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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. Learning objectives. Explain the need for chemotherapeutic treatment for patients with squamous cell carcinoma of the head and neck.

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role of chemotherapy in la hnc the art of timing and selection

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

learning objectives
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.
epidemiology
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

epidemiology1
Epidemiology

Five-year relative survival rate

  • More than 60% of patients present with locally-advanced disease.

Jemal et al. CA Cancer J Clin 2007

origins of treatment
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

department of veterans affairs va laryngeal cancer study group
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

results
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

summary
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.
eortc head and neck cancer cooperative group
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

results1
Results

Lefebre et al. J Natl Cancer Inst 1996

patterns of failure
Patterns of failure
  • Distant failures were lower in the induction arm. (p =.041)

Lefebre et al. J Natl Cancer Inst 1996

induction strategy conclusions
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.
concurrent chemotherapy
Concurrent chemotherapy
  • Table 2 of evolution of clinical trials with emphasis on operable trials
slide18

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

adelstein et al phase iii trial

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

results2
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

toxicity grade 3 5
Toxicity (grade 3-5)

Adelstein et al. J Clin Oncol 2003

conclusions
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.
radiation therapy oncology group rtog 91 11 study
Radiation Therapy Oncology Group (RTOG) 91-11 study

Is induction chemotherapy an essential component of organ preservation?

objective
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

intergroup study rtog 91 11

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

results3
Results

Forastiere et al. N Eng J Med 2003

rate of laryngeal preservation
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

rates of locoregional control
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

acute toxic effects
Acute toxic effects

Forastiere et al. N Eng J Med 2003

summary1
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.
5 year update on rtog 91 11
5-year update on RTOG 91-11

Chemotherapy does preserve larynx!!

Journal of Clinical Oncology, ASCO Annual Meeting Proceedings 2006

summary2
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?

tax 323 phase iii study
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

tax 323 study

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

results4
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

summary3
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.
tax 324 phase iii study
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

tax 324 phase iii study1

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

results5
Results

Posner et al. N Engl J Med 2007

toxicity effects
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

summary4
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.
subgroup update
Subgroup Update
  • Locally advance laringeal and hypopharyngeal cancer have greater risk of distant metastases and poorer locoregional control.

Posner et al. Ann Oncol 2009

tax 324 subgroup analysis
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

role of targeted therapy
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.
bonner et al phase iii trial
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

slide51

Bonner et al Phase III trial

424 patients

Locally advanced head and neck cancer

Cetuximab with XRT

- 400 mg m2 of body-sruface area x 1 wk prior

- 250 mg/m2 following doses

Radiotherapy alone

- 70-76 Gy

  • Inclusion criteria
  • Stage III or IV nonmetastatic oropharyngeal, hypopharyngeal,
  • or laryngeal squamous cell carcinoma.
  • previously untreated.
  • Karnofsky performance greater than 60.
  • adequate hematologic, hepatic and renal fx.
  • no other active cancer.

Bonner et al. N Engl J Med 2006

results6
Results

Bonner et al. N Engl J Med 2006

summary5
Summary
  • Addition of cetuximab to high-dose radiotherapy increases duration of locoregional disease control and survival.
  • There is no association with an excess of severe toxic effects.
conclusions1
Conclusions
  • Concomitant chemotherapy provided a pronounced effect on loco-regional control while induction chemotherapy had a better effect on distant metastases.
  • Toxicity when using chemotherapy agents has a limiting factor when treating patients with comorbidities.
  • Combination chemotherapy with taxanes, cisplatin and 5-FU for induction regimens could potentially lead to longer overall and progression-free survival with less toxicity.
  • Cetuximab as concomitant, induction or sequential treatment could have the potential to increase cure rates without increased toxicity.
ongoing studies
Ongoing studies
  • RTOG 0522: randomized phase III trial
      • Stage III and IV head and neck carcinomas
      • concurrent accelerated XRT/cisplatin versus concurrent accelerated XRT/cisplatin, and cetuximab (followed by surgery for selected patients).
  • Paccagnella
      • Taxotere, cisplatin and 5-FU induction chemotherapy followed by cetuximab/XRT vs chemoradiation.
other monoclonal antibodies and tki s for la hnscc
Other monoclonal antibodies and TKI’s for LA-HNSCC
  • Monoclonal antibodies
    • Nimotuzumab plus cisplatin/radiotherapy.
    • Panitumumab plus induction chemotherapy.
  • TKI’s
    • Lapatinib plus combined chemotherapy and XRT.
    • Erlotinib plus bevacizumab.
hpv in head and neck cont d
HPV in head and neck (cont’d)
  • Stina Syrjanen 1983
    • 40% of cancers contained histological and morphological similarities with HPV-related lesions.
  • Kreimer AE, et al (Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2))
    • Meta-analysis using 60 studies worldwide that used PCR detection.
      • Overall HPV prevalence of 26% (35.6% oropharyngeal, 23% oral, 24% laryngeal)
      • HPV 16 made up 86.7% of oropharyngeal cases. (95% CI)
      • HPV 18 was the second most common present. (1-5%)
  • D’Souza (J Infect Dis 2009 May 1;99(9))
    • Oral sex and open mouth kissing are associated with the development of oral HPV infection.
hpv in head and neck cont d1
HPV in head and neck (cont’d)
  • Mechanisms of carcinogenesis
    • E6 and E7 oncogenes enhance degradation of p53 and RB tumor suppressor genes.
      • Immortalization of oral keratinocytes.
  • HPV can be integrated, episomal or mixed to cell DNA.
    • Episomal forms tend to have larger tumor size.
  • Viral load tend to vary considerably.
    • Lower concentrations than cervical mucosa.
    • The higher the viral load, the better prognosis.
      • Mellin et al 2002 showed patients with > 190 HPV copies/Beta-actin had better clinical outcome and 3 year disease free survival.

Goon PK, et al. Head and Neck Oncology 2009, 1:36

interesting questions
Interesting questions

Will vaccination reduce cancer rates?

Should adults and men be vaccinated as well?