1 Northwestern University, The Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 2 University of Chicago and University of Chicago Cancer Research Center, Chicago, IL, USA
Received 17 January 2003; revised 27 March 2003; accepted 8 April 2003
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Abstract |
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Our aim was to explore the use of concurrent chemoradiotherapy in the management of patients with squamous cell carcinoma of the head and neck from an occult primary (HNCOP).
Patients and methods:
From 1991 to 2000, 25 patients with T0N2M0 or T0N3M0 HNCOP were entered into five sequential phase II clinical trials. Chemoradiotherapy consisted of a split course of radiotherapy with concurrent 5-fluorouracil and hydroxyurea either alone or with cisplatin, or paclitaxel. Two of the five protocols incorporated induction chemotherapy.
Results:
Nodal stage was N2a in five patients (20%), N2b in 13 (52%), N2c in one (4%) and N3 in six (24%). Twenty-two patients (88%) underwent neck dissection; 14 of 22 patients underwent neck dissection before initiating protocol therapy. Total radiation doses of 5575 Gy (median 60 Gy) were delivered; radiation fields included the potential sites of mucosal primaries and the neck bilaterally. Selected patients received a radiation boost to the involved neck. With a median follow-up of 3.9 years, three patients have progressed (one local, two distant) and seven patients have died. Deaths were due to disease progression (three) or unrelated causes (four). No metachronous primaries developed. The 5-year progression-free and overall survival was 87% and 75%, respectively.
Conclusion:
Combined-modality treatment with intensive chemoradiotherapy results in excellent disease control and long-term survival for patients with N2N3 HNCOP and compares favorably with traditional therapy.
Key words: chemotherapy, head and neck cancer, occult primary, radiotherapy, squamous cell carcinoma
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Introduction |
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Patients and methods |
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Results |
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The 5-year actuarial progression-free survival rate was 87% (Figure 1). Of the three patients who progressed or relapsed, two had N3 disease and one N2a disease; two of these three patients had supraclavicular lymph node involvement. Therefore, one of 19 patients with N2 and two of six patients with N3 disease relapsed/progressed (P = 0.13). The 5-year progression-free survival and overall survival for patients with N2 disease (n = 19) were 95% and 89%, respectively, whereas the 3-year progression-free and overall survival for the six patients with N3 disease were 50% and 33%, respectively. Moreover, the presence of supraclavicular involvement was associated with poor outcome; one of 22 patients without supraclavicular lymphadenopathy, and two of three patients with supraclavicular lymphadenopathy relapsed/progressed (P = 0.03). Finally, one of 15 patients with poorly differentiated squamous cell carcinomas and two of 10 patients with well or moderately differentiated squamous cell carcinomas relapsed (P = 0.54). Due to the small number of patients with disease progression, further prognostic factor analysis was not performed.
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Discussion |
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To the best of our knowledge only one series of HNCOP patients treated with chemoradiotherapy has been reported in the English language literature [11]. De Braud et al. reported results on 16 patients who received various chemotherapy regimens before, during, or after radiation therapy [11]. Chemotherapy consisted of cisplatin used concurrently with radiation or cisplatin and 5-FU used as adjuvant therapy before or after radiation therapy with or without neck dissection. In this small series, patients treated with combined chemotherapy and radiation therapy had improved response rates (81% complete responses versus 60%) and median survival rates (37 versus 24 months) than a historical control of patients treated without chemotherapy despite the presence of a higher percentage of patients with N3 disease in the former group.
Several retrospective studies have reported results on the management of HNCOP with surgery and/or radiotherapy (Table 4) [1221]. We do not list reports that included non-squamous histologies or patients treated with a palliative intent. However, the nodal stage distribution as well as the treatment modalities employed in these series are heterogeneous and the reported survival rates vary considerably, especially for N3 disease. Colletier et al. [15], who reviewed 136 patients with HNCOP from M. D. Anderson Cancer Center, have reported the higher survival outcomes with surgery followed by postoperative radiation therapy to date. Unlike our series, the authors excluded patients who had macroscopic residual disease after surgery. The majority of patients had stage N2a disease (n = 49), whereas in our series most patients had more advanced, stage N2b, disease. They reported a disease-specific survival of 69% and 71% for patients with N2 and N3 disease, respectively [15]. Patients with multiple lymph node involvement (i.e. stage >N2a) performed worse in their series.
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In recent randomized studies, single-agent and multi-agent concurrent chemoradiotherapy have been shown to be superior to radiation therapy alone for the non-surgical therapy of locoregionally advanced head and neck cancer [4]. The use of postoperative chemoradiotherapy appears promising but has not yet been established [22]. Given the rarity of HNCOP, prospective studies are difficult to conduct. Our data, which form the largest series reported, suggest that HNCOP should be treated in a similar manner to other head and neck squamous cell carcinomas with detectable primaries. Since all but three of our patients underwent neck dissection, we cannot discern the contribution of neck dissection in the outcome of HNCOP patients. Some reports have suggested that tumor control is superior with surgery and radiation therapy compared with radiation alone [19]. The role of neck dissection in the management of locoregionally advanced head and neck cancer is controversial [23, 24]. We recently reported that elective neck dissection may be safely omitted in N2 patients with head and neck cancer with a detectable primary who achieve a clinical complete response after induction chemotherapy or chemoradiotherapy [23]. This may apply to HNCOP tumors as well. Finally, induction chemotherapy may decrease the rate of distant metastasis, which is a common site of failure in patients with advanced N stage disease, and its potential use in advanced HNCOP warrants investigation.
Patients with HNCOP with supraclavicular lymphadenopathy represent a different clinical entity possibly due to the association of supraclavicular lymphadenopathy with infraclavicular neoplasms, such as lung cancer. Their long-term survival is <15% at 5 years [12, 16]. In our series three patients had lymphadenopathy extending to the supraclavicular region. Their outcome was poor; one had distant failure and one local. However, none of these patients developed a lung primary.
We conclude that the addition of systemic therapy to locoregional therapies results in high rates of locoregional and distant control and long-term survival for good performance status patients with stage IV (N2 or N3) HNCOP. Our results compare favorably with previous reports in which patients with HNCOP were treated with surgery and/or radiation therapy. Prospective multicenter studies will be required to establish further the role of concurrent chemoradiotherapy for HNCOP.
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Acknowledgements |
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Footnotes |
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References |
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2. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972; 29: 14461449.[ISI][Medline]
3. Fu KK. Neck node metastases from unknown primary. Controversies in management. Front Radiat Ther Oncol 1994; 28: 6678.[Medline]
4. Argiris A. Update on chemoradiotherapy for head and neck cancer. Curr Opin Oncol 2002; 14: 323329.[CrossRef][ISI][Medline]
5. Kies MS, Haraf DJ, Athanasiadis I et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998; 16: 27152721.[Abstract]
6. Vokes EE, Kies MS, Haraf DJ et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000; 18: 16521661.
7. Kies MS, Haraf DJ, Rosen F et al. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 2001; 19: 19611969.
8. 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 2003; 21: 320326.
9. Rosen FR, Haraf D, Brockstein B et al. Multicenter randomized phase II study of 1 h infusion paclitaxel, fluorouracil and hydroxyurea with concomitant hyperfractionated radiotherapy with or without erythropoietin for advanced head and neck cancer. Proc Am Soc Clin Oncol 2001; 20: A902.
10. Brockstein BE, Haraf DJ, Kies MS et al. Survival, patterns of failure, and risk factors for recurrence after intensive concomitant chemoradiation (CRT) for squamous cell head and neck cancer (SCHNC). Proc Am Soc Clin Oncol 2002; 21: A918.
11. de Braud F, Heilbrun LK, Ahmed K et al. Metastatic squamous cell carcinoma of an unknown primary localized to the neck. Advantages of an aggressive treatment. Cancer 1989; 64: 510515.[ISI][Medline]
12. Jesse RH, Perez CA, Fletcher GH. Cervical lymph node metastasis: unknown primary cancer. Cancer 1973; 31: 854859.[ISI][Medline]
13. Maulard C, Housset M, Brunel P et al. Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 1992; 102: 884890.[ISI][Medline]
14. Grau C, Johansen LV, Jakobsen J et al. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol 2000; 55: 121129.[CrossRef][ISI][Medline]
15. Colletier PJ, Garden AS, Morrison WH et al. Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: outcomes and patterns of failure. Head Neck 1998; 20: 674681.[CrossRef][ISI][Medline]
16. Marcial-Vega VA, Cardenes H, Perez CA et al. Cervical metastases from unknown primaries: radiotherapeutic management and appearance of subsequent primaries. Int J Radiat Oncol Biol Phys 1990; 19: 919928.[ISI][Medline]
17. Strojan P, Anicin A. Combined surgery and postoperative radiotherapy for cervical lymph node metastases from an unknown primary tumour. Radiother Oncol 1998; 49: 3340.[CrossRef][ISI][Medline]
18. McMahon J, Hruby G, OBrien CJ et al. Neck dissection and ipsilateral radiotherapy in the management of cervical metastatic carcinoma from an unknown primary. Aust N Z J Surg 2000; 70: 263268.[CrossRef][ISI][Medline]
19. Reddy SP, Marks JE. Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys 1997; 37: 797802.[CrossRef][ISI][Medline]
20. Harper CS, Mendenhall WM, Parsons JT et al. Cancer in neck nodes with unknown primary site: role of mucosal radiotherapy. Head Neck 1990; 12: 463469.[ISI][Medline]
21. Medini E, Medini AM, Lee CK et al. The management of metastatic squamous cell carcinoma in cervical lymph nodes from an unknown primary. Am J Clin Oncol 1998; 21: 121125.[CrossRef][ISI][Medline]
22. Cooper JS, Pajak TF, Forastiere AA et al. Patterns of failure for resected advanced head and neck cancer treated by concurrent chemotherapy and radiation therapy: an analysis of RTOG 9501/Intergroup phase III trial. Int J Radiat Oncol Biol Phys 2002; 54 (Suppl. 1): 2.
23. Argiris A, Stenson KM, Brockstein BE et al. Node dissection (ND) in the combined modality therapy of patients with locoregionally advanced head and neck cancer (HNC). Proc Am Soc Clin Oncol 2002; 21: A910.
24. McHam SA, Adelstein DJ, Rybicki LA et al. Who merits a neck dissection (ND) after definitive chemoradiotherapy for N2-N3 squamous cell head and neck cancer (SCHNC)? Proc Am Soc Clin Oncol 2002; 21: A911.
25. Friesland S, Lind MG, Lundgren J et al. Outcome of ipsilateral treatment for patients with metastases to neck nodes of unknown origin. Acta Oncol 2001; 40: 2428.[CrossRef][ISI][Medline]