cochrane reviews-radical chemo irradiation cervix

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Meta analysis of 19 randomized controlled trials (RCT) done between 1981 to 2000 (17 published and 2 unpublished)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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