group had partial response and none patients of study group and control group
had stable disease (?2 = 0.14, p = 0.699).
Acute Toxicity During Treatment
The incidence of nausea during treatment in both the groups are summarised in the table b. As per TOG criteria Table b shows that in the study group 10(40%) of the patients had Grade 1 Reactions ascompared to 6 (24%) in the control group whereas 2(8%) in the study group and 7 (28%) in the control group had Grade 2 Reaction and the incidence of Grade 3 was 2 (8%) and 5 (20%) in the study group and control group respectively( ?2=5.9,
p=0.11).
The vomiting during the treatment is statistically
significantly more in the control group. 22(84%) patient in study group had
Grade 0-1 vomitting and only 5(20%)
had in study group, whereas only 3(12%) had grade 2-3 vomitting in study
group, comparing to 11(44%) had grade 2 and 9(36%) had grade 3 vomitting in control group( ?2=23.548,p= <0.0001).
The
haematological toxicity is represented in the table b in three sub heads-
haemoglobin, Total
Leucocytes count and Absolute Neutrophil count. 4 (16%) and 5(20%) had grade 1, 21(84%) and 20(80%)
had grade 2
heamoglobin level in the study group and the control group(p=1).
Total
leucocyte count in the table b shows that study group had more grade 2 and 3 toxicity
{6(24%)
and 4(16%)} comparing to control group having 2(8%) grade 2 toxicity &1(4%) having grade 3 toxicity. 8(32%) in
study group and 19(76%) group had grade 0 toxicity, 7(28%) and 3(12%) 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.(?2=9.8,p=0.0106), absolute
neutrophil count shows the same pattern of toxicity
profile. 10(40%) and 20(80%) had grade 0, 8(32%) and 3(12%) had grade 1, 4(16%) and 1(4%) had grade 2toxicity in
the study and control group respectively. 3 (12%) developed grade 3 toxicity in the study group and 1(4%) in
control group. This difference was statistically
significant more in the study group compared to control group (?2=8.4,p=0.03).
There was no
nephrotoxicity found in 24(96%) in study group and 19(76%) in the control group, while
1(4%) and 4(16%) were found to have grade 1 toxicity in the study and control group respectively and.1(4%) was
found to have grade 2 toxicity in control group(p=.11)
Table b.
VI Discussion
The clinical feasibility of co ncurrent RT and paclitaxel was tested in phase I trials and a
maximum
tolerated dose (MTD) of 50 mg/m2 per week concurrently with radiation therapy was established . In
addition, the clinical efficacy of
paclitaxel has been tested in phase II and III studies for
metastatic and recurrent cervical cancer with objective response rates ranging between 36 and 47%.
In all these studies paclitaxel was used in conjunction with either
cisplatin
(4/7 studies) or carboplatin (3/7 studies) but was never used alone for CTRT. The majority of these
studies was phase I (4/7 studies), with one study being a combined
phase I/II study conducted by the GOG [60]. The number of patients enrolled in these studies varied
between 8 and 35 patients and the rates of progression free survival ranged between 39 and 88%. The dose limiting
toxicity was
primarily neutropenia in 4 studies [14,15] or diarrhea (14).
The present study was carried out on 50
histopathologically confirmed newly diagnosed cases of
Squamous cell Carcinoma cervix Stage IB to IVA. These cases were registered for treatment in
department of Radiotherapy at S.M.S hospital jaipur from December 2011 to June 2012.. In this
study there was no statistically significant toxicity between the study group
and control group for acute
skin reaction, nausea during treatment, acute diarrhea, haemoglobin
changes during treatment and
nephrotoxicity. The statistically significant
neutropenia was found in study group and vomiting in control group.
The tumour response in this study was evaluated in the 2nd, 4th, 5th week and at the end of
treatment. After the completion, patients were evaluated every month til 6th month. Reduction in the tumour size
was seen comparatively more in the study group and rendering them fit for
brachytherapy earlier then
the control group. In the 4th week of treatment 8% in the
study group and 4% in the control group had complete response and in the 5th week 20% in the study group and 16%
in the control group had complete response.
At end of the completion of treatment 76% in the study group and 72% in the control group were
found to have complete response to the treatment, 16% and 20% were found to have partial response in the study and
control group respectively. After 6 months of completing the treatment the result were equivalent in both the
groups, 84% had complete response and 8% had partial response. Though the difference in tumour response was not
statistically significant, the rate of
reduction in tumour size was found faster in study group at
the end of the treatment complete response was little
more in the study group. So
paclitaxel can be used as a
radiosensitizer concurrently with
radiotherapy in advanced inoperable patients in whom renal functions are not normal due to (1)
hydronehrosis
caused by advance disease,(2)Chronic renal disease.
VII.
Conclusions
Our study provides a
direct comparison between cisplatin and paclitaxel used as weekly
concurrent chemotherapy with definitive radiation for advanced carcinoma of the cervix. Our data indicate that the
overall response with the use of paclitaxel,
which is the study arm, are equal to those with cisplatin. Though not significant, but tumor response was more in
paclitaxel arm compared to cisplatin arm .However, the results were encouraging and it shall require
larger number of patients and longer follow up in order to arrive at a concrete conclusion as far as disease free
survival, cause specific survival, pelvic control rate, and long term sequel or complications are concerned.
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