International Scholarly Research Network

ISRN Oncology
Volume 2012, Article ID 390193, 6 pages
doi:10.5402/2012/390193

Clinical Study
External Beam Therapy in a Four-Field Box Technique with
Paclitaxel versus a Two-Field Technique with Cisplatin in Locally
Advanced Carcinoma Cervix: A Phase II Monocentric Trial

Vijayakumar Narayanan,1 Bibek Bista,2 and Samir Sharma2

1 Cancer Care Kenya, P.O. Box 39173, Nairobi, Kenya
2 B. P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal

Correspondence should be addressed to Vijayakumar Narayanan, drvijay@cancercarekenya.com

Received 14 November 2012; Accepted 13 December 2012

Academic Editors: G. Kovacs and C. Perez

Copyright © 2012 Vijayakumar Narayanan et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Introduction. External beam pelvic radiotherapy with cisplatin and brachytherapy is the standard of care for patients with advanced
cervical malignancy. This study was aimed at evaluating the toxicity of a two-field radiotherapy with cisplatin and brachytherapy
compared to a four-field box technique with paclitaxel and brachytherapy for stages IIB/IIIB cervical cancer. The differences in
response to the overall treatment were also examined. Methods. 35 patients were enrolled in this phase II prospective randomized
trial conducted from February 2006 to February 2007. In arm I, up to 40 Gy in 20 fractions followed by 10 Gy in 5 fractions in
split field with cisplatin 40 mg/M2 and, in arm II, 50 Gy in 25 fractions with paclitaxel 50 mg/M2 were given. Results. Toxicity
in genitourinary, lower gastrointestinal, and hematological tissues was significantly higher in arm I. The duration of concurrent
chemoradiotherapy in either arm was similar. The overall treatment time was less in arm II. No statistically significant difference
in the objective response was observed between arms. Conclusion. Two-field radiotherapy with cisplatin is a tolerable regime
but more toxic than four-field box radiotherapy with paclitaxel. The major setbacks are that a radiotherapy technique as well
as chemotherapy is different; hence, toxicity and outcome of treatment should be viewed as a collective response of the whole
treatment regimen and the small sample size.

1. Introduction tremendous breakthrough in cancer research and changes in

clinical practice, the nature of disease still remains the same.
The commonest gynecological cancer before the age of 50 Early carcinoma of the uterine cervix can be effectively
is carcinoma cervix. The incidence is high in developing managed either by surgery or by radiotherapy; the results
and underdeveloped countries. Women belonging to low are equivocal [5]. A randomized control trial (RCT) in
socioeconomic status show higher incidence [1]. Though Taiwan evaluating the side effects and quality of life of
there is no population-based cancer registry in Nepal, inci- surgery versus radiotherapy in early cervical cancer showed
dence of the age-standardized incidence rate and mortality that though initial complications were different, long-term
rate is estimated to be 26.4 per 100000 women and 14.1 complication and quality of life were similar in both modal-
per 100000 women, respectively. Similarly, the incidence of ities [6]. Patients with stages IIB and III are treated with
cervical cancer per 100000 women in India, Bangladesh, and irradiation alone. Concomitant use of chemotherapeutic
Sri Lanka is estimated to be 30.7, 27.6, and 17.7, respectively agents as radiosensitizer has shown to be beneficial in
[2]. Poor personal hygiene, poor nutritional status, multiple several randomized trials [7–9]. All positive trials showed
sexual partners, first coitus in young age, early child birth, a 43–46% reduction in the risk of recurrence and death,
promiscuity of the spouse, human papilloma virus infection, translating into 16% absolute benefit in disease-free survival
sexually transmitted diseases, and immunocompromised and 12% absolute benefit in total survival. The trials
states are cited as main risk factors [3, 4]. Though there is also showed a reduction in the rate of distant metastasis
2 ISRN Oncology

in the chemoradiotherapy arm. Two meta-analyses con- Grading of toxicity in lower gastrointestinal, genitouri-
firmed the finding [10, 11]. The National Comprehensive nary, and hematological tissues was done as per the Radi-
Cancer Network Guidelines [12] categorically recommend ation Therapy Oncology Group/European Organization for
pelvic radiotherapy with concurrent cisplatin containing Research and Treatment of Cancer (RTOG/EORTC) [16]
chemotherapy (Category I) and brachytherapy for advanced toxicity criteria. The gynecologist and radiation oncolo-
cervical cancer. A recent meta-analysis involving 18 RCT gist jointly evaluated the patients. Pretreatment evaluation
showed that chemoradiotherapy has better 3- and 5-year included a complete hemogram, biochemical profile, X-ray
survival rate compared to radiotherapy alone while the chest, ultrasonogram of abdomen and pelvis, and cystoscopy.
adverse effects were not statistically different [13].
Thus, chemoradiotherapy has been the standard rather 2.2. Treatment Plan. This was a double-blind prospective
than an option for treatment of advanced cervical cancer. randomized controlled study. So, a two-parallel-arm of treat-
However, there lies the problem of toxicity, and in order to ment modality was developed. The patients were randomly
circumvent this, trials are on the way to evaluate the new allocated to treatment arms based on a computer generated
drugs and different dosing schedules, which may result in a random number.
more acceptable toxicity profile. A prospective multicentric
study in eight Asian countries showed that concurrent 2.3. External Beam Radiotherapy. Homogenous irradiation
chemotherapy using cisplatin is feasible and produces good of the volume of tissue was planned in arm I by two parallel
survival outcome and reduced adverse effects [14]. opposed anterior and posterior fields, in which the upper
Radiation therapy in cervical cancer has made significant limit was on the lower border of L4 and the lower limit
advances in the past few decades. It is now suggested that a was at a 2-3 cm safety allowance from the lower extension of
Point A dose of 85–90 Gy is the optimum in cervical cancer growth, usually at the inferior margin of obturator foramen.
[15]. This dose is achieved by external beam radiotherapy Lateral margins were kept 2 cm beyond a true pelvic brim. In
and brachytherapy. Despite all these advances, treatment arm II, the plan was a four-field box/brick, in which, apart
response in advanced cancer of the cervix has a plateau of 30– from the anterior and posterior fields, two lateral fields were
45% at 5 years. The situation is still worse in developing and also set up. The anterior border of the target volume in the
underdeveloped countries, where the data available is often lateral portal was 4 cm anterior to the anterior margin of L5
heterogenous. Poor randomization, inadequate sample size, vertebral body while the posterior border was 2 cm anterior
nonuniform usage of chemotherapeutic drugs, poor docu- to the sacral hollow, usually at S2/S3 junction. Treatment
mentation, and irregular followup are pointed out as fallacies was given 5 days a week, 200 cGy/day, with all fields treated
of the trials. Follow-up investigations are different between a daily. In arm I, after a dose of 40 Gy, a midline block was
developed and an underdeveloped country. Investigations by placed and additional 10 Gy was given, whereas, in arm II,
magnetic resonance imaging (MRI) and positron emission no split field was used; all patients were given 50 Gy. Toxicity
tomography (PET) scans are routinely performed in the assessments were made every week and in between, when
former while in the latter they are neither easily accessible found necessary.
nor affordable for routine use. In this phase II randomized
study conducted in our institute, we compared one group
of patients treated with external beam radiation in a two- 2.4. Chemotherapy. In arm I, weekly cisplatin at a dose of
field technique with weekly cisplatin as per the institutional 40 mg/M2 was given. Cisplatin is considered as the most cyto-
protocol to a second group treated with a four-field box toxic drug for patients with advanced and recurrent squa-
technique with weekly paclitaxel. The primary aim of the mous cell carcinoma cervix [17]. Cisplatin is thought
study was the evaluation of toxicity of the two regimes in to enhance cell death through cytotoxic DNA crosslinks,
an underdeveloped country setting. Clinical management of hypoxic cell sensitization, and inhibition of cell damage
cancer patients in an underdeveloped country has its own repair [18].
challenge such as absence of infrastructure, nonavailability of In arm II, patients were given weekly paclitaxel in a dose
specialist services, affordability of treatment cost, and acces- of 50 mg/M2 . Paclitaxel is found to be effective and a well-
sibility of care. So, the result of this study can be a clinical tolerated radiosensitizer for patients with cervical cancer
guide to a radiation oncologist in such setup. [19, 20]. In vitro studies on paclitaxel revealed potentiation
The institutional ethics committee approved the study as of antitumor activity and recruitment of cells into most
per the institutional rules. radiosensitive phases of cell cycle, the G2/M [21].

2.5. Brachytherapy. After completion of the external beam

therapy, all patients were subjected to high-dose rate
2. Patients and Methods
brachytherapy (HDBT), which was based on a Manchester
2.1. Patients. The study enrolled patients with a pathologi- triple source system comprising an intrauterine device and
cally confirmed carcinoma cervix FIGO stages IIB and IIIB. two vaginal ovoids. 21 Gy to Point A was given in three
Eligibility criteria included an Eastern Cooperative Oncology sessions, each at an interval of 1 week.
Group (ECOG) performance status >2, chemotherapy naive,
prior treatment score 0 status, and negative para-aortic 2.6. Parametrial Boost. In the patients in arm II in whom a
nodes. significant distal parametrial disease was felt at the time of
ISRN Oncology 3

brachytherapy, an additional parametrial dose was given Table 1: Patient characteristics.

using opposed anterior and posterior fields with a half- Characteristics Arm I Arm II
beam block. 6–10 Gy in 3–5 fractions in 1 week, depending
Number of patients 16 19
on the dose already given by external beam therapy and
brachytherapy, was administered to boost the dose to a lateral Age in years
parametrium to 60 Gy. Median 42 50
Range 35–65 35–65
2.7. Definition of Response. Response to treatment was Histology
assessed in all patients included in the trial. Objective res- Squamous cell carcinoma 16 16
ponse was evaluated after 1 month after chemoradiotherapy Adenocarcinoma 0 3
as per the WHO criteria [22, 23]. Confirmation of the Stage
response was performed after 2 months. Complete response IIB 8 11
was defined as the disappearance of all disease; partial IIIB 8 8
response was defined as at least a 30% decrease in the sum of
the longest diameter (LD) of target lesion. Progressive disease Table 2: Treatment days for the first phase (CCRT).
was defined as at least 20% increase in the LD of target lesion.
It was decided to evaluate the response earlier if there was any Number of days taken to
clinically evident or suspected progression of the disease. complete the first phase Arm I Arm II
(CCRT)
2.8. Toxicity Criteria. Toxicity was evaluated in all patients Mean 36 35
who enrolled in treatment. Toxicity was graded according to Median 37 34
the RTOG/EORTC criteria. Dose and schedule modifications Range 30–41 32–42
were based on weekly blood counts and biweekly assessment SD 3.04 2.96
of clinical toxicity. It was decided to interrupt the treatment
in the event of Grade 2 or the previously mentioned hema-
Table 3: Complications of the genitourinary system.
tological or Grade 3 or the previously mentioned nonhe-
matological toxicity till resolution of the problem. It was also Genitourinary toxicity Arm I Arm II
decided to withdraw patients from the trial in the event of Number of patients with G0
any Grade IV toxicity. 8 (50%) 19 (100)
toxicity
Number of patients with >G0
8 (50%) 0 (0%)
2.9. Statistical Methods. t-test was used to compare the time toxicity
required for completion of external beam therapy and for Chi square test yielded a P value <0.001, which indicates that the proportion
evaluation of the response to treatment, assuming that the of patients developing genitourinary complications is significantly less in
variance was different in each group. Chi square test was arm II.
used to evaluate the difference between the rate of severe
complications (>G0) between the groups. Table 4: Complications of the lower gastrointestinal system.

Lower gastrointestinal toxicity Arm I Arm II

3. Results Number of patients with G0
7 (46%) 12 (63%)
toxicity
From February 2006 to February 2007, the study was com-
Number of patients with >G0
pleted with 35 patients. In arm I, there were 16 patients and 9 (54%) 7 (37%)
toxicity
in arm II 19 patients. Patient characteristics are shown in
Chi square value yielded a P value 0.016 (<0.05) which indicates that the
Table 1. proportion of patients developing the lower gastrointestinal complication is
significantly less in arm II.
3.1. Administration of Therapy and Toxicity. The therapy was
administered in two phases. External beam radiotherapy and
weekly chemotherapy, that is, the concurrent chemoradio- of arm I. The results are provided in Table 2. Difference
therapy (CCRT), were given in first phase and high-dose rate in the rate of complication (>G0) as per RTOG/EORTC in
brachytherapy (HDBT) in the second phase. both groups in the case of genitourinary system (GUS), lower
The mean number of days required for completion of the gastrointestinal system (LGI), and hematological system was
first phase of the treatment, that is, CCRT in both groups, evaluated. The data is presented in Tables 3, 4, 5, 6, and 7
was 36 and 35 days, respectively. Assuming that the variance with the results.
was different in each group, t-test was used. The value of t
was calculated to be 0.67 and with degree of freedom of 36.05 4. Discussion
(which was calculated assuming that the variance in both
groups is not the same and unknown), and the P value >0.05, The primary end point of this study was toxicity related
which is statistically insignificant. This indicates that time to concurrent chemo-irradiation. Hence, only patients with
taken for treatment in arm II is statistically similar to that Eastern Cooperative Oncology Group (ECOG) performance
4 ISRN Oncology

Table 5: Hematological complications. the statistically significant supremacy of one regimen over
the other in terms of toxicity as an attribute of either the
Hematological toxicity Arm I Arm II technique of radiotherapy or the radiosensitizer is used. Both
Number of patients with G0 factors had contributed to the less toxicity observed in arm II.
8 (50%) 19 (100%)
toxicity Only controlled trials can provide an answer to the supe-
Number of patients with >G0 riority of one drug over other, but considering the economic
8 (50%) 0 (0%)
toxicity aspect of both drugs in the context of a country where
Chi square test yielded a P value <0.001, which indicates that the proportion majority of the people are below poverty line, we would
of patients getting hematological complications is significantly less in arm II.
like to suggest Cisplatin as a radiosensitizer in concurrent
chemo irradiation in advanced cervical cancer. Paclitaxel
Table 6: No. of days required to complete treatment. should be given to those patients who can afford the drug
Total number of days to for minimizing toxicity and can be used in otherwise unfit
Arm I Arm II patients, for example, those with impaired renal functions.
complete the treatment
Mean 71.44 66.16 Acceptable geometry for the conventional Manchester triple
system placement following optimal tumor shrinkage was
Median 69 64
observed in arm II, where the treatment technique was four-
Range 61–87 55–84 field box. Such a response was not present in the two-field
SD 7.74 7.88 technique. In the box technique irradiation where two lateral
Assuming that the variance was different in each group, a t-test was used. portals are also used, there is dual advantage of the sparing
The value of t was calculated to be 1.99 and with a degree of freedom of 32.2 portion of small bowel and bladder anteriorly and rectum
(which was calculated assuming that the variance in both groups is not the posteriorly as well as yielding more dose to the tumor. In the
same and unknown); the P value <0.025, which is statistically significant.
This indicates that time taken for overall treatment in arm II is significantly two-field technique, the use of midline shield for splitting
less than that of arm I. the portal after 40 Gy in order to spare the bladder and the
rectum results in less dose to the tumor. Such a setting is not
Table 7: Response to treatment. required in the box technique.
In the present study, we did not give any priority to the
Number of patients with complete subjects and they were given the time slots for brachytherapy
Arm I Arm II
response/recurrence
as per the existing waiting list. Being the only center in
CR after 3 followups 12 (75%) 18 (94.7%) the entire country with HDBT facility, the waiting list is
Recurrence 4 (25%) 1 (5.3%) long. Thus, extrinsic factors also play a crucial role in the
Complications completion of treatment. Locoregional control is inversely
Proctitis 1 0 proportional to the total duration of radiation treatment in
Vulval edema 1 0
carcinoma cervix [24, 25]. Even then, no statistically signif-
icant difference was observed in the response to treatment
Pulmonary metastasis 1 0
in either arm. The small sample (n = 35) is not adequate
Pulmonary metastasis, vulval edema, and proctitis were noted in one to find out the statistical significance in response rates.
patient each in arm I. For comparison of differences in terms of response
determined as per WHO, first two rows were used, and calculation yielded a
Large trials are necessary to arrive at a definite conclusion.
P value 0.096 (Fishers exact test 0.156), which is statistically not significant. The overall time to complete the treatment is less in arm
II, partly due to less toxicity during treatment. In general,
patients take more than 2 months for completion of the
status ≤2 were recruited for the trial. All of them were entire treatment, which is not desirable as it may adversely
eligible for CCRT with either cisplatin or paclitaxel. A high affect the outcome of treatment. The setback of radiotherapy
dropout was expected in patients with a performance status services in Nepal is due to the lack of strategic planning.
more than 2, so they were excluded. All patients completed Increasing workload and inadequate resources potentially
the first phase of their treatment, that is, CCRT, though exacerbate inequalities in the standard of care. Waiting time
statistically significant difference were observed in the study for treatment is an inevitable consequence of inadequate
arms, in terms of genitourinary, lower gastrointestinal, and resource, underutilization of the available resource, or both.
hematological toxicity. Paclitaxel plus the box technique was Considering the evidence-based oncology in cervical
found to be less toxic than cisplatin plus a two-field technique cancer, we find that the enormous amount of data available
(P < 0.001). It should be noted that the toxicity reported is inconvenient and is not appropriate in the context of a
was self-limiting, requiring no interruption of treatment or country like Nepal. We feel that our ultimate responsibility
no dose reduction. There is no significant difference in the is to the individual patient, and to a management according
duration of completion of external beam radiotherapy (XRT) to her predicament should be the prime concern.
with weekly chemotherapy in either arm.
This study has a major drawback. In this study, the tech-
nique of radiotherapy as well as the sensitizer chemotherapy 5. Conclusions
is different in both arms. Hence, toxicity and the outcome
of treatment should be viewed as a collective response of the CCRT is the standard of care in advanced cervical cancer.
whole treatment regimen. It is not possible to conclude that Two-field external beam radiotherapy with weekly cisplatin
ISRN Oncology 5

is a tolerable regime, but more toxic than the four-field gynecologic oncology group and Southwest oncology group
box external beam radiotherapy with weekly paclitaxel. The study,” Journal of Clinical Oncology, vol. 17, no. 5, pp. 1339–
treatment can be given in an outpatient setting and is 1348, 1999.
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Conflict of Interests
[13] N. Wang, Q. L. Guan, K. Wang et al., “Radiochemotherapy
The authors declare that they have no conflict of interests. versus radiotherapy in locally advanced cervical cancer: a
meta-analysis,” Archives of Gynecology and Obstetrics, vol. 283,
no. 1, pp. 103–108, 2011.
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The authors acknowledge the help of Dr. Jissy Vijo Paulose
for locally advanced cervical cancer in East and Southeast
for statistical assistance and Sheeba Vijayakumar for editorial Asia,” International Journal of Radiation Oncology, Biology and
assistance. Physics, vol. 77, no. 3, pp. 751–757, 2010.
[15] P. J. Eifel, W. W. Thoms Jr., T. L. Smith, M. Morris, and M.
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