Introduction

Advancing the treatment for head and neck cancer is always high on the agenda of clinical investigation in radiation oncology, and the presentations at ASTRO this year focused on the most recent trends. Radiation therapy and surgery continue to play the central roles in local, curative management, and improvements in radiotherapy and systemic agents have improved outcomes for patients with advanced, unresectable disease. However, very few areas of radiation oncology practice induce major, life altering normal tissue consequences so routinely, and presentations this year dealt with these issues. Lastly, the growing biotechnology revolution is affecting this and all other areas of radiation oncology. Molecular diagnosis, staging, and outcome assessment show promise by facilitating more rational, individualized decisions regarding the use of toxic therapies. Molecular targeted treatments are sure to add cancer control benefit and reduced toxicity.^1-3 Since molecular progression in head and neck cancer via alterations in proto-oncogenes and tumor-suppressor genes is becoming better understood,¹ it seems likely that the future described by ASTRO keynote speakers Doctors David Botstein of Princeton University (“Genome-Wide Patterns of Gene Expression in Cancer”) and John Mendelsohn of MD Anderson Cancer Center (“Augmentation of Chemotherapy and Radiotherapy by Epidermal Growth Factor Receptor (EGFR) Inhibition”) will greatly impact head and neck cancer care.

Two invited commentators summarized the current situation well during the scientific sessions. Dr. Jay Cooper of New York University Department of Radiation Oncology used the example of “Bernier’s Laws”, named for Jacques Bernier MD of Switzerland and chairman of the EORTC Head and Neck Cancer Committee. While intentionally overstating the situation for some cancers, they serve to illustrate the general status of the advanced head and neck cancer patient today:

1. Three year control rarely exceeds 30-50%.
2. Below clavicle failure is 20% almost irrespective of disease site.
3. Novel therapies often increase control but also increase serious acute toxicity; hopefully they increase late toxicity less intensely.

Dr. Cooper noted that we continue to balance the “angels and demons” of our treatments, only with difficulty making the net result more “angelic”!

In a panel discussion entitled “Pharmacy versus physics versus fractionation: What’s the score in head and neck normal tissue protection?”, Dr. Andy Trotti of H. Lee Moffit Cancer Center, University of South Florida, took the opportunity to frame the right questions, a too infrequent act in our high technology driven specialty. He asserted that we need a relevant, adequately broad, and stable toxicity profile of each therapy so cross comparison is possible among therapies. He pointed to metrics for cure, such as survival, local control, and organ preservation, as examples on Dr. Cooper’s “angelic” side of the folcrum that are easy to cross compare.

To date, we have relied on toxicity scores developed for non-oncologic types of care that give poor measure of the cancer patient experience. For example, our patients frequently have multiple simultaneous toxicities varying in degree over time, much higher total toxicity burdens than with other therapies, and their side effects are cumulative and changing over time. In most studies, only one grade ^3-4 toxicity is reported per patient, though most patients suffer more than one. Perhaps we should report the total grade ^3-4 events per study arm, or as some investigators now do report an “AUC” of toxicity.⁴ The new CTCAE 3.0 nomenclature for toxicity (www.ctep.cancer.gov/forms/CTCAEv3.pdf) is a good start toward improving this situation. Dr. Trotti and others will elaborate on this important problem in an upcoming issue of the Journal of Clinical Oncology. This laudable effort will help bring needed perspective to our current balance of “angels and demons”, and make for better study designs in the future.

With this in mind, the 2003 ASTRO presentations are summarized by approaches taken to improving therapeutic benefit:

1. Altered fractionation
2. Better radiation delivery and target definition/delineation
3. Chemoradiotherapy and/or use of novel combination therapies
4. Molecular identification of groups likely to fail therapy or suffer unusually intense side effects
5. Use of normal tissue response modifiers to reduce toxicity

Altered fractionation

Accelerated fractionation is believed to reduce the likelihood of radiation therapy failure due to cellular re-population during treatment. Hyperfractionation, with or without some acceleration, has allowed dose escalation maintaining equitoxicity and 10-15% improvement in local control in phase III randomized controlled trials. ^5-16 This year at ASTRO, Lauve and colleagues at Virginia Commonwealth University undertook parotid sparing dose escalation with “sliding window” IMRT in a phase I trial for locally advanced squamous cell carcinoma, from 68.1-73.8 Gy in 30 fractions over forty days. The MTD appears to be 70.8 Gy at 2.36 Gy/fraction with satisfactory parotid sparing.¹⁷

Two studies presented at ASTRO showed that IMRT offered effective local control with lower late toxicity rates than historical data, but significant acute toxicity, especially when combined with chemotherapy. Amosson, et al at Baylor ¹⁸ reported that the Simultaneous Modulated Accelerated Radiation Therapy (SMART) boost technique “provides excellent local control with decreased xerostomia.” Total prescribed boost dose in the 55 patients was 60 Gy in 25 fractions of 2.4 Gy, and the mean delivered dose was 63.8 Gy. Complete response was 89.1% and local/regional relapse was 23.6%. Acute grade III mucositis was high, occurring in 47.3% of patients treated, perhaps partly because 20% of the patients received chemotherapy in addition to RT. Severe late xerostomia was 13.3% and “moderate” xerostomia was 20%, rates which appear to be improved over historical data for non-IMRT techniques. Unfortunately, the applicability of this technique is reduced because concurrent chemotherapy causes intolerable acute toxicity. However, these findings are consistent with those of Huang, et al at UCSF,¹⁹ who used multi-field IMRT in 65 patients with oropharyngeal squamous cell carcinoma and more standard daily fraction sizes. Results showed 90% control, 33% late grade II xerostomia, and a smaller but non-trivial number of patients with severe acute mucositis.

At UCSF, 73% of the patients received chemotherapy, many more than on the accelerated Baylor trial, so there may be a steep dose/fraction response curve in this range for the acute effects. The highest mean dose per fraction was about 2.12 Gy to a total of 72 Gy, with as high as 78.1 and 80.8 Gy to the CTV and PTV respectively. Hopefully, publications of this data will detail volume factors, pretreatment patient performance, and more detailed toxicity outcomes so better cross comparison is possible.

The results of the German ARO 95-6 randomized trial were presented offering another view of the problem. In this trial treatment time was held constant at six weeks (42 days), and patients received either 77.6 Gy alone to the GTV (HART) or 70.6 Gy with concurrent 5-FU/Mitomycin C chemotherapy (C-HART). No IMRT was used. While not specified in detail, both arms were said to be equitoxic with similar late morbidity. Local regional control and overall survival at the median 5-year follow up was 40% and 28% in the HART arm, and 50% and 34% in the V-HART arm, both significantly different.20 C-HART was deemed more effective, but is it more “angelic”, in Dr. Cooper’s terms, than less accelerated courses?

The toxicity of each arm of DAHANCA trials 6 and 7 was also reported at ASTRO 2003. 21 In this large Danish cooperative group trial, 1,485 patients were randomized to 68 Gy in 34 fractions either five or six days per week. In the DAHANCA 7 trial a hypoxic cell sensitizer was given to all patients. While there was increased acute confluent mucositis (32% versus 55%), and some other acute toxicities were increased, these generally healed and no difference in late toxicity was reported. Although the tumor control outcomes are reported elsewhere, the authors stated they were better in the 6 fraction per week group. The researchers indicate this has become the new Danish acceleration standard protocol for studies. Interestingly, this pattern of treatment is said to be less resource consumptive than other acceleration schemes in the Danish healthcare system. Again, it is difficult to compare the toxicity burden of this treatment with standard therapy or chemoradiotherapy.

Two fractionation trials address acceleration in the postoperative situation. A cooperative group trial from Italy was presented by Antagnoni and colleagues ²² in which no apparent difference in local control and late toxicity was seen comparing 60 Gy/30 fractions versus 64 Gy/25 fractions using an “early plus late” biphasic concomitant boost. Acute confluent mucositis was 50% in the accelerated arm versus 25% in the standard one. With only 226 evaluable patients, however, the power to detect a significant local control difference may not have been adequate.

A Swiss study, presented by Zouhair and colleagues 23 was non-randomized and delivered 66 Gy in a pattern of six fractions every five days of each week (bid fractions given each Friday), and data suggested reasonable tolerance levels with 14% local regional relapse at a median follow up of 21 months. As predicted by Dr. Bernier via Dr. Cooper, the distant failure rate was 20%, so the group judged this would be another feasible way to accelerate radiation treatment but would probably require chemotherapy to help control distant metastasis.

Only time will tell if the toxicity of acceleration will be outweighed by the advantages, but these studies bring us closer to knowing.

Better Radiation Delivery and Target Definition/Delineation

Multiple abstracts addressed ways to refine treatment delivery, mostly through improvements in IMRT technique and enhanced specificity of target delineation. Patterns of failure were reviewed by presenters from the University of Michigan ²⁴ and Stanford ²⁵ using IMRT to reduce parotid dose. The former group concluded that, in patients with ipsilateral clinically positive neck, contralateral “normal” nodal targets above the jugulodigastric nodes in level II could be excluded from the clinical target volume (CTV) yielding improvement in parotid DVHs. However, ipsilateral retropharyngeal nodes should be included in the CTV to at least the base of the skull. Almost all local regional relapse occurred in-field (within CTV) in their group, with only 4/136 regional failures in spite of good parotid sparing.

The Stanford group also obtained better xerostomia outcomes in a cohort matched analysis using IMRT 25, and concluded that most local regional relapse was within the GTV. The 2/60 marginal failures were considered predictable, one in the CTV at approximately the 30 Gy isodose contour, and the other at the IMRT field/supraclavicular field margin. The predicted advantages of IMRT seem to be forthcoming, including the chance to escalate dose, but this technique will not substitute for adequate dose.

Can we better understand the needed targets to include in GTV and CTV without always resorting to patterns of failure? Or, can we at least know how to better deliver radiation to the targets that we understand? Physicians at the University of Washington led by Dr. David Schwartz have been studying co-registered PET/CT for staging and IMRT planning in the head and neck.²⁶ Dr. Schwartz presented findings of patients undergoing preoperative PET/CT, which was then used in simulated IMRT plans. The scans and planning were then compared to the actual neck dissections. The method showed 100% sensitivity and negative predictive value in 13 heminecks, though Dr. Schwartz acknowledged that aggressive “leveling of the blocks” analysis was not used during pathology review, which could have reduced these figures. Compared to theoretical IMRT plans, much smaller therapeutic volumes were needed when planned with PET/CT fusion than using conventional RTOG H-0022 specifications. This work will most certainly evolve with the addition of more specific molecular imaging, as promoted by the NCI, more complete pathologic review, and further clinico-radiologic comparison of relapse pattern outcomes.

In related presentations, PET strongly predicted for negative neck dissection²⁷ even when enlarged post radiation therapy nodes were present, and tools to enhance target delineation using indirect magnetic resonance lymphangiography²⁸ and a 3-D nodal atlas of anatomy and prior probability of involvement²⁹ were discussed. Finally, a study from University of Michigan addressed dose constraints related to hearing loss,³⁰ indicating that the use of IMRT will require much more precise definition of organ tolerance.

Chemoradiotherapy and/or use of Novel Combination Therapies

Chemoradiotherapy has been shown in randomized controlled trials to provide better outcomes in certain head and neck cancer situations. These include:

1. Better laryngeal preservation in advanced laryngeal ^31,32 and hypopharyngeal ³³ cancers, with equivalent survival compared to laryngectomy/postoperative irradiation therapy
2. Better local control and survival in oropharyngeal squamous cell carcinoma when it is surgically or medically unresectable ^34-37
3. Locally advanced nasopharyngeal carcinoma ³⁸

 Research in this area remains strong, especially with newer agents such as Taxotere® and Gemzar® used with or without more classic agents such as 5-FU, Platinol®, and Paraplatin®. Indeed, 40 of 100 head and neck cancer abstracts presented at ASCO 2003 dealt with chemoradiotherapy, as did our ASTRO presentation of the German randomized control trial discussed earlier.¹⁷ Dr. Haffty’s group from Yale reported a negative randomized control trial comparing radiotherapy plus mitomycin C (MC) versus porfiromycin (methyl-mitomycin C), a potentially better hypoxic cell sensitizer, that affirmed mitomycin C as an active agent with radiation therapy in head and neck cancer.³⁹

Attempting to validate the results of the Intergroup-0099 study of chemoradiotherapy in nasopharyngeal carcinoma, two groups reported meta-analyses of 10 and 13 randomized controlled trials, respectively. The ten trials chosen by the Dutch group⁴⁰ confirmed a strong advantage of chemoradiotherapy in advanced stage nasopharyngeal carcinoma, while a Canadian analysis that included 13 trials suggested the strongest evidence is only for improved disease-free survival. The Canadian group noted that among their reviewed studies, only the Intergroup-0099 trials showed increased overall survival, and thus the significant increase in toxicity with this regimen should be carefully considered.⁴¹ Perhaps more precise stratification of patients more likely to benefit from chemotherapy will help. This appears to be likely given the apparent predictive value of EBV DNA probes in plasma reported this year at ASTRO ^42,43 that indicate a high distant failure probability when persistent after treatment or slowly falling during therapy.

At ASCO 2003, there was a great deal of interest in studies using EGFR inhibitors in addition to chemotherapy or chemoradiotherapy, either in the form of the oral small molecule tyrosine kinase inhibitor gefitinib (Iressa®) or injectable monoclonal antibody agents active against the extracellular domain receptors such as cetuximab (Erbitux®). Five of the 100 abstracts at ASCO head and neck sessions were related to this therapy, while seven others explored diagnostic or prognostic implications of EGFR or related receptor levels. Since more than 90% of head and neck cancers over-express EGFR (1), it seems likely that more will be revealed regarding these important regulators of growth and radiation response in the future.

One study with an EGFR-inhibitor presented at ASTRO reported that treatment with cetuximab does not appear to impair surgical wound healing. However, the authors emphasized that in this trial radiation therapy plus cetuximab was completed 6-8 weeks prior to surgery. Further research with patients who undergo surgery while actively receiving EGFR inhibitor therapies will be important for establishing adverse effects of this therapy on wound healing.⁴⁴

Molecular Identification of Groups Likely to Fail Therapy or Suffer Intense Side Effects

EGFR: A presentation by Dr. Ang of MD Anderson Cancer Center of their multicenter analysis of patients in a prior RTOG trial examined the implications of EGFR.⁴⁵ Unstained biopsy slides in 147/268 patients were retrieved and tested using quantitative EGFR-immunohistochemistry directed to the extracellular domain. They concluded that EGFR expression level is a strong prognostic factor and robust predictor of poor tumor response to radiation. Since there was no difference in these findings between standard and accelerated fractionation arms, they concluded that EGFR is not a marker for tumor cell proliferation during fractionated radiation therapy. EGFR expression is certain to become an important factor in clinical trial design and stratification.

Plasma proteomic micro-arrays: Looking for markers of response more broadly, a group at Stanford reported early experience with plasma proteomic micro-arrays (SELDI-TOF mass spectroscopy analysis).⁴⁶ These proved highly capable of detecting known cancer and distinguishing those patients from controls. They reported a sensitivity of 96%, specificity of 90%, and positive predictive value of 92%. Future directions for this group include screening, evaluation of response, and attempt to identify proteins responsible for the observed differences in cancer patients and controls.

Molecular marker for late toxicity: Ozsahin and colleagues from Lausanne, Switzerland found a molecular marker for late toxicity.⁴⁷ A rapid assay of CD4 and CD8 apotosis after 8 Gy in vitro radiation of peripheral blood was used, and low T lymphocyte radiation-induced apoptosis was shown to highly correlate with late effects (grade 2-3) in multiple organs between individuals.

Use of Normal Tissue Response-Modifiers to Reduce Toxicity

While no abstracts were presented to further elucidate use of cytoprotective agents in head and neck cancer, there was an excellent review provided by Dr. Brizel in the previously mentioned panel discussion on normal tissue protection. He focused on Ethyol® (amifostine) and palifermin (rHuKGF) as the most active agents. Ethyol® has proven salivary protective properties when used with radiation, and may also protect the mucosa. It also has more broad protective properties with chemotherapy. Ethyol® is FDA approved for the treatment of radiation- and chemotherapy-induced xerostomia in head and neck cancers. Palifermin has growing evidence to support a role in mucosal protection.

Conclusion

There were no pivotal trials presented or major paradigm shifts proposed for the management of head and neck cancers at the 45th annual ASTRO meeting. Results presented in the areas of fractionation, delivery, chemoradiotherapy, molecular markers, and normal tissue protection reflect incremental advances in the management of head and neck cancers.

Improvements in fractionation and delivery were reported at ASTRO. Accelerated fractionation has demonstrated improved local control, but acute toxicity is a persistent problem with this approach. The greatest promise for improving the delivery of radiotherapy is in IMRT. But while it may be possible to decrease the dose to parotids, toxicity is still a problem because the submandibulars, which produce most of the basal saliva, cannot be spared with IMRT. However, the predicted advantages of IMRT seem to be forthcoming, including the chance to escalate dose, but this technique will not substitute for adequate dose.

Chemoradiotherapy continues to be an area of active investigation. Results presented at ASTRO show an advantage in advanced nasopharyngeal cancinoma. However, Canadian researchers pointed out that evidence only exists for improved disease-free survival, not overall survival. Thus, the increased toxicity of this approach must be carefully weighted with the advantage. Perhaps more precise stratification of patients more likely to benefit from chemoradiotherapy will help. Also, application of newer drugs such as Gemzar® and Taxotere® may improve both results and toxicity profiles.

Despite these incremental advances in management, head and neck continues to result in unacceptable levels of morbidity and mortality and persistent, innovative research is needed.

References

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