Head and neck squamous cell cancer (HNSCC) management is evolving rapidly. Approaches under exploration include induction chemotherapy, altered fractionation radiation with chemotherapy, intensity modulated radiation therapy (IMRT) and the use of biologically targeted drugs to enhance radiation. Improvements in outcomes are being slowly realized, however, at a cost of significant acute and chronic morbidity. Where are we headed in 2007? In this review, we discuss some of the interesting reports from this year’s American Society for Therapeutic Radiology and Oncology that focused on head and neck cancer management.

Targeted Therapies in HNSCC
Pre-Clinical Studies

It is known that the epidermal growth factor receptor (EGFR) is highly expressed in HNSCC and is associated with poor prognosis.¹ The level of EGFR expression strongly impacts survival and patterns of relapse in irradiated patients with advanced head and neck carcinoma.² Less is known regarding the significance of EGFR expression in particular patient populations. In this regard, Settle et al. analyzed 103 patients treated with definitive chemo-radiation with locally advanced head and neck cancer. African-Americans had a worse outcome overall. Researchers explored whether EGFR expression in the tumor specimens by immunohistochemistry predicted outcomes in this group of patients. Although retrospective in nature, African-Americans (AA) with high levels of EGFR expression fared considerably worse than AA patients with lower levels of EGFR.³

Patient samples were characterized with a staining intensity (SI) system on a scale of 0-97 as well as a ChromaVision Automated Cellular Scoring System that quantified EGFR expression based on color, color purity and intensity. Patients of African-American background demonstrated a median survival of 34 months versus a median survival of 71 for patients with an EGFR score greater than or less than the median. Of interest would be a comparison of outcomes in AA men and woman versus Caucasian men and woman based on EGFR expression in an effort to better tailor more aggressive therapy based on biomarker expression. Further validation of these interesting results from a small number of patients is warranted.

Additional pre-clinical studies presented at the American Society for Therapeutic Radiology and Oncology (ASTRO) 2006 included combination results of AZ2171, a pan-vascular endothelial growth factor receptor (VEGFR) inhibitor with radiation in human head and neck squamous cell cancer (HNSCC) models in vivo. A dose enhancement factor of 1.1-1.9 was reported with single fraction radiation (15 Gy) with either 3 or 6 mg/kg of AZ2171 in nude mice harboring FaDu HNSCC flank xenografts.⁴

Clinical Studies with Targeted Therapies in HNSCC

There were few reports at this year’s ASTRO regarding mature clinical results with trials examining novel biologic agents and radiation in HNSCC. Maturing results from recent clinical trials await review. A small pilot study of gefitinib (250 mg daily) in combination with weekly paclitaxel (36-45 mg/m2) and once daily radiation (66-76Gy) reported a high incidence of tongue dysethesias.⁵ Seven of nine patients entered experienced this symptom, all of whom received 50-70 Gy to the oral tongue; 6 of 7 patients developed grade 3/4 mucositis and gabapentin appeared to relieve the pain in 2 patients treated with this approach. No comment was made on the duration of this symptom after chemo-radiation was concluded.

RTOG 0522 is currently accruing patients. This is a randomized Phase III study of chemo-radiation with or without cetuximab delivered weekly during therapy. Patients can be treated with 3-D conformal radiation using concomitant boost or with IMRT using accelerated radiation with an additional fraction delivered per week (6 fractions/week). RTOG 0234, a randomized Phase II study combining post-operative radiation with weekly cetuximab and either weekly docetaxel or cisplatin for patients with high risk head and neck cancer features after surgery.

Concurrent Chemo-Radiation in Locally Advanced HNSCC

Some of the interesting abstracts presented at ASTRO 2006 included mature results regarding neck control in HNSCC patients presenting with nodal disease treated with chemo-radiation at Memorial Sloan-Kettering Cancer Center. The issue of the necessity of a neck dissection in patients with nodal presentations was challenged. Rengan et al. reported that of 86 patients presenting with palpable disease, 69 experienced a complete clinical response (CCR) at the completion of therapy. Excluding 4 patients who underwent immediate neck dissections (all pathologically negative), the long-term 10 year nodal failure rate was 14% if a CCR was obtained and a resultant median survival of 12.2 years. In contrast, 14 of 17 patients who did not experience a CCR were found to have positive disease after neck dissection with a very poor median survival of 1.4 years.⁶

We currently await the results of RTOG 0129, a phase III study comparing once daily radiation with chemotherapy versus concomitant boost radiation with chemotherapy. In the interim, single institution studies provide additional glimpses into the outcomes and toxicities of this aggressive strategy. The efficacy of accelerated radiation using concomitant boost (70Gy) with concurrent cisplatin (100 mg/m2 days 1, 22 and 43) in patients with locally advanced nasopharyngeal cancer was discussed.⁷ An impressive crude local control rate of 93% was reported with a local-regional control rate of 96% in 45 patients treated with this aggressive regimen at a median follow-up of 27 months. High rates of local control were seen in the 29 patients with T3-4 disease. The distant failure rate was only 4% and the disease free survival was 86%. The expected grade 3 mucositis rate in approximately 55% of patients was observed; 2 patients experienced brain necrosis with long-term follow-up. Interestingly, 90% of these patients were treated with erythropoietin with more recent reports suggesting potential detrimental effects of using this marrow stimulant. It doesn’t appear that local control rates here were affected negatively.

The Beth Israel group also updated their results in patients treated with a similar concomitant boost radiation with concurrent chemotherapy in patients with locally advanced laryngeal cancer.⁸ With a median follow-up of 34 months, an actuarial 3-year local-regional control rate of 80% was observed with a DFS rate of 65%. Understanding the limitations underlying comparison among different studies, the local control rates appear similar to outcomes seen in RTOG 99-14, the RTOG phase II study evaluating concomitant boost radiation with chemotherapy.⁹ Acute toxicities appeared similar to previous reports in the literature. Of concern was the reported 29% chronic dysphagia with 8 patients still with PEG tubes at the last follow up and a 15% osteoradionecrosis rate.

Under investigation over the last decade has been the use of inter-arterial cisplatin in combination with radiation in patients with HNSCC. The efficacy and safety of hyperfractionated radiation with intra-arterial cisplatin, termed HYPERRADPLAT was discussed at this years ASTRO meeting.¹⁰ Fifty patients with >T2 disease received cisplatin at 150 mg/m2 delivered intra-arterially when patients reached the boost phase of treatment, receiving from 71.6-81.6 Gy at 1.2 Gy BID. Thirty-eight patients presented with N2-N3 disease; 90% of patients were reported to have a CCR at the primary site with 82% achieving a CCR in the neck. The 3-year cause-specific survival and overall survival was 58% and 44%, respectively, with an overall recurrence rate of 48% noted (24% with distant failure). Grade 3 mucositis was 78% with 4% experiencing grade 4 mucositis.

Minimal information on the use of docetaxel with radiation for head and neck cancer exists in the literature. RTOG 0234, which recently completed accrual, examined the use of weekly docetaxel (15 mg/m2) with cetuximab and radiation in the post-operative setting. Karasawa and colleagues presented at this years ASTRO conference early outcomes data in patients with stage III/IV HNSCC treated with weekly docetaxel (10 mg/m2) and hyperfractionated radiation (1.2 Gy BID to 72 Gy).¹¹ Of the 35 patients entered into this trial from 2003-2006, 12 presented with hypopharyngeal cancers and 9 with laryngeal cancers. With a median follow-up of only 8 months there were 6 local and 6 nodal failures. Tumor volumes >100 cm³ fared particularly poorly along with primary site of disease (hypopharynx with 51% relapse free survival rate). At first glance this data appears underwhelming with early follow-up; however, this trial as mentioned contained a large number of hypopharynx cases, which are typically difficult to control.

Induction Chemotherapy Followed By Chemo-Radiation

Induction chemotherapy prior to concurrent chemo-radiation is back under investigation in locally advanced HNC. Currently, there are two Phase III randomized trials comparing induction chemotherapy followed by concurrent chemo-radiation to concurrent chemo-radiation alone (DECIDE and PARADIGM trials). Dr. Lillian Siu from Princess Margaret Hospital in Toronto presented discussion at the Presidential Course on HNC regarding this issue. Meta-analysis from Pignon et al. demonstrated no significant 5-year survival benefit with sequential chemotherapy in 15 trials incorporating 5FU and cisplatin.¹² Newer agents under evaluation include the taxanes with the hope of reducing distant metastasis as local control improves in patients with locally advanced HNC. Dr. Siu reviewed the recent results of the TAX 324 trial, a Phase III randomized trial for locally advanced HNC patients comparing sequential TPF (docetaxel, cisplatin, 5-fluorouracil (5-FU)) to PF (cisplatin, 5-fluorouracil) for every 3 weeks for 3 cycles prior to concurrent carbotaxol and radiation to 70 Gy.¹³ The overall survival at 2 years was 67% for TPF versus 54% for PF (HR 0.7, P=0.0058).

A similar trial from Madrid also demonstrated an improved survival with very similar outcomes at 2 years.¹⁴ This particular trial used cisplatin with radiation rather than carboplatin and used paclitaxel rather than docetaxel. In addition, the 5-fluorouracil dose in the PCF regimen was only 500 mg days 2-6 for the 3 cycles administered rather than 1000 mg with each cycle in TAX 324. Over 80% of the patients in each study were stage IV and, in the Madrid study, 55% presented with T4 disease. From a pattern of failure standpoint, 14% of patients in the Madrid trial failed distantly.

EORTC 24971, presented at the American Society for Clinical Oncology (ASCO) annual meeting in 2006 was also discussed at this year’s ASTRO symposium by Dr. Siu. This trial randomized “unresectable” HNC patients to either induction TPF x 4 or PF x 4 followed by RT alone and surgery held in reserve as needed.¹⁵ In this study, the 5-FU was reduced in the TPF arm to 750 mg D1-5 every 3 weeks for the 4 cycles vs. 1000 mg every 3 weeks in the PF arm. Docetaxel was used in this study rather than paclitaxel. Once again, the regimen containing a taxane produced a significant survival advantage (45% vs. 34% at 2 years; HR 0.73, P=0.0052) although the survival in the TAX 324 and the Madrid trial, both of which utilized concurrent chemo-radiation had survivals rates of approximately 20%, differences in patient selection notwithstanding.

Regarding toxicity, the take home message appeared to be that there was a higher rate of febrile neutropenia with the use of a triple combination regimen but a lower induction mucositis rate; perhaps in part due to lower doses of 5-FU in the triple combination arms in 2 of the studies. At this point in time, we still do not know if the addition of induction chemotherapy provides a superior survival advantage over concurrent chemo-radiation. Accrual to the DECIDE and Paradigm trials are therefore important to resolve this question. In the mix is the addition of biologically targeted agents that might provide less toxicity with improved outcomes as well.

Finally, Dr. Siu reviewed the updated results of RTOG 91-11, a randomized Phase III trial that compared induction cisplatin (5-FU + cisplatin x 2 cycles) followed by radiation to concurrent cisplatin and radiation to radiation alone. In the induction arm, patients experiencing a complete response went on to receive an additional cycle of chemotherapy prior to radiation or surgery if response was suboptimal. Only 10% of 10 patients entered into his trail had T4 disease.¹⁶ The median follow up was 6.9 years. Although the local-regional control rate was clearly higher with concurrent chemo-radiation (with local-regional control rates similar between induction chemotherapy and radiation alone) and the distant metastasis rate was lower in the arms containing chemotherapy, the overall survival was not statistically different between any of the arms (59% for induction chemotherapy, 55% for concurrent chemo-radiation and 54% for radiation alone).

PET imaging, IMRT and Adaptive Planning in HNSCC 

The use of PET registration to enhance contour acquisition for HNSCC planning continues to be an important area of investigation. Lotti et al. evaluated the use of PET-CT fusion for treatment planning and noted changes in gross tumor treatment volume delineation in 38% of patients (16 of 42)¹⁷. At the University of Colorado, we also felt that PET imaging appeared to impact on clinical management both in the pre-treatment and post-treatment setting in 20% and 28% of patients, respectively. However, in our early experience with 111 patients, we surmised that in a majority of patients PET findings were of uncertain significance so as to not influence clinical decisions.¹⁸

Shintani and colleagues utilized PET imaging in the post-operative setting prior to adjuvant radiation to ensure adequate target coverage and detect new occult areas of uptake.¹⁹ The investigators noted positive PET findings in 24/91 patients resulting in biopsies. Positive histological findings were detected in 45% of patients leading to management changes in 15% of this subgroup. The authors acknowledge that there was a high rate of false positives and thus follow through biopsies were recommended to confirm PET findings prior to altering treatment volumes, dose, etc.

Functional imaging of molecular biomarkers is an exciting avenue of research with the potential to provide valuable information of targeting of novel biologic agents towards the tumor. A very interesting approach was reported using a novel tagged molecule to seek out angiogenesis related molecules expressed on HNSCC.²⁰ In this regard, (18F) Galact –RGD targets the Alpha V Beta 3 integrin (αvβ3) receptor and was injected (133-200 MBq) into 10 patients with HNSCC. There was uptake reported using the ECAT Exact PET scanner in 8/10 patients with a SUV uptake ranging from 2.2-6.0. Expression of αvβ3 in these 8 patients was noted primarily in the microvessels. No uptake was reported in tumors that were < 7 mm. This certainly warrants additional studies both in the pretreatment setting, during and after treatment to see if decreases in uptake to the αvβ3 receptor correlate with outcomes.

This year’s presidential course focused on critical issues related to HNSCC. Dr. Nancy Lee focused on IMRT for nasopharyngeal cancer including a review of RTOG 88-17, a phase III randomized study comparing radiation alone to concurrent chemo-radiation with concurrent and consolidative cisplatin + 5-fluorouracil. Rarely has there been a study demonstrating such a huge difference in outcomes with 5-year survivals approaching 70% in the combined arm in contrast to 40% in the radiation-alone arm.²¹ A recent meta-analysis confirmed the benefits of combined therapy with a survival benefit of 20% in the patients receiving concurrent chemo-radiation.²² The implementation of IMRT in the management of this disease has resulted in excellent outcomes—an update of the UCSF experience with a median follow up of 30 months in 120 patients demonstrates a progression free survival rate of 97% at 4 years²³. Local control rates of >90% are routinely reported now, however, distant metastasis remains a problem with rates in the range of 30-40%. RTOG 0615 will open soon to accrual. This Phase II trial incorporates bevacizumab, an anti-VEGF antibody during and after chemo-radiation to test the tolerability and safety of this combination in an effort to reduce distant metastasis and improve progression free and overall survival.

Radhe Mohan, PhD, supplemented the discussion on IMRT with an in depth look at adaptive radiation during the Presidential symposium on HNSCC. Integrative radiation therapy (IGRT) attempts to take into account daily anatomic changes in both patient and tumor as well as biologic changes in the tumor. In addition, emerging technology may allow for motion tracking during radiation delivery to provide greater accuracy in radiation dose delivery. Ahamad et al. prospectively looked at 12 patients who underwent 2 CT scans per week while undergoing IMRT for local advanced HNSCC. The goal was to try and define “trigger points” that would lead to intervention and replanning. To this end, it was observed that the dose to the ipsilateral parotid gland increased by 6.1 Gy for every 10% loss of body weight. In addition, the mean dose to the high risk CTV areas gradually increased in the 6 patients analyzed and the coverage of the CTVs was maintained. Due to small numbers in this analysis, a specific “trigger point” for re-planning was not offered. Further studies are underway to evaluate this issue.²⁴

Conclusions

The management of HNC continues to evolve rapidly. ASTRO 2006 provided some nice summaries of what is currently being investigated in regards to biologically targeted therapies. RTOG 0522 is underway comparing chemo-radiation to chemo-radiation with cetuximab, the anti-EGFR antibody, in locally advanced HNC patients. RTOG 0234 has completed accrual and it will be very interesting to evaluate the outcomes using less intensive chemotherapy regimens with the addition of cetuximab in patients with high-risk cancer in the post-operative setting. IMRT and image guided technical advances may provide more accurate radiation delivery, and perhaps we will see an even greater integration of biology and physics in the years to come. Finally, induction chemotherapy remains a controversial issue, although clearly we have seen benefits to adding a taxane as part of the induction strategy in terms of improved outcomes. Time will tell if this approach proves superior to chemo-radiation and if it is worth the cost and extra toxicity that might come along for the ride.

References

² Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350-6.

³ K. M. Settle, R. Taylor, J. Papadimitriou et al. The Prognostic Significance of EGFR Expression in African American Patients with Squamous Cell Carcinomas of the Head and Neck. Proceeding from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract #2429.

⁴ Imagumbai T, Komaki R, Milas, L et al. Inhibition of VEGFR-1, -2, and -3 Signaling by AZD2171 Enhances the Anti-tumor Efficacy of Radiation Therapy in a Mouse Xenograft Model. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2659

⁵ Sharp HJ, J. C. Morris, VanWaes C, et al. A High Incidence of Oral Dysesthesias Unrelated to Mucositis in a Pilot Trial of Gefitinib, Paclitaxel and Concurrent External Beam Radiation in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN) Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 1101.

⁶ Rengan R, Pfister DG, Lee NY, et al. Long term neck control rates after complete response to chemoradiation in patients with advanced head and neck cancer. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 29.

⁷ Hu K, Choi W, Huang H, et al. Accelerated Fractionated Radiation By Concomitant Boost (AFX-CB) With Concurrent High Dose Cis-platinum (CDDP) For Advanced Nasopharyngeal Carcinoma. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2368.

⁸ Eaton M, Hu K, Culliney B, et al. Single Institution Experience with Accelerated Fractionated Radiation by Concomitant Boost (AFX-CB) and Concurrent Chemotherapy for Advanced Larynx Carcinoma. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2410.

⁹ Ang KK, Harris J, Garden AS, et al.  Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: radiation therapy oncology group phase II trial 99-14. J Clin Oncol. 2005;23(13):3008-15.

¹⁰ Arnold SM, Warren GW, Valentino J, et al.  Long Term Results Of Regional Control In Stage III-IV Node Positive Patients With Squamous Cell Carcinoma Of The Head And Neck Using Hyperfractionated Radiation Therapy And Intraarterial Chemotherapy (HYPERRADPLAT). Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2427.

¹¹ Karasawa K, Haruyama T, Ito S, and Ikeda K.  Hyperfractionated Radiotherapy With Concurrent Docetaxel For Advanced Head And Neck Cancer. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2434.

¹² Pignon JP, Bourhis J, Domenge C and Designe L.  Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355(9208):949-55.

¹³ Posner M. Docetaxel added to Induction Therapy in Head and Neck Cancer. Scientific special session. Proceedings of the 42nd Annual ASCO meeting, June 2-6, Atlanta GA 2006.

¹⁴ Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al, Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005;23(34):8636-45.

¹⁵ Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: Abstract #5516.

¹⁶ Forastiere A, Maor M, Weber R, et al. Long-term results of Intergroup RTOG 91-11: A phase III trial to preserve the larynx--Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: Abstract #5517.

¹⁷ Lotti C, Versari A, Paiusco M, et al. The Impact of PET-CT Registration in IMRT-planning for Head and Neck Cancers. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2383.

¹⁸ McCammon R, Furuya C, Raben D, et al. The Influence of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography (PET) on the Clinical Management of Patients with Head and Neck Cancer. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 1094.

¹⁹ Bayouth JE, Tan H, Wacha J, et al. Intensity Modulated Radiotherapy for Oral Cavity Cancer. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2427.

²⁰ Beer AJ, Grosu AL, Sarbia M, et al. Non-Invasive Imaging of Alpha-v-Beta-3-Expression in Head-and-Neck Cancer Patients with (18F)Galacto-RGD and Positron Emission Tomography. Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract # 2388.

²¹ Al Sarraf, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998;16(4):1310-7.

²² Langendijk JA, Leemans CR, Buter J, et al. The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol. 2004;22(22):4604-12.

²³ Lee N, Xia p. Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002;53(1):12-22.

²⁴ Ahamad A, Dong L, Zhang L, et al. Is There a Trigger Point for Adaptive Replanning During Head & Neck IMRT? Proceedings from the 48th Annual ASTRO meeting, November 5-9th, Philadelphia, PA. 2006. Abstract #181.