A Prospective Randomized Trial of Neoadjuvant Chemotherapy and Surgery Versus Concurrent Chemoradiation Therapy in Patients With Stage IB2-IIB Squamous Carcinoma of the Uterine Cervix
Cancer of the uterine cervix is a major health problem in the developing countries including
India and is the commonest cancer amongst women in India with nearly 1,00000 new women
diagnosed to have this cancer every year. It is also the main cause of cancer related
mortality among women in India. At the Tata Memorial Hospital, approximately 1600 new
patients with cervical cancer are registered every year, of which nearly 70% present in
locally advanced stages.
A majority of patients diagnosed with stage IB cervical cancer in India have bulky tumours
(more than 4 cm in size) and have now been classified as stage IB2 as per the new FIGO
staging (1). These tumours are associated with a high incidence of pelvic lymph node
metastases. Finan et al (2) noted positive pelvic nodes in 15.5% of patients with stage Ib1
disease versus 43.8% with stage Ib2. Positive paraaortic nodes were present in 1.8% of
patients for stage Ib1 disease versus 6.3% of patients with stage Ib2. The result of radical
surgery and radical radiation therapy alone or in combination in these tumours has been
reported to be much inferior to stage IB1 tumours (60-65% vs. 85-90% five year survival).
The incidence of pelvic lymph node metastasis and the results of treatment of stage IB2
tumours are more or less similar to those with stage IIB tumours.
The ability of radiotherapy or surgery to cure locally advanced cervical cancer is limited
by the size of the tumour, high incidence of pelvic lymph node metastases and potential for
systemic spread. Besides, the doses required to treat large tumours exceed the limit of
toxicity in normal tissue. Efforts to overcome this problem have included the use of
different chemotherapy drugs in different schedules. Chemotherapy has been used in the
management of locally advanced cervical cancers along with radiation therapy and surgery in
different ways e.g. neoadjuvant, adjuvant and concurrent.
The standard approach to using chemotherapy in the treatment of patients with locally
advanced disease is the use of concurrent chemoradiation. The concurrent use of single drug
and multiple drug regimens with radiotherapy has been tested in women with cervical cancer.
Recent data from prospective randomised trials and two meta-analyses (3-12) has
unequivocally shown significant survival advantage (both disease free and overall survival)
with the use of concurrent chemoradiation using platinum based chemotherapy compared to
radical radiation alone in patients with locally advanced cervical cancer (stages IB2-IIIB).
A significant reduction in distant metastases was also noted in the concurrent
chemoradiation therapy arm. This has led to acceptance of concurrent chemoradiation therapy
as the new standard of care for locally advanced cervical cancer. The meta-analyses of these
trials showed that the beneficial effect on survival was more evident in stage IB2 and stage
II B tumours compared to stage III B tumours (which constituted only about 35% of total
number of patients).
An alternative approach is to use chemotherapy prior to local therapy, which could be
surgery or radiation. Some theoretical benefits of neoadjuvant chemotherapy (hereinafter
abbreviated as NACT) like eradication of micrometastases have long been advanced but never
proven. It certainly helps in the reduction of tumour bulk in some patients with locally
advanced disease. Some of these latter patients are then able to undergo surgery which is
otherwise not possible. The downside to NACT is the delay in institution of definitive
treatment in the 20 to 30% patients who don't respond to chemotherapy. The randomized
trials of NACT followed by radiation therapy versus radiation therapy alone showed no
improvement in survival (13-19). It is possible that the failure to show a survival benefit
with NACT followed by radiation is due to the selection of chemoresistant clones which are
also radioresistant. A second explanation (also advanced for the failure of NACT approach in
head and neck cancers) is that NACT just selects out the patients (the ones who respond) who
have biologically favourable disease and confers no benefit by itself. Surgical removal of
the tumour after chemotherapy will however have no interaction with biochemical resistance
of the remaining clones. It therefore has the potential of providing a benefit additive to
chemotherapy and radiotherapy. In their papers Sardi et al (20, 21) reported on their
randomized trial of NACT (bleomycin, vincristine and cisplatin) followed by surgery plus
radiation versus either surgery plus radiation or radiation as the control arm in patients
with stage 1B, 2B and 3B cervical cancer. There was a high response rate to NACT in stage 1B
patients (90% in 1B1 and 83.6% in 1B2). The overall survival in the whole group of stage 1B
patients was superior in the NACT arm (n=102) compared to the control arm (n=103) (81% Vs
66%, p = 0.025). The resectability rate among stage 1B2 patients given NACT was 100% (n =
61) compared to 85% in the controls (n = 56). In stage 2B the resectability rate in the NACT
arm was 80% (n = 76) compared to 56% in the control arm (n = 75). However there was no clear
survival advantage of the NACT arm over controls in stages 2B and 3B. Although this trial
has reported a survival advantage of NACT followed by surgery in a subgroup of patients its
results are not definitive. The treatment offered in the control arm of this trial (attempt
at surgical removal upfront in stages 1B and 2B or radiation only in stages 2B and 3B) was
not standard by current standard and the numbers in various groups were small. In order to
be considered a therapeutic option in locally advanced patients, NACT followed by surgery
must be compared to the current therapeutic standard, which is concurrent chemoradiation.
The chemotherapeutic options for cervical cancer at present are different from the one used
by Sardi et al. The combination of ifosfamide and cisplatin or paclitaxel and carboplatin is
likely to show a higher response rate compared to the regimen used by Sardi et al, which was
bleomycin, vincristine and cisplatin.
Considering these results from the literature, it appears logical to compare neoadjuvant
chemotherapy followed by surgery with concurrent chemoradiation in patients with stage IB2
to IIB squamous carcinoma of the cervix.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Disease Free Survival
Sudeep Gupta, MD, DM
Tata Memorial Hospital, Mumbai-400012,India
India: Department of Atomic Energy
119 of 2003