Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head and neck from an occult primary

A. Argiris1,+, S. M. Smith2, K. Stenson2, B. B. Mittal1, H. J. Pelzer1, M. S. Kies1, D. J. Haraf2 and E. E. Vokes2

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

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 55–75 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 N2–N3 HNCOP and compares favorably with traditional therapy.

Key words: chemotherapy, head and neck cancer, occult primary, radiotherapy, squamous cell carcinoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Squamous cell carcinomas of the head and neck from an occult primary (HNCOPs) are uncommon, accounting for 1–2% of all head and neck cancers [1]. The majority of HNCOPs involve level II and III lymph nodes. The presence of an occult mucosal primary is assumed based on the well-studied patterns of spread for mucosal squamous cell malignancies of the upper aerodigestive track [2]. Therefore, patients with HNCOP are treated with locoregional therapies and are potentially curable [1, 3]. Traditional management of stage IV (N2 or N3) HNCOP involves neck lymph node dissection followed by postoperative radiation therapy [1, 3]. The radiation field often encompasses the neck lymph nodes as well as the putative mucosal primary sites, such as the nasopharynx, oropharynx and hypopharynx. However, the doses and field of radiation therapy remain controversial. Many series have shown that the addition of radiation therapy to surgery decreases the incidence of emergence of an overt mucosal primary and improves local control for advanced neck disease [3]. Although chemotherapy given concurrently with radiotherapy has now become an integral part of the standard non-surgical treatment for locally advanced head and neck cancer [4], the role of chemotherapy for HNCOP tumors has not yet been established. There is a dearth of literature in terms of the management of patients with HNCOP with combined-modality therapy including chemoradiotherapy, mainly because of the rarity of this presentation. In protocols conducted at the University of Chicago and Northwestern University and affiliated institutions, we have allowed the enrollment of patients with stage IV HNCOP. We now report a subset analysis of these consecutive studies that spans a decade and, to the best of our knowledge, represents the largest series of patients with HNCOP treated with concurrent chemoradiotherapy as a part of combined modality therapy. We also compare our results with other series that included patients with HNCOP tumors treated with traditional therapy without chemotherapy.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with HNCOP were identified through a search of a database that includes all patients with locoregionally advanced head and neck cancer treated on phase II chemoradiotherapy protocols at the University of Chicago and Northwestern University and affiliated institutions since 1991. Patients with stage IV (T0N2M0 or T0N3M0) HNCOP were eligible for participation. Results from these studies have been published previously [59]. All regimens included concomitant administration of 5-fluorouracil (5-FU) and hydroxyurea with either once-daily or twice-daily radiation therapy (FHX regimen) (Table 1). In two protocols (6126 and 9502) induction chemotherapy was given as well. The last three protocols (7929, 8626 and 9502) incorporated twice-daily radiation therapy with the addition of paclitaxel to the FHX regimen (T-FHX regimen), whereas the 6950 protocol incorporated cisplatin with FHX (C-FHX regimen). Informed consent has been obtained from all patients. The data collected included demographics, clinical presentation, performance status, smoking and alcohol habits, response to therapy, toxicities, disease-free survival and overall survival. All patients were staged according to the American Joint Committee on Cancer 1997 staging classification system. Actuarial curves for overall survival and progression-free survival were calculated using the Kaplan–Meier method. Fisher’s exact tests were used to analyze relapse rates. Statistical analysis was performed using a commercially available software package (SPSS for Windows; SPSS, Inc., Chicago, IL, USA). From August 1991 to August 2000, 25 patients with T0N2M0 or T0N3M0 squamous cell carcinomas were treated on the five consecutive chemoradiotherapy study protocols described above. We included in the analysis one patient who withdrew from protocol therapy after 1 week of the planned 4 weeks of concomitant chemoradiotherapy and was subsequently treated with radiation therapy alone, as well as another patient who had a history of tongue cancer that was treated surgically 13 years earlier. All patients underwent evaluation with panendoscopy with directed biopsies of potential mucosal primary sites, computed tomography (CT) scan of the chest, CT or magnetic resonance imaging of the neck, and bone scan, as previously reported [59], whereas two patients underwent tonsillectomy as a part of the evaluation for an occult primary.


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Table 1. Multimodal treatment (n = 25)
 

    Results
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 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics are shown in Table 2. The median time from the onset of symptoms to diagnosis was 2 months. The most common presenting symptom was neck mass. Six patients reported neck pain and four patients had dysphagia. Eastern Oncology Co-operative Group (ECOG) performance status was 0 in 17 patients (68%), ECOG 1 in seven (28%) and ECOG 2 in one (4%). The nodal stage was N2a in five patients (20%), N2b in 13 (52%), N2c in one (4%) and N3 in six (24%). The left neck was involved in 16 patients, the right neck in seven patients and both sides in two patients. In 21 patients neck lymph node level information was available: 14 patients (67%) had level II involvement (eight with level II-only involvement), eight patients (38%) had level III involvement (two with level III-only involvement) and three patients (14%) had multiple lymph node involvement that included the supraclavicular region. Six patients were noted to have extracapsular tumor extension on neck dissection performed before initiating protocol therapy. Fifteen patients had grade 3 squamous cell carcinomas (60%), seven patients grade 2 (28%) and three patients grade 1 (12%).


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Table 2. Patient characteristics (n = 25)
 
Twenty-two patients (88%) underwent modified radical neck lymph node dissection either before any other therapy (n = 14), after induction chemotherapy but before chemoradiotherapy (n = 3) or after chemoradiotherapy (n = 5). Three patients did not undergo neck dissection for the following reasons: one had previously undergone excisional biopsy of the involved nodes, one had severe co-morbidities and eventually died of an unrelated cause, and one had an attempted neck dissection before chemoradiation but was deemed unresectable (the latter patient was never disease-free). Unilateral neck dissections were performed in 20 patients, and bilateral in two. Radiation doses delivered ranged from 55 to 75 Gy with a median of 60 Gy. The field of radiation included the potential mucosal primaries, including the nasopharynx, oropharynx and hypopharynx, and the neck bilaterally. Some patients received a radiation dose towards the higher end of the dose spectrum due to the delivery of a boost radiation dose to the involved lymph nodes. Toxicities were expected (Table 3) and related to the protocol therapy prescribed. One patient died free of disease 6 months post chemoradiotherapy initiation and 1.5 months post neck dissection possibly from mucous plugging. This death was considered as possibly related to treatment. In no patient did the occult primary emerge or a second primary develop.


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Table 3. Worst grade toxicities of non-surgical therapy
 
Response and survival outcomes
Pathological complete response was noted in two of three patients who underwent neck dissection after induction chemotherapy and in four of five patients who had neck dissection after chemoradiotherapy. The median follow-up of surviving patients was 3.9 years (range 2.2–11.1). Of a total of 25 patients, three have progressed or relapsed; two patients relapsed at distant sites (in both cases the lung) and one patient never became disease-free and died of local progression. The three patients who relapsed or progressed were treated on protocols 7929, 8626 and 9502, respectively (see Table 1 for protocol treatment details).

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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Figure 1. Kaplan–Meier survival curve for progression-free survival.

 
The 5-year actuarial overall survival rate was 75% (Figure 2). Seven patients died; three due to disease progression and four due to other causes; one patient possibly due to treatment-related toxicity (see above), one patient due to pneumonia 9 years later, one patient by committing suicide within 2 months of treatment completion but after re-evaluation, and one patient of ruptured intraabdominal aneurysm more than 2 years after diagnosis.



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Figure 2. Kaplan–Meier survival curve for overall survival.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Due to the rarity of HNCOP, the role of chemotherapy has not been adequately investigated and no prospective studies have been conducted. We report an excellent progression-free survival and overall survival with the use of intensive chemoradiotherapy in five sequentially developed and similar therapeutic protocols. Our results indicate a potential survival benefit from comprehensive radiotherapy and concurrent chemotherapy in the management of HNCOP. However, this treatment is associated with considerable acute toxicity, and this needs to be considered in the therapeutic decision. Patients eligible for protocol therapy had good performance status and normal organ function, and therefore could be considered selected. On the other hand, the majority of our patients had multiple or >3 cm lymph nodes involved (52% had stage N2b) and may have been selected for this reason for protocol participation by their treating physicians. Moreover, a significant percentage of the patients reported had poorly differentiated tumors that may have contributed to increased sensitivity to chemoradiotherapy. In comparison with other patients with detectable primaries treated on the same protocols, the reported patients with HNCOP tumors appear to have performed better. This may be explained by the fact that T stage is a major prognostic factor. Accordingly, a retrospective analysis of our studies showed that T stage (T4 versus others) is an independent prognostic factor [10]. Nevertheless, differences in biological behavior between HNCOP and head and neck cancers with overt primaries may exist.

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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Table 4. Survival of patients with squamous cell carcinoma of the head and neck from an occult primary treated with surgery and/or radiotherapy (selected series); 3- to 5-year survival rates are reported
 
The predominant pattern of failure in HNCOP is neck relapse or distant metastases [1], whereas mucosal primaries above the clavicle emerge in ~10% of patients [3]. Some reports suggested an advantage for bilateral or comprehensive radiotherapy versus ipsilateral neck radiotherapy [14, 19]; however, there is no conclusive evidence to support the notion that the use of comprehensive radiotherapy is better than radiation to the ipsilateral neck [1, 3]. When surgery is the only treatment the rate of metachronous mucosal malignancies is high, up to 54% [14]. The most common metachronous primary sites are the oropharynx (base of tongue or tonsil), oral cavity and hypopharynx (mostly piriform sinus). A metachronous mucosal malignancy may either represent the occult primary that emerged or a second primary. In our series no patient developed a metachronous primary. This observation is intriguing and may suggest that systemic therapy can contribute to the eradication of occult primaries.

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.


    Acknowledgements
 
This study was supported in part by the University of Chicago/Northwestern University Oral Cancer Center (P50 DE11921-04), University of Chicago Cancer Research Center (P30 CA14599), the Francis Lederer Foundation, the Geraldi Norton Memorial Corporation, the Robert and Valda Svendsen Memorial, and Bristol-Myers Squibb, Princeton, NJ.


    Footnotes
 
+ Correspondence to: Dr A. Argiris, 676 N. St Clair, Suite 850, Division of Hematology-Oncology, Northwestern University, The Feinberg School of Medicine, Chicago, IL 60611, USA. Tel: +1-312-695-4441; Fax: +1-312-695-6189; E-mail: a-argiris@northwestern.edu Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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