COCHRANE reviews-Radical Chemo irradiation Cervix
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COCHRANE reviews-Radical Chemo irradiation Cervix

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    COCHRANE reviews-Radical Chemo irradiation Cervix COCHRANE reviews-Radical Chemo irradiation Cervix Presentation Transcript

    • 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    •  Meta analysis of 19 randomized controlled trials (RCT) done between 1981 to 2000 (17 published and 2 unpublished)  Methodology :  Trials using concurrent chemotherapy with radiation therapy (with or without surgery) were compared with radiation therapy alone (with or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.
    • THANK YOU !!!