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Optimizing Treatment in Head & Neck Cancers - Are Molecular Markers the Answer?

Posted on: Friday, 11 November 2005, 03:02 CST

By D'cruz, Anil K; Mulherkar, Rita

The last decade has witnessed a paradigm shift in the management of head and neck cancers, characterized by more aggressive and intensive locoregional treatment. The addition of chemotherapy to the treatment algorithm in conjunction with radiotherapy has improved locoregional control rates. This has also resulted in a large number of patients being treated with an organ preservation approach thus avoiding mutilating and ablative surgery. Initial reports in the early 1990s showed that the addition of chemotherapy to radiotherapy resulted in similar control rates to the then standard of care of surgery followed by postoperative radiotherapy in the treatment of laryngeal and hypopharyngeal cancers1,2. The important difference however was that nearly two-thirds of patients in the non-surgical arm were able to retain their larynx.

Subsequently, meta-analysis of randomized trials showed that the benefit of adding chemotherapy to radiotherapy was best seen when the two were used concurrently as against sequentially3,4. More recently the benefit of concurrent chemo-radiotherapy has also been seen in the postoperative adjuvant setting5,6. There is therefore enough level I evidence to suggest that concurrent chemo- radiotherapy is today the standard of care for the majority of patients with head and neck cancer.

However, these benefits of an improvement in locoregional control and organ preservation come at a cost. The concurrent use of chemo- radiotherapy is toxic with up to 70 per cent of patients experiencing grade III or IV toxicity. Moreover, a similar number of patients require intensive support by way of hospitalization and supplemental tube feeding to help them complete the prescribed treatment. This naturally translates into increasing treatment costs and a burden on existing health care facilities. This is a cause of major concern as the majority of head and neck cancer patients particularly in our country, present with advanced disease stages that qualify them for chemo-radiotherapy treatment protocols either upfront or as adjuvant therapy.

It is therefore important to balance the benefits of these intensive regimes against the anticipated side effects of toxicity and costs. This could best be achieved by identifying a subset of patients at the highest risk for tumour recurrence who could then be targeted with these intensive protocols while others could be treated with conventional regimes and spared from unnecessary toxicity and hospitalization. It would also be beneficial in improving the outcomes for patients treated on organ preservation protocols to be able to identify treatment responders upfront. As of today these subgroups of patients are identified based on clinical tumour node metastasis (TNM) and histological parameters.

The currently used TNM staging system has its limitations in that Stages III and IV locally advanced but operable cancers form a heterogeneous group comprising 14 different T and N stage combinations. A T3 glottic cancer with cord fixity and no nodes would behave much differently from a similar cancer with nodes or from a cancer with cartilage invasion.

Grade of differentiation, depth of infiltration, presence of lympho-vascular or perineural invasion, nodal involvement and extracapsular extension of disease are important histological parameters in identifying a poor prognostic subgroup but these are often unavailable to the treating clinician at the time of initial decision making. Moreover, treatment response varies among patients with these adverse factors as well. Other parameters are therefore required to identify the high risk group in order to optimize target therapy and thus maximize the therapeutic gain afforded by chemo- radiotherapy.

Molecular markers are increasingly being studied to compliment clinical and histological parameters to identify this high risk group of patients. Aberrant expression of growth factor receptors, cell proliferation markers as well as dysregulation of cell signaling molecules are commonly seen in solid squamous cell carcinomas and may serve as markers for poor prognosis. Markers for neck metastasis include proliferation markers such as PCNA and Ki67(7). However, these have been reported as significant predictors of metastases, in addition to clinical T stage and neck palpation7. Cellular DNA content has also been an extensively studied parameter for both haematological and solid tumours. DNA diploid tumours are known to have a better prognosis with the best predictors of metastasis being depth of muscle invasion, double DNA aneuploidy, and histologie differentiation of the tumour8. Das et al9, in this issue, report that the DNA ploidy pattern of metastatic lymph node, rather than primary tumours appears to be a significant prognostic marker. In the metastatic lymph node, aneuploidy with higher S phase fraction was found to be significantly related to early recurrence and poor prognosis. These are suggested as prognostic markers for similarly staged intra-oral squamous cell carcinoma. These findings are relevant as involvement of regional nodes is the single most important factor in influencing the prognosis of head and neck cancers.

As of today, there is no single marker that can predict treatment response or survival in patients treated with multimodality therapy. However, it is important to note that many such markers do show promise and there will be a time in the not so distant future when patient's treatment will be individualized and based on the biology of the patient's cancer. Gene expression profiling techniques combined with proteomics could help to define and select useful genetic and biomarkers of progression which could be used in combination with the TNM staging system and histological factors. These markers could well serve as potential therapeutic targets in drug development.

References

1. The Department of Veteran Affairs Laryngeal Cancer Study Group, Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991; 324: 1685-90.

2. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatric A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organisation for Research and Treatment of Cancer phase III trial. EORTIC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996; 88 : 890-9.

3. Pigeon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data. Lancet 2000; 355 : 949-55.

4. Browman GP, Hudson DI, Mackenzie RJ, Bestic N, Zuraw L, Cancer Care Ontario Practice Guidelines Initiative Head and Neck Cancer Disease Site Group. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck 2001; 23 : 579-89.

5. Bernier J, Domenge C, Ozsahin M, Matus/.ewsku K, Lefebvre JL, Greinen RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Mcd 2004; 350 : 1945-52.

6. Cooper JS, Pajak TF, Forestiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy in high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004; 350 : 1937-44.

7. Liu M, Lawson G, Jamart J, Ide C, Coche E, Wevnand B, et al. Predictive value of the fraction of cancer cells immunolabeled for proliferating cell nuclear antigen or Ki67 in biopsies of head and neck carcinomas to identify lymph node metastasis: comparison with clinical and radiologic examinations. Head Neck 2003; 25 : 280-8.

8. Byers RM, El-Naggar AK, Lee YY, Rao B, Fornage B, Terry NH, et al. Can we detect or predict the presence of occult nodal metastases in patients with squamous carcinoma of the oral tongue? Head Neck 1998; 20 : 138-44.

9. Das SN, Khare P, Patil A, Pandey RM, Singh MK, Shukla NK. Association of DNA of metastatic lymphnode with disease-free survival in patients with intraoral squamous cell carcinoma. Indian J Med Res 2005; 122 : 216-23.

Anil K. D'cruz & Rita Mulherkar*

Surgery Department, Tata Memorial Hospital

Mumbai (adcruz@vsnl.com)

* Genetic Engineering, Advanced Centre for Treatment, Research & Education in Cancer

Navi Mumbai 410208, India

e-mail: rmulherkar@actrec.res.in

Copyright Indian Council of Medical Research Sep 2005

Source: Indian Journal of Medical Research

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