Head and neck cancer (HNSCC) remains a challenging disease to treat, and we continue to be faced with expanding options that include reconsideration of induction chemotherapy and newer targeted therapies that are focused on blocking specific aspects of the cancer signaling process. Local control above the clavicles is improving in subsites of the head and neck, however, we know that aggressive therapy comes at a price—severe acute and chronic morbidity. In this review, we discuss some of the interesting reports from 2006 American Society of Clinical Oncology meeting in Atlanta, Georgia, that relate to new developments in head and neck cancer management and research. This includes discussion of presentations related to targeted therapies, induction chemotherapy and follow-up results of landmark Phase III trials related to organ preservation.

Targeted Therapies in HNSCC - Pre-Clinical Studies

It is known that the epidermal growth factor receptor (EGFR) is an early marker for HNSCC development, and is associated with poor prognosis.¹,² In the HNSCC arena, ASCO 2006 was notable for a succession of phase I/II clinical trials combining EGFR and angiogenic inhibitors with chemotherapy and radiation. Bench to bedside translation is providing important preliminary information that relates to assisting investigators in predicting response of patients with HNSCC to EGFR inhibitors. Collaborating groups from Vanderbilt University and the University of Colorado analyzed 47 specimens of patients with HNSCC using both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The rationale was based on lung cancer data suggesting a correlation to outcomes with EGFR inhibition using small molecule tyrosine kinase inhibitors (TKIs) based on FISH data. Of the 41 samples analyzed by FISH, 26 (63%) demonstrated EGFR high polysomy and/or gene amplification (FISH+). The patients with FISH (+) findings were associated with a strong trend toward a worse relapse free survival (p = 0.057, Wilcoxon test). The FISH results did not correlate with pEGFR, total EGFR or pAKT in FISH (+) or FISH (-) samples. ³

A strong correlation to outcomes in patients with HNSCC treated surgically was also noted based on p53 status.⁴ Samples from 423 specimens were analyzable using gene chip approaches. The median survival for patients with p53 mutations within the tumor was 3.1 years compared to 5.4 years in patients with WT p53 (p = 0.01). Similar to what has been reported in EGFR analysis, this finding remained independent of tumor site in multivariate analysis. It would have been interesting if the authors had evaluated whether p53 status correlated with EGFR status and outcomes.

Recent analysis of EGFR status appeared to demonstrate not only that high EGFR expression correlated with outcomes to radiotherapy but that patients with high EGFR benefited from accelerated radiation.⁵,⁶ Metges et al looked to analyze outcomes of HNSCC patients included in the GORTEC 99-02 prospective phase III trial which compared conventional radiotherapy (RT) plus 5FU and carboplatin (FUP) to RT with a concomitant boost approach and FUP or “very accelerated” RT alone based on analysis of serum and tumor expression of EGFR, VEGF and P53.⁷ Over 200 specimens were available for evaluation from a cohort of approximately 800 patients entered into the study. Although the median follow-up was relatively short and this was a subgroup analysis, findings ran counter to previous publications in that high EGFR was predictive of better survival on multivariate analysis (p=0.01) whereas p53 and VEGF levels were not correlative of outcomes. No correlations were observed between VEGF and EGFR levels in the serum or tumor; a trend toward higher VEGF was seen in patients that were p53 negative (p=0.07).

Clinical Studies - Chemo-Radiation and Targeted Agents

A multitude of trials incorporating EGFR inhibitors with chemotherapy (CT) and radiotherapy (RT) were presented at ASCO 2006. With induction regimens generating greater interest, cetuximab (400 mg/m2 week 1 then 250 mg/m2 weekly) was administered concurrently with weekly paclitaxel (135 mg/m2), and carboplatin (AUC 2) for 6 cycles to CT naïve patients with locally advanced HNSCC. This was delivered prior to either surgery and post-operative RT, RT alone or definitive CT-RT based on response/biopsies. (See schema below.)

Cetuximab is an FDA approved human-murine monoclonal antibody with activity against the external domain of the EGFR. This phase II study entered 47 patients. From a toxicity standpoint it appeared that the addition of cetuximab to induction chemotherapy was well tolerated with the typical rash reported in 50% of the patients. It appeared that cetuximab did not result in additional toxicity with induction chemotherapy. Sixteen (34%) patients had grade 3/4 leukopenia; 22 (47%) with grade 3 folliculitis; and 2 (4%) with serious hypersensitivity. All 41 evaluable patients achieved a response in the primary site, 7 (17%) PR and 34 (83%) CR. At the time of presentation, there was 1 local failure, 2 distant failures and 1 patient with both local and distant failure. No significant correlations were observed between EGFR expression and tumor response, however, cetuximab was combined with 2 chemotherapy agents that have significant activity in HNSCC so this may have muddled the findings somewhat.⁸

Previous studies by Merlano, et al had established in the early 1990s that alternating chemo-radiation was superior to radiotherapy alone in patients with locally advanced HNSCC.⁹ This chemo-radiation strategy was explored further with the addition of cetuximab to weekly cisplatin and infusional 5-FU (weeks 1,4 and 7) alternating with a conventional radiotherapy regimen (2 Gy/fraction weeks 2-3, 5-6 and 8-10).¹⁰ The initial phase of the study added cetuximab to radiotherapy alone followed by a second phase adding cetuximab to the chemotherapy regimen as well. Nine patients were entered at the time of submission of this abstract so it is difficult to draw too many conclusions. As expected, toxicities, including stomatitis and dysphagia requiring intravenous nutritional support, were observed. The authors reported that a majority of the patients experienced moist desquamation within the irradiated field at cumulative RT dose of 50-66 Gy; this might have been due to several factors related to the type of radiation energy used, the type of immobilization device incorporated and the radiation dose prescription as well as the added toxicity of the alternating chemotherapy along with cetuximab.

Small molecule tyrosine kinase molecules are also under continued investigation in HNSCC. In this regard, gefitinib (250 mg daily) in combination with chemotherapy (docetaxel, 60 mg/m2 D1, 22 and carboplatin, AUC 5, D1, 22) as induction was explored by the Minnie Pearl Cancer Center prior to concurrent chemo-radiotherapy (docetaxel weekly at 20 mg/m2 with 68.4 Gy) plus gefitinib (250 mg daily) in a Phase II trial of patients with locally advanced, untreated HNSCC. Forty-five patients were entered and the actuarial PFS and OS reported at 1 year was 68% and 86%, respectively. Again, expected mucositis and myelosuppression were observed in a majority of patients; however, it was suggested that gefitinib at the dose delivered did not provide additional toxicity over expected with a combined modality regimen.¹¹ Fixed dose gefitinib was part of the trial design for this particular study; a recently completed multicenter Phase II study has evaluated 250 vs 500 mg of daily gefitinib with concurrent chemo-radiation.

Erlotinib as a brief induction was recently studied in a Phase I setting with concurrent docetaxel, conventionally fractionated radiotherapy (1.8 Gy/fraction to 70.2 Gy) and continued daily erlotinib through and after chemo-radiation for up to 2 years in patients with untreated locally advanced HNSCC. The dose escalation in this study included both docetaxel and erlotinib (D (mg/m2)/E (mg): 15/50, 15/100, 20/100, 20/150). To this end, no PK alterations in docetaxel were observed in the 23 patients entered and dose limiting toxicities (DLTs) included grade 3/4 mucositis at the 2nd and 3rd dose level and a death 30 days after completion of chemo-radiation plus erlotinib at dose level 1. A complete response was reported in 15 patients.¹² Another Phase I trial combining erlotinib with full dose cisplatin (100 mg/m2 days 1, 22, 43) and conventional radiotherapy (70.2 Gy) established 150 mg as the acceptable dose of erlotinib. An 85% pathologic complete response rate was reported in the 13 patients who completed therapy.¹³

Lapatanib differs from gefitinib and erlotinib as a small molecule tyrosine kinase inhibitor based on activity against both EGFR and ErbB-2. A dose of 1500 mg was considered the MTD in a dose finding phase I trial with cisplatin (100 mg/m2 days 1, 22 and 43) and conventional radiation (66-70 Gy) in 17 patients with locally advanced HNSCC with no unexpected lapatanib related acute side effects.¹⁴

Anti-angiogenic approaches in the definitive HNSCC setting are also under investigation. Seiwert et al presented preliminary data regarding toxicity when combining bevacizumab with hydroxurea, 5-FU and concurrent radiation (upfront or with re-irradiation) every other week in patients with poor prognosis HNSCC. Dose limiting toxicities included elevated transaminases, neutropenia, and a thrombosis. Grade 3 mucositis was seen in >70% of 27 patients treated on dose level 4 (bevacizumab at 10 mg/m2) which was the expanded level with ~15% experiencing hand-foot syndrome. Additional DLTs reported in this trial included esophageal bleed (tumor bed, grade 5), stroke (grade 4), carotid rupture (3 wks post RT, grade 5), and neck ulceration requiring a carotid stent (3 months post RT, grade 4) and an unexplained sudden death. A 2 year survival of 26% was encouraging in this difficult patient population and this approach is currently under investigation in a Phase III randomized setting.¹⁵

Chemotherapy and Targeted Agents

Cetuximab has demonstrated activity in patients with recurrent or metastatic HNSCC in several randomized trials with cisplatin or as monotherapy in the upfront and chemo-refractory setting. In the former, there was a trend toward an improved progression free survival (4.2 v. 2.7 months, P = 0.9) with a 22% risk reduction in progression and a statistically beneficial outcome in patients with a skin rash. ¹⁶ In the latter, cetuximab alone in 103 patients demonstrated a response rate of 13% and a median survival of 5.9 months.¹⁷

Recently published and building upon the experience of Burtness and others, Bourhis et al enrolled 53 patients into a randomized multicenter Phase I/II trial evaluating safety and tolerability issues when combining cetuximab with either cisplatin (100 mg/m2) delivered every 3 weeks or carboplatin (AUC 5) with infusional 5-FU (escalating doses of 600, 800 and 1000 mg over 5 days). The most common side effects were leucopenia (38%), asthenia (25%) and thrombocytopenia (15%). The response rate was 36% and as has been reported in many trials. No alterations of chemotherapy pharmacokinetics with the addition of cetuximab were observed. A median overall survival of 9.8 months was noted with no significant difference between patients treated with carboplatin or cisplatin.¹⁸

Vermoken reported on the early toxicity of a Phase III trial (EXTREME) comparing 440 patients randomized to 6 three-weekly cycles of cisplatin (100 mg/m2 IV on day 1) or carboplatin (AUC 5, day 1) and 5-FU (1000 mg/m2/day continuous infusion for the first 4 days of each cycle) with or without cetuximab (which continued until progression or unacceptable toxicity). Although it was too early to report results in regards to the primary endpoint of overall survival, a preplanned interim analysis of toxicity revealed 14 deaths in the first 140 patients treated, this is concerning, however, the authors concluded that the deaths were unrelated to the study drugs.¹⁹ It appears that this study is better powered to answer the question of the potential benefits of cetuximab when added to chemotherapy in a concurrent fashion in patients with refractory or metastatic HNSCC. We anxiously await mature follow up from this important trial.

Looking at small molecule TKIs in the metastatic setting, the results of a Phase II study of lapatanib were disappointing with minimal activity demonstrated as monotherapy in patients with recurrent or metastatic HNSCC regardless of previous treatment with an EGFR inhibitor.²⁰ Erlotinib in combination with cisplatin and docetaxel has demonstrated encouraging response rates in an ongoing study. Thirty-seven patients enrolled to date were treated with docetaxel 75mg/m2 and cisplatin 75mg/m2, intravenously every 3 weeks plus fixed dose daily oral erlotinib (150 mg). Using RECIST criteria to determine response, 32 patients were evaluable with complete responses measured in 3 patients, partial responses in 18 patients and 8 patients experiencing a stabilization of disease for an overall response rate of 66% and disease control rate of 91%.²¹

The Southwest Oncology Group explored the use of BAY 43-9006 (sorafenib), FDA approved for advanced renal cancer, with activity against multiple signaling pathways including the RAS/RAF/MEK/ERK pathway. Additionally attractive is its dual activity against angiogenic related molecules such as VEGFR-2 and 3 as well as PDGFR-B. A phase II trial to evaluate the efficacy of BAY 43-9006 in chemotherapy naive patients with metastatic or recurrent HNSCC. Toxicity in 27/37 enrolled patients included one cerebral ischemia and an asymptomatic pulmonary embolus (both grade 4). Grade 3 toxicities consisted of hand/foot syndrome, stomatitis or oral pain, and one episode each of anorexia, dysphagia, hypertension, and ulceration. Anorexia and fatigue were the most common grade 2 events. Overall, this drug, at 400 mg BID continuously every 28 days, was well tolerated and mature response data will be presented after accrual of a planned 40 patients. ²²

Advanced Salivary Gland Cancers

Treatment of advanced salivary gland cancers is a challenging endeavor and an area in need of advancements and innovations in therapy. Based on data suggesting that a majority of salivary gland cancers express EGFR, Licitra and colleagues presented early response and toxicity results with cetuximab in patients with refractory or metastatic salivary gland cancers: 23/30 patients had adenoid cystic carcinoma (ACC) and approximately 40% of patients had been previously treated with chemotherapy. Seven out of 22 evaluable patients at this early stage are progression-free at > than 6 months with minimal toxicity observed and a majority of patients experiencing grade 2 skin rash. Correlative analyses are planned in regards to EGFR expression by IHC and FISH and we look forward to more mature follow-up results. ²³

Along a similar path, investigators evaluated response in patients with advanced ACC treated with a combination of bortezomib (B), a selective inhibitor of the 26S proteasome involved in the ubiquitin-proteasome degradation pathway. Only patients with evidence of disease progression were eligible for study entry, those with disease stabilization for > 9 months were ineligible. Subsequent treatment consisted of B 1.3 mg/m2 IV push on days 1,4,8, and 11, every 21 days, until progression. Doxorubicin 20 mg/m2 IV on days 1 and 8 was added at the time of progression. Although no significant responses were seen in the 25 patients enrolled, 6 pts (64%) had SD, with a median progression-free survival of 8.5 months. ²⁴ The most common toxicity was sensory neuropathy (14%) with mild myelosuppression seen across the board.

Finally, ZD6474, a small molecule TKI, is under investigation in patients with medullary thyroid carcinoma, inhibiting RET kinases (often expressed in hereditary medullary carcinoma) along with VEGFR2 and EGFR. In this ongoing Phase II study, the authors elected to present information on the initial 16 patients entered. A majority of 15 evaluable patients experienced stabilization of disease with daily fixed dose ZD6474 (300mg) with 3/15 patients experiencing partial responses. Objective tumor assessments have demonstrated partial responses in 3 patients. Calcitonin levels decreased by >50% from baseline for at least 4 weeks in 12/15 patients. ²⁵ This represents very early response data but is highly encouraging given that options for this disease have been quite limited; it remains to be seen if survival will be extended.

Induction Chemotherapy

Over the past decade, concurrent chemo-radiotherapy has emerged as the “standard of care” for organ preservation, debates about the optimal chemotherapy regimen notwithstanding. With improving local control rates above the clavicles, and therefore, a change in the failure patterns with increasing rates of distant metastasis, investigators have begun to re-explore induction chemotherapy as a way of improving outcomes further. Potential advantages of induction chemotherapy include reducing tumor burden prior to concurrent chemo-radiotherapy and providing the treating oncologist with predictive information as to the future utility of organ preservation. Disadvantages might include added toxicity without survival benefit and a delay of definitive radiotherapy leading to greater resistance of surviving cancer cells. Phase II studies have demonstrated the feasibility of regimens using platinum combinations with 5-FU and paclitaxel with patholgical response rates above 85% and 5-year progression free survival rates at 85%. ²⁶ There are several important randomized trials underway to validate the survival benefits of induction chemotherapy including studies through Dana Farber and University of Chicago.

In the interim, a phase IIB study at ASCO 2006 treated patients with advanced laryngeal cancer with induction TPF: docetaxel 75 mg/m2/d1, cisplatin 100 mg/m2/d1 and 5 Fluorouracil 1000 mg/m2/d1-4) for 3 cycles prior to following the RTOG 91-11 concurrent chemo-radiation approach. The study was a one stage design, with the primary endpoint recurrence free survival using a planned sample size of 250 patients. In this regard, the authors close to present data with 103 patients entered to date. After a median follow up of two years the larynx preservation rates were similar; however, the disease free survival (DFS) rates were 85% for the induction group vs. 66% for the concurrent group, p = 0.017. No comment was made as to the differences in metastatic disease that might account for the better DFS vs. a delay in local progression events. As expected higher rates of myelosuppresion were seen with the induction regimen. ²⁷

The group at University of Alabama at Birmingham evaluated a regimen combining 3 cycles of induction chemotherapy (docetaxel 75 mg/m2 and cisplatin, 75 mg/m2) followed by weekly docetaxel with concurrent once daily radiation in a patient group presenting with stage III/IV A-B HNSCC. ²⁸ Critical findings from this Phase I/II trial included a radiologic response rate of 75% with the induction regimen and in the initial 18 patients evaluated for response, none developed progressive disease. Docetaxel is a powerful radiosensitizer and can be quite toxic when delivered with radiation. The phase I component of this study determined that 20 mg/m2 was the MTD. It was a little disconcerting that approximately 45% of patients required an extended duration of feeding tube support suggesting greater subacute toxicity, although most were subsequently removed after 6 months. Amifostine given subcutaneously during chemo-radiation was well tolerated.

Paccagnella and colleagues reported on a randomized Phase II trial of concurrent chemo-radiation or induction TPF followed by concurrent chemo-radiation. ²⁹ Using typical entry and stratification criteria for locally advanced HNSCC, patients were randomized to concurrent chemo-radiation (2 cycles of cisplatin 20 mg/m2 days 1-4, 5FU 800 mg/m2 96 hours c.i. weeks 1 and 6 during RT (66-70 Gy, Arm A) or 3 cycles of neoadjuvant TPF (docetaxel 75mg/m2 day1, cisplatin 80mg/m2 day1, 5FU 800mg/m2 96 hours c.i) followed by the same chemo-radiation regimen (Arm B). The planned sample size was 96 patients to detect a difference in CR (primary endpoint) up to 15% in favor of arm B. This was accomplished in the 84 patients evaluable at the end of chemo-radiation based on RECIST criteria with a radiological CR of 20% (95% CI 8-37%) in arm A and 64% (95% CI 45-80%) in arm B. Toxicities during induction TPF consisted primarily of G3-4 granulocytopenia 56% with febrile neutropenia in 7.5% of patients). There did not appear to be any increase in mucositis rates between he 2 arms at the completion of chemo-radiation and there were no increased treatment delays seen in group B during chemo-radiation despite the induction regimen.

Addition of Taxanes to Induction Regimens

Does adding a taxane contribute anything to an induction regimen containing platinum and 5-FU? EORTC 24971 reported their final analysis regarding this question at ASCO 2006. ³⁰ Patients with locally advanced HNSCC were randomized to PF (platinum, 5-FU) or TPF received 4 cycles of this regimen prior to receiving conventional or accelerated or hyperfractionated radiation with surgery incorporated for advanced neck disease. With 358 patients accrued (181 PF, 177 TPF) progression free survival at a median follow up of 32 months was significantly improved with TPF (HR 0.72, p = 0.0071; median 8.2 vs 11.0 mo). Even more important, with a median follow up of 51 months, an overall survival benefit was realized with TPF (HR 0.71, p = 0.0052; median 14.2 vs 18.6 mo). Somewhat discouraging in this author’s view is the low estimated 3-year survival rates of 36.5% for TPF despite this aggressive approach.

Calais et al further validated the benefits of adding a taxane (in this case docetaxel) to an induction regimen of platinum and 5-FU in a GORTEC study for patients with locally advanced larynx and hypopharynx cancer. ³¹ One of the primary goals was to see whether a TPF regimen would improve organ preservation. To this end, patients treated without docetaxel received a typical platinum and 5-FU dosing approach for 3 cycles (P 100 mg/m2/d1 and F: 1000 mg/m2 continuous infusion (CI) d1 to 5). Patients receiving docetaxel were dosed at 75 mg/m2/d1, with reduced platinum and 5-FU at 75mg/m2/d1 and 750mg/m2 CI d1-5 respectively for 3 cycles. Patients with complete or partial response and who recovered normal larynx mobility received conventional radiation to 70 Gy. A statistically superior response rate to induction therapy was seen in the group receiving TPF with a larynx preservation of 80% vs 57.6% for PF. With a median follow up of 35 months the 3-year actuarial larynx preservation rate was 73% following TPF vs 63% using the PF regimen. Longer follow up is needed to determine if TPF using docetaxel improves disease free and overall survival.

Finally, RTOG 91-11 was a landmark trial designed to evaluate a larynx preservation approach comparing sequential to concurrent chemo-radiation for patients with locally advanced larynx cancer excluding very advanced T4 disease involving cartilage destruction. ³² In this earlier report in 2003, concurrent chemo-radiation was considered statistically superior to radiotherapy alone or to sequential therapy in regards to larynx preservation and local-regional control rates. Overall survival rates were similar across the 3 arms of therapy. In this update at ASCO 2006, with mature 5 year outcomes, there appeared to be no difference in laryngectomy-free survival between induction chemotherapy followed bay radiation vs. concurrent chemo-radiation although both remained superior to radiation alone. ³³ Concurrent chemo-radiation remained superior to sequential therapy and radiation alone in regards to local-regional control (68.8% compared to 54.9%, p = 0.0018 for sequential or induction chemotherapy and 51% for radiation alone, p = 0.0005)). Not surprisingly, no statistical difference was seen in local-regional control between sequential chemo-radiation and radiation alone. Interestingly, in contrast to the initial report, at 5 years there was no real difference in disease free survival between the sequential vs. concurrent chemo-radiation arms (38.6% and 39% respectively); however, both remained superior compared to radiation alone (27.3%). Again, no overall survival differences were observed across all 3 arms.

Conclusions

ASCO 2006 provided additional glimpses into the future of care for patients with advanced HNSCC. Targeted therapies have been rapidly integrated into the therapeutic armamentarium for patients with advanced head and neck cancer; it appears that at early glance, toxicities are reasonable with EGFR inhibitors and chemo-radiation. Anti-angiogenic approaches with anti-VEGF antibodies also show some promise when combined with chemo-radiation and perhaps in the future we will see trials incorporating both targeted strategies with radiation or chemo-radiation. Concurrent chemo-radiation remains the accepted standard approach for larynx preservation; however, at 5 years, the advantages are nullified in regards to disease free survival over sequential chemo-radiation. Thus, at ASCO 2006, induction chemotherapy or induction chemotherapy with targeted agents is clearly back under the microscope with taxane-based regimens appearing to offer the greatest advantages in terms of response and improved organ preservation rates; results of phase III trials with and without induction therapy will tell us whether this truly translates into a survival advantage and sets the new standard of care.

References

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