Role of chemotherapy in LA-HNC: the art of timing and selection

1. Role of chemotherapy in LA-HNC: the art of timing and selection Cesar Rodriguez Valdes, M.D. James Graham Brown Cancer Center Department of Medical Oncology

2. Learning objectives • Explainthe need for chemotherapeutic treatment for patientswith squamouscell carcinoma of the head and neck. • Identify the different chemotherapy strategies in the treatmentof locally advancedsquamous cell carcinoma of the head andneck. • Discuss trials evaluating different timing of chemotherapyfor patients with locallyadvanced squamous cellcarcinoma of the head and neck. • Discuss the role of cetuximab and other targeted agents in LA-HNSCC. • Overview of HPV in head and neck cancer.

3. Epidemiology • More than 90% of head and neck cancers are of squamous cell histology. • HPV prevalence in young adults. • An estimated 39,000 American men and women developed head and neck cancer in 2005. Oral cavity & pharynx 25,420 3% Jemal et al. CA Cancer J Clin 2010

4. Epidemiology Five-year relative survival rate • More than 60% of patients present with locally-advanced disease. Jemal et al. CA Cancer J Clin 2007

5. Origins of treatment Chemotherapy • improve cure rates • enhance functional outcome • preserve larynx Radiation Radical surgical resection Historical treatment prior to 1991 30-50% cure rates Jemal et al. CA Cancer J Clin 2007

6. Induction chemotherapy

8. Department of Veterans Affairs (VA) Laryngeal Cancer Study Group 332 patients Stage III and IV laryngeal cancer Induction chemo followed by XRT -3 cycles of 5-FU and cisplatin -66-76 Gy Laryngectomy with adjuvant XRT Assessment after 2nd cycle Salvage laryngectomy 3rd cycle and XRT VALCSG. N Eng J Med 1991

9. Results • Local recurrence was increased in the induction chemotherapy/radiation arm (p=0.0005), but fewer distant metastases occurred (p=0.016). VALCSG. N Engl J Med 1991

10. Summary • Treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx. • Overall survival is not compromised if induction chemotherapy is used instead of surgery.

12. EORTC Head and Neck Cancer Cooperative Group 202 patients Locally advanced hypopharyngeal cancer Induction chemo followed by XRT - cisplatin [100 mg/m2] on day 1 - 5-FU [1000 mg/m2 per day] on days 1-5 Radical surgery with adjuvant XRT - 50-70 Gy Complete response after 2nd or 3rd cycle Radical surgery followed by XRT - 50-70 Gy Radiation therapy - 70 Gy Lefebre et al. J Natl Cancer Inst 1996

13. Results Lefebre et al. J Natl Cancer Inst 1996

14. Patterns of failure • Distant failures were lower in the induction arm. (p =.041) Lefebre et al. J Natl Cancer Inst 1996

15. Induction strategy conclusions • Median duration of survival is equivalent if induction chemotherapy or surgery are used. • Increased laryngeal function preservation in 3 and 5 year follow-ups. • 64% two years out (VA) and 35% in 5 years (EORTC) • Fewer distant metastases occur with induction chemotherapy at the expense of local progression. • Quality of life can be improved with organ preservation.

16. Concurrent chemotherapy • Table 2 of evolution of clinical trials with emphasis on operable trials

17. Issue: Volume 21(1), 1 January 2003, pp 92-98

18. Adelstein et al Phase III trial • Principal study objective: • Evaluation of overall survival. • Additional objectives: • Disease -specific survival and complete response rate. • Toxicity. • Recurrence patterns. Is chemotherapy really needed to cure? Adelstein et al. J Clin Oncol 2003

19. Radiotherapy - 70 Gy in 35 fractions of 2Gy over 7 weeks 5-FU and cisplatin with split XRT - cisplatin [75 mg/m2] on day 1 every 4 weeks - three courses of 5-FU [1000 mg/m2 per day] for 4 days - 60-70 Gy in split doses on 1st and 3rd chemo course Concurrent chemo and XRT - cisplatin [100 mg/m2] on days 1,22 and 43 - 70 Gy Adelstein et al Phase III trial 295 patients Locally advanced head and neck cancer • Inclusion criteria • Stage III or IV with no distant mets • SCC or undifferentiated ca. • ECOG of 0 or 1 • adequate hematologic, hepatic and renal fx • normal serum calcium • - no prior treatment or previous malignancy Complete response after 2nd cycle Surgical resection followed 3rd cycle CRT 3rd cycle and XRT Adelstein et al. J Clin Oncol 2003

20. Results • Concurrent treatment had better overall survival than radiation (p=.014) *Complete response not statistically significant between XRT and concurrent (p=.07); split XRT response includes mid-treatment surgical resection patients. ** Disease specific survival in concurrent was better than XRT (p=.01); no statistical difference in split. Adelstein et al. J Clin Oncol 2003

21. Toxicity (grade 3-5) Adelstein et al. J Clin Oncol 2003

22. Conclusions • Concurrent treatment with single-agent cisplatin had better overall survival than radiation therapy alone. (p=.014) • Disease specific survival is statistically better in concurrent chemotherapy treatment. • Toxicity was greater when chemotherapy was added to the radiation treatment.

23. Radiation Therapy Oncology Group (RTOG) 91-11 study Is induction chemotherapy an essential component of organ preservation?

24. Objective • Is induction chemotherapy an essential component of organ preservation? • Assess the efficacy and toxicities of cisplatin when added concurrently to radiation. • Compare the rates of laryngeal preservation associated with the different treatment options. Forastiere et al. N Eng J Med 2003

25. Radiotherapy - 70 Gy in 35 fractions of 2Gy over 7 weeks 5-FU and cisplatin followed by XRT - cisplatin [100 mg/m2] of body-surface area on day 1 - 5-FU [1000 mg/m2 per day] for 120 hrs - 50-70 Gy Concurrent chemo and XRT - cisplatin [100 mg/m2] on days 1,22 and 43 - 50-70 Gy Intergroup study RTOG 91-11 547 patients Locally advanced laryngeal cancer • Inclusion criteria • - Curable with sx • Karnofsky greater than 60 • WBC greater than 3,500 • platelets greater than 100,000 • normal calcium and CrCl at least 50ml/min Complete or partial response after 2nd cycle Radical surgery followed by XRT 3rd cycle and XRT Forastiere et al. N Eng J Med 2003

26. Results Forastiere et al. N Eng J Med 2003

27. Rate of laryngeal preservation Median follow-up: 3.8 yrs: CRT vs induction (p=0.005): - 84%/72% CRT vs XRT (p=0.001): - 84%/67% Induction vs XRT (p=0.27): - 72%/67% Forastiere et al. N Eng J Med 2003

28. Rates of locoregional control 2-yr follow-up: CRT vs induction (p=0.004): - 80%/64% CRT vs XRT (p=0.001): - 80%/58% Induction vs XRT (p=0.15): - 64%/58% Forastiere et al. N Eng J Med 2003

29. Acute toxic effects Forastiere et al. N Eng J Med 2003

30. Summary • Concurrent treatment has better locoregional control and larynx preservation rates over induction chemotherapy or radiation alone. • Laryngectomy free survival was similar between induction chemotherapy and concurrent treatment. • Disease free survival is improved in chemotherapy arms compared to radiation alone. • Overall survival was statistically similar in all arms. • Toxicity was higher compared to radiotherapy alone.

31. 5-year update on RTOG 91-11 Chemotherapy does preserve larynx!! Journal of Clinical Oncology, ASCO Annual Meeting Proceedings 2006

32. Summary • Concomitant chemotherapy provided a pronounced effect on loco-regional control while induction chemotherapy had a better effect on distant metastases. Are induction and concomitant chemotherapies complimentary?

33. How to give effective chemotherapy and reduce toxicity?

34. Volume 357 October 25, 2007 Number 17

35. TAX 323 Phase III Study • Primary objective: • Evaluation of progression-free survival. • Secondary: • Overall survival • Best overall response rate after completing treatment. • Duration of response • Toxic effects • Health related quality of life. Vermorken et al. N Engl J Med 2007

36. PF - Cisplatin 100 mg/m2 on day 1 - 5-FU 1000 mg/m2 per day for 5 days TPF - Docetaxel 75mg/m2 on day 1 - Cisplatin 75mg/m2 on day 1 - 5-FU 750mg/m2 per day for 5 days TAX 323 Study • Inclusion criteria • Stage III or IV considered unresectable • previously untreated • ECOG of 0 or 1 • adequate hematologic, hepatic and renal fx • normal serum calcium 358 patients Stage III and IV head and neck cancer Assessment after 2nd cycle Complete 4 cycles followed by XRT Discontinuation of chemotherapy

37. Results • TPF showed had more cases of neutropenia and alopecia. • PF has more cases of death, thrombocytopenia, stomatitis, nausea and vomiting. Vermorken et al. N Engl J Med 2007

38. Summary • Cisplatin and fluorouracil with docetaxel as induction chemotherapy showed significant improvements in progression free and overall survival over cisplatin and fluorouracil alone. • Triple regimen was better tolerated and allowed for fewer treatment delays.

39. Volume 357:1705-1715, October 25, 2007 Number 17

40. TAX 324 Phase III Study • Primary objective: • Evaluation of overal survival. • Secondary: • Progression-free survival. • Response rates after induction chemotherapy. • Toxic effects Posner et al. N Engl J Med 2007

41. PF - Cisplatin 100 mg/m2 on day 1 - 5-FU 1000 mg/m2 per day for 5 days TPF - Docetaxel 75mg/m2 on day 1 - Cisplatin 100mg/m2 on day 1 - 5-FU 1000mg/m2 per day for 4 days TAX 324 Phase III Study • Inclusion criteria • Stage III or IV considered unresectable or • or candidate for organ preservation. • previously untreated • ECOG of 0 or 1 • adequate hematologic, hepatic and renal fx • no other active cancer 501 patients Stage III and IV head and neck cancer 25% reduction after 2nd cycle Complete 3 cycles followed by weekly carboplatin and XRT (70 Gy) Salvage therapy Posner et al. N Engl J Med 2007

42. Results Posner et al. N Engl J Med 2007

43. Toxicity effects • TPF arm had more grade 3 and 4 hematologic toxic effects. • TPF had fewer treatment delays. Posner et al. N Engl J Med 2007

44. Summary • Longer overall and progression-free survival are seen with induction TPF chemotherapy followed by chemoradiation compared to cisplatin and 5-FU alone. • TPF reduced risk of death by 30% compared with PF. • A nonsignificant reduction in overall toxic effects was seen in the TPF group. • TPF group had a significant reduction in locoregional failure over PF. • No difference was seen for distant metastases.

45. Subgroup Update • Locally advance laringeal and hypopharyngeal cancer have greater risk of distant metastases and poorer locoregional control. Posner et al. Ann Oncol 2009

46. TAX 324 Subgroup analysis • Estimated 3-year survival of 57% in TPF group compared with 40% in the PF group. Posner et al. Ann Oncol 2009

47. Targeted therapy

48. Role of targeted therapy • EGFR is a cell-surface protein that regulates growth and differentiation of cells. • Over-expressed in up to 90% of head and neck cancers compared to normal mucosa. • Correlation with decreased survival. • Monoclonal antibodies can bind to the extracellular domain of EGFR and prevent downstream signaling.

49. Volume 354:567-578, February 9, 2006 Number 6

50. Bonner et al Phase III trial • Primary objective: • Evaluate the duration of control of locoregional disease. • (absence of progression at scheduled follow-ups.) • Secondary: • Overall survival. • Progression-free survival. • Response rates. • Safety. Bonner et al. N Engl J Med 2006