Chemo-radiation in Carcinoma Cervix

By – Dr. Satyajeet RathModerator – Prof. Kamal Sahni

Date- 09/12/16

Rationale of Concurrent CT-RT

• Both Cisplatin and 5-FU are potent radiosensitizers.• Concurrent use with RT seems to be synergistic.• Failure rates with RT alone

• II B - 25-50%• III – 50-75%

• Concept useful in other sites - H&N, lung, esophagus, bladder, anus• Radiobiologically, CT-RT

• Inhibits the repair of SLDs from radiation• Sensitizing cells to radiation• Synchronizes cells to a particular radiosensitive phase of the cycle (G2 phase)• Direct cytotoxicity

• Britten et al. * – CT+RT increase rates of deaths of tumour cells.

* Britten RA, Evans AJ, Allalunis-Turner MJ, Pearcey RG. Effect of cis- platin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines. Int J Radiat Oncol Biol Phys 1996;34:367-74

Indications

• As a definitive treatment in stage IB2 to IVA carcinoma cervix• As a adjuvant treatment in post-radical hysterectomy in early stage

cases with high risk pathological features (positive lymph nodes, positive parametria, positive margins).

RoadmapConcurrent chemo-radiotherapy in 1980s

Rose et al., Keys et al., Peters et al., Whitney et al., Morris et al. - 1999

NCI Clinical announcement- 1999

Pearcey et al. – NCI Canada

Green Meta-analysis, Lancet 2001

Lukka Meta-analysis, Clinical Oncol 2002

Green Meta-analysis update, Cochrane database systemic review-2005

Cochrane database systemic review update - 2010

Concurrent chemotherapy in 1980s

Studies Stages Arms Results

Hreschyshyn et al (1979)1

GOG 04IIIB-IVA RT alone vs RT + HU Superiority in DFS and OS rates in

RT+ HU arm.Significant toxicity (47%) in HU arm.

Leibel S et al (1987)2

RTOG groupIIIB-IVA RT alone vs RT+ Misonidazole Median survival in control arm 1.9

yrs. vs 1.6 yrs. for Misonidazole arm.

Stehman et al (1988)3

GOG 56 groupIIB-IVA RT + HU vs RT+ Misonidazole No difference in terms of PFS or

OS in two arms.Although a trend favouring the HU arm.

1. Hreschyshyn et al, Hydroxyurea or placebo combined with radiation to treat stages IIIB/IVA cervical cancer confined to pelvis. Int J Radiat Oncol Biol Physc, 1979;5:317.2. Leibel et al. Radiotherapy with or without Misonidazole for patients with stage IIIB or IVA squamous cell carcinoma of uterine cervix. Prelimnary report of a Radiation Therapy Oncolgy

group randomised trial. Int J Radiat Oncol Biol Physc, 1987;13:541.3. Stehman et al: randomised trial of hydroxyurea versus Misonidazole adjunct to radiation therapy in carcinoma cervix. A prelimnary report of a gynaecological oncology group study, Am J

Obstet Gynecol, 1988;159:87

• A series of five randomized trials in a variety of disease stages matured around then:

• Collectively, 1894 women were analysed and compared cisplatin based chemoRT to RT alone (RTOG 9001, GOG 123, SWOG 87-97) and hydroxyurea (GOG 85 and 120). All showed a significant reduction in the risk of recurrence and death with cisplatin-based chemoRT.

GOG 85 [1] Whitney et al, JCO 1999

RTOG – 9001 [2] Morris M et al, NEJM 1999

GOG 120 [3] Rose PG et al, NEJM 1999

SWOG 8797/GOG 109 [4] Peters WA et al, Gynecol Oncol 1999

GOG 123 [5] Keys HM et al, NEJM 1999

1. Whitney CW, Sause W, Bundy BN, et al: Randomised comparison of fluorouracil plus cispla- tin versus hydroxyurea in stage IIB/IVA in carcinoma of the cervix. J Clin Oncol 17:1339-1348, 1999

2. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with plevic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999

3. Rose PG, Bundy BN, Watkins EB, et al: Con- current cisplatin-based radiotherapy and chemother- apy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999 4. Peters WA, Liu PY, Barrett RGW, et al: Cis- platin, 5-Fluorouracil plus radiation therapy are supe- rior to radiation therapy as adjunctive therapy in high risk, early stage carcinoma of the

cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a Phase III inter group study. Presented at Soc Gynecol Oncol 30th Annual Meeting, San Fransisco, CA, February 5-9, 1999

5. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation and adjuvant hysterectomy com- pared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999

• Ca Cervix Stage IIB,III and IVA with negative para-aortic nodes • 177 patients received cisplatin (50 mg/m2 IV) on days 1, 29, 5-FU (IV infusion, 1 g/m2 for 4 days) day2-

day5 and 30 to 33• 191 patients received hydroxyurea (80 mg/kg orally twice weekly). • Primary end points – PFS, OS• Median Follow up – 8.7 yrs

Journal of Clinical Oncology, Vol 17, No 5 (May), 1999: pp 1339-1348

GOG 85, Whitney et al. (1999)

P = .033

With a median follow-up for survivors of 8.7 years, the 5-year survival rate in the cisplatin/5-FU arm was 60%, compared with 47% for women in the hydroxyurea arm.

CF HU P valuePercentage Progression 43% 53% 0.033

Percentage death 45% 57% 0.018

P = .018

Adverse effects• predominately hematologic or gastrointestinal in both treatment groups. • Severe life threatening Leukopenia was more common in the HU regimen (P , .00001).

[only six CF patients (4%) compared with 46 HU patients (24%)]. • Grade 3 or 4 gastrointestinal toxicity was slightly more common (not statistically significant)

for patients randomized to CF (8%) than for the HU group (4%).• The late major complications rate (grade 3 and grade 4) was 16.2% at 3 yr for CF group and

16.5% at 3 yr for HU group.

GOG 85

Staged as IIB - receive 40.8-Gy/24 fraction EBRT to the whole pelvis, 40 Gy was to be delivered to point A via one or two intracavitary applications (tandem and colpostats) of radium or its equivalent. If necessary, a parametrial boost was given to bring them point-B dose to 55 Gy.

Staged as III or IVA - receive 51 Gy in 30 fractions, Point A received 30 Gy from one or two Intracavitary implants. Point B received 60 Gy from both sources with or without a parametrial boost.

• Three-arm randomized trial, 526 pts• stage II B (localized disease with parametrial involvement), stage III (extension of the tumor to the pelvic wall),

or stage IV A (involvement of the bladder or rectal mucosa).• From April 1992 to April 1997.

(N Engl J Med 1999;340:1144-53.)

RT + Hydroxyurea RT+ weekly Cisplatin RT+Hydoxyurea+Cisplatin+5FuVs Vs

177 Pts. 176 Pts. 173 Pts.

GOG 120, Rose et al. (1999)

Staged as IIB - receive 40.8-Gy/24 fraction EBRT to the whole pelvis, 40 Gy was to be delivered to point A via one or two intracavitary applications (tandem and colpostats) of radium or its equivalent. If necessary, a parametrial boost was given to bring them point-B dose to 55 Gy.

Staged as III or IVA - receive 51 Gy in 30 fractions, Point A received 30 Gy from one or two Intracavitary implants. Point B received 60 Gy from both sources with or without a parametrial boost.

GOG 120

RT+HU

RT+Cisplatin

RT+HU/Cis/5FU

P value

PFS 64% 67% 47% <0.001 (for both Cisplatin arms)

No. of deaths

89 59 (0.002)

57 (0.004)

• 526 pts• Median FU – 35 mnths• Primary end point – OS, PFS

• Patients who received the platinum-based regimens had significantly longer progression-free survival than those who received hydroxyurea (P<0.001 for both comparisons)

• The highest combined frequency of grade 3 (moderate) and grade 4 (severe) adverse effects was associated with treatment with radiotherapy and the three-drug regimen (Frequency in the other two groups was similar. )• Both grade 3 and grade 4 leukopenia in the group given radio-therapy combined

with treatment with cisplatin, fluorouracil, and hydroxyurea were more than double the frequencies in the other two groups (P<0.001).• Both grade 3 and grade 4 granulocytopenia in the group given radiotherapy

combined with cisplatin, fluorouracil, and hydroxyurea therapy were approximately double those in the other two groups (P<0.001).• Not mentioned delayed toxicity.

Adverse effects :

GOG 120

J Clin Oncol 25:2804-2810. © 2007

• The analysis included 526 patients. • The median follow-up among surviving patients was 106 months.• The overall incidence of late complications is similar

GOG 120 update, Rose et al. (2007)

RTOG 9001, Morris et al. (1999)

(N Engl J Med 1999;340:1137-43.)

• Between 1990 and 1997, 403 women with advanced cervical cancer

• Stages IIB through IVA or• Stage IB or IIA with a tumor diameter of at least

5 cm or involvement of pelvic lymph nodes• Primary end points – DFS, OS• Median FU– 43 mnths

• RT Alone Arm ( receive 45 Gy of radiation to the pelvis and para-aortic lymph nodes ) Or

• RT + CT Arm (45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation).

• Patients were then to receive 1 or 2 applications of low-dose-rate ICRT (40 Gy to Point A), with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group.

Overall survival rates were significantly better among patients treated with radiotherapy and chemotherapy than among those treated with radiotherapy alone (73 percent vs. 58 percent, P=0.004)

RTOG 9001

Disease-free survival at five years was 67 percent in the combined-therapy group and 40 percent in the radiotherapy group, according to Kaplan–Meier analysis (P<0.001)

RTOG 9001

RT + CT RT P valueDFS 67% 40% <0.001OS 73% 58% 0.004

• Acute moderate (grade 3) and severe (grade 4) side effects significantly more with combined therapy than with radiotherapy alone

• No significant differences in the late effects between the treatment groups.

RTOG 9001

J Clin Oncol, 2004;22:872-880.

• Median FU – 6.6 yrs• Patients with stage IB to IIB disease who received CTRT had better overall and disease-free

survival than those treated with EFRT (P-0.0001). • Patients with more advanced stage disease IIIB-IVA, only PFS was improved (P-0.05), while

no statistical improvement in locoregional disease control or OS were noted.• Late complications of treatment was similar for the two treatment arms

RTOG 9001 update, Eifel et al. (2004)

RTOG 9001 Update

(N Engl J Med 1999;340:1154-61.)

• Women with bulky stage IB cervical cancers (tumor, >4 cm in diameter).

• 369 women• Primary end point – PFS, OS• Median FU - 36 mnths

Radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area) once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant extrafascial hysterectomy.

GOG 123, Keys et al. (1999)

P < 0.001

The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively.

GOG 123

The disease recurred in 37% in RT alone arm and 21% in CT-RT arm.

The relative risk of death in the combined-therapy group as compared with the group given radiotherapy alone was 0.54 (95 percent confidence interval, 0.34 to 0.86). (P=0.008).

The three year survival rates were 74 percent in the group given radiotherapy alone and 83 percent in the combined- therapy group

GOG 123

P - 0.008

21 % vs 2%14 % vs 5%

CTRT vs RT

GOG 123

GOG 123 Update, Stehman et al. (2007)

Am J Obstet Gynecol. 2007 November ; 197(5): 503.e1–503.e6.

Three hundred seventy-four patients entered this trial. There were 369 evaluable patients; 186 were randomly allocated to receive RT alone 183 to receive CT+RT. Radiation dosage was 45 Gy in 20 fractions followed by low dose-rate intracavitary application of 30 Gy to Point A. Chemotherapy consisted of intravenous cisplatin 40 mg/m2 every week for up to six weekly cycles. Total extrafascial hysterectomy followed the completion of RT by six to eight weeks. Median FU – 101 mnths

71% vs 60%

78% vs 64%

GOG 123 update

p< 0.004

p< 0.015

CT-RT RT alone P value6-yr PFS 71% 60% <0.0046-yr OS 78% 64% <0.015

• Late adverse events- • At last follow-up there were 118 patients alive on the irradiation-only regimen and 135

patients alive on the combination regimen who could be assessed for long-term adverse effects.

• Long-term adverse effects on the gastrointestinal tract, genitourinary tract, and skin were uncommon in both regimens.

GOG 123 update

Conclusion : The concurrent administration of concurrent cisplatin reduces the relative risk of recurrence and death by approx. 40%, compared with patients of RT alone

Journal of Clinical Oncology, Vol 18, No 8 (April), 2000: pp 1606-1613

Patients with clinical stage IA2, IB, and IIA carcinoma of the cervix,

Initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium

• Patients were randomized to receive • RT (116 pts) or RT + CT (127 pts.). • Patients in each group received 49.3 Gy RT in 29

fractions to a standard pelvic field. • Chemotherapy consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT

SWOG 8797/GOG 109, Peters et al.,1999

SWOG 8797

CT-RT RT P value

4-yr PFS 80% 63% 0.0034-yr OS 81% 71% 0.007

Primary end point – PFSSecondary end point – OSMedian FU – 42 mnths

SWOG 8797

• Median FU – 62 mnths (5.2 yrs) • 5 yr OS – 80% vs. 66% (p value - significant), in favour of CT-RT• Benefit from the addition of CT was most evident among women with tumors larger than 2cm

(P=0.17, for size < 2 cm; P=0.009 for size > 2 cm)

SWOG 8797/GOG 109 update, Monk et al.,2005

Study Authors Year Arms Median FU

Patients

RT details Stage Surgery OS Benifit PFS/DFSBenifit

RTOG 9001

Morris 1999 RT(PA)Vs RT+CF

43 mnths

403 45 Gy/25# + PAf/bICRT 40 Gy to point A

Bulky IB + IIB-IVA

N.A 73% vs 58%(0.004)

67% vs 41%(<0.001)

Eifel 2004 6.3 yrs

GOG 123

Keys 1999 RTVs RT+C

36 mnths

369 45 Gy/25# f/bICRT 30 Gy LDR to point A

Bulky IB

Adjuvant extrafascial hysterectomy

78% vs 64% (0.015)

71% vs60%(0.004)

Stehman 2007 101 mnths

SWOG 8797

Peters 1999 RTVsRT+CF

42 mnths

243 49.3 Gy/29# IA2,IB,IIA

Rad Hysterectomy+ Pelvic LND

80% vs 66%(0.003)

80% vs 63%(0.007)

Monk 2004 62 mnths

GOG 120

Rose 1999 RT+HUVs RT+CVsRT+CFH

35 mnths

526 IB – 40.8/24# f/b 40 Gy point AIIB/IVA – 51Gy/30# f/b 30 Gy point A

IIB-IVA NA 10 yr OS-53% vs53% vs34%

10 yr PFS 46% vs 43% vs26% Rose 2007 106

mnths

GOG 85

Whitney 1999 RT+CFVs RT+HU

8.7 yrs 368 Same as GOG 120 IIB-IVA NA 5 yr OS60% vs 47%

Fallacies of Randomized CCRT trials

• No identical protocol in the randomized trials.

• Differences in inclusion criteria of the patients.

• No uniformity in Chemotherapy arm.

• No uniformity in RT arm

JCO February 15, 2002 vol. 20 no. 4 966-972

• Total 253 patients with stage IB to IVA squamous cell cervical cancer with central disease ≥ 5

cm or histologically confirmed pelvic lymph node involvement

• 127 pts. randomized to be treated with cisplatin (40 mg/m2 weekly) and RT, and

• 126 patients were treated with RT alone

• 50.4 Gy to the pelvis combined with brachytherapy.

Pearcey et al., NCIC, JCO 2002

• Median follow-up was 82 months.

CT-RT RT alone P valuePFS NA NA 0.333-yr OS 69% 66% 0.425-yr OS 62% 58%

Lancet 2001; 358: 781–86

• Systematic review of all known randomised controlled trials done between 1981 and 2000 • 17 published, two unpublished studies of chemoradiation for cervical cancer.• 4580 randomised patients • Cisplatin was the most common agent used.

Green Meta-analysis., Lancet 2001

Results for overall survival

The HR of 0·71 across all trials represents a 29% reduction in the risk of death or an absolute improvement in survival of 12% (95% CI 8–16), from 40% to 52%.

PFS benefit

Benefit in Local recurrence and Distant metastasis

• Significant reduction in the rates of local recurrence (OR - 0.61, P – 0.00001) and systemic recurrence (OR - 0.57, P - 0.00001)

9% 4%

16% 8%

Toxicity

Conclusions :

• Chemoradiation improves overall survival (hazard ratio 0·71, p<0·0001) [whether platinum was used (0·70, p<0·0001) or not (0·81, p=0·20).]

• Greater beneficial effect was seen in trials that included a high proportion of stage I and II patients (p=0·009).

• Absolute benefit • PFS – 16%• OS – 12%

• A significant benefit of chemoradiation on both • Local (p<0·0001) and • Distant recurrence (p<0·0001)

• Grade 3 or 4 haematological and gastrointestinal toxicities were significantly greater in the concomitant chemoradiation group than the control group.

• There was insufficient data to establish whether late toxicity was increased in the concomitant chemoradiation group.

Clinical Oncology (2002) 14: 203–212

Lukka Meta-analysis., 2002

• A systematic review of 8 randomized trials of cisplatin administered concurrently with external beam radiotherapy versus radiotherapy without cisplatin for cervical cancer was combined with a meta-analysis of results abstracted from published reports of the trials.

Absolute reduction in the risk of death of 11% (95% CI, 7% to 15%).

• Six trials showed a trend in improvement in local control (except the Wong and Tseng study)

• Distant metastatic rates improved with Cisplatin based chemo-RT

The original review was based on nineteen trials (17 published and two unpublished) including 4580 patients. This update includes twenty four trials (21 published, 3 unpublished) and 4921 patients, although due to patient exclusion and differential reporting 61% to 75% were available for the analyses.

The Cochrane Library 2005, Issue 3

Patients with locally advanced cancer of the uterine cervix (FIGO stage IB-IVA).

Green Meta-analysis update, Cochrane 2005

• Two trials compared radiation plus hydroxyurea with cisplatin-based chemoradiation alone (Whitney 1999) and cisplatin-based chemoradiation with or without hydroxyurea (Rose 1999). • One further trial of cisplatin-based chemoradiotherapy used different radiotherapy

on the control and treatment arms (Eifel 2004). • Eight trials compared radiation alone with non-cisplatin based chemoradiation,

using 5-fluorouracil, mitomycin-C, bleomycin, epirubicin, Adriamycin and cyclophosphamide, either as single agents or in combined regimens.• Two of these trials gave further adjuvant chemotherapy in the chemoradiation arm

• The HR of 0.69 across all trials (95% CI = 0.61 to 0.77, P < 0.00001) represents a 31% reduction in the risk of death or an absolute improvement in survival of 10% (95%CI = 7 to 13%) from 60% to 70%.• Absolute improvement in progression-free survival of 13% (95% CI =10-16%) from

50% to 63%. • Similar benefit with platinum vs non-platinum• No suggestion that the scheduling of chemotherapy , the use of hydroxyurea in the

control arm or the frequency of chemotherapy, altered the effect of chemoradiation.• Greater benefit for stage I-II.• Significantly more serious GI and hematological toxicities

Conclusions :

Cochrane Database of Systematic Reviews 2010

18 RCTs (15 eligible)N=3452

To assess the effect of chemoradiotherapy on all outcomes.

Cochrane Meta-analysis 2010

Individual Patient data (IPD) meta-analysis

Trend towards greater benefit of OS for early stage disease: 10% improvement for IB-IIA, 7% for IIB, 3% for III-IV.

However, there was no significant trend for the analysis of DFS by stage (test for trend, P = 0.073)

• 5-yr OS improved by 6% (p<-0.001)• Similar benefit for platinum (10 trials) vs non-platinum• Greater benefit for adjuvant chemotherapy (2 trials, 19% OS benefit at 5 years)• There were similar and significant absolute benefits of chemoradiotherapy on 5-yearlocoregional DFS (8%, P < 0.001), time to locoregional recurrence/ progression (6%, P = 0.00009) and metastases-free survival (7%, P < 0.001).

Toxicity

• Trials that used HU on the control arm, a high level of serious haematological toxicity was evident on both arms (slightly greater on the control arm, OR - 0.74, 95% CI- 0.53 to 1.03, P = 0.08)

• There was a significant increase in serious GI toxicity for the groups of trials • Platinum-based chemoradiotherapy (P = 0.000002), • Chemoradiotherapy plus additional chemotherapy (P = 0.001) • Additional radiotherapy on the control arm (P = 0.000002).

• Data on late toxicity were not recorded for the majority of trials in the meta-analysis. The available data suggest that only a small number of women across all trials (1% to 3%) experienced serious late toxicities, including nine deaths

Comparing the benefits of Meta-analysis

Benefit of CRT Green, 2001 Green, 2005 Cochrane, 2010 (IPD Meta-analysis)

No. of studies 19 total - 17 + 2(unpublished)

24 total – 21 + 3(unpublished)

13

Patients 4580 randomised2865-3611 available

4921 randomised3578 available

3452 randomised3000 available

Absolute PFS Benefit 16% (47 to 63%) 13% (50 to 63%) 8% DFS Benefit(50 to 58 %)

Absolute OS Benefit 12% (40 to 52%) 10% (60 to 70%) 6% (60 to 66%)

• Meta-analysis including Cisplatin+RT vs RT alone

• Superior benefit in OS & PFS with Cisplatin+RT

• Significantly enhanced toxicity with Cisplatin + RT (as in Cochrane 2010)

Meng et al., Onco targets and therapy, 2016

Forrest plot for OS

Toxicity of CT-RT

• 4580 pts – 19 RCTs

J.M. Kirwan et al., Radiotherapy and Oncology 68 (2003) 217–226

Grade 1 and 2 toxicities• All grade 1 and 2 haematological toxicities were higher in the chemoradiation arms than the control.• No significant increase in combined grade 1 and 2 toxicity for GIT, GUT, or dermatological toxicities Grade 3 and 4 toxicities• Significant differences were seen in grade 3 and 4 haematological and gastrointestinal toxicities • Grd 3 or 4 GI Toxicity in 8% of patients in the CRT groups suffering severe or life threatening adverse events • No difference in grade 3 and grade 4 genitourinary (GUT) toxicity

Long term toxicity• Long-term toxicity was only described in 8 trials, of which seven reported no

statistical difference in the incidence of long-term side effects

Conclusion : • In view of the consistency and extent of the survival benefit for CRT the

additional acute toxicity appears to be acceptable.

• 7,336 patients – Pattern of care, • 1,753 – Pattern of survival • 12 institutions and were diagnosed between January 1, 2006, and December 31, 2008 • Primary end point - OS• 5-year cumulative survival, 70.2% v 47.3% (CT-RT vs RT alone)

Nandkumar et al., POCSS, Journal of Global Oncology, 2015

• Optimal RT is defined as administering at least 45 Gy by external beam (minimum of 20 fractions) plus intracavity brachytherapy (any dose)

• 5-year cumulative survival, 70.2% v 47.3% (CT-RT vs RT alone)

Comparative Trials of Chemoradiation Regimens

GOG 165 (2005)

J Clin Oncol 23:8289-8295. © 2005

Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes wereeligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, andhigh- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT.

• Closed prematurely • There have been 121 deaths reported. There was a difference in OS at 4 years with 36% of patients dead of

disease on arm I compared with 45% of patients on arm II• No difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at

distant sites in the PVI FU arm.

Gonzalez et al

J Clin Oncol 29:1678-1685. © 2011

Arm A: cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m2 on day 1, plus gemcitabine, 1,000 mg/m2 on days1 and 8) or Arm B: cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A.

Toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P-0.001 )

Con Gem-Cis Con CTRT P value

3-yr PFS 74.4% 65% 0.029

OS 80% 69% 0.022

Toxixities 86.5% 46.3% 0.001

Way forward - New Combinations

• Carboplatin• Paclitaxel + Carboplatin• Gemcitabine• Capecitabine• Bevacizumab• Cetuximab• Ertotinib• Celecoxib

No randomised phase III trial

• 5-year survival with this approach for LACC has reached a plateau of 50- 60% and this also comes at the cost of high toxicities • Protocols other than CCRT like induction chemotherapy or consolidative

chemotherapy have shown inconclusive advantage over CCRT alone and needs further exploration in well-designed trials

Thank you