SA Journal of Oncology

ISSN: (Online) 2523-0646, (Print) 2518-8704

Page 1 of 9 Original Research

A retrospective review of conventional versus

hypo-fractionated pelvic radiotherapy for
locally advanced cervical cancer, in limited-
resource countries: The Uganda experience

Authors: Background: Cervical cancer incidence in Uganda is 54.8 per 100 000 population. We annually
Awusi Kavuma1
treat over 800 new cervical cancers (40% of the workload), which is challenging to treat
Israel Luutu1
Solomon Kibudde1 such numbers in limited resources settings. From July 2011, we commenced the use of
Cissy Bangidde1 hypo-fractionated radiotherapy (HFRT) of 45 Gy/15 fraction (#) as an alternative to
conventional fractionated radiotherapy (CFRT) of 50 Gy/25#, for treatment of locally
Affiliations:
advanced cervical cancer (LACC).
1
Department of
Radiotherapy, Uganda Cancer Aim: To compare the 5-year follow-up treatment outcomes between CFRT and HFRT.
Institute, Kampala, Uganda
Settings: The study analysed patients treated at the Uganda Cancer Institute – a limited
Corresponding author:
resource institution.
Awusi Kavuma,
[email protected] Methods: This was a non-randomised, retrospective study, where 414 patients’ files were
Dates: reviewed according to demographic, clinical, radiotherapy fractionations and outcomes.
Received: 28 May 2021 Inclusion criteria were International Federation of Gynecology and Obstetrics stages IIB–IIIB
Accepted: 09 July 2021 cervical cancer cases and had completed external beam radiotherapy and intracavitary
Published: 22 Sept. 2021 radiotherapy.
How to cite this article: Results: Squamous cell carcinomas were 93.6% and adenocarcinomas were 3.0%. The median
Kavuma A, Luutu I, Kibudde S,
age was 49.5 (interquartile range [IQR]: 40.0–56.0) years. Stages IIB/IIIA/IIIB were 36.2%,
Bangidde C. A retrospective
review of conventional versus 8.2%, 55.6%, respectively. Human immunodeficiency virus serology was positive, negative,
hypo-fractionated pelvic and unknown in 70 (16.9%), 116 (28.0%) and 228 (55.1%), respectively. Concurrent chemo-
radiotherapy for locally radiation was administered in 182 (44.0%) patients. Conventional fractionated radiotherapy
advanced cervical cancer,
and HFRT were 221 (53.4%) and 193 (46.6%), respectively. At 6 months, the overall response
in limited-resource countries:
The Uganda experience. S. rate was 73.3% for CFRT compared with 67.6% for HFRT (p = 0.085), whilst the grades
Afr. j. oncol. 2021;5(0), a186. 0–1 toxicities were 94.5% and for 94.7% CFRT and HFRT, respectively (p = 0.080). At
https://doi.org/10.4102/sajo. 60 months, the survival probabilities were 44.9% for CFRT and 46.6% for HFRT (p = 0.293).
v5i0.186
Conclusion: There is no significant statistical difference between CFRT and HFRT for the
Copyright: treatment of LACC. The HFRT could be considered for high volume limited resource
© 2021. The Authors.
Licensee: AOSIS. This work settings.
is licensed under the
Keywords: cervical cancer; conventional-radiotherapy; hypo-fractionated radiotherapy;
Creative Commons
Attribution License. limited-resource countries; 5-year survival rate.

Introduction
Cervical cancer is the fourth most common cancer in women worldwide, and the second
commonest in developing countries.1 There were 570 000 cases and 311 000 deaths because of
cervical cancer in 2018 globally.1 The mortality is 10 times higher in developing countries, where
about 80% of new cases occur.2 In the United States (US), most cancer-treatment facilities treat less
than three intact cervical cancer patients per year.3 The cervical cancer incidence in Uganda is 54.8
per 100 000 population.1 The Department of Radiotherapy, Uganda Cancer Institute annually
treats over 800 new cervical cancer patients, accounting for nearly 40% of the workload; it is
Read online: challenging to optimally treat such large numbers in centres with limited resources. Locally
Scan this QR advanced cervical cancers (LACCs) account for nearly 60% of all cervical patients. Concomitant
code with your
smart phone or chemo-radiation therapy is the mainstay of treatment for patients with locally advanced or
mobile device recurrent cervical cancer.4,5,6 About 65% of patients with stage IIB and 30% – 45% with stage IIIB
to read online.
can potentially be cured.4,7,8

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 Page 2 of 9 Original Research

The concept of biologically effective dose (BED) is a measure

of true biologically dose delivered by a particular combination
Materials and methods
of dose per fraction and total dose to a particular tissue. Patients and methods
Biologically effective dose is used in radiotherapy to compare This was a retrospective cohort study of cervical cancer
and quantify treatment expectations for tumours and normal patients staged according to the International Federation of
tissues. The BED is related to the equivalent total doses of Gynecology and Obstetrics (FIGO) IIB–IIIB2 who received
2-Gray (Gy) fractions by the EQD2. The BED normalised in radiotherapy at the centre from January 2011 to December
2.0 Gy fractions, in given by: 2012. All data were collected after approval from the Research
and Ethics Committee of the Uganda Cancer Institute.
 d   2   [Eqn 1] Inclusion criteria were patients with histologically confirmed
EQD2 = nd 1 +  / 1 + α / β 
 α / β    cervical cancer and had completed both the planned external
beam radiotherapy (EBRT) and intra-cavitary (ICT)
where n is the number of fractions, d is the daily dose, and
treatments. A total of 417 LACC patient’s files, FIGO stages
α / β is the therapeutic ratio.
IIB-IIIB were reviewed in 2020. The review was according to
the demographic and clinical data, treatment waiting time
Assuming an α / β of 10 for early radiation effects (acute
(calculated as the time between the patient’s registered date
toxicity) and tumour response,9,10 50 Gy/25 fraction (#) and
in department and the date of the first EBRT treatment),
45 Gy/15# have EQD2 values of 50.0 and 48.8, respectively.
treatment fractionations, toxicities, responses and 5-year
Assuming an α / β of 3, for the late radiation effects (late
survival probabilities. In addition to the information retrieved
toxicity) and organs at risk, 50 Gy/25# and 45 Gy/15#
from the files, the researchers also made phone calls to get
have EQD2 values of 50.0 and 54.0, respectively. For the late
current patient status/updated information from the patient
radiation effects, assuming an α / β of 3, 50.0 Gy/25# and
or next of kin. We developed and tested a REDCAP – for
45.0 Gy/15# have BED values of 70–84 and 72–90, respectively.
online project data collection tool.
Shuhasis et al.,11 reported on a comparative study that
evaluated the role of hypo-fractionated radiotherapy (HFRT) Chemo-radiation
(45.0 Gy/18#) with concurrent weekly Cisplatin versus Pre-treatment evaluation and staging included detailed
conventional radiotherapy (50.0 Gy/25#) with concurrent history, thorough clinical examination including bimanual
weekly Cisplatin in advanced cervical cancer. No significant pelvic examination, chest radiograph, trans-abdominal/pelvic
difference in response with respect to local regional control ultrasound, digital rectal examination, complete blood count,
and toxicity in both arms was seen. Other than the lower hypo- liver and renal functional tests. A similar protocol was
fractionated dose, the sample size used in this study was very followed during external beam simulation, target delineation,
low. Because of the limited treatment facilities and the 2D treatment planning, and treatment with patient in supine
proximity of the corresponding EQD2 values for tumour position.13 Radiation field borders were: (1) superiorly: L4-L5
response/organs at risk and early/late effects, the department inter-disc space; (2) inferiorly: below the obturator foramina or
used HFRT of 45.0 Gy/15# as an alternative to the conventional 3 cm below the inferior extent of the vaginal disease; and (3)
fractionated radiotherapy (CFRT) of 50 Gy/25# from 2011 to laterally: 1 cm – 2 cm lateral to the true pelvis. About 30 min,
2015. The purpose of this study is to compare the clinical before conventional simulation and daily treatments, patients
outcomes in patients with locally advanced cervical cancer were advised to drink 500 mL of water, to minimise bladder
(stages IIB-IIIB) treated with two regimens of CFRT of 50.0 toxicity. The EBRT was delivered by parallel opposed anterior-
Gy/25# in 5 weeks and HFRT of 45.0 Gy/15# in 3 weeks. The posterior and posterior-anterior portals using a Cobalt-60
primary end-points were local control and overall survival. beam. The planned regimen included whole pelvis EBRT,
administered as 50 Gy/25# for the CFRT and 45 Gy/15# for
The referral system is that clinical officers and midwives in the HFRT regimen. All patients referred from January 2011 to
health centres II/III are trained to recognise the clinical features June 2012 were treated with the CFRT regimen and those
of cervical cancer and then refer the patient to health centre IV, referred from July 2012 onwards were treated with HFRT
where a pap smear/biopsy can be performed. Cancer staging regimen. Patients with anterior-posterior separation of more
and treatments are carried out at regional and national referral than 22.0 cm were treated with the CFRT regimen. Weekly
hospitals. At the Uganda Cancer Institute, cervical cancer is Cisplatin of 40 mg/m2 was administered to patients deemed
managed in the setting of a multidisciplinary team including fit for concurrent chemo-radiation,5,6,13 irrespective of their
radiologists, gynaecological-oncologists, medical oncologists, sero-status. Weekly CBC (Haemoglobin ≥ 10.0 g/dL), Urea
radiation-oncologists, medical physicists, radiation-therapists, and creatinine levels were checked prior to chemo
oncology nurses, palliative care specialists, etc. involved in administration. The cut-off CD4 level was 200 cells/mm3 for
management of cervical cancer. The treatment protocol the human immunodeficiency virus (HIV) seropositives. The
followed the national guidelines for the management and EBRT was followed with a single insertion of low-dose-rate
treatment of cervical cancer.12 The cancer treatment is Cs-137 ICT delivering 30 Gy to point A. Patients were offered
subsidised by the Government of Uganda, and at the time of the departmental follow-up protocol; first review at six weeks,
the treatment. the patients were contributing about $50.00 for then every three months for the first six months, six months
the entire course of chemo-radiation treatment. up to one year and 12 months thereafter up to 60 months.

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 Page 3 of 9 Original Research

Assessment of treatment outcomes were computed using the Kaplan–Meier method. A

p-value < 0.05 was considered statistically significant.
The analysis was according to age at diagnosis, histology,
Other statistical parameters included: p-values and
degree of differentiation, Eastern Cooperative Oncology
inter-quartile range (IQR).
Group (ECOG) status, HIV serology, radiation dose, ±
Cisplatin, ICT, tumour response at ICT, treatment
duration, response and complications during EBRT/follow- Ethical considerations
up, retreatments in the 5-year period and survival probabilities. This study is a retrospective review. The project was approved
The retreatments were palliative doses, for example, by the Uganda Cancer Institute Research and Ethics
10.0 Gy/1#, 20.0 Gy/5# or 20 Gy single dose of Cs-137 insertion Committee (UCIREC reference 05-2020).
to point A. The study also evaluated the delays in the clinical
workflow of the radiotherapy process, starting from when the The use of patients’ data was approved by the Uganda
patient is registered, doctor-clerking, planning/simulation to Cancer Institute Research and Ethics Committee. All methods
the first fraction of treatment delivery. The response to EBRT were performed in accordance with the relevant guidelines
was assessed basing on the clinical information documented and regulations.
in the patient’s files while on treatment, at the time of ICT, and
subsequent follow-up visits. At the time of ICT, the attending
doctor documented whether there was no residual (clinically
Results
visible) tumour, if there was a presence of tumour – its size Figure 1 shows study’s inclusion and exclusion diagram.
and presence of discharge or bleeding. This information was
used to score response basing on the RECIST criteria14 as: SD = Histological results were squamous cell carcinoma (SCC)
stable disease, PR = partial response, CR = complete response, poorly, moderately, well differentiated, adenocarcinoma and
DP = disease progression at ICT. The scoring was: CR for no others, contributing 38.2%, 26.3%, 19.8%, 2.6%, 13.1%,
tumour seen, PR for tumour < 1.5 cm diameter, SD for tumour respectively. The age ranged from 24 to 80, with a median of
> 1.5 cm, and DP for necrotic/bleeding tumour filling the 49.5, and peak age-group of 40–49 years. Stages IIB, IIIA and
cervix. The information given by the patient on subsequent IIIB were 36.2%, 8.2% and 55.6%, respectively. The HIV
visits, for example, no complaint, pain, discharge, bleeding serology was positive, negative and unknown in 70 (16.9%),
and visual speculum examination were used to score the 116 (28.0%) and 228 (55.1%), patients respectively. Of those
patient’s case as SD, PR, CR and DP on follow-up. The overall whose serology statuses were known, 62.4% were negative
response rate (ORR) was defined as the proportion of patients and 37.6% were positive. Patients ECOG status were
who had PR or CR to the treatment. categorised as 0, 1 and 2, contributing 1.2%, 85.0% and 13.8%,
respectively. The median waiting time to start EBRT was
The treatment-related side effects were evaluated using 11.0 (IQR: 4.0–21.0 days). Concurrent chemotherapy was
Radiation Therapy Oncology Group (RTOG) criteria,15 based administered in 182 (44.0%) patients and only 93 (51.2%) of
on skin reactions, gastrointestinal and genitourinary these completed the prescribed number of cycles. Logistical
complications as documented in the patient’s file. The reasons (83.8%) were the main cause for not completing the
toxicities were graded as: prescribed chemotherapy followed by clinical factors (17.8%).
Table 1 shows the demographic, clinical and pathological
• Grade 0: no complications or symptoms characteristics of all patients included in the review. The
• Grade 1: (mild toxicity), for example, increased urinary/
bowel frequency, anorexia, nausea, vomiting, mild
abdominal and rectal pains, dry desquamation A total of 978 cervical cancer paents, were referred for
radiotherapy from January 2011 to December 2012.
• Grade 2: (moderate toxicity) moderate diarrhoea, moderate
abdominal and rectal pains, intermittent bleeding 564 (57.7%) paents were excluded from the analysis because of:
• Grade 3: Skin ulceration, bloody stool and GI bleeding, ° 167 (17.1%) paents had early disease (IA–IIA), including those who had
fibrosis, obstruction hysterectomy – all these were treated convenonally with 50 Gy/25#.
• Grades 4: (severe toxicity), for example, severe abdominal ° 252 (25.8%) paents had FIGO stage IVA–IVB and/or poor ECOG status -
these were treated palliavely with 10 GY/single fracon or 20 Gy/5#
pains, wet desquamation, necrosis and fistula. or 30 Gy/10#.
° 57 (5.8%) paents absconded before starng/ compleng EBRT – these
were not analysed any further.
Statistical analysis ° 88 (9.0%) paents completed EBRT (47 had HFRT and 41 had CFRT),
but did not receive ICT – these were also excluded from final analysis.
The sample size was determined using the Leslie Kish
formula, which is appropriate for comparison between A total of 414 (42.3%) paent’s files with LACC were analysed
two groups when endpoint is qualitative and the minimum
for each group was 135 patients’ cases. However, this
study being retrospective, we preferred the inclusion of all 221 (53.4) treated 193 (46.6%) treated
patients in the study period. All statistical analyses were with CFRT with HFRT
performed using a statistical software package (STATA
CFRT, conventional radiotherapy; HFRT, hypo-fractionated radiotherapy; ICT, intra-cavitary;
version 12). Quantitative data were presented by numbers, LACC, locally advanced cervical cancer; EBRT, external beam radiotherapy.
percentages and median as appropriate. Survival rates FIGURE 1: Inclusion ad exclusion criterion of the patients.

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 Page 4 of 9 Original Research

TABLE 1: Clinical and pathological characteristics of all included patients in the review.
Columns by: Dose (Gy) HFRT CFRT Overall
n % Median IQR n % Median IQR n % Median IQR
Number 193 46.6 - - 221 53.4 - - 414 100.0 - -
Age in years - - 49.0 41.5–56.0 - - 49.0 40.0–56.5 - - 49.0 40.0–56.0
Group in years, n (%)
< 50 years 98 50.8 - - 111 50.2 - - 209 50.5 - -
≥ 50 years 95 49.2 - - 110 49.8 - - 205 49.5 - -
Histology
Squamous cell carcinoma (SCC)
 Well-differentiated 29 15.0 - - 53 24.0 - - 82 19.8 - -
 Moderately differentiated 58 30.1 - - 51 23.1 - - 109 26.3 - -
 Poorly differentiated 78 40.4 - - 80 36.2 - - 158 38.2 - -
 Undifferentiated 16 8.3 - - 27 12.2 - - 43 10.4 - -
Adeno-squamous cell carcinoma 0 0.0 - - 5 2.3 - - 5 1.2 - -
Adenocarcinoma 6 3.1 - - 0 0.0 - - 6 1.4 - -
Others (papillary SCC, clear cell SCC, 6 3.1 - - 5 2.3 - - 11 2.7 - -
CIS-SCC, anaplastic carcinoma)
Stage at presentation
Stage IIB 71 36.8 - - 88 39.8 - - 159 38.4 - -
Stage IIIA 14 7.3 - - 23 10.4 - - 37 8.9 - -
Stage IIIB 108 56.0 - - 110 49.8 - - 218 52.7 - -
Serology status
Negative 53 27.5 - - 63 28.5 - - 116 28.0 - -
Positive 30 15.5 - - 40 18.1 - - 70 16.9 - -
Unknown 110 57.0 - - 118 53.4 - - 228 55.1 - -
ECOG status
ECOG 0 1 0.5 - - 4 1.8 - - 5 1.2 - -
ECOG 1 159 81.5 - - 195 88.2 - - 352 85.0 - -
ECOG 2 28 18.0 - - 22 10.0 - - 57 13.8 - -
Treatment
Median waiting time (days) - - 7.0 3.0–15.0 - - 13.0 6.0–28.0 - - 11.0 4.0–21.0
EBRT median duration (days) - - 21.0 20.0–23.0 - - 39.0 36.0–44.0 - - 32.0 21.8–39.3
EBRT+ICT median duration (days - - 55.0 40.0–81.0 - - 65.0 52.0–84.0 - - 62.0 48.0–84.0
Concurrent chemotherapy
Yes 89 46.1 - - 93 42.1 - - 182 44.0 - -
No 104 53.9 - - 128 57.9 - - 232 56.0 - -
Patient re-treatment
No 178 92.2 - - 198 89.6 - - 376 90.8 - -
Yes 15 7.8 - - 23 10.4 - - 38 9.2 - -
IQR, interquartile range; HFRT, hypo-fractionated radiotherapy; CFRT, conventional fractionated radiotherapy; CIS, Carcinoma in situ; ICT, intra-cavitary; ECOG, eastern cooperative oncology group;
EBRT, external beam radiotherapy; GY, Gray.

number of patients with anterior–posterior separation 46.6% for HFRT (p = 0.293). The study also evaluated the
≥ 22.0 cm were 15 (3.6%) – they were all treated with the CFRT survival probability patterns for patients with known HIV
regimen. The median treatment duration was 55.0 days (IQR: serology (HIV-positive vs. HIV-negative), stage IIB, IIIA, IIIB
40.0–81.0 days) for HFRT compared with 65.0 days (IQR: and patients less than 50 years versus those more than 50 years
52.0–84.0 days) for CFRT. At ICT, 9.1%, 36.0%, 48.6%, 0.8% of age. Figure 2a–d shows their corresponding Kaplan-Meier
had SD, PR, CR and DP for CFRT compared with 12.6%, survival probabilities. The results show that the 5-year
41.3%, 38.1%, 0.8% for HFRT (p = 0.193). Table 2 shows a survival probabilities for stage IIB, IIIA and IIIB patients were
summary of response and follow-up at different periods, 56.0%, 42.4% and 38.1%, respectively. The corresponding
chosen as per departmental follow-up protocol. At six months, p-values are: IIB versus IIIB = 0.002, IIB versus IIIA = 0.005
the ORR was 73.3% for CFRT compared with 67.6% for HFRT and IIIA versus IIIB = 0.415. The 5-year survival probabilities
(p = 0.085). Table 3 summarises the toxicities at different for HIV-positive and HIV-negative were 30.6% and 44.9%,
periods. At six months, the grades 0–1 toxicities were 94.5% respectively (p = 0.021). The 5-year survival probabilities for
and for 94.7% CFRT and HFRT, respectively (p = 0.080). Only patients < 50 years and those ≥ 50 years of age were 37.9% and
38.1% patients in the CFRT completed the total prescribed 51.8%, respectively (p = 0.008). Table 4 shows a comparison
dose (EBRT + ICT) within the intended treatment time of stage according to patient’s age at presentation.
7–8 weeks compared with 50.8% in the HFRT who completed
intended treatment time within 5–6 weeks. Re-treatments
during the 5-years of follow-up were 10.4% and 7.8% for Discussion
CFRT and HFRT, respectively (p = 0.354). At five years, the The retrospective analysis of CFRT versus HFRT regimens
survival probabilities were 44.9% for CFRT compared with shows that the 5-year overall survival (OS) for CFRT and

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 Page 5 of 9 Original Research

TABLE 2: Summary of response at intra-cavitary and follow-up at different TABLE 3: Summary of toxicities at different follow-up periods.
periods. Dose fractionation HFRT CFRT Total P
Columns by: Dose HFRT CFRT Total P n % n % n %
(Gy)
n % n % n %
Number 193 46.6 221 53.4 414 100.0
Number 193 46.6 221 53.4 414 100.0
Toxicity at the end of treatment
Status at Brachytherapy 0.174
1 – Mild toxicity 151 78.2 168 76.1 319 77.0
Complete response 88 45.6 120 54.3 208 50.2 -
2 – Moderate toxicity 40 20.7 49 22.1 89 21.5
Partial response 74 38.3 79 35.7 153 37.0 -
3 – Severe toxicity 2 1.1 4 1.8 6 1.5 0.355
No response 29 15.0 18 8.1 47 11.4 -
Toxicity grade at 3 months
Progressive disease 2 1.0 4 1.9 6 1.5 -
0 – No complaint 51 35.9 86 51.2 137 44.2
Status at 3 months 0.158
1 – Mild toxicity 89 62.7 78 46.4 167 53.9
Alive (sub-total) 143 74.1 175 79.2 318 76.8 -
Complete response 64 33.2 91 41.2 155 37.4 - 2 – Moderate toxicity 2 1.4 4 2.4 6 1.9 0.016
Partial response 62 32.1 58 26.2 120 29.0 - Toxicity grade at 6 months
No response 10 5.2 14 6.3 24 5.8 - 0 – No complaint 45 39.8 78 53.8 123 47.7
Progressive disease 7 3.6 12 5.4 19 4.6 - 1 – Mild toxicity 62 54.9 59 40.7 121 46.9
Lost to follow-up 38 19.7 37 16.7 75 18.1 - 2 – Moderate toxicity 5 4.4 8 5.5 13 5.0
Dead 12 6.2 9 4.1 21 5.1 - 3 – Severe toxicity 1 0.9 0 0.0 1 0.4 0.080
Status at 6 months 0.085 Toxicity grade at 12 months
Alive (sub-total) 114 80.3 144 86.2 258 83.5 - 0 – No complaint 40 46.0 52 57.1 92 51.7
Complete response 52 36.6 84 50.3 136 44.0 - 1 – Mild toxicity 41 47.1 33 36.3 74 41.6
Partial response 44 31.0 40 24.0 84 27.2 - 2 – Moderate toxicity 3 3.4 6 6.6 9 5.1
No response 5 3.5 7 4.2 12 3.9 - 3 – Severe toxicity 2 2.3 0 0.0 2 1.1
Progressive disease 13 9.2 13 7.8 26 8.4 - 4 – Potentially 1 1.1 0 0.0 1 0.6 0.175
Lost to follow-up 18 12.7 18 10.8 36 11.7 - life-threatening toxicity
Dead 10 7.0 5 3.0 15 4.9 - Toxicity grade at 24 months
Status at 12 months 0.075 0 – No complaint 35 53.0 34 51.5 69 52.3
Alive (sub-total) 87 76.3 91 63.6 178 69.3 - 1 – Mild toxicity 26 39.4 27 40.9 53 40.2
Complete response 44 38.6 55 38.5 99 38.5 - 2 – Moderate toxicity 2 3.0 5 7.6 7 5.3
Partial response 20 17.5 22 15.4 42 16.3 - 3 – Severe toxicity 3 4.5 0 0.0 3 2.3 0.229
No response 10 8.8 3 2.1 13 5.1 - Toxicity grade at 36 months
Progressive disease 13 11.4 11 7.7 24 9.3 - 0 – No complaint 31 66.0 26 59.1 57 62.6
Lost to follow-up 18 15.8 34 23.8 52 20.2 -
1 – Mild toxicity 13 27.7 16 36.4 29 31.9
Dead 9 7.9 18 12.6 27 10.5 -
2 – Moderate toxicity 3 6.4 2 4.5 5 5.5 0.653
Status at 24 months 0.409
Toxicity grade at 48 months
Alive (sub-total) 66 75.9 66 72.5 132 74.2 -
0 – No complaint 27 77.1 25 75.8 52 76.5
Complete response 37 42.5 36 39.6 73 41.0 -
1 – Mild toxicity 8 22.9 8 24.2 16 23.5 0.893
Partial response 15 17.2 18 19.8 33 18.5 -
Toxicity grade at 60 months
No response 5 5.7 7 7.7 12 6.7 -
0 – No complaint 25 78.1 24 82.8 49 80.3
Progressive disease 9 10.3 5 5.5 14 7.9 -
Lost to follow-up 11 12.7 18 19.8 29 16.3 - 1 – Mild toxicity 7 21.9 4 13.8 11 18.0
Dead 10 11.5 7 7.7 17 9.6 - 2 – Moderate toxicity 0 0.0 1 3.4 1 1.6 0.428
Status at 36 months 0.952 HFRT, hypo-fractionated radiotherapy; CFRT, conventional fractionated radiotherapy.
Alive (sub-total) 47 72.3 45 70.3 92 71.3 -
Complete response 32 49.2 30 46.9 62 48.1 - HFRT were 44.9% and 46.6%, respectively (differences are
Partial response 7 10.8 7 10.9 14 10.9 - statistically insignificant (p = 0.293). At 60 months of follow-
No response 3 4.6 4 6.3 7 5.4 -
up, the tumour control rates and survival probabilities were
Progressive disease 5 7.7 4 6.3 9 7.0 -
Lost to follow-up 10 15.4 13 20.3 23 17.8 -
comparable between CFRT and HFRT. There were significant
Dead 8 12.3 6 9.4 14 10.9 - statistical differences in toxicity at 3–6 months of follow-up.
Status at 48 months 0.879 but were limited to grades 0 (no complaint) – grade 1 (mild
Alive (sub-total) 35 74.5 32 74.4 67 74.4 - symptoms). The average 5-year survival probability of 45.8%
Complete response 28 59.6 26 60.5 54 60.0 - patients in this study is lower than 58.0% published by other
Partial response 3 6.4 4 9.3 7 7.8 -
studies,7,8 for locally advanced cervical cancer. A number of
No response 3 6.4 2 4.7 5 5.6 -
factors may contribute to this, for example, not completing the
Progressive disease 1 2.1 0 0.0 1 1.1 -
Lost to follow-up 9 19.1 7 16.3 16 17.8 - prescribed treatments (EBRT, ICT and chemotherapy) within
Dead 3 6.4 4 9.3 7 7.8 - the stipulated times, high prevalence of HIV within the
Status at 60 months 0.953 patients, inadequate treatment resources, etc. During
Alive (sub-total) 32 91.4 29 87.9 61 89.7 - treatment, the toxicities were mainly mild for both CFRT and
Complete response 27 77.1 25 75.8 52 76.5 -
HFRT, whilst during follow-up, the toxicities ranged from no
Partial response 3 8.6 3 9.1 6 8.8 -
complaint to mild. The grade 3 – 4 treatment-related toxicity
Progressive disease 2 5.7 1 3.0 3 4.4 -
Lost to follow-up 2 5.7 2 6.1 4 5.9 -
profiles for both groups in our study are much lower than
Dead 1 2.9 2 6.1 3 4.4 - other studies16,17 that reported values in range of 18.0% –
HFRT, hypo-fractionated radiotherapy; CFRT, conventional fractionated radiotherapy. 21.6%. Our study being retrospective, it is possible that severe

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 Page 6 of 9 Original Research

1 CFRT: n = 221 HFRT: n = 193 a 1 Negave: n = 116 Posive: n = 70 b

P-value = 0.293 P-value = 0.021

0.8 0.8

Survival probability
Survival probability

0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72

Time (months) Time (months)

Stage IIB: n = 159 Stage IIIA: n = 37 Stage IIIB: n = 218 c < 50 years: n = 209 ≥ 50 years: n = 205 d

1 P-values: IIB vs IIIB = 0.002 1 P-value = 0.008

IIB vs IIA = 0.005
IIIA vs IIIB = 0.415
0.8 0.8
Survival probability
Survival probability

0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72

Time (months) Time (months)

CFRT, conventional radiotherapy; HFRT, Hypo-fractionated radiotherapy; n, number of patients; p, statistical significance.
FIGURE 2: Kaplan–Meier survival probability comparison for (a) CFRT versus HFRT, (b) HIV negative versus positive, (c) FIGO stage IIB, IIIA, IIIB (d) age < 50 versus
≥ 50 years.

TABLE 4: Comparison of stage according to patients’ age at presentation. side-effects occur within the first 3 months and almost half of
Columns by: Stage Stage 2B Stage 3A Stage 3B Total P
at presentation
the patients developing late recto-sigmoid and bladder
N % n % n % complications did so within the first year after treatment, with
Number 159 38.4 37 8.9 218 52.7 414 - almost all complications developing within 3–4 years after
Age group in years       radiotherapy. This is in agreement with our results shown in
20–29 1 16.7 0 0.0 5 83.3 6 - Table 2, where the grade 3–4 toxicities were observed within
30–39 32 39.5 9 11.1 40 49.4 81 -
the first 24 months. A retrospective 30-year follow-up of 1456
40–49 47 38.5 9 7.4 66 54.1 122 -
patients (stages IB-IVA) treated with EBRT and ICT to doses in
50–59 50 39.7 11 8.7 65 51.6 126 -
the range of 70–90 Gy indicated that the incidence of significant
60–69 21 35.0 6 10.0 33 55.0 60 -
70–79 7 38.9 2 11.1 9 50.0 18 -
morbidity was closely correlated with doses higher than 80
80+ 1 100.0 0 0.0 0 0.0 1 0.940 Gy.20 The dose ranges of 75–80 Gy used in our study are
subsequently not expected to cause grave side effects.

toxicities could have been missed. McArdle et al.18 reported

The results show that SCC was the commonest histology, in
that toxicity profiles were lower in sub-Saharan African agreement with known literature. The mean age at diagnosis
countries. As shown in Table 3, for the first 3–6 months of of about 50 years agrees with other literature reviewed.8
follow-up, the proportions of patients with no complaint as The HIV sero-status was known in 46.6% patients in CFRT
expected were higher for CFRT compared with HFRT (p = compared with 43.0% in HFRT, and of these 18.1% and 15.5%
0.016). After 1 year of follow-up, the toxicity profiles became were positive, respectively. A large portion of patients had
comparable. The outcomes in our study may not adversely no HIV-serology results because at that time, screening was
change, based on a 10-year follow-up retrospective study of of voluntary testing compared with routine testing practiced
442 cervical cancer patients with stage IIB-IVA after currently. In this study, the seropositives are nearly 40%
radiotherapy.19 This study showed that early treatment-related compared with 7.1%, which was the HIV/AIDS prevalence

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 Page 7 of 9 Original Research

rate for women aged 15 years and above, around that time compared with the previous study, where it was 289 (±122
in Uganda.21 This could be attributed to both HIV and s.d.) cells/mm3.
cervical cancer being sexually transmitted, with patients
who are infected with HIV having a higher risk of having There was a significant survival difference between stage IIB
humanpapilloma virus (HPV) infection as well. and stages IIIA / IIIB (56.0% vs. 42.4% / 38.1% with p-values
of 0.005 / 0.002). The survival probabilities in this study for
Most of the patients were in ECOG 1–2, other higher ECOG stage IIB and IIIB are much lower compared with other
status were not observed in the review as those patients were published data8,27 that showed values of about 75% and 60%,
frail for radical treatments. Concurrent chemo-radiation was respectively. The treatment outcomes in this analysis could
administered in 44.0% patients and only 51.2% of these be compromised by the long treatment duration (EBRT +
completed the prescribed number of cycles. Logistical ICT), as it is well known that the overall treatment time
reasons (83.8%) were the main cause for not completing should be kept as short as possible (preferably less than
the prescribed chemotherapy followed by clinical factors 56 days) for conventional fractionation.4 This problem was
(17.8%). Most patients had stage IIIB disease (52.7%) with aggravated by having one low-dose-rate Cs-137 unit,
hydronephrosis, raised serum creatinine levels and end stage resulting in long waiting times for patients to receive
renal failure, where Cisplatin-based chemotherapy is brachytherapy.
contraindicated. McArdle et al.18 reported that more than
60% of the cervical cancer patients in sub-Saharan Africa The proportion of patients who completed the prescribed
were ineligible for chemotherapy at presentation, which is in radiation dose in the intended time was low in both
groups, but much worse in the CFRT group. Factors that
agreement with our results.
majorly contributed to this include: One low-dose-rate
(LDR) ICT unit that can treat maximum two patients per
As much as the results in Table 4 show that there is a
day, EBRT machine breakdown and patients’ socio-
noticeable presentation of young age group 20–29 with more
economic factors. Patient-related logistical issues such as
advanced stage IIIB disease, the overall comparison of
accommodation, transport, feeding, etc. affected some
patients’ age and stage at presentation is not statistically
patients not to complete their prescribed treatments on
significant (p = 0.940). Further analysis, however, showed
time. The addition of chemotherapy to a hypo-fractionated
that young (age < 50 years) patients had poor outcomes in
treatment may have caused negligible toxicity concern, as
terms of response and survival probabilities, compared with
the HFRT group treatment completion rate was higher
older patients (age ≥ 50 years) and the differences are
compared with the CFRT.
statistically significant (p = 0.008). This agrees with other
studies,22,23 which showed that young age was an
unfavourable prognostic factor, especially in more advanced Limitations of this study
stages. On the contrary, Gao et al.24 showed that cervical • Treatments were 2-fields (anterior-posterior [AP] and
cancer had the same prognosis in the elderly as well as the posterior-anterior [PA]) 2D treatment planning:
young women. ■ Conformal 4-field techniques are preferable especially
when utilising HFRT.
There was a significant survival difference between the HIV ■ Inability to escalate dose to ≥ 80.0 Gy from both EBRT
seronegative and HIV seropositive patients (44.9% vs. and ICT, which may be required for most of the LACC.
30.6%, p = 0.021). Gichangi et al.25 reported that HIV • Treatments were carried out on Cobalt-60 unit with relatively
infection was significantly associated with higher risk of low dose rate (≈0.6 Gy/min) – patient’s movements during
residual tumour post-EBRT. The serology results can be the long treatment times may affect response.
correlated with patients’ age, as the younger generations • Some patients inappropriately received chemotherapy
are more sexually active, hence more prone to HIV infection. during radiation therapy treatment (e.g. partially
Our results show that the median (IQR) age for HIV received, during weekends, after radiation course).
seropositive patients was 42.0 (9.0) compared with 49.5 • Often the brachytherapy insertions were not received
(13.0) for HIV seronegatives. The survival probability for within the stipulated time – the then available low-dose
seropositive patients has substantially improved compared rate Caesium-137 unit could treat at most two patients
with that seen about two decades ago at the centre. In this per day.
analysis, the 2-year survival probabilities for seropositive • A comprehensive toxicity profiles especially the adverse
was 61.4% in comparison with a previous study,26 where the treatment related side effects could have been unnoticed.
2-year survival probability for seropositive was 40.0%. The • This has been a retrospective cohort study, mainly
improvement can partially be attributed to the increased observational and descriptive. This allows limited
use of free antiretrovirals (ARVs), which are known to preliminary commentary on the equivalence or non-
enhance the patient’s general well-being. The immune- inferiority of HFRT versus CFRT for the treatment of LACC.
status of seropositive patients in this study was much
higher, with average cluster of differentiation 4 (CD4) Our department is to start a prospective randomised trial to
counts of 444 (±246 standard deviation [s.d.]) cells/mm3 evaluate a HFRT 45.0 Gy/15# schedule of radiotherapy

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 Page 8 of 9 Original Research

delivered in 3 weeks versus the CFRT 50.0 Gy/25# regimen Authors’ contributions
delivered in 5 weeks for the treatment of LACC. All patients
This research was realised by A.K. and I.L. who were mainly
will be treated with IMRT photon energies 6 mega-voltage
involved in research initiation, data collection, analysis and
(MV) or 10 MV, with weekly chemotherapy (Cisplatin 40 mg/m2
write-up. C.B. was involved in data collection and analysis.
weekly) followed by brachytherapy (HDR 8.0 Gy × 3#) to point
S.K. was involved in data analysis and the final write-up.
A, once a week for three fractions starting in the last week of
pelvic EBRT. The objective will be to compare the short-term
clinical outcomes in patients with LACC treated with the Funding information
two regimens. There are currently two National Institutes of This work was supported by the Varian Medical Systems
Health prospective phase II, randomised clinical trials, Inc., Palo Alto, California, United States.
comparing concomitant chemotherapy CFRT with HFRT,
followed by brachytherapy, enrolling cervical cancer
patients.28,29 The first28 compares 50 Gy/25# with 37.5 Gy/15#, Data availability
plus brachytherapy 28 Gy to point A with weekly Cisplatin. Raw and derived data supporting the findings of this study
The second29 compares 45.0 Gy/25# with 40.0 Gy/15#, plus were generated at the Department of Radiotherapy, Uganda
brachytherapy with weekly Cisplatin. Cancer Institute. The data that support the findings of this study
are available on request from the corresponding author, A.K.
The shorter regimen of 45.0 Gy/15# can be beneficial in
several ways to both the patients and the institutions
Disclaimer
providing the healthcare , for example: (1) The overall The views and opinions in this article are those of the authors
machine time is shorter with HFRT, therefore resulting into and do not reflect the official position or policy of any
reduced time patients take whilst waiting to start EBRT. affiliated agencies of the authors, and the Publisher.
(2) HFRT can result in better patient compliance, because of
shorter hospital stays. (3) For the hospitals, more patients References
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