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Prof. Enrico Cortesi Medical Oncology Dpt

Mediterranean School of Oncology (MSO) and Mediterranean Task force for Cancer Control (MTCC) Postgraduate Course Moroccan Cancer Society “ Cervical Cancer: from Epidemiology to Treatment “ Medical Treatment Marrakech, Saturday, 25 April 2009. Prof. Enrico Cortesi Medical Oncology Dpt.

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Prof. Enrico Cortesi Medical Oncology Dpt

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  1. Mediterranean School of Oncology (MSO)and Mediterranean Task force for Cancer Control (MTCC)Postgraduate CourseMoroccan Cancer Society“Cervical Cancer: from Epidemiology to Treatment “Medical TreatmentMarrakech, Saturday, 25 April 2009 Prof. Enrico Cortesi Medical Oncology Dpt

  2. Treatment options Surgery External beam Radiotherapy (adjuvant or exclusive ) +/- Chemotherapy +/- Brachytherapy Chemotherapy

  3. Staging of cervical cancer

  4. Treatment by stage Earlier stage disease and smaller lesions Clinical STAGES 1A - 1B1/ IIA (<4 cm) Surgery or pelvic RT and brachytherapy (in 1A2, 1B1 and IIA <4 cm) +/- CRT if positive pelvic and/or para-aortic nodes or if positive surgical margins

  5. Treatment by stage Selected Bulky IB2, IIA (>4 cm), IIB, IIIA , IIIB and IV A Surgery + Pelvic CRT and brachytherapy +/- para-aortic CRT if positive nodes Or Pelvic CRT/ brachytherapy +/- Para-aortic CRT if positive nodes

  6. Treatment by stage • Surgery if feasible +/- IORT or CRT Local recurrence • CRT if not done before Chemotherapy alone +/- palliative RT + BSC IV B (distant M+)

  7. What is the role of Chemotherapy? • In association with RT •  Concomitant standard •  Neoadjuvant (NACT) •  Adjuvant • Metastatic Disease investigational

  8. What is the role of Chemotherapy? investigational In association with RT  Concomitantstandard  Neoadjuvant (NACT)  Adjuvant

  9. Mechanisms of interaction between CHT and RT • Change in the slope of the RT sensitivity curve (CDDP, ADM, 5FU, MMC) • Inhibition of repair of sublethal damage (CDDP, BLM, HU) • Synchronization in a more radiosensitive cell cycle (HU) • Selective cytotoxicity and increase hypoxic cells radiosensitivity (CDDP, MMC) • Some activity on clones resistant to radiotherapy (TXL) Perez CA et al. Semin Radiat Oncol 7:45-65, 1997

  10. Rational of RT with concomitant CHT • Synergy between RT and cytotoxic drugs • Direct effect of CHT on primary tumor and on distant metastases • Activity on different cell populations

  11. 1996 - Consensus Conference on cervical carcinoma: sequential CH to RT • NA (CT  RT) with cisplatin-containing regimens followed by radiotherapy has been studied in several randomized trial… Tumor response to NACT in more than 50% of patients, but no improvement in LC or in OS … • In some large trial, NACT was inferior to standard pelvic RT in terms of LC and OS. • adjuvant (RT  CHT) has small data, and no randomized trials have been reported Tattersall MH. J Natl Cancer Inst Monogr. 21:101-3 1996

  12. 1996 - Consensus Conference on cervical carcinoma: Concomitant CH/RT “There is no evidence that hydroxyurea or any other concomitant chemotherapy agent should be incorporated into standard practice”* Optimal management of locally advanced cervical carcinoma: radiation therapy is the mainstay of treatment ** *Tattersall MH. J Natl Cancer Inst Monogr. 21:101-3 1996 **Keys H, Gibbons SK. J Natl Cancer Inst Monogr. 21 1996

  13. Randomized Trials on CRT…

  14. Five clinical Trials on concomitant CRT

  15. 1999 - Something changed...The NCI Clinical Announcement “Strong consideration should be given to the incorporation of concomitant cisplatin based chemotherapy in women who require radiation therapy for treatment of cervical cancer”

  16. 268 patients SWOG -8797 trial (Adjuv) PFS OS • “The addition of concurrent cisplatin based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.” p= 0,03 p= 0,07 Peters et AL; Journal of Clinical Oncology, Vol 18, No 8 (April), 2000: pp 1606-1613

  17. 430 patients RTOG 9001 Trial (Exclusive) PFS • “The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer”. p= 0,04 OS p= < 0,01 Morris et Al; NEJM, 1999; 340, 1137-1143 Eifel, et al. J Clin Oncol. 2004;22:872-880

  18. 374 patients GOG 123 trial (Neoadjuv) PFS • “Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers”. p< 0,001 p= 0,008 OS Keys et Al, NEJM, 1999; 340: 1154-1161

  19. GOG 120 trial (Exclusive) 526 patients OS Stage IIB Stage III Overall survival by treatment and number of patients at risk (for death) at 60 and 120 months Rose, P. G. et al. J ClinOncol; 25:2804-2810 2007

  20. 2001 meta-analysis on Concomitant CRT… • Significative Advantage (p<0.0001): • OS (> 12%) • DFS (> 16%) • Local Control • Reduction of Distant metastases • Better results in > I-II stages and with CDDP based CH • 19 randomized trials • 12 based on CDDP (+/- BLM, VCR, 5FU) • 7 non CDDP (MMC, 5FU, BLM, EADM) • 4580 pz Green JA et al., Lancet 358:781, 2001

  21. Suggested treatment • …. application to less developed countries requires the regimen to be cheap and easy to administer …. • ….. cisplatin once a week fits this criteria. Green JA et al., Lancet 358:781, 2001

  22. 2001 - CHT + RT in cervical cancer • Standard Treatment is: • Concomitant Chemoradiotherapy • Platinum based • Optimal Radiotherapy

  23. Only CDDP? The study was closed prematurely when a planned interim futilityanalysis indicated that PVI FU/RT had a higher treatment failurerate (35% higher) and would, most likely, not result in an improvementin progression-free survival compared with weekly cisplatin/RT. PVI FU does not show improved outcome over weeklycisplatin Lanciano R et al, JCO 23:8289, 2005

  24. Only CDDP ? No differences in terms of tumor response rate or treatment toxicity Veerasarn V et al, Gynecol Oncol 104:15, 2007

  25. 2006 – The COCHRANE Review • 24 Randomized Trials • 15 Platin based • 8 without platin (MMC, 5FU, BLM, EADM..) • 4921 pz

  26. Cochrane Review • Significative advantage for CRT  OS (10%), DFS (13%) and LC • Advantage for metastases not significant • Advantages not limited to platinum based CRT • > advantages with adjuvant CT • Correlation with stage (I-II vs III-IV) • > G3-4 acute toxicities with CRT • Late toxicities not comparable

  27. Capecitabine and radiotherapy ASCO 2008: phase II study • Background: • Roleof Capecitabine asradiosensistizer in rectalcancer • Thymidinephosphorilasehighlyconcentrated in cervicalcancertissuecomparedwithhealthytissue • Encouragingactivityasradiosensitizer in cervicalcancer in phase I and II studies Dunst J et Al, JCO , 2002; 20:3983-3991 Miwa M. et Al, Eur. J. Cancer, 1998; 1274-1281 Torecillas L.et Al, Eur. J. Cancer Suppl. 2003; 52 Padilla et Al, Eur J. Cancer Suppl 2005, 257

  28. Capecitabine and radiotherapy ASCO 2008: phase II study Adjuvant capecitabine 1000 mg/mq bid, 1-14, q 21 X 6 cylcle 8 weeks Radiotherapy (EBRT+ Brachytherapy) + Capecitabine 825 mg/mq bid on RT days 60 patients with stage IIB- IIIB cancer of the cervix Primary end point: ORR Secondary endpoint: TTP, PFS, OS, Safety, disease control rates

  29. Key Conclusions • High efficacy of this non-platinum based regimen in locally advanced cervical cancer: PFS compares favourably with cisplatin based chemoradiotherapy • This is the first study to evaluate adjuvant capecitabine in this setting: Capecitabine raised no safety concerns and may play a role in prolonging TTP • Long term follow up is ongoing.

  30. What is the role of Chemotherapy? investigational In association with RT  Concomitant standard  Neoadjuvant (NACT)  Adjuvant

  31. Neoadjuvant chemotherapy: a possible role Tumor size reduction  to facilitate local therapy Inoperable tumors  Radically resectable tumors Increase of radiosensitivity and decrease of hypoxic cell fraction Action on micrometastases Response to NACT can be considered as a prognostic factor

  32. Phase II studies on NACT Gonzalez-Martin A. et Al.Gynecol Oncol. 2008 Sep;110(3 Suppl 2):S36-40.

  33. NACT Surgery 872 patients Dose of CDDP between 100 to 300 mg/mg in 10- to 21-Day cycles Patients population with less advanced disease ( 1/3 stage IB + 2/3 Stage II ) RESULTS highly significant effect of NACT , which translates into an absolute gain in 5-year OS of 14% (from 50% to 64%) EJC 39:2470, 2003

  34. Neoadjuvant chemotherapy meta-analysis MRC - 2003 Comparison 1 Comparison 2 • 18 trials : CHTRT vs RT • 2074 pt • Stages IIB-IVA • 5 trials : CHTCH +/- RT vs RT • 872 pt • Stages IB-II EJC 39:2470, 2003

  35. NACT RTmeta-analysis MRC - 2003 CT  14 day cycles CT ≤ 14 day cycles } p= 0.005 } p= 0.046 Advantage for NACT if: • Cycle lengths ≤ 14 d • dose intensity CDDP >25 mg/m2/w No differences NACT is detrimental if • Cycle lenghts > 14 d EJC 39:2470, 2003

  36. Why NACT is not so used today? Meta-analysis did not support the administration of NACT before RT alone Meta-analysis suggested an advantage of NACT before surgery, when compared with RT alone (but this control arm is evidently inferior) Radiotherapy was given only to a part of the population analysed in comparison No Phase III study to select the best drug to use in Neoadjuvant setting NACT is still considered investigational, new studies are required Gonzalez-Martin A. et Al.Gynecol Oncol. 2008 Sep;110(3 Suppl 2):S36-40.

  37. EORTC 55995 trial is ongoing… NACTSurgery CDDP total dose 225 mg/mq Dose intensity at least of 25 mg/mq/week For a maximum of 8 weeks Stage IB2-IIB cervical cancer CRT CDDP 40 mg/mq/week x 6 weeks+ External beam RT 45-50 Gy From 2002, planned accrual 686 patients Inclusion criteria: age 18-75, stages IB2-IIB, PS<2 Waiting for the results… Gonzalez-Martin A. et Al.Gynecol Oncol. 2008 Sep;110(3 Suppl 2):S36-40.

  38. CRT: conclusions standard • Concomitant CRT (> platinum) • Locally advanced disease ( IB2) • Positive nodes options • NACT  RT : maybe, with the right schedule and high DI • NACT  Surgery : waiting for results from Ph III Trials • Adjuvant CHT after RT : more studies are required • Optimal RT

  39. What is the role of Chemotherapy? investigational In association with RT  Concomitant standard  Neoadjuvant (NACT)  Adjuvant Metastatic Disease

  40. Metastatic disease • Prognosis is poor for patients with advanced cervical cancer, who are no longer amenable for surgical resection or radiotherapy  1 year survival is less than 20% • For several years cisplatin alone has been considered the most active drug in this setting • Single-agent cisplatin showed 20% to 30% ORR, 7 months of PFS; 7.1 months of OS. • A number of studies have been conducted to identify other active agents to be used alone or in combination with CDDP Long HJ, et al. J Clin Oncol. 2005;23:4626-4633. Moore DH et Al, JCO 2004; 22: 3113-3119

  41. Metastatic disease First line drugs: • Carboplatin • Cisplatin • Paclitaxel • Gemcitabine (?) • Topotecan (?) First line combination therapies: • Cisplatin/ Paclitaxel • Carboplatin/ Paclitaxel • Cisplatin/ Topotecan • Cisplatin /Gemcitabine (?)

  42. “Cisplatin Plus Paclitaxel Improves Response Rates and Progression-Free Survival in Women With Stage IV B, Persistent, or Recurrent SquamousCell Cervical Carcinoma Compared With Cisplatin Alone, PHASE III study” Cisplatin + Paclitaxel vs Cisplatin Alone  Phase 2 data showed an objective response rate (RR) 46% with paclitaxel/cisplatin vs 17% with cisplatin alone Moore DH et Al, JCO 2004; 22: 3113-3119

  43. Summary of Study Design Quality of life (QoL) and tumor measured after each cycle Cisplatin (50 mg/m2) Day 1 of a 21-day cycle 6 cycles total N = 134 Patients with stage IVB, recurrent, or persistent squamous cell cervical cancer (N = 264*) Cisplatin (50 mg/m2)/Paclitaxel (135 mg/m2) ** Day 1 on a Q3W schedule 6 cycles total N = 130 *N = 264 for intent-to-treat analysis **Paclitaxel given as a 24-hour infusion followed immediately by cisplatin. Moore DH et Al, JCO 2004; 22: 3113-3119

  44. Main Findings Moore DH et Al, JCO 2004; 22: 3113-3119

  45. Other Outcomes Moore DH et Al, JCO 2004; 22: 3113-3119

  46. Key Conclusions • Cisplatin/paclitaxel significantly increased RR and PFS over cisplatin alone • Median OS and QoL were not significantly different between arms • Cisplatin/paclitaxel appropriate for palliative treatment of stage IVB cervical carcinoma Moore DH et Al, JCO 2004; 22: 3113-3119

  47. Cisplatin + Topotecan vs Cisplatin alone “Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group” • Topotecan/cisplatin and MVAC (methotrexate, vinblastine, • doxorubicin, cisplatin) • both superior to cisplatin in phase 2 trials Long HJ et Al; JCO 2005;23:4626-4633.

  48. Objectives Gynecologic Oncology Group (GOG) Study 179 • To compare efficacy and safety of topotecan/cisplatin vs MVAC vs cisplatin in patients with advanced cervical cancer • MVAC arm not included in analysis due to treatment-related deaths (this arm closed early) Long HJ, et al. J Clin Oncol. 2005;23:4626-4633.

  49. Summary of Study Design Topotecan 0.75 mg/m2 Days 1-3 + Cisplatin 50 mg/m2 Day 1 every 3 weeks (n = 147) Patients with advanced (stage IVB) recurrent or persistent cervical carcinoma (N = 356) Cisplatin 50 mg/m2 Day 1 every 3 weeks (n = 146) Maximum of 6 cycles for nonresponders† MVAC* Methotrexate 30 mg/m2 Days 1, 15, and 22 + Vinblastine 3 mg/m2 Days 2, 15, and 22 + Doxorubicin 30 mg/m2 Day 2 + Cisplatin 70 mg/m2 Day 2 every 4 weeks (n = 63) *MVAC arm closed early because of treatment-related deaths; trial continued as 2-arm study. †Patients achieving partial response with acceptable toxicity could continue treatment beyond 6 cycles. Long HJ, et al. J Clin Oncol. 2005;23:4626-4633.

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