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  • Welcome. My name is Corey J. Langer, MD, FACP, and I am Professor of Medicine at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, Pennsylvania. This presentation will review recent advances in the therapy of head and neck cancer using a case-based approach.
  • HPV, human papillomavirus; OP, oropharynx;.   Head and neck cancer is growing in incidence. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. Patients typically are older (older than 50 years of age) with a history of tobacco and alcohol use. Over the past 5-10 years, a cohort of nonsmokers or minimal smokers has emerged who are human papillomavirus (HPV) positive; these patients tend to have cancers of the oropharynx. The predominant histology has been and remains squamous cell carcinoma, and at least in the early stages of disease, these cases are highly curable with long-term survival rates of > 80%. Locally advanced disease has a much poorer prognosis with 5-year survival rates of < 40% and the majority of disease deaths in head and neck cancer are caused by uncontrolled locoregional relapse.
  • SPT, second primary tumor.   Approximately one third of patients present with early stage I or II disease. In that group, second primary tumors pose a far greater risk than recurrences of the original primary tumor, and it is not unusual to see patients who have successfully been treated for 2, 3, or even 4 cancers of the head and neck only to succumb to their fifth or sixth head and neck cancer diagnosis.   Approximately two thirds of patients have stage III or IV disease. Multimodal therapy is the standard approach in this setting and usually consists of a combination of surgery, radiation, and, increasingly, chemotherapy. The rate of local recurrences far exceeds the rate of distant recurrences, and this feature distinguishes head and neck cancer from other epithelial malignancies such as colorectal, breast, and lung cancer where distant relapse is the most frequent cause of death.
  • Prognosis is based on disease stage, with stage I and II patients having the highest 5-year survival rates of 85% and 70%, respectively. Stage III and IV patients have 5-year survival rates of 55% and 30%, respectively, and those with locally advanced, unresectable disease have a 5-year survival rate of only 10%.
  • SCCHN, squamous cell carcinoma of the head and neck.   In the 1970s, active cytotoxics were identified that yielded high rates of response in the neoadjuvant setting. In the 1980s, phase III trials tested these neoadjuvant approaches in the context of definitive local treatment. A decrease in the incidence of distant metastasis was observed, but unfortunately, these studies showed no evidence of improved locoregional control or survival. In selected circumstances, the induction approach coupled with radiation was particularly effective in preserving the larynx and avoiding surgery.
  • DM, distant metastasis; SCCHN, squamous cell carcinoma of the head and neck.   In the 1990s, randomized trials of chemoradiation emerged. Compared with radiation alone, chemoradiation resulted in improvements in locoregional control and survival. It also resulted in a significant increase in acute and late toxic effects. Investigators noted improvements in organ preservation rates and site-specific benefits, not only in the larynx, but in the nasopharynx and the oropharynx as well. In some of these trials, distant metastasis predominated as the first site of recurrence, contrasting with previous findings.
  • HPV, human papillomavirus; LRC, locoregional control; OP, oropharynx; OS, overall survival; PF, cisplatin/5-fluorouracil; PFS, progression-free survival; SCCHN, squamous cell carcinoma of the head and neck.   During the last 10 years, chemoradiation in the postoperative, high-risk setting has emerged as a superior treatment approach, particularly for patients with positive margins or evidence of extracapsular nodal extension. Cetuximab in combination with radiation has resulted in improved locoregional control and survival. There has also been a renewed interest in neoadjuvant treatment with the introduction of taxanes, particularly docetaxel, which in the context of radiation has led to improvements in distant failure rates and overall survival (OS).   In addition, HPV has emerged as a marker of outcome, particularly in nonsmokers with oropharyngeal carcinoma. These patients have achieved far better outcomes than head and neck cancer patients whose disease is caused by tobacco and alcohol use.
  • CT, computed tomography; DL, direct laryngoscopy; FNA, fine-needle aspirate; LN, lymph node; OP, oropharynx; PE, physical examination; PET, positron emission tomography; WF, white female; W/U, workup.   The first case patient is a 57-year-old white female minimal past cigarette smoker who presents with a 4-week history of sore throat, 10-lb weight loss, and pain on swallowing. She notes a lump on the left side of her neck. Physical exam reveals a 3 cm left tonsillar mass that extends to the posterior oropharynx and multiple bilateral lymph nodes ranging in size from 1-2 cm. A computed axial tomography scan confirms these findings. A fine-needle aspirate of the left cervical node shows classical squamous cell carcinoma and the remaining workup, including positron emission tomography and direct laryngoscopy, is negative for other sites of disease.
  • OP, oropharynx; WF, white female.   This slide shows the patient’s computed axial tomography scan. The primary mass in the left oropharynx extending into the posterior pharyngeal wall is visible as are necrotic lymph nodes in both sides of the neck.
  • What is the stage of her cancer? 1) stage III, 2) stage IVA, 3) stage IVB, or 4) stage IVC. Please submit your answer now.
  • As with all epithelial malignancies, the TNM system is used to stage squamous cell carcinoma of the head and neck. T1 tumors are 2 cm or smaller or confined to a single anatomic subsite. T2 tumors are somewhat larger—2-4 cm—with extension to an adjacent subsite or causing impairment of the vocal cord. T3 tumors are still larger, > 4 cm, or exhibit fixation to the vocal cord. T4 tumors have massive local invasion or involvement of adjacent organs. According to these definitions, the case patient has T2 disease; the tumor is > 2 cm but < 4 cm.
  • Nodal staging is as follows: N1, a single unilateral node measuring 3 cm or smaller; N2a, a single unilateral node larger than 3 cm but not larger than 6 cm; N2b, multiple unilateral nodes on the same side but none larger than 6 cm; N2c, a contralateral node or bilateral nodes, none larger than 6 cm; and N3, any node > 6 cm. Based on this paradigm for nodal staging, the case patient has N2c disease.
  • SCCHN, squamous cell carcinoma of the head and neck.   Stage I and stage II disease are defined as T1N0 and T2N0, respectively. This patient has nodal involvement and, therefore, does not have stage I or II disease. The nodal disease is bilateral, or N2c as noted previously, and this patient falls into the stage IVA category with T2N2M0 disease.
  • RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil.   What is the most appropriate therapeutic strategy for this patient? 1) concurrent radiation and full-dose cisplatin, 2) induction therapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by radiation and low-dose concomitant chemotherapy, 3) concurrent radiation and cetuximab, 4) any of the above, or 5) none of the above. Please submit your answer now.
  • 5-FU, 5-fluorouracil; CI, confidence interval; HR, hazard ratio; RT, radiation therapy; SCCHN, squamous cell carcinoma of the head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil.   This slide summarizes most of the important phase III trials investigating current therapy for locally advanced head and neck cancer including a number of trials examining the efficacy of platinum-based chemotherapy plus radiation compared with radiation alone, a landmark trial conducted by Bonner and colleagues evaluating the role of cetuximab plus radiation vs radiation alone, and several induction trials evaluating TPF vs cisplatin and 5-fluorouracil (PF) induction regimens, followed by radiation or low-dose radiation and carboplatin. The survival hazard ratios (HR) for the comparisons consistently ranged from 0.70-0.75, indicating a survival benefit for each of these approaches. In aggregate, an approximate 10% absolute improvement in 2- and 5-year survival rates was obtained with each treatment strategy relative to the comparator approach.
  • HNC, head and neck cancer; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; NPC, nasopharyngeal carcinoma; ORR, overall response rate; RR, relative risk.   This meta-analysis was published almost a decade ago and includes 63 randomized trials conducted over a nearly 30-year period in more than 10,000 patients with a median follow-up of 6 years. The introduction of platinum-based chemotherapy to radiation reduced the relative risk of death to 0.89. Concomitant approaches yielded the greatest absolute benefit in the 5-year OS rate at 8% compared with only 1% for adjuvant approaches and 2% for induction. The P value for improved survival with concomitant chemoradiation was < .0001.
  • CMT, combined modality therapy; MACH-NC, meta-analysis of chemotherapy in head and neck cancer.   An updated meta-analysis of chemotherapy in head and neck cancer included 24 additional trials for a total of nearly 18,000 patients. Median follow-up at this point was 5 years and in this more homogeneous population, an 8% absolute improvement (4.5% at 5 years in the updated analysis) in long-term survival for combined modality approaches, specifically concurrent chemoradiation, was observed.   There were no differences in the survival benefit based on anatomic site including oral cavity, oropharynx, hypopharynx, or larynx. There were also no major differences regarding T or N staging. However, age clearly made a difference: patients younger than 50 years of age had a 24% absolute improvement in survival, but that survival benefit tended to decrease as patients aged; those older than 70 years of age had only a 3% improvement in survival. This finding raises an important question: should elderly patients be treated with an aggressive combined modality approach featuring cisplatin?
  • 5-FU, 5-fluorouracil; Carbo, carboplatin; cDDP, cisplatin; CT, chemotherapy; F/U, follow-up; LA-SCCHN, locally advanced squamous cell carcinoma of the head and neck; LV, leucovorin; RT, radiation therapy.   This slide highlights several individual trials from North America and abroad. The themes of these trials are very similar: radiation alone vs radiation and concomitant platinum-based chemotherapy, often including cisplatin either alone or combined with 5-fluorouracil. In each case, an approximately 15% to 30% absolute improvement in long-term survival is obtained with combined chemoradiation. These are some of the most impressive improvements in survival observed in solid tumor oncology.
  • Concomitant chemoradiation clearly improves locoregional control, can facilitate organ preservation, and has a beneficial impact on survival. But there are negative effects as well: The incidence of severe acute mucositis goes up 2-fold and in some cases 3-fold; there is often a tendency to use this approach excessively, sometimes in patients with earlier-stage disease; and there can be long-term functional deficits in speech, swallowing, and mobility even with preservation of head and neck organs.
  • CR, complete response; HP, hypopharynx; HR, hazard ratio; L, larynx; LP, larynx preservation; OS, overall survival; PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; PR, partial response; T, docetaxel; TPF, docetaxel, cisplatin, 5-fluorouracil.   An alternative approach is to use induction therapy to cytoreduce tumors and then use local modalities after the tumor volume has decreased. In the past 5-10 years, there has been a number of studies adding taxanes to standard 5-fluorouracil/platinum induction regimens. Most of these studies have featured docetaxel. With 1 exception, these studies used subsequent radiation alone or radiation with low-dose weekly platinum. In each study, the addition of a taxane was associated with a significant improvement in local control rates, in response rates, both partial and complete responses, and in progression-free survival (PFS). At least 2 studies also demonstrated a significant improvement in OS and we will review those studies now.   For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Oncology%20June%202006/Tracks/Head%20and%20Neck/Capsules/5506.aspx   For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Oncology%20June%202006/Tracks/Head%20and%20Neck/Capsules/5516.aspx   For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Oncology%20June%202006/Tracks/Head%20and%20Neck/Capsules/SPS24.aspx
  • 5-FU, 5-fluorouracil; AF, accelerated fractionation; CF, conventional fractionation; HF, hyperfractionation; HR, hazard ratio; PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; R, randomization; SCCHN, squamous cell carcinoma of the head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil.   The first study was conducted by Vermorken and colleagues comparing TPF with PF followed by radiation; surgery was used as salvage treatment. The trial enrolled patients with unresectable head and neck cancer. The doses used in the standard arm were 100 mg/m^2 of cisplatin on Day 1 and 1 g/m^2 daily continuous infusion of 5-fluorouracil on Days 1-5 for up to four 21-day cycles. In the experimental arm, docetaxel was added at 75 mg/m^2 on Day 1 and both cisplatin and 5-fluorouracil doses were attenuated. Patients had the option of either going on to conventional once-daily fractionated radiation or accelerated or hyperfractionated regimes with a concomitant boost at the conclusion of radiation.
  • OS, overall survival; PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; TPF, docetaxel, cisplatin, 5-fluorouracil.   An improvement in median PFS was observed with TPF vs PF ( P = .007) and that translated into an OS advantage with a log-rank P value of .02.
  • HR, hazard ratio; OS, overall survival; PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; TPF, docetaxel, cisplatin, 5-fluorouracil.   A similar study, TAX 324, was conducted by Posner and colleagues, also comparing TPF with PF. Unlike the study by Vermorken and colleagues, the doses of 5-fluorouracil and cisplatin in the experimental arm were not attenuated. A significant improvement in OS with TPF vs PF was also observed in this trial: the 3-year OS rates were 62% vs 48%, respectively, with a very impressive P value of .006 and an HR of 0.70.
  • Carbo, carboplatin; CB, concomitant boost; chemoRT, chemoradiation therapy; DFCI, Dana-Farber Cancer Institute; RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil.   An important question is whether induction therapy improves outcomes in the context of full-dose chemoradiation. The Southwest Oncology Group intended to proceed with a phase III trial addressing this question in oropharyngeal cancer, but unfortunately with the dissolution of the head and neck committee in the Southwest Oncology Group, this trial has not gone forward. There have been 2 other phase III trials, the PARADIGM trial orchestrated through the Dana-Farber Cancer Institute and the DECIDE trial orchestrated by the University of Chicago. Although both of these trials have since been closed to accrual, neither met the intended accrual targets.   The PARADIGM trial is examining TPF followed by an adaptive strategy featuring low-dose carboplatin and radiation in patients with excellent responses. Patients with less impressive responses received full-dose platinum therapy with concomitant boost radiation. The control arm received full-dose platinum with concomitant boost radiation. The trial was slated to accrue 300 patients, but accrued only 150.   The DECIDE trial compared split-course radiation with 5-fluorouracil and hydroxyurea vs the same approach preceded by 2 cycles of TPF. Docetaxel is continued during concurrent chemoradiation in the experimental arm. This trial was originally slated to accrue 400, and ultimately, it accrued fewer than 300 patients, although the time to accrual was sufficiently prolonged that the investigators believe that the trial is still adequately powered to address this question.   As of yet, the final data from these trials are not available, but they are expected in the next 1-2 years and should provide some insight into whether the use of induction therapy can improve outcomes with full-dose chemoradiation.
  • MCH-1 HN Slides V3 7-17-06.ppt 07/16/10 12:27 EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; SCCHN, squamous cell carcinoma of the head and neck.   An alternative therapeutic approach for the treatment of head and neck cancer involves targeting the epidermal growth factor receptor (EGFR). Expression of EGFR is ubiquitous in squamous cell malignancies of the head and neck: ≥ 95% of patients express EGFR, a far greater proportion than in other epithelial malignancies. There is a clear correlation between the intensity of EGFR expression and outcome; those with relatively low levels of EGFR expression tend to have better survival rates. In the context of patients treated with radiation, high levels of EGFR are correlated with an increased risk of locoregional failure but no increased risk in distant metastasis.
  • EGFR, epidermal growth factor receptor; IgG, immunoglobulin G.   The only approved agent in head and neck cancer that targets EGFR is cetuximab. Cetuximab is a chimerized antibody exclusive for EGFR and its heterodimers. It prevents repair and survival of tumor cells that have been damaged by the effects of chemotherapy and radiation, potentiates apoptosis, inhibits cell cycle progression, decreases the production of angiogenic factors, and ultimately inhibits tumor invasion and metastases.
  • RT, radiotherapy.   Work by Milas and colleagues has shown synergy between cetuximab and radiation. In A431 xenografts, multiple doses of cetuximab grafted onto a single dose of radiation led to radiation enhancement ratios that were nearly 4-fold higher than with radiation alone.
  • AJCC, American Joint Committee on Cancer; C, cetuximab; RT, radiation therapy.   These observations in the preclinical arena ultimately led to phase I, phase II, and phase III studies evaluating the role of cetuximab in the context of standard radiation in head and neck cancer. Bonner and colleagues published the results of this critical phase III trial 3 years ago . Patients were randomized to radiation alone or to radiation plus concomitant cetuximab. To be eligible, patients had to have locoregionally advanced squamous cell carcinoma of either the oropharynx, hypopharynx, or larynx, and they needed to be candidates for definitive potentially curative radiotherapy with measurable disease and no previous treatment. The primary endpoint was duration of locoregional control. Secondary endpoints included OS, toxicity, and quality of life.
  • C, cetuximab; EGFR, epidermal growth factor receptor; RT, radiation therapy.   Patients were well matched in both treatment arms. Median age was approximately 57 years. There was no age cutoff in this trial; patients older than 80 years of age were enrolled. The ratio of men to women was approximately 4:1. Oropharynx was the primary tumor site in approximately 60% of patients whereas the larynx was the primary tumor site in approximately 25% of patients. Among patients who had their tumors assayed for EGFR expression, expression rates were uniform in both treatment arms; EGFR was detectable in approximately 80% of patients, and it was unknown in another 20% with insufficient tumor specimens.
  • C, cetuximab; RT, radiation therapy.   The only safety signal in this trial was skin reaction, as one would expect with an agent that targets EGFR. The incidence of grade 3/4 acneiform rash was almost 2-fold higher in the cetuximab arm (34% compared with 18%). There was no obvious exacerbation of radiation-induced mucositis by contrast to studies evaluating platinum therapy in the same setting; nor was there any obvious increase in the incidence of dysphasia, xerostomia, or fatigue. There were, as one would expect, infusion reactions associated with cetuximab that would not be seen in the control arm, but only 3% of patients experienced grade 3/4 infusion reactions.
  • C, cetuximab; RT, radiation therapy.   The addition of cetuximab was associated with a significant improvement in locoregional control at both 1 and 2 years, with a log-rank P value of .02. No significant improvement in the incidence of distant recurrences or second primary malignancies was observed in the combination arm, although there was a trend favoring the cetuximab arm. The cetuximab arm demonstrated an 8% advantage in the locoregional control rate at 2 years and a near doubling in median time to locoregional progression from 14.9 months in the control group to 24.4 months in the cetuximab group, with a P value of .005.
  • C, cetuximab; CI, confidence interval; HR, hazard ratio; RT, radiation therapy.   This outcome in turn translated into a 20-month improvement in median OS, from 29 months with radiation alone to 49 months with cetuximab plus radiation ( P = .018). The 2-year OS rate difference was 7% and the 3-year rate difference was 13% in favor of cetuximab. At 5 years, the difference in survival rates was maintained at 9%.
  • EGFR, epidermal growth factor receptor; HR, hazard ratio; RT, radiation therapy.   Bonner and colleagues also conducted an analysis of outcomes at a median follow-up of 5 years according to pretreatment characteristics. All patient subgroups demonstrated an improvement with the addition of cetuximab. This improvement was pronounced in patients with oropharyngeal carcinoma, T1-T3 disease as opposed to T4, those who received concomitant boost radiation as opposed to once-daily radiation, those with nodal involvement N1-N3, those with better performance status, male patients, those with EGFR expression measuring ≤ 50%, suggesting some potential saturation phenomenon, and finally, patients aged younger than 65 years.
  • CT, computed tomography; PET, positron emission tomography; SCCHN, squamous cell carcinoma of the head and neck.   The Radiation Therapy Oncology Group (RTOG) is formally testing whether the addition of cetuximab to standard full-dose platinum and radiation is better than chemoradiation alone. RTOG 0522 randomized patients to concomitant boost radiation with 2 doses of cisplatin per cycle vs full-dose radiation, cisplatin, and cetuximab during the concurrent approach. This trial was originally slated to accrue 720 patients; however, it accrued so rapidly that it was decided based on a pooled survival analysis to increase the accrual to 945 patients. The accrual completed in March 2009 and the results should be available in approximately the next 2 years.
  • 5-FU, 5-fluorouracil; P, cisplatin; PR, partial response; RT, radiation therapy; SCC, squamous cell carcinoma; T, docetaxel; TL, total laryngectomy.   European investigators are examining targeted therapy with an induction platform that integrates TPF followed by either full-dose platinum and radiation or cetuximab and radiation. This is the only trial that directly compares platinum/radiation therapy with cetuximab/radiation therapy. Patients with relatively poor responses to induction go on to surgical salvage with total laryngectomy and postoperative radiation. Patients with good responses are randomized to full-dose radiation with either platinum or cetuximab. Preliminary data from this trial, presented by Lefebvre and colleagues at the 2009 Annual Meeting of the American Society of Clinical Oncology, showed far better safety in the cetuximab arm.
  • HPV, human papillomavirus.   The next question regarding the initial case patient is: what is the likelihood that this patient’s tumor is HPV positive? 1) 25% to 35%, 2) 40% to 50%, 3) 60% to 65%, or 4) 80% to 85%. Please submit your answer now.
  • HPV, human papillomavirus.   In the context of chemoradiation, what absolute percentage improvement in survival is one likely to see in a patient whose primary tumor is HPV positive compared with a patient who is HPV negative? 1) 5% to 10%, 2) 10% to 15%, 3) 15% to 25%, or 4) 25% to 35%. Please submit your answer now.
  • HPV, human papillomavirus; SCCHN, squamous cell carcinoma of the head and neck.   Finally, is smoking a cofactor in prognosis in patients whose head and neck tumors are HPV positive, yes or no? Please submit your answer now.
  • HNC, head and neck cancer; HPV, human papillomavirus; OC, oral cavity; OP, oropharynx.   Gillison and colleagues examined outcome based on HPV status and found that patients who were HPV positive were far more likely to have oropharyngeal carcinoma, generally with primary tumors on the tonsil or at the base of the tongue. HPV-negative patients generally had laryngeal, oral cavity, and hypopharyngeal tumors. HPV-positive patients were younger and exhibited an even distribution of men and women compared with a 3:1 distribution for the HPV-negative group. Risk factors among HPV-positive patients included sexual transmission rather than tobacco or alcohol use. The incidence of HPV-positive tumors is increasing whereas the incidence HPV-negative tumors is decreasing. HPV-positive patients with head and neck cancer tend to be younger and therefore have fewer comorbidities relative to HPV-negative patients. Based both on a lower incidence of comorbidities and generally better clinical behavior, HPV-positive patients have a much better prognosis.
  • AUC, area under the curve; RT, radiation therapy. Some of the first data examining the influence of HPV on prognosis were from an Eastern Cooperative Oncology Group (ECOG) study by Fakhry and colleagues. Patients with oropharynx and larynx cancer received induction therapy with paclitaxel and carboplatin followed by full-dose radiation and weekly paclitaxel.
  • HPV, human papillomavirus; OP, oropharynx; OS, overall survival; PFS, progression-free survival.   Of patients with oropharyngeal and laryngeal carcinoma, 40% proved to be HPV positive. Response rates were significantly higher in the HPV-positive group, 82% vs 55% in the HPV-negative group after induction therapy, and that difference translated into a significant improvement in 2-year PFS ( P = .02) and OS ( P = .005); HPV-positive patients experienced more than a 30% improvement in the 2-year OS rate relative to HPV-negative patients.
  • AFX-C, accelerated fractionation by concomitant boost; SFX, standard fractionation.   More recently, Gillison and colleagues have looked at a much larger cohort from the RTOG 0129 study in which the incidence of HPV-positive tumors was 64%. In study RTOG 0129, patients were randomized to full-dose radiation given either once daily or with accelerated concomitant boost, each coupled with cisplatin. Patients were stratified by tumor site, nodal stage, and performance status. The investigators looked at both HPV16 by fluorescence in situ hybridization and P16 by immunohistochemistry and the statistical analysis included both OS and PFS with comparisons by log-rank test and Cox proportional hazard.
  • CI, confidence interval; HPV, human papillomavirus.   Of 721 patients, 60% had oropharyngeal primary tumors. Of these, 75% had HPV determination. A total of 64% of 323 patients with HPV determination were HPV positive and there was good correlation between fluorescence in situ hybridization and P16 immunohistochemistry analysis.
  • HPV, human papillomavirus; PS, performance score.   The HPV-positive group tended to be younger, was more likely to be white (92% vs 75%; P < .001), and had better performance status relative to the HPV-negative population (68% of HPV-positive patients had a Zubrod performance score of 0 vs 56% of HPV-negative patients; P = .03). HPV-positive patients also tended to have lower T stage, T2 or 3 vs T4, and to have far fewer pack-years of smoking: more than 50% had smoked < 20 pack-years compared with only 22% in the HPV-negative group.
  • HPV, human papillomavirus; OS, overall survival; PFS, progression-free survival.   The difference in 5-year OS rates according to HPV status was nearly 30% with a log-rank P value < .001.   A commensurate improvement in PFS was also observed: the 2-year PFS rate was more than 20% higher in the HPV-positive group vs the HPV-negative group ( P < .001). HPV-positive patients are also far less likely to develop second primary tumors, < 4% vs 11% in the HPV-negative group ( P = .01). Intriguingly, there was no significant difference in the incidence of distant metastases between the 2 groups ( P = .26).
  • CI, confidence interval; HPV, human papillomavirus; HR, hazard ratio; OS, overall survival.   Smoking is clearly still a cofactor among HPV-positive patients: the HR for death is 1.91 for HPV-positive patients with ≥ 20 pack-years of smoking compared with HPV-positive group who have < 20 pack-years. For HPV-negative patients with < 20 pack-years, the HR is 2.25 vs HPV-positive patients with < 20 pack-years, and for HPV-negative patients with ≥ 20 pack-years, the HR increases to 4.30.   HPV-positive patients with ≥ 20 pack-years and HPV-negative patients with < 20 pack-years represent an intermediate group who fare better than HPV-negative patients with ≥ 20 pack-years, but worse than HPV-positive patients with < 20 pack-years. The cooperative groups now are trying to establish dedicated protocols for this intermediate cohort.
  • HPV, human papillomavirus; IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival.   HPV status is a strong and independent predictor of OS and PFS for patients with oropharyngeal cancer. The rates for locoregional but not distant recurrence are lower in HPV-positive patients. P16 immunohistochemistry is highly correlated with tumor HPV status and is a valid surrogate marker that is easier to determine. Tobacco use appears to modify the biologic behavior of an HPV-positive tumor. At a minimum, HPV status or P16 status should be a stratification factor in clinical trials that include patients with oropharyngeal primary tumors.
  • HPV, human papillomavirus; MOA, mechanism of action, Tx, treatment.   The cooperative groups now are mounting separate trials for HPV-positive and HPV-negative patients. The goal in the HPV-positive cohort is to deintensify treatment and emphasize toxicity mitigation. HPV-negative trials will likely intensify therapy and add new agents with new mechanisms of action.
  • RT, radiation therapy.   The case patient opts for concurrent radiation and cetuximab. She receives 6 weekly doses of cetuximab and > 50 Gy of radiation therapy but then develops grade 3 acneiform rash across her face and chest.
  • RT, radiation therapy; Tx, treatment.   What should you do next? 1) suspend both radiation and cetuximab, 2) suspend cetuximab only, 3) treat the rash with topical clindamycin ointment and oral doxycycline but continue both radiation and cetuximab, or 4) apply topical steroids. Please submit your answer now.
  • EGFR, epidermal growth factor receptor; HSR, hypersensitivity reaction; TKI, tyrosine kinase inhibitor.   Rash is ubiquitous with the EGFR inhibitors; 70% to 80% of patients will experience some level of rash. However, the rash reaches grade 3 severity in 10% or fewer patients. At a minimum, clindamycin ointment or gel is used for treatment. In many patients oral tetracycline, doxycycline, or minocycline is useful. Over time, the rash tends to recede from the face and chest to the hands and feet and often the hairline. In patients who receive more than 8-10 weeks of cetuximab, which generally is not the case with concomitant radiation therapy, nail dystrophy or fissures often occur.   The incidence of hypersensitivity reactions is approximately 3% to 5% and is worse in the hypersensitivity reaction belt, which intriguingly is centered in the Carolinas and in Tennessee in the United Sates where the rates are as high as 20%. Cardiac toxicity is rare and hypermagnesemia has been observed only in the context of platinum-based therapy. Hypermagnesemia is often severe; however, its clinical effects are uncertain. Diarrhea is far less common with cetuximab than with oral tyrosine kinase inhibitors.
  • EGFR, epidermal growth factor receptor.   The skin reaction algorithm shown on this slide was developed by Lynch and colleagues in 2007. For milder rash, using topical hydrocortisone or clindamycin gel is reasonable; for moderate rash, continuing these agents and adding oral antibiotics is the proper approach; and finally, for more severe rash, a methylprednisolone dose pack is often introduced in addition to the treatments mentioned above and, in some cases, the dose of the EGFR inhibitor can be reduced or suspended for 1-2 cycles.   It is important to be proactive in managing the skin reactions associated with EGFR-targeted therapy: avoiding sun exposure, using thick, alcohol-free emollient creams, and, as with any cancer patient, using sunscreen with sun protection factors of 15 or higher are important measures. KEY POINT: Skin rash can be managed with appropriate intervention.
  • Bx, biopsy; CT, computed tomography; HNC, head and neck cancer; LN, lymph node; PE, physical examination; WM, white male.   The second case patient is a 68-year-old white male smoker with 80 pack-years of smoking history who presents with hoarseness and a nodule on the right side of his neck. Physical examination shows a 2.5-cm supraglottal mass on the right and a 1.5-cm ipsilateral node. A computed axial tomography scan of the head and neck confirms these findings. Biopsy of both the node and the primary tumor demonstrates keratinizing squamous cell carcinoma. The remaining workup is negative.
  • Bx, biopsy; CT, computed tomography; R, right; SGL, supraglottal larynx.   This image shows a bulging mass in the supraglottal larynx on the right with a distinct 1.5-cm posterior triangle right neck node. Computed tomography of the chest and brain are negative. The laryngoscopy confirms involvement in the false vocal cord extending to the true vocal cord on the right and the medial wall of the pyriform sinus, but the vocal cord remains mobile.
  • What is the stage of this patient’s cancer? 1) stage II, 2) stage III, 3) stage IVA, or 4) stage IVB. Please submit your answer now.
  • SCCHN, squamous cell carcinoma of the head and neck.   As with the first case, the tumor is between 2-4 cm extending to an adjacent subsite or impairment of the vocal cord; in this particular case there is no vocal cord impairment. The patient also has involvement of a single node measuring 3 cm or less, so the patient’s nodal status is N1. According to the head and neck TNM staging matrix, this patient falls into the stage III category with T2N1M0 disease.
  • LND, lymph node dissection; RT, radiation therapy.   Which of the following is considered standard treatment? supraglottal laryngectomy followed by lymph node dissection, radiation with low-dose concurrent platinum and weekly cetuximab, primary radiation and concurrent full-dose platinum with salvage surgery reserved for recurrence, all of the above, or A and C. Please submit your answer now.
  • 5-FU, 5-fluorouracil; cDDP, cisplatin; CR, complete response; CVI, continuous venous infusion; NR, nonresponse; PR, partial response; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group.   Forastiere and colleagues published the results of a major phase III trial examining the role of chemotherapy and radiation for organ preservation in advanced laryngeal cancer. Study 9111 compared radiation alone with concurrent radiation and platinum chemotherapy vs what many consider to be the control arm, induction platinum and 5-fluorouracil followed by definitive local radiation. To enroll, patients had to have biopsy-proven, previously untreated stage III or IV squamous cell carcinoma of either the glottic or supraglottic larynx, good performance status (Karnofsky score ≥ 60), no evidence of distant metastases, and potentially resectable tumors. The primary endpoint was survival with preservation of laryngeal function.
  • 5-FU, 5-fluorouracil; cDDP, cisplatin; DFS, disease-free survival; DMFS, distant metastasis-free survival; FS, free survival; KPS, Karnofsky performance score; LFS, laryngectomy-free survival; OS, overall survival; RT, radiation therapy; SGL, supraglottal larynx; SS, statistically significant.   In total, 547 patients were accrued and the demographics were fairly standard for a larynx population: the median age was slightly younger than 60 years, the majority had good performance status, 68% had supraglottal tumors, and 28% had N2 or N3 involvement.   The 2-year laryngectomy-free survival rate was significantly higher in the concomitant platinum/radiation therapy arm: 66% vs 59% for the induction approach and 53% for radiation alone. Toxicity was also much greater with concomitant cisplatin and radiation, particularly nausea, vomiting, and esophagitis. The addition of platinum therapy to radiation led to a statistically significant improvement in laryngectomy-free survival, with a P value of .01. There was, however, no significant difference in OS.
  • CT, chemotherapy; RT, radiation therapy.   This slide shows larynx preservation rates over time, illustrating that concurrent radiation and cisplatin chemotherapy yields the best results.
  • ECE, extracapsular extension; LN, lymph node; R, right.   The patient expresses that there is “no cancer like no cancer,” and he opts to undergo surgery. Pathology confirms an extracapsular extension in the right cervical node as well as microscopic involvement in 3 adjacent lymph nodes; a total of 4/48 lymph nodes are found to be involved.
  • XRT, radiation therapy.   What is the next step? 1) postoperative radiation, 2) postoperative radiation plus high-dose platinum, 3) postoperative radiation and cetuximab, or 4) none of the above. Please submit your answer now.
  • DDP, cisplatin; CT, chemotherapy; DFS, disease-free survival; ECE, extracapsular extension; F/U, follow-up; LN, lymph node; LRC, locoregional control; OS, overall survival; RT, radiation therapy; SCCHN, squamous cell carcinoma of the head and neck.   There have been 3 relatively recent trials that have compared radiation alone with concurrent platinum and radiation in the adjuvant setting. The RTOG study 9501 and the European Organization for Research and Treatment of Cancer (EORTC) study 22931 are similar studies; both employed full-dose chemotherapy, in this case cisplatin at 100 mg/m^2. In both studies, the investigators observed a significant improvement in locoregional control and disease-free survival with the addition of platinum-based therapy. In the EORTC trial, a significant improvement in OS was noted. A provocative trend toward improved OS was also evident in the RTOG study. A much smaller study by Bachaud and colleagues compared weekly platinum plus radiation with radiation alone and they also observed a significant improvement in locoregional control, disease-free survival, and OS.
  • ECE, extracapsular extension.   In the last 1-2 years, investigators have established this risk stratification paradigm. For patients with no nodal involvement and favorable prognosis, the standard of care is surgery alone. For patients with lower risk prognosis, the standard of care usually entails somewhat lower doses of radiation, 56-60 Gy. Patients who fall into an intermediate-risk group, without extracapsular extension and with negative resection margins, should receive radiation therapy alone with 60-66 Gy. Finally, for high-risk patients such as the case patient, concomitant full-dose radiation and cisplatin is the standard of care. Investigators are now designing separate trials for the intermediate- and high-risk groups.
  • SCCHN, squamous cell carcinoma of the head and neck.   RTOG 0234 is a recently completed trial that examined radiation therapy and cetuximab combined with either weekly cisplatin or weekly docetaxel. In total, 238 patients were accrued.
  • CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; RT, radiation therapy; OS, overall survival.   The incidence of dermatitis and mucositis was similar between the 2 treatment arms, but perhaps paradoxically myelosuppression was less frequent in the docetaxel arm. A trend toward improved outcome was also observed with docetaxel vs cisplatin. Patients treated with docetaxel exhibited somewhat higher 2-year overall and disease-free survival rates vs cisplatin. Using data from study RTOG 9501 as a benchmark, docetaxel was associated with significantly better disease-free survival, with an HR of 0.72 and a P value of .03, raising the possibility that other chemotherapy agents and the introduction of cetuximab might ultimately result in better outcomes in high-risk patients. This possibility still needs to be tested prospectively in the context of phase III trials.
  • CT, computed tomography; CXR, chest x-ray; HNC, head and neck cancer; FNA, find-needle aspirate.   The case patient presents 2 years later with a mild cough. A chest x-ray suggests pulmonary nodules. Computed tomography confirms multiple lesions in the lungs ranging in size from 5-20 mm and, unfortunately, a fine-needle aspirate confirms squamous cell carcinoma that is identical to the original histology of the head and neck tumor in the supraglottal larynx.
  • What is the best therapeutic option at this point? 1) observation because he is minimally symptomatic, 2) single-agent chemotherapy, 3) platinum-based chemotherapy alone, 4) platinum-based chemotherapy plus cetuximab, or 5) single-agent cetuximab. Please submit your choice now.
  • 5-FU, 5-fluorouracil; MS, median survival; RR, response rate; SCCHN, squamous cell carcinoma of the head and neck.   According to the results of historic trials that compared monotherapy with combination approaches, platinum combined with 5-fluorouracil clearly yielded better response rates (approximately 30%) compared with the constituent single agents. However, in this somewhat older trial published nearly 20 years ago by Jacobs and colleagues, there was no significant difference in survival between the regimens, with median survival clustering around 5-6 months.
  • 5-FU, 5-fluorouracil; MS, median survival; RR, response rate; SCCHN, squamous cell carcinoma of the head and neck.   The same results were obtained in a phase III study by Forastiere and colleagues published in 1992 comparing cisplatin/5-fluorouracil vs carboplatin/5-fluorouracil vs a control arm of single-agent methotrexate. The response rate was significantly higher for the cisplatin/5-fluorouracil arm vs the methotrexate arm ( P < .001) and the difference between response rates with carboplatin/5-fluorouracil and methotrexate was of borderline significance ( P = .05), but there was no significant difference in median survival. Nevertheless, because of higher response rates and at least a trend toward improved survival outcomes, combination platinum-based therapy has become the standard of care in the relapsed setting.
  • MS, median survival; Pac, paclitaxel; PF, platinum/5-fluorouracil; PPac, platinum/paclitaxel; PFS, progression-free survival; SCCHN, squamous cell carcinoma of the head and neck.   In more recent trials, the median survival has increased slightly to 8-9 months with PFS rates of approximately 4 months when using multiagent therapy. These outcomes are generally better than with single-agent therapy in the same setting.
  • PBS, phosphate-buffered saline.   Similar to radiation, cetuximab and platinum are synergistic. In an A431 xenograft model, cetuximab or cisplatin alone do not have much impact on tumor size compared with the control, but when cetuximab and cisplatin were combined, tumor growth was suppressed, demonstrating a synergistic effect.
  • PS, performance score.   These preclinical findings led ECOG to conduct a phase III, placebo-controlled study comparing platinum alone vs platinum plus cetuximab.
  • CDDP, cisplatin; EGFR, epidermal growth factor receptor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.   The results showed a significantly higher response rate with cetuximab, 26% vs < 10% in the control group ( P = .029), a trend toward improved PFS with a median of 4.2 months for cetuximab plus cisplatin vs 2.7 months for cisplatin alone ( P = .09), and a nonstatistically significant trend toward improved OS. Unfortunately, with only 123 patients accrued, this trial was underpowered to show a significant survival advantage. Of note, patients with rash seemed to fare somewhat better than those without rash, with higher response rates, longer PFS, and statistically significantly improved OS.
  • 5-FU, 5-fluorouracil; AUC, area under the curve; OS, overall survival; PD, progressive disease; PFS , progression-free survival; SCCHN, squamous cell carcinoma of the head and neck.   The definitive study was published in 2008 by Vermorken and colleagues comparing standard 5-fluorouracil and platinum therapy, either carboplatin or cisplatin, with the same combination administered with cetuximab. In the experimental cohort, cetuximab was continued as maintenance therapy after the chemotherapy was concluded. More than 440 patients were accrued. The entry criteria were identical to ECOG trials: patients with recurrent or metastatic disease who were no longer curable and had good performance status (Karnofsky score ≥ 70), at least 1 measurable lesion by either magnetic resonance imaging or computed tomography scan, adequate end-organ indices, and no recent surgery or radiation within 4 weeks of study entry.
  • 5-FU, 5-fluorouracil; SCCHN, squamous cell carcinoma of the head and neck.   The demographic data indicate that this study involved a somewhat younger population than previous trials; the median age was 56-57 years. The ratio of men to women was approximately 9:1 and fewer than 50% of patients had metastatic disease. The majority had locoregional recurrence and fewer than 10% had a primary presentation with metastatic disease. The majority had undergone prior radiation or prior radiation and surgery.
  • CET, cetuximab; CI, confidence interval; CTX, chemotherapy; HR, hazard ratio; OS, overall survival; SCCHN, squamous cell carcinoma of the head and neck.   The results show a survival advantage with cetuximab, as was observed in the context of radiation and locally advanced disease; the addition of cetuximab was associated with a 2.7-month improvement in median OS and the survival advantage persisted over time. This is possibly the first trial that has perturbed the natural history of platinum-treated, advanced, incurable head and neck cancer, certainly the first trial in 25-30 years. Moreover, the addition of cetuximab did not exacerbate the typical adverse event profile seen with platinum-based chemotherapy.
  • The case patient opts for none of the choices presented in the previous question. He opts to enroll in an ongoing phase III randomized trial comparing platinum-based chemotherapy with chemotherapy plus bevacizumab.
  • 5-FU, 5-fluorouracil; PS, performance score; SCCHN, squamous cell carcinoma of the head and neck.   This trial is an ongoing ECOG effort that is open throughout North America through the Cancer Trials Support Unit and compares a standard platinum doublet, either platinum and docetaxel or platinum/5-fluorouracil, with the same regimen combined with bevacizumab. The trial recently opened in the middle of 2009 and it is slated to accrue more than 400 patients.
  • 5-FU, 5-fluorouracil; DDP, cisplatin.   The patient initially responds to treatment with combination bevacizumab, 5-fluorouracil, and platinum. He has a 60% reduction in lung metastasis but then develops a new liver metastasis during maintenance therapy with bevacizumab.
  • EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.   What is the next proven step? 1) single-agent cetuximab, 2) erlotinib or gefitinib, 3) docetaxel plus an EGFR tyrosine kinase inhibitor, 4) single-agent methotrexate, 5) single-agent pemetrexed, or 6) combination therapy with capecitabine and lapatinib. Please submit your choice now.
  • CR, complete response; CT, chemotherapy; ORR, overall response rate; OS, overall survival; PR, partial response; SD, stable disease; TTP, time to progression.   Cetuximab is the only agent in early 2010 that is approved in the platinum-refractory setting in head and neck cancer, and approval is based on work by Vermorken and colleagues. Cetuximab monotherapy in platinum-exposed patients demonstrated an overall response rate of 13% and a median OS of approximately 6 months. Other trials in which a platinum agent has been added to cetuximab in the same setting show no obvious improvement in either overall response rate or median OS. Cetuximab clearly compares favorably with best supportive care or other cytotoxic options where the response rates in the relapsed setting decrease to 3% and the median survival is approximately 3.5 months. Therefore, cetuximab garnered approval in the platinum-refractory setting based on phase II data alone.
  • CI, confidence interval; CR, complete response; NCI, National Cancer Institute; ORR, overall response rate; PD, progressive disease; PR, partial response; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease.   What about the other choices? Cohen and colleagues from the University of Chicago mounted a phase II trial evaluating full-dose gefitinib, 500 mg daily, in the palliative setting. The response rate was 11% and the disease control rate, obtained by combining stable disease and responses, was 53%. Median survival was fairly promising at slightly more than 8 months. As with other EGFR inhibitors, patients who developed skin rash did better and median OS in that group was not reached at the time of the initial analysis compared with 5.3 months in patients with no skin rash; the P value for this difference was .001.
  • CI, confidence interval; HR, hazard ratio; OS, overall survival; SCCHN, squamous cell carcinoma of the head and neck.   More recently, a phase III study comparing gefitinib with methotrexate in platinum-refractory and platinum-ineligible head and neck cancer was published. No obvious difference in OS between methotrexate and either gefitinib at 250 or 500 mg/day was observed. However, platinum-resistant patients may represent a cohort for which a potential survival advantage exists. Specifically, methotrexate was associated with significantly improved OS vs gefitinib in this group, with a P value of .01 vs gefitinib 250 mg/day and .02 vs gefitinib 500 mg/day. In patients who were not eligible for platinum-based chemotherapy, there was no obvious difference between the EGFR tyrosine kinase inhibitors at either dose or methotrexate.
  • PS, performance score; SCCHN, squamous cell carcinoma of the head and neck.   Argiris and colleagues recently presented the results of a phase III trial from ECOG. Study 1302 enrolled patients with head and neck cancer previously treated with a platinum-based regimen or who had a performance score of 2. Participants were randomized to either single-agent docetaxel given weekly or the combination of docetaxel and gefitinib. The study recruited 271 patients; 60% had a performance score of 2.
  • AE, adverse event; MTTP, median time to progression; OR, odds ratio; OS, overall survival; PFS, progression-free survival.   As would be expected, there was more toxicity with the combination of docetaxel and gefitinib, particularly diarrhea and rash. The overall response rate was 12% with the combination vs 6% with single-agent docetaxel, but this difference was not statistically significant. Likewise, median time to progression was nonsignificantly higher at 3.5 months with docetaxel plus gefitinib vs 2 months in the control arm. There was no obvious difference in median OS between the 2 arms: 6.8 vs 6.0 months, respectively. Therefore, single-agent therapy in this setting is probably still the standard of care.
  • MCH-1 HN Slides V3 7-17-06.ppt 07/16/10 12:28 EGFR, epidermal growth factor receptor; SCCHN, squamous cell carcinoma of the head and neck.   Soulieres and colleagues have published data investigating erlotinib in the recurrent/metastatic setting. Treatment consisted of full-dose erlotinib at 150 mg daily. The majority of patients in this trial, approximately 75%, had locoregional recurrence either alone or combined with metastatic disease. EGFR staining was strong for nearly 90% of patients, and virtually all patients enrolled (99%) had received previous chemotherapy.
  • MCH-1 HN Slides V3 7-17-06.ppt 07/16/10 12:28 EGFR, epidermal growth factor receptor; PR, partial response; RR, relative risk; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease.   The response rate was modest at 4.3%. An additional 38% of patients had stable disease for a median of 16 weeks. Median survival was 6 months and, similar to gefitinib, survival was generally better in those with skin rash. Among patients with grade ≥ 2 skin rash, median survival was 7.4 months compared with only 4.0 months in those without skin rash. The P value for this difference was .045. The toxicities included acneiform rash and diarrhea, both of which are typical for the EGFR tyrosine kinase inhibitors.
  • EGFR, epidermal growth factor receptor; PFS, progression-free survival; RR, relative risk; SCCHN, squamous cell carcinoma of the head and neck.   There are also data available on the use of lapatinib, a combined EGFR and HER2 kinase inhibitor, both in patients who have been previously exposed to EGFR tyrosine kinase inhibitors as well as in those who are naive to these agents. Disease control rates approach 40% among patients without previous exposure, which is impressive. At the University of Pennsylvania, we are mounting a phase II study combining capecitabine with lapatinib in this setting.
  • OS, overall survival; PFS, progression-free survival; RR, relative risk; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease.   Erlotinib has been investigated in combination with bevacizumab. The 2 drugs can be combined at full dose. In the phase II component of a phase I/II study, the response rate was 15% with median OS of 6.8 months; however, 3/48 patients experienced serious bleeding events, one of which proved fatal.
  • OS, overall survival; PS, performance score; RR, relative risk; SCCHN, squamous cell carcinoma of the head and neck.   Bevacizumab has also been combined with standard cytotoxics. The trial shown on this slide by Argiris and colleagues was a consortium effort including the University of Pittsburgh, Case Western Reserve University, and the University of Miami. The study investigated pemetrexed plus bevacizumab, each administered at full dose every 3 weeks.
  • CI, confidence interval; CR, complete response; PD, progressive disease; PR, partial response; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease; TTP, time to progression.   A total of 25 patients were enrolled and the results demonstrated a 36% response rate with nearly 60% additional patients experiencing stable disease; only 1 patient had progressive disease at the first evaluation. The median time to progression was impressive at 7 months, but once again bevacizumab was associated with a considerable rate of bleeding events: 16% of patients experienced grade 3-5 bleeding, 1 of which proved fatal. As a result, the protocol has since been amended to exclude any patient with a history of bleeding related to head and neck cancer in the prior 6 months.
  • HPV, human papillomavirus; LA, locally advanced; SCCHN, squamous cell carcinoma of the head and neck; Tx, treatment.   In conclusion, HPV-positive patients currently constitute a separate prognostic and therapeutic cohort. They experience far better outcomes than patients who are HPV negative, and therefore, trials aimed at deintensifying therapy in this population are warranted. Concurrent chemoradiation is the standard treatment paradigm; it has yielded improved survival compared with radiation alone in the treatment of locally advanced head and neck cancer. Docetaxel has garnered approval as a component of induction therapy for locally advanced disease and is particularly beneficial in patients with node involvement.   Cetuximab has also been approved in the context of radiation for locally advanced disease and in the platinum-refractory setting as second-line therapy for metastatic or recurrent patients. Treatment for metastatic recurrent disease is still poor, but cetuximab appears to augment the efficacy of standard frontline platinum-based therapy and is likely to be approved in first-line recurrent and metastatic disease in the near future. Finally, there are a number of targeted agents that are undergoing further intensive investigation.
  • C:\Documents And Settings\User\Desktop\Head And Neck

    1. 1. Corey J. Langer MD, FACP Director, Thoracic Oncology Abramson Cancer Center Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, Pennsylvania Recent Advances in the Treatment of Head and Neck Cancer This program is supported by an educational grant from Bristol-Myers Squibb
    2. 2. Head and Neck Cancer <ul><li>Estimated 39,250 cases in US in 2005* </li></ul><ul><ul><li>5th leading cancer in US </li></ul></ul><ul><ul><li>10% of all cancers worldwide </li></ul></ul><ul><li>> 11,000 deaths—3% of all cancer deaths </li></ul><ul><li>Patients typically aged > 50 yrs, with tobacco and alcohol use </li></ul><ul><li>Emerging cohort of HPV-positive cancers in the OP </li></ul><ul><li>Histology: > 90% squamous cell carcinoma </li></ul><ul><li>Early-stage disease (I, II) curable: > 80% </li></ul><ul><li>Locally advanced disease has poorer prognosis </li></ul><ul><ul><li>5-yr survival rate: < 40% </li></ul></ul>*Oral cavity, pharynx, and larynx.
    3. 3. Outcomes <ul><li>Stages I and II </li></ul><ul><ul><li>1/3 of patients </li></ul></ul><ul><ul><li>Curative results: 60% to 80% </li></ul></ul><ul><ul><li>SPTs: greater risk than recurrence </li></ul></ul><ul><li>Stages III and IV </li></ul><ul><ul><li>2/3 of patients </li></ul></ul><ul><ul><li>Multimodal treatment </li></ul></ul><ul><ul><li>40% to 80% local recurrence </li></ul></ul><ul><ul><li>10% to 30% distant disease </li></ul></ul>
    4. 4. Head and Neck Cancer: Prognosis Cases, % 5-Yr Survival, % Stage I 15 85 Stage II 20 70 Stage III 25 55 Stage IV 25 30 Unresectable 15 10
    5. 5. Historical Perspective: Systemic Therapy in SCCHN <ul><li>1970s: active cytotoxics identified and studied </li></ul><ul><ul><li>High rates of response in neoadjuvant setting </li></ul></ul><ul><li>1980s: randomized trials of neoadjuvant therapy </li></ul><ul><ul><li>Chemosensitivity correlated with radiosensitivity </li></ul></ul><ul><ul><li>No detriment to delay in definitive local therapy </li></ul></ul><ul><ul><li>Decrease in distant metastases </li></ul></ul><ul><ul><li>No sign of improvement in locoregional control or survival </li></ul></ul><ul><ul><li>Coupled with radiation, effective in larynx preservation </li></ul></ul>
    6. 6. Historical Perspective: Systemic Therapy in SCCHN <ul><li>1990s: randomized trials of chemoradiation </li></ul><ul><ul><li>Improved locoregional control and survival [1-3] </li></ul></ul><ul><ul><li>Increased acute/late toxic effects </li></ul></ul><ul><ul><li>Increased organ preservation rates </li></ul></ul><ul><ul><li>Site-specific benefits [4,5] : </li></ul></ul><ul><ul><ul><li>Oropharynx </li></ul></ul></ul><ul><ul><ul><li>Nasopharynx </li></ul></ul></ul><ul><ul><ul><li>Larynx </li></ul></ul></ul><ul><ul><li>DM predominant recurrence in some trials, where local control appears enhanced </li></ul></ul>1. Calais G, et al. J. Natl. Cancer Inst. 1999;91:2081-2086. 2. Brizel DM, et al. N Engl J Med. 1998;338:1798-1804. 3. Bourhis J, et al. Hematol Oncol Clin North Am. 1999;13:769-75. 4. Al-Sarraf M, et al. J Clin Oncol. 1998;16:1310-1317. 5. Wolf GT, et al. Head Neck. 1995;17:279-283.
    7. 7. Historical Perspective: Systemic Therapy in SCCHN <ul><li>2000-2009 </li></ul><ul><ul><li>Chemoradiation superior in post-op high-risk setting </li></ul></ul><ul><ul><li>Cetuximab/radiation: improved LRC/survival </li></ul></ul><ul><ul><li>Renewed interest in neoadjuvant therapy [1] </li></ul></ul><ul><ul><ul><li>Taxanes </li></ul></ul></ul><ul><ul><ul><li>Increasing significance of isolated distant failure </li></ul></ul></ul><ul><ul><ul><li>Risk-based approaches (positive N, primary site) </li></ul></ul></ul><ul><ul><li>Randomized trials taxane + PF show increased PFS/OS vs PF [1,2] </li></ul></ul><ul><ul><li>Emergence of HPV as a marker of outcome, particularly in nonsmokers with OP cancer [3] </li></ul></ul>1. Posner M, et al. N Engl J Med. 2006;354:634-636. 2. Vermorken JB,, et al. N Engl J Med. 2007;357:1695-1704. 3. Gillison ML. Eur J Cancer. 2009;45:383-385.
    8. 8. Case 1 <ul><li>57-yr-old WF minimal past cigarette smoker presents with 4-wk history of sore throat and 10-lb weight loss, as well as pain on swallowing. She notes a lump in the L side of her neck. PE reveals a 3-cm L tonsillar mass extending to the posterior OP and multiple bilateral 1- to 2-cm LN. CT is confirmatory. FNA of L cervical LN shows classical squamous cell carcinoma. Remaining W/U including PET and DL is negative for other sites of disease. </li></ul>
    9. 9. 57-Yr- Old WF With OP Cancer Primary Mass Lymph nodes
    10. 10. What is the stage of her cancer? <ul><li>III </li></ul><ul><li>IVA </li></ul><ul><li>IVB </li></ul><ul><li>IVC </li></ul>
    11. 11. Head and Neck Tumor Stages <ul><li>T1: tumor 2 cm or less or confined to the anatomic subsite of origin </li></ul><ul><li>T2: tumor 2-4 cm, extending to an adjacent subsite, or impairing vocal cord mobility </li></ul><ul><li>T3: tumor > 4 cm or fixing a vocal cord </li></ul><ul><li>T4: tumor with massive invasion or involving an adjacent organ </li></ul>
    12. 12. Head and Neck Lymph Node Stages <ul><li>N1: single node, 3 cm or smaller </li></ul><ul><li>N2a: single node > 3 cm but not > 6 cm </li></ul><ul><li>N2b: multiple nodes, none > 6 cm </li></ul><ul><li>N2c: a contralateral node or bilateral nodes, none > 6 cm </li></ul><ul><li>N3: any node > 6 cm </li></ul>
    13. 13. TNM Staging in SCCHN NCCN practice guidelines in oncology: head and neck cancers. Available at: http://www.nccn.org. Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 T1 T2 T3 N0 N1 N1 N1 M0 M0 M0 M0 Stage IVA T4a T4a T1 T2 T3 T4a N0 N1 N2 N2 N2 N2 M0 M0 M0 M0 M0 M0 Stage IVB T4b Any T Any N N3 M0 M0 Stage IVC Any T Any N M1
    14. 14. What is the most appropriate therapeutic strategy? <ul><li>Concurrent RT and full-dose cisplatin </li></ul><ul><li>Induction therapy with TPF followed by radiation and low-dose concomitant chemotherapy </li></ul><ul><li>Concurrent RT and cetuximab </li></ul><ul><li>Any of the above </li></ul><ul><li>None of the above </li></ul>
    15. 15. Nonsurgical Treatment Options for SCCHN 1. Pignon JP, et al. Lancet. 2000;355:949-955. 2. Bonner JA, et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print]. 3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704. 4. Posner MR, et al. N Engl J Med. 2007;357:1705-1715. Rx Regimens HR (95% CI) Absolute Benefit 2-Yr, % 5-Yr, % RT + concurrent Ctx [1] 0.81 (0.76-0.88) 7 8 RT + Cetuximab [2] 0.73 (0.56-0.94) 9 10 TPF -> RT [3] 0.70 (0.54-0.90) 11 NA TPF -> RT + carboplatin [4] 0.74 (0.67-0.82) 12 NA
    16. 16. <ul><li>63 randomized trials (1965-1993) </li></ul><ul><li>n = 10,717 (excludes NPC trials) </li></ul><ul><li>Median follow-up: 6 yrs </li></ul><ul><li>ORR: 0.89 (32% vs 36% at 5 yrs) </li></ul>Meta-Analysis of Chemotherapy in HNC (MACH-NC) Pignon JP, et al. Lancet. 2000;355:949-955. Trials N RR P Value Absolute Benefit (5 Yrs), % Adjuvant 8 1854 0.98 NS 1 Induction 31 5245 0.95 NS 2 Concomitant 26 3727 0.81 < .0001 8
    17. 17. MACH-NC: An Update <ul><li>24 added trials—93 randomized studies, 17,346 patients </li></ul><ul><ul><li>Median follow-up: 5 yrs </li></ul></ul><ul><li>MACH-HN I: 8% abs benefit CMT </li></ul><ul><li>MACH-HN II: more homogenous population </li></ul><ul><li>Age matters </li></ul><ul><ul><li>Younger than 50 yrs of age: 24% increased survival </li></ul></ul><ul><ul><li>Older than 70 yrs of age: 3% increased survival </li></ul></ul>Pignon JP, et al. Radiother Oncol. 2009;92:4-14.
    18. 18. Concurrent Chemoradiation in LA-SCCHN: Long-term Survival Results N F/U, Yrs RT (Control) CT/RT P Value Agents Used French trail 226 3 31 51 .002 Carbo/5-FU German trial 270 3 24 48 < .0003 cDDP/5-FU/LV NP intergroup 193 3 47 78 .005 cDDP->DDP/ 5-FU Duke U 116 5 28 42 .05 cDDP/5-FU Intergroup 199 3 23 37 .01 cDDP Greek 83 3 18 52 < .001 cDDP
    19. 19. Pros and Cons of Chemoradiation <ul><li>Improves locoregional control </li></ul><ul><ul><li>Facilitates organ preservation </li></ul></ul><ul><ul><li>Beneficial impact on survival </li></ul></ul><ul><li>Doubles the rate of severe acute mucositis </li></ul><ul><li>Use may be excessive based on stage </li></ul><ul><li>Long-term functional deficits in speech, swallowing, mobility </li></ul>
    20. 20. Randomized Trials of PF ± Taxane Induction Therapy Trials Study Eligibility N T + PF CR/PR, n/N (%) PF CR/PR, n/N (%) TPF/PF PFS, Mos TPF/PF OS, Mos P Value (HR) Hitt JCO 2005 Stage III-IV 382 33/47 (80) 14/54 (68) 20 12 43 37 2 yrs: 66%/61% .035 (0.67) TAX 323 ASCO 2006 Unresectable 358 (68) (54) 11 8 18.6 14.2 3 yrs: 24%/18% .005 (0.71) Gortec ASCO 2006 L/HP II-IV 205 43/39 (82) 30/30 (60) LP: 63%/41% .036 TAX 324 ASCO 2006 III-IV 501 17/55 (72) 15/49 (64) 2-yr PFS: 53%/42% 70 30 3 yrs: 62%/48% .006 (0.7)
    21. 21. Cisplatin/5-FU vs Docetaxel + Cisplatin/ 5-FU in SCCHN: Study Design Planned sample size: 358 patients Number of events: 260 progression events needed to show 50% increase in PFS (10-15 months; HR: 0.67) <ul><li>Unresectable SCCHN </li></ul><ul><li>Stratification: </li></ul><ul><li>Institution </li></ul><ul><li>Primary Site </li></ul>R TPF x 4 q3wk PF x 4 q3wk Radiation CF, AF, or HF Neck dissection Neck dissection Follow Surgery? Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704.
    22. 22. PFS and OS Pts at Risk, n PF 181 112 52 37 25 19 11 5 1 TPF 177 129 79 48 23 16 5 3 1 Pts at Risk, n PF 181 149 97 72 49 32 20 13 4 TPF 177 163 127 89 57 36 21 9 1 Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704. Copyright © 2007 Massachusetts Medical Society. All rights reserved. 100 90 80 70 60 50 40 30 20 10 0 PFS (%) Mos 0 6 12 18 24 30 36 42 54 48 TPF PF P = .007 100 90 80 70 60 50 40 30 20 10 0 OS (%) Mos 0 6 12 18 24 30 36 42 54 48 TPF PF P = .02 TPF PF
    23. 23. TAX 324 TPF vs PF: OS Posner MR, et al. N Engl J Med. 2007;357:1705-1715. Copyright © 2007 Massachusetts Medical Society. All rights reserved. TPF 62% PF 48% Log rank P = .006; HR: 0.70 TPF 67% PF 54% Survival Time (Mos) Survival Probability (%) 0 6 12 18 24 30 36 42 48 54 60 66 72 0 10 20 30 40 50 60 70 80 90 100 TPF (n = 255) PF (n = 246) Pts at Risk, n TPF PF 255 234 196 176 163 136 105 72 52 45 37 20 11 246 223 169 146 130 107 85 57 36 32 28 10 7
    24. 24. Ongoing Randomized Trials: Definitive ChemoRT ± Induction *All powered to show survival difference of 10% to 15%. † 50% accrued as of May 2008. Trial Eligibility Target N * Control Tx Experimental Tx DeCIDE † U Chicago N2-3 400 280 DHFX TPF x 2 DHFX Paradigm DFCI Stages III-IV 300 150 Cisplatin CB-RT TPF x 3 Carbo-RT or D-CB-RT SWOG Oropharynx 400 Cisplatin RT TPF x 1-3 surgery or cisplatin-RT
    25. 25. Incidence of EGFR Expression in Solid Tumors Arteaga C, et al. Semin Oncol. 2003;30:3-14. Tumor Type EGFR Expression, % SCCHN ≥ 95 NSCLC 40-80 Colorectal 25-77 Glioblastoma 40-60 Breast 14-91 Esophageal 35-88 Pancreatic 30-50 Gastric 33-74 Bladder 31-72 Prostate 41-100 Ovarian 35-70
    26. 26. Cetuximab (IMC-C225): Properties <ul><li>IgG1 (chimerized antibody) </li></ul><ul><li>Exclusive for EGFR and its heterodimers </li></ul><ul><li>Prevents repair and survival of tumor cells damaged by the effects of chemotherapy and radiotherapy </li></ul><ul><ul><li>Potentiates apoptosis </li></ul></ul><ul><ul><li>Inhibits cell cycle progression </li></ul></ul><ul><ul><li>Decreases production of angiogenic factors </li></ul></ul><ul><ul><li>Inhibits invasion/metastasis </li></ul></ul>88 299 Fab Fc
    27. 27. A431 Xenografts: Can Certuximab Improve Radiotherapy Results? <ul><li>A431 human tumor xenografts used to test whether certuximab enhances tumor response to radiotherapy </li></ul><ul><li>Certuximab + RT treatment of A431 xenografts substantially delayed tumor growth </li></ul><ul><ul><li>Three certuximab doses with a single 18 Gy RT dose associated with a near 4-fold decrease in tumor growth vs 18 Gy RT alone </li></ul></ul>Milas L, et al. Int J Radiat Oncol Biol Phys. 2004;58:966-971.
    28. 28. Phase III Study Design <ul><li>Stratified by </li></ul><ul><li>Karnofsky score: 90-100 vs 60-80 </li></ul><ul><li>Regional nodes: negative vs positive </li></ul><ul><li>Tumor stage: AJCC T1-3 vs T4 </li></ul><ul><li>RT fractionation: concomitant boost vs once daily vs twice daily </li></ul>Arm 2 (RT + C) Radiation therapy + Cetuximab wkly R A N D O M I Z E Arm 1 (RT) Radiation therapy Bonner JA,, et al. N Engl J Med. 2006;354:567-578.
    29. 29. Patient Characteristics Bonner JA, et al. N Engl J Med. 2006;354:567-578. RT RT + C Median age, yrs (range) 58 (35-83) 56 (34-81) Male/female, % 79/21 81/19 Primary tumor site, % Oropharynx Hypopharynx Larynx 63 13 24 56 17 27 EGFR, % Detectable Nondetectable Unknown 80 1 19 79 0 21
    30. 30. Most Common Adverse Events *Listed for its relationship to cetuximab. † P < .05 ‡ P < .001, Fisher’s exact test. Bonner JA, et al. N Engl J Med. 2006;354:567-578. Toxicity, % RT (n = 212) RT + C (n = 208) All Grades Grades 3/4 All Grades Grades 3/4 Skin reaction 91 18 97 † 34 ‡ Mucositis/stomatitis 93 52 91 54 Dysphagia 63 30 64 25 Xerostomia 70 3 64 4 Fatigue/Malaise 50 5 52 4 Infusion reaction* -- – 14 ‡ 3 †
    31. 31. Locoregional Control Bonner JA, et al. N Engl J Med. 2006;354:567-578. *Kaplan-Meier estimates. Locoregional Control, % RT (n = 213) RT + C (n = 211) 1 yr* 2 yrs* 59 48 69 56 Log rank P value 0.02 <ul><li>Distant/second primary control </li></ul><ul><li>1 yr* </li></ul><ul><li>2 yrs* </li></ul>71 56 77 62
    32. 32. Overall Survival Bonner JA , et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print]. RT (n = 213) RT + C (N=211) Median survival,* mos 29.3 49 <ul><li>95% confidence limits </li></ul>21-38 36-58+ 2 yrs, % 55 62 3 yrs, % 44 57 5 yrs, % 36.4 45.6 Log rank P value .018 HR (95% CI) 0.71 (0.54-0.95)
    33. 33. Forest Plot of the HRs by Pretreatment Characteristics: 5-Yr Median Follow-up Improvement With Cetuximab Bonner JA , et al. Lancet Oncol. 2009 Nov 6. [Epub ahead of print]. Tumor: oropharynx Tumor: hypopharynx Tumor stage: T1-T3 Region: other RT fract: once daily Overall stage: IV Nodal stage: N1-N3 Karnofsky 90-100 Sex: male EGFR unknown EGFR positive ≤ 50% Age < 65 yrs Tumor: larynx Tumor stage: T4 Region: US RT fract: twice daily RT fract: concomitant boost Overall stage: II-III Nodal stage: N0 Karnofsky 50-80 Sex: female EGFR positive > 50% Age ≥ 65 yrs 0.0 0.6 1.2 1.8
    34. 34. <ul><li>Postoperative stage III or IV SCCHN </li></ul><ul><li>Stratified by </li></ul><ul><li>Nodal disease </li></ul><ul><li>Zubrod score </li></ul><ul><li>Prior radiation </li></ul><ul><li>PET/CT </li></ul><ul><li>Primary site </li></ul>Phase III Trial of Cisplatin Chemoradiation ± Cetuximab in Advanced SCCHN R A N D O M I Z E Radiotherapy Wks 1-6 + Cisplatin 100 mg/m 2 Days 1, 22 Cetuximab 400 mg/m 2 Day 1, then 250 mg/m 2 Wks 2-8 + Radiotherapy Wks 2-7 + Cisplatin 100 mg/m 2 Days 8, 20 Following chemoradiotherapy, patients with poor response can proceed to surgery. RTOG foundation. Available at: http://www.rtog.org.
    35. 35. Targeted Therapy With an Induction Chemotherapy Platform: TREMPLIN <ul><li>Previously untreated SCC larynx/hypopharynx suitable for TL </li></ul><ul><li>Primary endpoint: larynx preservation 3 mos after treatment </li></ul><ul><li>Secondary endpoints: larynx function preservation and survival 18 mos after treatment </li></ul>Total laryngectomy + postop RT RT 70 Gy + Cisplatin 100 mg/m² on Days 1, 22, 43 RT 70 Gy + Cetuximab 400 mg/m² 1 wk prior to RT then 250 mg/m² wkly on Wks 1-7 TPF 3 cycles, 1 cycle q3wks T 75 mg/m² on Day 1 P 75 mg/m² on Day 1 5-FU 750 mg/m² on Days 1-5 R < PR ≥ PR Lefebvre J, et al. ASCO 2009. Abstract 6010.
    36. 36. What is the likelihood the patient’s tumor is HPV positive? <ul><li>25% to 35% </li></ul><ul><li>40% to 50% </li></ul><ul><li>60% to 65% </li></ul><ul><li>80% to 85% </li></ul>
    37. 37. What absolute percentage improvement in survival is one likely to see in a patient whose primary tumor is HPV positive compared with HPV negative? <ul><li>5% to 10% </li></ul><ul><li>10% to 15% </li></ul><ul><li>15% to 25% </li></ul><ul><li>25% to 35% </li></ul>
    38. 38. Is smoking a cofactor in prognosis in patients whose SCCHN is HPV positive? <ul><li>Yes </li></ul><ul><li>No </li></ul>
    39. 39. Emerging Influence of HPV in HNC Gillison ML, et al. J Natl Cancer Inst. 2008;100:407-420. Characteristic HPV Positive HPV Negative Anatomic site OP: tonsil, base of tongue Larynx, OC, hypopharynx Age Younger Older Male:female 1:1 3:1 Risk factors Sexual Tobacco/Etoh Cofactors Marijuana Diet/hygiene Clinical presentation Unknown or cystic primary Classical Incidence Increasing Decreasing Comorbidities Fewer Greater Prognosis Better Worse
    40. 40. ECOG 2399: Study Design R E G I S T E R R E S P O N S E R E S P O N S E Induction chemotherapy Paclitaxel 175 mg/m 2 Carboplatin AUC 6 q21days 2 cycles Concurrent chemoradiation RT 70 Gy/35 fx/7 wks Paclitaxel 30 mg/m 2 /wk Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269.
    41. 41. ECOG 2399: Efficacy by HPV Status Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269. HPV Positive, % (n = 38; 40%) HPV Negative, % (n = 58; 60%) P Value <ul><li>Response </li></ul><ul><li>Induction </li></ul><ul><li>Protocol </li></ul>82 84 55 57 .01 .07 2-yr PFS 86 53 .02 2-yr OS 95 62 .005 <ul><li>Survival, OP cancers </li></ul><ul><li>2-yr PFS </li></ul><ul><li>2-yr OS </li></ul>85 94 50 58 .05 .004
    42. 42. RTOG 0129 Arm 1 Standard Fractionation (SFX) 70 Gy/35 Fx/7 wks + Cisplatin 100 mg/m 2 on Days 1, 22, 43 R A N D O M I Z E <ul><li>Tumor Site </li></ul><ul><li>Larynx </li></ul><ul><li>2. Nonlarynx </li></ul>S T R A T I F Y Nodal Stage 1. N0 2. N1 or N2a-b 3. N2c or N3 Zubrod Performance Status 1. 0 2. 1 Arm 2 Accelerated Fractionation by Concomitant Boost (AFX-C) 72 Gy/42 Fx/6 wks + Cisplatin 100 mg/m 2 on Days 1, 22 Gillison ML, et al. ASCO 2009. Abstract 6003.
    43. 43. RTOG 0129: Results of Laboratory Analysis <ul><li>433/721 (60%) had oropharynx primary </li></ul><ul><li>323/433 (75%) had HPV determination </li></ul><ul><li>206 of 323 (64%) were HPV positive </li></ul><ul><li>198 of 206 (96%) were HPV16 positive </li></ul>Kappa = 0.80 (95% CI: 0.73-0.87) Gillison ML, et al. ASCO 2009. Abstract 6003. P16 Positive, n (%) P16 Negative, n (%) HPV positive 192 (96) 7 (4) HPV negative 22 (19) 94 (81)
    44. 44. Patient and Tumor Characteristics by HPV Status Gillison ML, et al. ASCO 2009. Abstract 6003. Variable HPV Positive HPV Negative P Value No. of patients 206 117 Age, median yrs 53.5 57.0 .02 White race, % 92.2 75.2 < .001 Zubrod PS 0, % 68.4 56.4 .03 T stage 2-3, % 75.2 60.7 .008 < 20 pack-yrs, % 51.0 22.2 < .001
    45. 45. 2-Yr Outcomes Gillison ML, et al. ASCO 2009. Abstract 6003. Variable, % HPV Positive HPV Negative P Value OS (2 yrs) 87.9 65.8 < .001 PFS 71.8 50.4 < .001 Local-regional failure 13.6 24.8 .004 Distant metastases 9.7 12.9 .26 Second primary tumor 3.9 11.1 .01
    46. 46. Tumor HPV, Smoking Status, and OS Adjusted for age, race, T stage, N stage, and treatment assignment Gillison ML, et al. ASCO 2009. Abstract 6003. Patients, n HR 95% CI HPV positive, < 20 pack-yrs 105 1.00 -- HPV positive, ≥ 20 pack-yrs 73 1.91 1.20-3.05 HPV negative, < 20 pack-yrs 26 2.25 1.44-3.50 HPV negative, ≥ 20 pack-yrs 62 4.30 2.40-7.71
    47. 47. Conclusions <ul><li>Tumor HPV status is a strong and independent predictor of OS and PFS for patients with oropharynx cancer </li></ul><ul><li>Rates for local-regional, but not distant, recurrence events were lower for the HPV-positive patient </li></ul><ul><li>P16 IHC is highly correlated with tumor HPV status and is a valid surrogate </li></ul><ul><li>Tobacco use appears to modify the biologic behavior of an HPV-positive tumor </li></ul><ul><li>Tumor HPV status or P16 must be a stratification factor in clinical trials that include oropharynx patients </li></ul>
    48. 48. Implications <ul><li>Separate trials for HPV-positive and HPV-negative patients </li></ul><ul><ul><li>HPV positive trials to deintensify Tx, emphasize toxicity mitigation </li></ul></ul><ul><ul><li>HPV negative trials intensifying Tx, adding new agents with new MOAs </li></ul></ul>
    49. 49. Case 1 <ul><li>Patient opts for concurrent RT and cetuximab. She receives 6 wkly doses of cetuximab and > 50 Gy RT, but then develops grade 3 acneiform rash across her face and chest </li></ul>
    50. 50. What should you do next? <ul><li>Suspend both RT and cetuximab </li></ul><ul><li>Suspend cetuximab only </li></ul><ul><li>Tx rash with topical clindamycin ointment and oral doxycycline, but continue RT and cetuximab </li></ul><ul><li>Apply topical steroids </li></ul>
    51. 51. Cetuximab <ul><li>Rash </li></ul><ul><ul><li>Ubiquitous, ~ 70% to 80%, but grade 3 in 10% </li></ul></ul><ul><ul><li>Acneiform to start </li></ul></ul><ul><ul><ul><li>Rx: clindamycin ointment or gel; oral doxycycline or minocycline; steroids; emollients </li></ul></ul></ul><ul><ul><li>Over time </li></ul></ul><ul><ul><ul><li>Recedes from face and chest to hands and feet and hairline </li></ul></ul></ul><ul><ul><ul><li>Nail dystrophy, fissures (antifungals, superglue!!) </li></ul></ul></ul><ul><li>HSR: 3% to 5% </li></ul><ul><ul><li>Worse in the HSR belt: Carolinas, Tennessee (20%) </li></ul></ul><ul><li>Cardiotoxicity: < 5% </li></ul><ul><li>Hypomagnesemia: persistent, often quite severe, clinical effects uncertain </li></ul><ul><li>Diarrhea: far less than seen with oral EGFR TKIs </li></ul>
    52. 52. A Sample Skin Reaction Algorithm Reassess after 2 wks; if reactions do not improve, proceed to next step Mild Continue EGFR inhibitor at current dose and monitor for change in severity No treatment Topical hydrocortisone 1% or 2.5% cream and/or Clindamycin 1% gel or Reduce EGFR inhibitor dose per label and monitor for change in severity; continue treatment of skin reaction Treat as above plus Methylprednisolone dose pack Reassess after 2 wks; if reactions worsen, dose interruption or discontinuation may be necessary Severe Continue EGFR inhibitor at current dose and monitor for change in severity; continue treatment of skin reaction Hydrocortisone 2.5% cream or Clindamycin 1% gel or Pimecrolimus 1% cream plus Doxycycline 100 mg BID or Minocycline 100 mg BID Moderate Reassess after 2 wks; if reactions do not improve, proceed to next step Lynch TJ Jr, et al. Oncologist. 2007;12:610-621.
    53. 53. Case 2: Laryngeal Cancer <ul><li>68-yr-old WM smoker (80 pack-yrs) presents with hoarseness and a nodule in the right side of his neck. PE reveals a 2.5-cm supraglottal mass on the right and a 1.5-cm ipsilateral LN. CT of the HNC confirms these findings. Bx of both node and primary demonstrates keratinzing squamous cell cancer. Remaining workup is negative. </li></ul>
    54. 54. Case 2: Imaging and Endoscopy Results <ul><li>CT neck </li></ul><ul><ul><li>R SGL mass </li></ul></ul><ul><ul><li>1.5-cm posterior triangle rt neck node </li></ul></ul><ul><li>CT chest and CT brain: negative </li></ul><ul><li>Laryngoscopy and bx- </li></ul><ul><ul><li>Large tumor involving rt false vocal cord extending to true vocal cord and medial wall of pyriform sinus on the same side </li></ul></ul><ul><ul><li>Mobile vocal cord </li></ul></ul><ul><ul><li>No contralateral spread </li></ul></ul>Becker M, et al. Eur Radiol. 1998;8:1541-1551. Graphic reproduced with permission.
    55. 55. What is the stage of this patient’s cancer? <ul><li>II </li></ul><ul><li>III </li></ul><ul><li>IVA </li></ul><ul><li>IVB </li></ul>
    56. 56. TNM Staging in SCCHN NCCN practice guidelines in oncology: head and neck cancers. Available at: http://www.nccn.org. Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 T1 T2 T3 N0 N1 N1 N1 M0 M0 M0 M0 Stage IVA T4a T4a T1 T2 T3 T4a N0 N1 N2 N2 N2 N2 M0 M0 M0 M0 M0 M0 Stage IVB T4b Any T Any N N3 M0 M0 Stage IVC Any T Any N M1
    57. 57. Which of the following is considered standard treatment for this patient? <ul><li>Supraglottal laryngectomy followed by LND </li></ul><ul><li>RT with low-dose concurrent cisplatin and wkly cetuximab </li></ul><ul><li>Primary RT and concurrent full-dose cisplatin, with salvage surgery reserved for recurrence </li></ul><ul><li>Any of the above </li></ul><ul><li>1 and 3 </li></ul>
    58. 58. RTOG 9111: Larynx Preservation Trial Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098. R A N D O M I Z E Location 1. Glottic 2. Supraglottic S T R A T I F Y T Stage 1. T2 2. T3, fixed cord 3. T3, no cord fixation 4. T4, with base of tongue ≤ 1 cm N Stage 1. N0, N1 2. N2, N3 Chemotherapy Arm 1: cisplatin 100 mg/m 2 /5-FU 1 gm/m 2 /24 hrs CVI x 120 o q3wks x 3 Arm 2: cisplatin 100 mg/m 2 Days 1, 22, 43 of RT Phase III larynx preservation trial: induction chemotherapy and radiation therapy vs concomitant chemotherapy and radiation therapy vs radiation therapy alone Arm 1: Arm 2: Arm 3: CR, PR x 3 d cycle RT CDDP/5-FU x 2 cycles NR surgery RT Radiation therapy + CDDP Radiation therapy
    59. 59. RTOG 9111: Larynx Preservation Trial <ul><li>The median follow-up among surviving patients, 3.8 years </li></ul><ul><li>Demographics: median age 59 yrs; 94% KPS  80; 50% N0; 68% SGL; 28% N2-3 </li></ul><ul><li>Conclusions </li></ul><ul><ul><li>RT/cDDP: stat signif  in LFS ( P = .01) </li></ul></ul><ul><ul><li>No SS diff in survival </li></ul></ul>Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098. Arm cDDP/5-FU  RT RT/cDDP RT Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173) 2-yr laryngectomy FS, % 59 66 53 5-yr DMFS, % 85 88 78 5-yr DFS, % 38 36 27 5-yr OS,% 55 54 56
    60. 60. Advanced Larynx Cancer: Preservation Larynx Preserved Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098. Copyright © 2003 Massachusetts Medical Society. All rights reserved. 0 20 60 80 100 Mos 0 20 40 60 40 Induction CT Concurrent CT ( P = .005 vs induction CT; P < .001 vs RT ) RT alone
    61. 61. Case 2 <ul><li>Patient feels there is “no cancer like no cancer” and opts to undergo surgery. Pathology confirms ECE in the R cervical node as well as microscopic involvement in 3 adjacent LNs. In total, 4 out of 48 LNs are involved. </li></ul>
    62. 62. What are you going to do next? <ul><li>Post-op XRT </li></ul><ul><li>Post-op XRT + high-dose platinum </li></ul><ul><li>Post-op XRT + cetuximab </li></ul><ul><li>None of the above </li></ul>
    63. 63. Adjuvant Trials: SCCHN RT ± CT (DDP) 1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944. 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952. 3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246. Trial RT (Gy) F/U, mos LRC, % DFS, % OS, % RTOG 9501 [1] ≥ 2 LN, ECE, + margins n = 459 (60-66) 46 81 vs 70 ( P = .01) 33 vs 25 ( P = .04) 45 vs 38 ( P = .19) EORTC 22931 [2] N2-3, ECE, + margins n = 350 (66) 60 82 vs 69 ( P = .007) 47 vs 36 ( P = .04) 53 vs 40 ( P = .002) Bachaud [3] + ECE n = 83 (> 60) 60 70 vs 55 ( P = .05) 45 vs 23 ( P < .02) 36 vs 13 ( P < .01)
    64. 64. Streamlining Adjuvant Therapy Began to design separate trials for intermediate-risk and high-risk groups Cooper JS, et al. N Engl J Med. 2004;350:1937-1944. Bernier J, et al. N Engl J Med. 2004;350:1945-1952. Ang KK, et al. Int J Radiat Oncol Biol Phys. 2001;51:571-578. Risk Stratification Category Standard of Care Favorable None Low 56-60 Gy Intermediate (ECE-/margin-) 60-66 Gy High (ECE+/margin+) 60-66 Gy + cisplatin
    65. 65. <ul><li>Postoperative stage III or IV SCCHN </li></ul><ul><li>Stratify </li></ul><ul><li>Nodal disease </li></ul><ul><li>Zubrod score </li></ul><ul><li>Prior radiation </li></ul>Phase II Adjuvant Chemoradiotherapy + Cisplatin or Docetaxel R A N D O M I Z E Cetuximab 400 mg/m 2 Day 1, then 250 mg/m 2 Wks 2-7 + Radiotherapy Wks 2-7 + Cisplatin 30 mg/m 2 Wks 2-7 (N = 238) Cetuximab 400 mg/m 2 Day 1, then 250 mg/m 2 Wks 2-7 + Radiotherapy Wks 2-7 + Docetaxel 15 mg/m 2 Wks 2-7 Kies MS, et al. ASTRO 2009. Abstract 29.
    66. 66. RTOG H-0234: Locally Advanced Resected Kies MS, et al. ASTRO 2009. Abstract 29. Graphic reproduced with permission. RT + Cetuximab + Cisplatin Docetaxel Grade 3/4 reactions, % Myelosuppression 28 14 Dermatitis 39 39 Mucositis 37 33 Outcome 2-yr OS, % 69 79 2-yr DFS, % 57 66 HR vs 95-01; P value (95% CI) 0.85; .19 (0.60-1.21) 0.72; .03 (0.50-1.02)
    67. 67. Case 2 <ul><li>2 yrs later, he presents with mild cough. CXR suggests pulmonary nodules; CT confirms multiple lesions in the lungs ranging in size from 5-20 mm. FNA confirms squamous cell carcinoma, identical to the original histology of the HNC. </li></ul>
    68. 68. What is the best therapeutic option for this patient? <ul><li>Observation </li></ul><ul><li>Single-agent chemotherapy </li></ul><ul><li>Platinum-based chemotherapy alone </li></ul><ul><li>Platinum-based chemotherapy + cetuximab </li></ul><ul><li>Single-agent cetuximab </li></ul>
    69. 69. Recurrent/Metastatic SCCHN Jacobs C, et al. J Clin Oncol. 1992;10:257-263. Randomized Trials: Combinations vs Monotherapy Intergroup n RR, % MS, Mos Cisplatin/5-FU 79 32 5.5 Cisplatin 83 17 5.0 5-FU 83 13 6.1
    70. 70. Recurrent/Metastatic SCCHN Forastiere AA, et al. J Clin Oncol. 1992;10:1245-1251. Randomized Trials: Combinations vs Monotherapy Intergroup n RR, % MS, Mos Cisplatin/5-FU 87 32 6.6 Carboplatin/5-FU 86 21 5.0 Methotrexate 88 10 5.6
    71. 71. ECOG and SWOG Phase II Trials in Recurrent/Metastatic SCCHN <ul><li>Single-agent therapy (MTX, Pac 96 hr, etc) </li></ul><ul><ul><li>MS: 6 mos </li></ul></ul><ul><ul><li>PFS: 2 mos </li></ul></ul><ul><li>Multiple-agent therapy (PF or PPac, etc) </li></ul><ul><ul><li>MS: 9 mos </li></ul></ul><ul><ul><li>PFS: 4 mos </li></ul></ul>
    72. 72. Cetuximab + Cisplatin Shows Synergistic Activity Fan Z, et al. Cancer Res. 1993;53:4637-4642. Graphic reproduced with permission. Tumor Size (cm 3 ) 2 4 Cetuximab Cisplatin 0 5 15 25 35 Cetuximab + cisplatin Days Cetuximab Cisplatin Control (PBS) A431 cells implanted A431 xenograft model 3 1 0 30 20 10
    73. 73. Cisplatin + Placebo vs Cisplatin + Cetuximab: Design <ul><ul><li>Cisplatin 100 mg/m ² Day 1 q28days </li></ul></ul><ul><ul><li>+ </li></ul></ul><ul><ul><li>Cetuximab 400 mg/m 2 x 1, then 250 mg/m 2 wkly </li></ul></ul>Burtness B, et al. J Clin Oncol. 2005;23:8646-8654. <ul><ul><li>Cisplatin 100 mg/m ² Day 1 q28days </li></ul></ul><ul><ul><li>+ </li></ul></ul><ul><ul><li>Placebo </li></ul></ul><ul><li>ECOG 5397 </li></ul><ul><li>Stratified: </li></ul><ul><li>New diagnosis vs recurrent </li></ul><ul><li>PS 0 vs 1 </li></ul>R A N D O M I Z E
    74. 74. Cisplatin + Placebo vs Cisplatin + Cetuximab: Results <ul><li>Data suggest that patients with rash may fare somewhat better </li></ul>Burtness B, et al. J Clin Oncol. 2005;23:8646-8654. Parameter CDDP + Cetuximab (n = 63 ) CDDP + Placebo (n = 60) P Value <ul><li>ORR, % </li></ul><ul><li>Low-mod EGFR, % </li></ul><ul><li>High EGFR, % </li></ul>26.3 40.0 11.8 9.8 11.5 5.9 .029 Median PFS, mos 4.2 2.7 .09 <ul><li>Median OS, mos </li></ul><ul><li>2-yr OS, % </li></ul>9.3 15.6 8.0 9.2 .21 NS
    75. 75. EXTREME: Platinum/5-FU With or Without Cetuximab in Recurrent/Metastatic SCCHN Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127. <ul><li>Recurrent/Metastatic SCCHN </li></ul><ul><li>Stage III/IV </li></ul><ul><li>No prior chemotherapy except if given for locally advanced disease > 6 mos prior to study entry </li></ul><ul><li>No nasopharyngeal carcinoma </li></ul><ul><li>(N = 442) </li></ul>Cetuximab 400 mg/m 2 then 250 mg/m 2 /wk until PD or unacceptable toxicity + Carboplatin AUC 5 Day 1 or Cisplatin 100 mg/m 2 Day 1 + 5-FU 1000 mg/m 2 Days 1-4 every 3 wks, 6 cycles Carboplatin AUC 5 Day 1 or Cisplatin 100 mg/m 2 Day 1 + 5-FU 1000 mg/m 2 Days 1-4 every 3 wks, 6 cycles R A N D O M I Z E Endpoints <ul><li>OS </li></ul><ul><li>PFS </li></ul><ul><li>Response rate </li></ul><ul><li>Disease control </li></ul><ul><li>Safety </li></ul><ul><li>Quality of life </li></ul>
    76. 76. Cetuximab + First-line Platinum in Recurrent or Metastatic SCCHN (EXTREME) Patient and Disease Characteristics Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127. Cetuximab + Platinum/5-FU (N = 222) Platinum/5-FU (N = 220) Median age, yrs (range) 56 (37-80) 57 (33-78) Male/female, % 89/11 92/8 <ul><li>Recurrence/metastasis, % </li></ul><ul><li>Loco-regional recurrence </li></ul><ul><li>Metastasis </li></ul>54 46 54 46 Primary metastatic disease, % 8 7
    77. 77. Cetuximab + First-line Platinum in Recurrent or Metastatic SCCHN: OS 127 153 83 118 65 82 47 57 19 30 173 184 220 222 8 15 1 3 HR : 0.797 (95% CI: 0.644-0.986) Strat. log-rank test: .0362 CTX only CET + CTX Survival Probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 3 6 9 12 15 18 21 24 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 10.1 mos 7.4 mos Pts at Risk, n CTX only CET + CTX Survival Time (Mos) Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
    78. 78. Case 2 <ul><li>Patient opts to enroll on the ongoing phase III randomized trial comparing platinum-based chemotherapy with chemotherapy plus bevacizumab </li></ul>
    79. 79. Phase III Randomized Trial of Cisplatin-Based Chemotherapy ± Bevacizumab Recurrent/ metastatic SCCHN, PS 0-1, no prior chemo Cisplatin doublet* + Bevacizumab 15 mg/kg every 21 days Cisplatin doublet* every 21 days Study Chair: A. Argiris Endpoint: survival N = 400 *Cisplatin/docetaxel or cisplatin/5-FU Status: activated 2009 R A N D O M I Z E
    80. 80. Case 2 <ul><li>Patient initially responds to treatment with bevacizumab and 5-FU-DDP, with 60% reduction in lung metastases but then develops new liver metastases during maintenance therapy with bevacizumab </li></ul>
    81. 81. What is the next “proven” treatment option? <ul><li>Single-agent cetuximab </li></ul><ul><li>Erlotinib or gefitinib </li></ul><ul><li>Docetaxel plus EGFR TKI </li></ul><ul><li>Single-agent methotrexate </li></ul><ul><li>Single-agent pemetrexed </li></ul><ul><li>Combination therapy with capecitabine and lapatinib </li></ul>
    82. 82. Comparison of Cetuximab-Based Therapy and Other Various Second-Line Therapies Vermorken JB, et al. J Clin Oncol. 2007;25:2171-2177. Cetuximab approved in platinum-refractory setting Treatment N ORR (CR + PR), % Disease Control (CP + PR + SD), % Median OS, Mos Median TTP, Mos Cetuximab monotherapy 103 13 46 5.9 2.3 Cetuximab + cisplatin or carbo 96 10 53 6.1 2.8 Cetuximab + cisplatin 79 10 56 5.2 2.2 <ul><li>Retrospective </li></ul><ul><li>All patients </li></ul><ul><li>Pts with CT alone </li></ul>151 43 3 0 15 9 3.4 3.6 N/A N/A
    83. 83. Gefitinib in SCCHN: Response Data <ul><li>Gefitinib 500 mg QD PO </li></ul><ul><li>N = 47 eligible patients </li></ul><ul><li>Half received previous palliative treatments </li></ul><ul><li>ORR: 11% (95% CI: 3.5-23.1) </li></ul><ul><li>Disease control (CR + PR + SD): 53% </li></ul><ul><li>Median survival of 8.1 mos </li></ul><ul><li>13% had disease control ≥ 6 mos </li></ul><ul><li>Skin toxicity strong predictor of survival </li></ul>*NCI audited data. Cohen EE, et al. J Clin Oncol. 2003;21:1980-1987. Response n (%)* CR 1 (2) PR 4 (9) SD 21 (45) PD 22 (47)
    84. 84. Gefitinib vs Methotrexate in Patients With Recurrent or Metastatic SCCHN: OS <ul><li>No significant difference in OS between treatment arms </li></ul><ul><li>Median survival: gefitinib 250 mg (5.6 mos), gefitinib 500 mg (6.0 mos), and methotrexate (6.7 mos) </li></ul><ul><ul><li>Gefitinib 250 mg vs methotrexate: HR = 1.22 (95% CI: 0.95-1.57; P = .12) </li></ul></ul><ul><ul><li>Gefitinib 500 mg vs methotrexate: HR = 1.12 (95% CI: 0.87-1.43; P = .39) </li></ul></ul><ul><li>Patients with platinum-resistant disease had a survival advantage when given methotrexate </li></ul><ul><ul><li>Gefitinib 250 mg vs methotrexate: HR = 1.62 (95% CI: 1.13-2.32; P = .01) </li></ul></ul><ul><ul><li>Gefitinib 500 mg vs methotrexate: HR = 1.50 (95% CI: 1.06-2.13; P = .02) </li></ul></ul>Stewart JS, et al. J Clin Oncol. 2009; 27:1864-1871.
    85. 85. <ul><li>Accrual: N = 271 </li></ul><ul><li>60% PS 2; 72% prior chemotherapy </li></ul>Docetaxel in PS 2 or Previously Treated Pts With Recurrent or Metastatic SCCHN R A N D O M I Z E D Docetaxel 35 mg/m 2 Days 1, 8, 15 q28days + Placebo Docetaxel 35 mg/m 2 Days 1, 8, 15 q28days + Gefitinib 250 mg/day x 28 days Argiris A, et al. ASCO 2009. Abstract 6011.
    86. 86. E1302: Phase III Trial of Docetaxel + Placebo vs Docetaxel + Gefitinib Argiris A, et al. ASCO 2009. Abstract 6011. Graphic reproduced with permission. Arm Docetaxel Docetaxel + Gefitinib P Value Patients, n 136 134 Grade 3/4 fatigue, n/% 12/3 11/0 Diarrhea, n/% 2/0 11/1 Grade 5 AEs, % 3 7 OR, % 6 12 .21 MTTP, mos 2.1 3.5 .047 PFS, mos 2.2 3.3 .18 OS, mos 6 6.8 .97
    87. 87. Erlotinib in Recurrent or Metastatic SCCHN <ul><li>N = 115 with recurrent/metastatic SCCHN </li></ul><ul><li>150 mg daily initial dose </li></ul><ul><ul><li>Dose reductions/escalations allowed based on tolerability of drug </li></ul></ul><ul><li>Locoregional recurrence (53%); metastatic disease (23%); both (24%) </li></ul><ul><li>EGFR positivity </li></ul><ul><ul><li>87% had strong EGFR staining intensity </li></ul></ul><ul><ul><li>50% had EGFR staining on > 80% of cells </li></ul></ul><ul><li>99% received previous chemotherapy </li></ul>Soulieres D, et al. J Clin Oncol. 2004;22:77-85.
    88. 88. Erlotinib in Recurrent or Metastatic SCCHN: Results <ul><li>5 PR (RR: 4.3%) </li></ul><ul><li>44 SD (38%) for median 16 wks </li></ul><ul><ul><li>Range to 90+ wks </li></ul></ul><ul><li>Median survival: 6 mos </li></ul><ul><li>Improved survival in patients with grade ≥ 2 skin rash </li></ul><ul><ul><li>Skin rash vs no skin rash (7.4 vs 4.0 mos; P = .045) </li></ul></ul><ul><ul><li>No difference on the basis of EGFR expression </li></ul></ul><ul><li>Adverse events (mostly mild) included acneiform rash (79%), diarrhea (37%) </li></ul>Soulieres D, et al. J Clin Oncol. 2004;22:77-85.
    89. 89. Phase II Study of Lapatinib in SCCHN <ul><li>EGFR-HER2 kinase inhibitor </li></ul><ul><li>Arm A: no previous EGFR exposure (n = 27) </li></ul><ul><li>Arm B: previous EGFR exposure (n = 15) </li></ul><ul><li>42 patients enrolled </li></ul><ul><li>Diarrhea (40%) </li></ul><ul><li>RR: 37% (arm A) and 20% (arm B) </li></ul><ul><li>PFS: 1.6 mos (arm A) and 1.7 mos (arm B) </li></ul><ul><li>U. Penn: phase II combination lapatinib with capecitabine </li></ul>Abidoye OO, et al. ASCO 2006. Abstract 5568.
    90. 90. Erlotinib Plus Bevacizumab in Recurrent/Metastatic SCCHN <ul><li>Phase I/II design: no more than 1 previous chemotherapy regimen </li></ul><ul><li>Phase I part escalated bevacizumab at 3 dose levels: 5, 10, 15 mg/kg </li></ul><ul><li>Phase II dose: erlotinib 150 mg PO QD plus bevacizumab 15 mg/kg IV every 21 days </li></ul><ul><li>Phase II part (N = 48) </li></ul><ul><ul><li>RR: 15%; SD: 54% </li></ul></ul><ul><ul><li>Median PFS: 3.8 mos </li></ul></ul><ul><ul><li>Median OS: 6.8 mos </li></ul></ul><ul><ul><li>3 serious bleeding events (1 fatal) </li></ul></ul>Vokes E, et al. ASCO 2009. Abstract 5504.
    91. 91. UPCI 05-002: Phase II trial of Pemetrexed/Bevacizumab Recurrent or metastatic SCCHN No previous chemotherapy PS 0-1 No invasion of major blood vessels No anticoagulation Pemetrexed 500 mg/m 2 IV on Day 1 + Bevacizumab 15 mg/kg IV on Day 1 every 21 days until progression Endpoints: TTP (primary), RR, OS Sample size: 40 patients
    92. 92. Phase II trial of Pemetrexed/Bevacizumab: Preliminary Results <ul><li>25 patients enrolled in 3 centers </li></ul><ul><li>Median number of cycles: 6 (range: 1-11) </li></ul><ul><li>Best response in 22 evaluable patients </li></ul><ul><ul><li>8 patients (36%) had an objective response (3 CRs, 5 PRs) </li></ul></ul><ul><ul><li>13 patients (59%) had SD </li></ul></ul><ul><ul><li>1 patient (5%) had PD </li></ul></ul><ul><li>With a median follow up of 8 mos, the median TTP was 7 mos (95% CI: 3.7-10.3) </li></ul><ul><li>4 (16%) grade 3-5 bleeding events </li></ul><ul><li>Protocol amended to exclude all pts with a history of bleeding related to SCCHN in previous 6 mos </li></ul>Argiris A, et al. ASCO 2008. Abstract 6069.
    93. 93. Conclusions <ul><li>HPV-positive patients constitute a separate prognostic and therapeutic cohort </li></ul><ul><li>Concurrent chemoradiation has yielded improved survival in treatment of LA-SCCHN </li></ul><ul><li>Docetaxel approved as component of induction Tx for locally advanced (esp N+) </li></ul><ul><li>Cetuximab approved with radiation and in metastatic/recurrent setting (2nd line) </li></ul><ul><li>Treatment for metastatic/recurrent SCCHN is still poor, but cetuximab appears to augment the efficacy of standard platinum-based therapy </li></ul><ul><li>Other targeted agents are undergoing further investigation </li></ul>

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