Source: Journal of Clinical Oncology, Vol 28, No 1 (January 1), 2010: pp. 1-3
Author: Danny Rischin

As advances in our understanding of the molecular biology of cancer have evolved in recent years, cancers that were once considered to be relatively homogeneous diseases are now being recognized as comprising distinct subtypes. These subtypes may differ in etiology, molecular profile, sensitivity to treatment, and prognosis. Examples include luminal (mainly estrogen receptor–positive), human epidermal growth factor receptor 2–positive, and basal breast cancer subtypes1; non–small-cell lung cancer associated with EGFR2 or EML4-ALK3 mutations; and melanoma associated with BRAF (V600E)4 or c-KIT mutations.5

In head and neck cancer, we have traditionally combined squamous cell carcinomas of the oral cavity, oropharynx, larynx, and hypopharynx in clinical trials. This has been justified on the basis of similar etiology (tobacco and alcohol) and similar sensitivity to radiotherapy and systemic therapy. However, it has also been recognized that there are differences in clinical behavior, treatment outcome, and prognosis with regard to primary site. Although surgery has remained the primary treatment for oral cavity cancers, organ preservation with primary chemoradiotherapy has been widely used over the last two decades for cancers of the oropharynx, larynx, and hypopharynx. It has become apparent over this same time period that a new subtype of oropharyngeal cancer resulting from human papilloma virus (HPV) has emerged.6 The proportion of HPV-associated oropharyngeal cancer has steadily increased, and in many countries, this subtype now represents the majority of new oropharyngeal cancers.7,8

HPV-associated oropharyngeal cancer differs from other oropharyngeal cancers with regard to risk factors, clinical features, sensitivity to treatment, and prognosis.9 Patients with HPV-associated oropharyngeal cancer have markedly superior survival after chemoradiotherapy compared with those with HPV-negative oropharyngeal cancer.10–12 Preliminary reports of the pattern of failure suggest that this is because of lower rates of locoregional failure, second malignancies, and death as a result of other causes.11,12 There does not seem to be a significant difference between the two in the rate of distant metastasis as site of first failure.

Over the last 5 years, two new treatment options for squamous cell carcinomas of the head and neck—taxane-based induction chemotherapy13,14 and concomitant cetuximab and radiation administration15—have emerged after widely publicized clinical trials. However, the designs of the initial randomized trials of both these approaches did not include comparisons with standard concomitant chemoradiotherapy regimens. We have learned that the regimen of docetaxel, cisplatin, and fluorouracil (TPF) improves overall survival compared with cisplatin and fluorouracil when followed by radiation alone14 or radiation and weekly low-dose carboplatin.13 Although it had been clearly established that induction chemotherapy decreases distant metastases,16 the improvement with TPF, surprisingly, was demonstrated to be a result of improvement in locoregional control.13 The pivotal trial15 showing that the addition of cetuximab to radiation produced superior results compared with radiation alone was first presented in 2005; however, we do not have any results from randomized trials comparing this regimen with a standard concomitant chemoradiotherapy regimen. It is clear that both of these treatment approaches are being widely used in clinical practice, but with the currently available evidence, there remains considerable uncertainty about the relative efficacy and indications of these approaches compared with standard concomitant chemoradiotherapy regimens. Ongoing and recently completed trials should better define the role of induction chemotherapy and epidermal growth factor receptor–targeted therapy concurrent with irradiation.

In this issue of Journal of Clinical Oncology, Kies et al17 report the results of a phase II trial incorporating cetuximab into a short weekly regimen of carboplatin and paclitaxel induction followed by what the authors describe as risk-based local therapy. Although the overall results are good, it is difficult to determine the relative contributions of induction chemotherapy, cetuximab, HPV status, and risk-based local therapy. On the basis of the results of a trial18 involving patients with relapsed or metastatic head and neck cancer, which demonstrated that the addition of concurrent and maintenance cetuximab to chemotherapy improved overall survival and response rates, it was reasonable to anticipate that the addition of cetuximab to induction chemotherapy might also be beneficial. However, Kies et al report that complete response rates achieved with their regimen did not seem to be better than those reported using the same regimen without cetuximab.19 Furthermore, in contrast to the TPF regimen, the weekly carboplatin and paclitaxel regimen, while clearly an active induction regimen, has not been demonstrated to be superior to the cisplatin and fluorouracil regimen.

In the trial by Kies et al,17 the majority of patients had oropharyngeal cancer (41 of 47; 87%). We know that 12 of 26 tumors tested were HPV positive, and this group had a better prognosis than the HPV-negative group, which included four nonoropharyngeal primaries. If we assume that the detected HPV-positive rate of oropharyngeal cancer of 55% was the same in the untested patients, we can estimate that 22 patients (47%) in this trial had HPV-associated oropharyngeal cancer. Because we now know that patients with HPV-associated oropharyngeal cancer have achieved excellent outcomes with standard chemoradiotherapy in multicenter trials, the presence of a high proportion of HPV-positive patients confounds the interpretation of efficacy in phase II trials of novel regimens.

As Kies et al17 note, patients with HPV-associated oropharyngeal cancer frequently present with small primaries (T1-2) and advanced nodal stage. The risk-based approach adopted by the authors, which they suggest may be applicable to HPV-positive patients, involved administering induction chemotherapy to decrease distant metastases and potentially contribute to locoregional control and then decreasing the intensity of local therapy on the basis of stage and site (eg, radiotherapy alone for selected patients with T1-2 disease) to decrease toxicity and improve functional outcomes. However, this induction regimen, which required granulocyte colony-stimulating factor support in 64% of patients, resulted in significant toxicity, with grade 3 rash in 45% of patients, grade 2 neuropathy in 15%, and grade 3 neuropathy in 2%, which in turn precluded use of planned cisplatin during irradiation in several patients. Although radiation alone was administered in 50% of patients after induction chemotherapy, it is noteworthy that 38% of patients received altered fractionation with concomitant boost, a regimen that is associated with an increase in acute and late toxicity.20,21 The authors report good functional outcomes; however, it is unclear whether these outcomes are superior to what could be achieved with concurrent chemoradiotherapy regimens using modern radiotherapy techniques in a similar patient population.

Because we know that advanced nodal stage is a major risk factor for distant metastases,22 one may be inclined intuitively to think that the HPV-positive group with more advanced nodal stage (86% with N2-3 v 65% in HPV-negative group)12 may be more likely to benefit from induction chemotherapy. Enthusiasm for incorporating induction chemotherapy into the treatment of this good-prognosis population should be tempered by the fact that the higher N stage does not seem to be associated with an increased risk of distant metastases compared with HPV-negative patients.11,12 The rates of distant metastasis as site of first failure in HPV-positive oropharyngeal cancer were 9.7% and 5% in recent clinical trials11,12 compared with 13% and 6% in the HPV-negative group, respectively, and did not exceed the locoregional failure rates in the HPV-positive population, which were 13.6% and 6%, respectively. It is possible that longer follow-up may reveal higher rates of isolated distant failure. In HPV-positive oropharyngeal cancer, whether a decrease in distant metastases after induction chemotherapy improves overall survival, which was 88% and 92% at 2 years in these recent trials,11,12 remains an open question.

In view of the excellent survival outcomes in HPV-associated oropharyngeal cancer with standard cisplatin-based chemoradiotherapy regimens, there is considerable interest in exploring less intensive regimens in this group of patients that may decrease both acute and late toxicity while preserving efficacy. Regimens that could be tested in clinical trials include less intensive concomitant chemoradiotherapy regimens, concomitant epidermal growth factor receptor–targeted therapies and irradiation, and radiation alone in selected patients. It is not apparent from the small series reported by Kies et al17 that the strategy of induction chemotherapy and risk-based local therapy improves the therapeutic ratio for patients with HPV-positive oropharyngeal cancer.

Because HPV-associated oropharyngeal cancer is a distinct entity with a much better prognosis than HPV-negative oropharyngeal cancer, the time has come to conduct separate clinical trials in HPV-associated oropharyngeal cancer to define optimal treatment. In randomized trials that do include both HPV-positive and HPV-negative patients, HPV or p16 status should be included as a stratification factor. Recent trials highlighting the good outcomes in HPV-associated oropharyngeal cancer have in turn drawn our attention to the poor prognosis of the HPV-negative group. Future trials of novel and/or intensive chemoradiotherapy strategies intended to improve efficacy should focus on HPV-negative patients.

Author’s disclosures of potential conflicts of interest:
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Danny Rischin, Merck Serono (U) Stock Ownership: None Honoraria: None Research Funding: Danny Rischin, Merck Serono, sanofi-aventis Expert Testimony: None Other Remuneration: None

References:
1. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423, 2003.

2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139, 2004.

3. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566, 2007.

4. Curtin JA, Fridlyand J, Kageshita T, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147, 2005.

5. Curtin JA, Busam K, Pinkel D, et al: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346, 2006.

6. Gillison ML, Koch WM, Capone RB, et al: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:709–720, 2000.

7. Näsman A, Attner P, Hammarstedt L, et al: Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: An epidemic of viral-induced carcinoma. Int J Cancer 125:362–366, 2009.

8. Chaturvedi AK, Engels EA, Anderson WF, et al: Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26:612–619, 2008.

9. Vidal L, Gillison ML: Human papillomavirus in HNSCC: Recognition of a distinct disease type. Hematol Oncol Clin North Am 22:1125–1142, vii, 2008.

10. Fakhry C, Westra WH, Li S, et al: Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100:261–269, 2008.

11. Gillison ML, Harris J, Westra W, et al: Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol 27:15s; 2009 (suppl; abstr 6003.

12. Rischin D, Young R, Fisher R, et al: Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial. J Clin Oncol 27:15s; 2009 (suppl; abstr 6004.

13. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705–1715, 2007.

14. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695–1704, 2007.

15. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578, 2006.

16. Pignon JP, le Maitre A, Maillard E, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4–14, 2009.

17. Kies MS, Holsinger FC, Lee JJ, et al: Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: Results from a phase II prospective trial. J Clin Oncol 28:8–14, 2009.

18. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127, 2008.

19. Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320–326, 2003.

20. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7–16, 2000.

21. Trotti A, Fu KK, Pajak TF, et al: Long term outcomes of RTOG 90-03: A comparison of hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63:S70–S71, 2005 (suppl.)

22. Brockstein B, Haraf DJ, Rademaker AW, et al: Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: A 9-year, 337-patient, multi-institutional experience. Ann Oncol 15:1179–1186, 2004.

Author’s affiliation:
Department of Medical Oncology and Head and Neck Service, Peter MacCallum Cancer Centre; and University of Melbourne, Melbourne, Australia