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Mayur Mayank
07.06.2013
INTRODUCTION
COCHRANE REVIEW 2001
COCHRANE REVIEW 2005
COCHRANE REVIEW 2010
CONCLUSION
INTRODUCTION
Carcinoma cervix
2nd most common malignancy diagnosed in
females throughout the world
Most common malignancy found in females
in the developing nations
Staging : As per FIGO clinical staging
Treatment : Radical chemo irradiation
for FIGO Stages I B2 to IV A
For early stage disease (I B/ IIA) the efficacy
of surgery and radical chemo irradiation is
equivalent.
The choice of treatment depends on patient
characteristics.
For stages II B to IV A, optimal treatment
consists of radical chemo irradiation.
Ref : Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical
cancer; Fabio Landoni, Andrea Maneo, Alessandro Colombo, Franco Placa, Rodolfo
Milani, Patrizia Perego, Giorgio Favini, Luigi Ferri, Costantino Mangioni; THE LANCET ;
Vol 350 • August 23, 1997
In the year 1999, the National Cancer
Institute (NCI), USA, based on results of
5 randomized controlled trials, issued an
alert to use concurrent chemotherapy
with radiation therapy in the treatment of
carcinoma cervix.
Ref : Concurrent Chemotherapy and Radiation for Locally Advanced
Cervical Cancer: The New Standard of Care Gillian M. Thomas Seminars in
Radiation Oncology, Vo110, No 1 (January), 2000." pp 44-50
TABLE SHOWING THE FIVE KEY
PHASE III TRIALS AND THEIR
RESULTS
6
The Cochrane Collaboration has till now
conduced 3 meta analyses to validate
the role of concurrent chemo irradiation
in the management of carcinoma cervix
2001
2005
2010
COCHRANE REVIEW 2001
Meta analysis of 19 randomized controlled trials (RCT) done between 1981 to 2000 (17 published and 2 unpublished)
Methodology :
Trials using concurrent chemotherapy with radiation therapy (with or without surgery) were compared with radiation therapy alone (with or without surgery) *, with or without adjuvant chemotherapy in the experimental arm
Chemotherapy used was Cisplatin, Carboplatin or non platinum drugs like 5 fluorouracil, Mitomycin C, Bleomycin, Vincristine and epirubicin
Trials using radio sensitizers or radio protectors were excluded from the review. Use of hyperthermia was also excluded from the review.
* For the purposes of this review, hydroxyurea was considered an inactive
agent and was allowable with local treatment.
Primary Outcomes :
Overall survival (OS)
Progression free Survival (PFS)
Secondary outcomes :
Local and distant recurrence
Acute and late toxicity
RESULTS
Overall Survival
Platinum : improved (HR 0.71; p <0.0001)
Non platinum : improved (HR 0.81; p 0.20)
The benefit was seen more in stage I and II
patients
Absolute benefit in OS – 12%
Progression Free Survival Improved (HR 0.61; p < 0.0001)
Absolute benefit in PFS – 16%
Local recurrence : decreased (OR 0.61; p < 0.0001)
Distant recurrence : decreased (OR 0.57; p < 0.0001)
Increase in Grade 3/4 hematological and gastrointestinal toxicity in the concurrent chemo irradiation group.
Insufficient data to comment on increase in late toxicity in the concurrent group.
COCHRANE REVIEW 2005
Updated the results of the prior review.
Included total of 24 trials (21 published
and 3 unpublished) from 1981 to 2004.
Inclusion and exclusion criteria were
same as the review in 2001.
Primary and secondary outcomes
assessed were same as the previous
review.
RESULTS
Overall Survival
Platinum : improved (HR 0.68; p <0.00001)
Non platinum : improved (HR 0.72; p 0.008)
The benefit was seen more in stage I and II
patients
Absolute benefit in OS – 10%
Progression Free Survival Improved (HR 0.66; p < 0.0001)
Absolute benefit in PFS – 13%
Local recurrence : decreased (OR 0.59; p < < 0.00001)
Distant recurrence : decreased (OR 0.81; p 0.06)
Increase in Grade 3/4 hematological and gastrointestinal toxicity in the concurrent chemo irradiation group.
Insufficient data to comment on increase in late toxicity in the concurrent group.
Both the reviews in 2001 and 2005
showed improvements in OS, PFS and
recurrence rates with chemo irradiation.
Interpretation of benefits was difficult
due to :
Use of different treatments in the control arm
of the studies
Heterogeneity in trial results
Inconsistency in definition of outcomes
between trials
COCHRANE REVIEW 2010
Individual patient data (IPD) meta
analysis was done to obtain
Time to event analysis of local and distant
recurrence
Reliable estimates of effects in patient
subgroups
Better attribution of relative toxicities
18 trials were identified and 15 were included for the main analysis. Out of these 2 trials used adjuvant chemotherapy after chemo irradiation in the experimental arm.
Methodology :
Trials using concurrent chemotherapy with radiation therapy (with or without surgery) were compared with radiation therapy alone (with or without surgery) , with or without adjuvant chemotherapy in the experimental arm
Chemotherapy used was Cisplatin, Carboplatin or non platinum drugs like 5 fluorouracil, Mitomycin C, Bleomycin, Vincristine and epirubicin
Trials using radio sensitizers or radio protectors were excluded from the review. Use of hyperthermia was also excluded from the review.
Individual patient data (IPD) were
obtained from all the RCTs and the data
was analyzed with individual patient
characteristics.
The patient characteristics were put into
different sub groups and the analysis
was done based on the different sub
groups of the patient characteristics.
In view of the importance of 2 trials using hydroxyurea in the control arm (Rose et al and Whitney et al) and 1 trial using extended field radiation therapy (Morris et al) in the control arm, to the NCI alert, these trials were analyzed alongside the main comparison to establish how sensitive the effect of chemo irradiation was to different trial designs.
OUTCOMES MEASURED
Primary Outcome :
Overall survival (OS) - time from
randomisation until death by any cause
Other Outcomes :
Loco regional disease free survival (DFS) –
time from randomisation until loco regional
recurrence or progression or death by any
cause.
Metastases-free survival - time from
randomisation until first metastasis or death by
any cause
Overall DFS - time from randomisation until loco
regional recurrence, metastasis or death by any
cause
Time to metastases - time from randomisation
until first metastases
Acute and late toxicity data
PATIENT CHARECTERISTICS
RESULTS
Overall survival (OS)
Data obtained from 13 trials not using
adjuvant chemotherapy in the experimental
arm
HR 0.81; p < 0.001
19% relative reduction in the risk of death with
chemo irradiation compared with radiotherapy
Absolute survival benefit of 6% at five years
(from 60% to 66%)
Data obtained from 2 trials which used adjuvant
chemotherapy after chemo irradiation, in the
experimental arm
HR 0.46; p < 0.001
54% relative reduction in the risk of death with
chemo irradiation compared with radiotherapy
Absolute survival benefit of 19% at five years
(from 60% to 79%)
RESULTS OF ALL OUTCOMES
Stage wise analysis
5 year survival benefit
Stage I b – II a : 10%
Stage II b : 7%
Stage 3 – IV a : 3%
No significant trend for
analysis of DFS by stage
SUB GROUP ANALYSIS FOR
SURVIVAL
Acute and late toxicity
Increase in Grade 3/4 hematological and
gastrointestinal toxicity in the concurrent
chemo irradiation arm
Data was insufficient to comment on the late
toxicity
Sensitivity Analysis
3 trials which were amongst the 5 trials based on which the NCI gave the alert regarding concurrent chemo irradiation in management of carcinoma cervix
Had a different study design
Sensitivity analysis done to check the efficacy of chemo irradiation on different study designs
RESULTS
Trials using hydroxyurea in control arm
HR 0.63; p < 0.001
Absolute survival benefit of 15% (from 45% to
60%) at 5 years
Trial using extended field radiotherapy in
control arm
HR 0.50; p < 0.001
Absolute survival benefit of 21% (from 50% to
71%) at 5 years
However, there trials had a different study design.
Survival in the control arm was also less compared to the main group which was analyzed.
Hence, the best estimate of the effect of chemo irradiation over radiotherapy remains that from the unconfounded analysis of 6% at 5 years.
CONCLUSION
Concurrent chemotherapy when
administered with radiation therapy in
the management of carcinoma cervix,
has an OS and DFS advantage.
The time to develop metastasis and the
loco regional recurrence is also delayed
with the use of concurrent
chemotherapy.
The advantage is seen with both
platinum and non platinum drugs.
The role of adjuvant chemotherapy after
radical chemo irradiation is still
controversial as there have been only 2
RCTs which have used this protocol and
the number of patients is not sufficient.
The survival advantage of 3% in stage III/IV A patients is also controversial as the number of patients in that sub group were not sufficient.
There is a mild increase in acute toxicity with the concurrent regimen.
The data for the late toxicity is not sufficient in any of the trials for a proper analysis.
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