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Combined radio-chemotherapy in Cervical carcinoma

Combined radio-chemotherapy in Cervical carcinoma. Ekkasit Tharavichitkul, MD The division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University 11 th Febuary 2012, Novotel Rayong Rim Pae Resort. from Povada et al., ESMO. Treatment schema of cervix cancer.

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Combined radio-chemotherapy in Cervical carcinoma

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  1. Combined radio-chemotherapyin Cervical carcinoma Ekkasit Tharavichitkul, MD The division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University 11th Febuary 2012, Novotel Rayong Rim Pae Resort

  2. from Povada et al., ESMO

  3. Treatment schema of cervix cancer Adapted from Povada et al.

  4. NCCN guidelines

  5. NCCN guidelines

  6. Key concepts of radio-chemotherapy • Produce tumor cell ‘ sensitization’ • Cell cycle synchronization • Concurrent activity against tumor cells which are partially resistant to one modality alone • Decrease ability to repair radiation-induced cellular damage • Rationale for radio-chemotherapy • No delay in Definitive radiation • No prolongation of total treatment time • Addition of cytotoxic intracellular interactions

  7. History of RCT • At 1960’s RCT started • Hydroxyurea (HD) • In 1974, Piver et al reported the efficacy of hydroxyurea in response rate but not OS • In 1983, Piver et al. reported the 5-yr survival rates of 94% (HD group) vs. 53% (placebo) • In 1987, Piver et al. reported the survival advantage over radiation alone • However, not become the standard of care due to its significant myelosuppression • In 1996, NIH consensus: no data that HD should be incorporated into the standard practice

  8. The next generation; Nitroimidazole (hypoxic cell sensitizer) • the GOG study showed HD was shown to be superior in locoregional treatment failure rates (18% vs 23.6%) and recurrence rates (37% vs.44%) * Stehman 1988,1993 • Fluorouracil • Thomas G et al.(1998) • Concurrent 5 FU and radiation • No survival benefits

  9. from Povada et al., ESMO

  10. NCI announcement 22/2/1999 • Five different large, randomized clinical trials showed women benefitted from the use of radiation therapy and chemotherapy given together • Cisplatin-based chemotherapy improved overall survival in woman with advanced cervix cancer • HR: 0.54-0.74 • OS: 9-18%

  11. Phase III studies of CCRT • Positive studies • Advanced clinical stage • GOG 85 (Whitney et al.) • RTOG 90-01 (Morris et al.) • GOG 120 (Rose et al.) • Bulky stage IB2 (RCT followed with surgery) • GOG 123 (Keys et al.) • Stage IA2, IB with high-risk factors (positive surgical margin, positive LNs, PMI) • SWOG 8797/GOG 109 (Peters et al.) • Negative study • NCIC (Pearcey et al.)

  12. In the ends of 199x • GOG 85 • The Gynecologic Oncology Group (GOG) 388 patients with stage IIB–IVA cervical cancer to receive • Group I: RT + cisplatin and 5-fluorouracil (5-FU) infusion for 4 days • Group II: RT + Hydroxyurea (HD) • Patients on the cisplatin-containing treatment arm had significantly better progression-free and overall survival (survival 63% versus 47% at 5 years). • With a median follow-up of 8.7 years this difference in survival has been maintained. In addition, significantly less leukopenia occurred with cisplatin and 5-FU than with hydroxyurea

  13. GOG 120 (Rose et al., 1999, 2007): • 526 patients with IIB–IVA (surgically staged -PAN) randomized to WP + LDR brachytherapy (total 81 Gy point A dose) + 3 different chemo regimens: • Group I: Weekly cisplatin • Group II: Cisplatin/5FU/HD • Group III: HD • Cisplatin arms decreased stage IIB and III 10-year LR (21–22 vs. 34%) and improved PFS (43–46 vs. 26%), OS (53 vs. 34%). • No difference in grade 3–4 late toxicities among three regimens.

  14. RTOG 90-01 (Morris et al., 1999; Eifel et al., 2004): • 386 patients with surgically staged IIB–IVA, IB–IIA ≥ 5 cm, or LN + randomizedto • Group I: EFRT + brachytherapy (total 85 Gy point A dose) • Group II: WP RT + brachytherapy (total 85 Gy point A dose) + cisplatin/5FU • RCT improved 8-year OS (67 vs. 41%), DFS (61 vs. 46%),and decreased LRF (18 vs. 35%) and DM (20 vs. 35%) • RCT had a non-significant increase in PAN failures (8 vs. 4%)

  15. GOG 123 (Stehman et al., 2007; Keys et al., 1999): • 369 patients with IB2 randomized to • Group I: WP + LDR RT (total 75 Gy to point A) followed by adjuvant simple hysterectomy • Group II: same RT + concurrent weekly cisplatin (40 mg/m2) × 6c followed by same surgery • Chemo-RT improved 5-year PFS (71 vs. 60%) and OS (78 vs. 64%), without increasing serious late adverse effects

  16. GOG 109/SWOG 8797 (Peters et al., 2000): • 243 patients s/p radical hysterectomy with IA2, IB, IIA, and + LN or + margin or + parametria ; • Group I: WP RT (49.3 Gy with 45 Gy to PAN if common iliac LN+) • Group II: WP RT + cisplatin/5FU every 3 weeks × 4c (RCT+ACT) • Post-op chemo-RT improved 4-year PFS (80 vs. 63%) and OS (81 vs. 71%) • Re-analysis demonstrated that RCTdecreased LR by 50%and DM by 30%. 20% OS benefit from chemo for tumors >2 cm and patients with 2 + LN

  17. NCIC (Pearcey et al., 2002): • 353 patients with IA, IIA >5 cm, or IIB randomized • Group I: WP45 Gy + LDR 35 Gy ×1 or HDR 8 Gy ×3 • Group II: same RT + weekly cisplatin 40 mg/m2 x6c. • No difference in 5-year OS (62 vs. 58%) • Possible reasons: shorter treatment duration, only imaging-based staging, more anemia in the chemotherapy arm, smaller sample size

  18. Rose, 2003

  19. Meta-analysis • 4580 randomized patients, 2865-3611 patients (62-78%) were available for analysis • RCT improves • OS (HR 0.71, p<0.0001) Whether platinum was use (0.70, p<0.0001) or not (0.81,p=o.20) • PFS (0.61, p<0.0001) and distant recurrence (0.57,p<0.0001) • Greater benefit in stage I and II patients (p=0.009) • The absolute benefit in PFS and OS was 16% and 12%, respectively • ASE is greater but late toxicity is not clear

  20. Brady ,2011L

  21. Neo-adjuvant chemotherapy • Advantages • Tumor size reduction may facilitate local therapy; RT or Sx • Transformation of inoperable tumor in radically operable one • Treatment of micro-metastasis disease • Disadvantages • Delay in curative treatment (20-30% no response) • Develop of radioresistant cellular clones • Development of cross-resistance with radiotherapy

  22. NACT

  23. Other radio-sensitizers Carboplatin • Fewer GI, renal and neuropathy than cisplatin • Different phase I/II studies with different schedules • Weekly schedule AUC2 is safe and active • Not compared in a phase III study with cisplatin

  24. A randomized phase III trial of concurrent chemoradiotherapy in locally advanced cervical cancer: Preliminary results • IIB–IIIB cervical cancer patients were randomized to have Tegafur-Uracil (UFT) 225 mg/m2/day orally, 5 days a week and carboplatin 100 mg/m2 IV over 30–60 min, weekly on day 1 (Group A) or carboplatin alone (Group B) with standard radiotherapy both arms. 469 patients Group A (n = 234) or Group B (n = 235). • The tumor response at 3-month follow-up time showed no significant difference • The patients in Group A, who had Hb < 10 gm/dL had the relatively better change to complete response of 1.48 compared to that in Group B (P 0.025, 95% CI 1.07, 2.04). • No severe toxicity or adverse event had been reported • The median follow-up time for Group A and Group B was 12.6 and 11.8 months,respectively. There was no statistical difference in PFS and OS • Tegafur-Uracil and carboplatin showed no difference in tumor response rate or treatment toxicity compared to carboplatin alone. The combination drugs might have benefit in poor prognostic patients such as the baseline Hb < 10 gm/dL Veerasarn, Gynecol Oncol, 2006

  25. Other radio-sensitizers • Nedaplatin • Platinum derivative developed in Japan • Fewer nephrotoxicity than cisplatin but hematologic toxicity is the dose-limiting factor • Phase I study:12 patients, recommended dose weekly 35 mg/m2 • All 12 patients achieved complete response

  26. Other radio-sensitizers • Gemcitabine • Phase I study; 19 pts MTD not determined. Low toxicity profile and highly active (90% OR) (ASCO 2005, Abstr 5142) • Phase II: 65 pts IIB-IIIB RT and weekly cisplatin 35 mg/m2 or weekly gemcitabine 150mg/m2. Similar Overall response rate and toxicity. Higher CR rate with gemcitabine (ASCO 2007, abstr 16012)

  27. Capcitabine • FIGO stage IIB-IIIB cervical cancer received capecitabine, 825 mg/m(2) twice daily (Monday-Friday), during radiation (45 Gy per 25 fractions external-beam radiotherapy and 26 Gy high-dose rate brachytherapy to point A, maximum 8 weeks), followed by six cycles of capecitabine, 1,000 mg/m(2) twice daily (days 1-14 every 21 days). • ORR in 60 patients was 88% (95% confidence interval [CI], 77.4%-95.2%), • CRs in 80% of patients • The 1-year PFS and OS rates ; 86% (95% CI, 77%-95%) and 95% (95% CI, 89%-100%) • At 23 months, 76% of patients were progression free (95% CI, 65%-88%) and CR was maintained in 90% (95% CI, 81%-99%) of the 48 patients achieving a CR. • G3-4 toxicity in 3 patients : reversible grade 4 hypokalemia, grade 3 diarrhea, and grade 3 hand-foot syndrome. • Well-tolerated option Domingo, ( Lorvidhaya V)The oncologist, 2009

  28. Paclitaxel Geara, Radiation Oncol, 2010

  29. Combination therapy Duen˜as-Gonza´lez A, et al • The combination of Cis + Gem (concurrent +adjuvant) vs. Cisplatin weekly in locally advanced cervical cancer • It caused 9 % improvement in 3-yrs progression-free survival (PFS) but not for OS • The more acutely toxic combined chemotherapy in the study arm (72% of patients had grade 3/4 acute hematologic toxicity compared with 24% who were treated with concurrent cisplatin alone) • No significance in median time, (49 days vs.45 days ) • No significance in the planned application of brachytherapy(92% and 95% in the study and control arms,respectively). Duenas-gonzalez A, (Pattaranuthaporn) JCO,2010

  30. Schema of Trial Baseline cervical biopsy and FDG-PET scan Administer C225 on days 1, 8, and 15 Repeat cervical biopsy and FDG-PET scan Administer definitive chemo-radiation and C225 Repeat cervical biopsy and FDG-PET scan Follow for tumor recurrence and survival

  31. Preparation of chemotherapy Courtesy of ฝ่ายเภสัชกรรม รพ มหาราชนครเชียงใหม่

  32. Cisplatin administration • In chloride-containing solution • i.v. in 0.5-2 hr • Prehydration at least 500 cc • Posthydration at least 1,000 cc • i.v. mannitol 12.5-25 g before cisplatin

  33. Cisplatin toxicities • N/V: very high emetic risk • Nephrotoxicity • Cumulative glomerular & tubular damage • Return to normal with time • Ototoxicity • Damage to inner ear • Irreversible, high-frequency loss • Recommend audiogram q 2-3 cycles • Peripheral neuropathy • Cumulative & reversible • Others • Visual impair • Seizure • Arrhythmia • Pancreatitis • Acute ischemic vascular events • Glucose intolerance

  34. Dose modifications • Chemotherapy was interrupted • Leukocyte count <3,000/cc • Platelet count <75,000/cc • Fever >38.0 C Grade 3-4 non-hematologic toxicity • Neprotoxicity • Chemotherapy was resumed when hematologic and nonhematologic toxicity recovered to Grade I

  35. Toxicities

  36. Conclusions • Platinum based regimens for chemoradiation remain the standard • Weekly cisplatin at 40 mg/m2 during 5-6 weeks of pelvic EBRT with or without chemotherapy during BT is the current standard of care and 3-weekly cisplatin/5-FU is also validated by level I evidence • Meta-analysis results indicate no particular benefit to cisplatin as compared with other types of chemotherapy • 5-FU alone is not recommended as a concurrent regimen with radiation • Neo-adjuvant chemotherapy remains controversial and is currently under investigation by the EORTC (55994) and other groups • Adjuvant chemotherapy; interesting • Results with Bevacizumab, Cetuximab, Erlotinib, Capecitabine or Sorafenib in combination with cisplatin and radiation therapy are expected

  37. Thank you for your attentions

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