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Patterns of Failure in Head and Neck Carcinoma of Unknown Primary: Insights from a Tobacco-Associated Cancer Cohort
, Jifmi Jose Manjali1,2, Ashwini Budrukkar1,2, Monali Swain1,2, Debanjali Dutta1,2, Amrendra Kumar1,2, Sahil Sood1,2, Shwetabh Sinha1,2, Anuj Kumar1,2, Samarpita Mohanty1,2, Tejpal Gupta1,2, Vedang Murthy1,2, Pankaj Chaturvedi2,3, Devendra Arvind Chaukar2,3, Prathamesh Pai2,3, Gouri Pantavaidya2,3, Anuja Deshmukh2,3, Deepa Nair2,3, Shivakumar Thiagarajan2,3, Richa Vaish2,3, Kumar Prabhash2,4, Amit Joshi2,4, Vanita Noronha2,4, Nandini Menon2,4, Jai Prakash Agarwal1,2
-
Received: ,
Accepted: ,
This article was originally published by Thieme Medical and Scientific Publishers Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Objective
We report the patterns of failure and survival with carcinoma of unknown primary of the head and neck (CUP-HN).
Materials and Methods
This is a retrospective audit of CUP-HN patients treated with curative radiotherapy (RT) between January 2006 and December 2020. All patients received RT to the neck—definitive RT (DRT) or surgery (Sx) + adjuvant RT (ART), ± chemotherapy.
Results
Of the 108 eligible patients, 81 (75%) used tobacco. Positron emission tomography with computed tomography was performed in 102 patients (94.4%). Seventy-five patients (69.4%) were treated with DRT ± chemotherapy, while 33 (30.6%) underwent Sx + ART ± chemotherapy. Median lymph node size was significantly different between DRT and ART groups (5 vs. 3.5cm, p = 0.001). At a median follow-up of 60 months, 35.1% patients had a neck failure (within treatment portal 37, outside portal 1). Nine patients (8.3%) developed 10 sites of subsequent mucosal primary (SMP)—all occurred in the oral cavity, six of whom had received comprehensive mucosal irradiation (CMI). Three-year survival outcomes were significantly better with Sx + ART compared to DRT (local control in neck: 96.8 ± 3.2 vs. 50.6 ± 6.2, p < 0.001, locoregional control: 89.7 ± 5.7 vs. 48.6 ± 6.3, p < 0.001), progression-free survival: 80.7 ± 7.1 vs. 38.7 ± 6, p < 0.001, and overall survival [OS]: 67.2 ± 8.5 vs. 41.9 ± 6.2, p = 0.01), respectively. After propensity score matching, all survival outcomes (except OS) were better with Sx + ART compared to DRT.
Conclusion
All SMPs developed in the oral cavity in this tobacco-driven population. Inclusion of oral cavity for CMI may be considered in tobacco-driven populations; however, this has to be weighed against the toxicity involved.
Keywords
Introduction
Treatment of carcinoma of unknown primary of the head and neck (CUP-HN) region remains controversial. Recent recommendations for managing CUP-HN are largely based on Western studies, which primarily focus on treatment for human papillomavirus (HPV)-related cancers.12 However, adopting these recommendations in populations with varying clinical/demographic profiles (lower HPV incidence and higher rates of smoking and oral cavity primaries) may not be appropriate.345
The aim of this study was to assess the patterns of failure, the incidence of subsequent mucosal primary (SMP), and the survival outcomes in CUP-HN.
Material and Methods
We queried our institutional database on CUP-HN patients who received radiotherapy (RT) from January 2006 to December 2020. This project was approved by the Institutional Review Board (IRB no: 900919). The data was collected from electronic medical records maintained at our institute.
Inclusion/Exclusion
The study included patients with histologically proven carcinoma of HN with no clinically/radiologically detected primary with age > 18 years and who had received RT with radical intent. Patients with extracervical lymphadenopathy/distant metastases or incomplete treatment were excluded.
Management
Patients were evaluated with biopsy, contrast-enhanced computed tomography (CT) of HN or positron emission tomography with CT (PET-CT), and triple endoscopy. For the purpose of the study, the side of the neck with major bulk of disease was referred to as ipsilateral (I/L) and the other side as contralateral (C/L) neck. Patients were considered for surgical (±adjuvant treatment) or nonsurgical treatment as per discussion in the multidisciplinary tumour board based on the extent of the disease and operability. As per institutional policy, patients with relatively low nodal burden (N1/N2a/b) were considered for upfront surgery (Sx). Sx included selective, modified radical, and radical dissection of the unilateral (U/L) or bilateral (B/L) neck. C/L neck dissection was considered in patients with gross lymph nodes (LNs) in the C/L neck or heavy lymph nodal burden on the I/L neck. Adjuvant RT (ART) was considered in patients with extranodal extension (ENE) and/ or multiple LNs (≥ 2). Definitive RT (DRT) was considered in patients with multiple LNs and/or with overt clinicoradiological ENE. A dose of 66 to 70 and 60 Gy in conventional fractionation was used in the definitive and adjuvant settings, respectively. Uninvolved LN regions (C/L and I/L) were electively treated in cases with high lymph nodal burden. Comprehensive mucosal irradiation (CMI) was employed as per the discretion of the treating physician, especially when p16 (HPV) immunohistochemistry (IHC) or HPV/Epstein–Barr virus (EBV) polymerase chain reaction (PCR) were positive. Uninvolved LN regions and mucosa (CMI) were irradiated to a dose equivalent to 50 Gy/25#. Patients were treated with two-dimensional RT, three-dimensional conformal RT, or intensity-modulated RT (IMRT) as per the physician's discretion. Patients in whom upfront local therapy was deemed not suitable, neoadjuvant chemotherapy (NACT) was used for tumor downstaging. Concurrent chemotherapy (CCT) along with ART or DRT was used in those with pathological/clinical/radiological evidence of ENE. Patients were followed up every 3 months for the first 3 years, 6 monthly for the next 2 years, and annually thereafter. PET-CT was done at the first follow-up in patients after DRT or if there was a suspicion of recurrence.
Patient details including demographic data, biopsy histology, IHC/PCR for HPV/EBV, surgical technique, RT dose, RT technique, and follow-up information were retrieved. The primary objective of the study was to evaluate response to DRT, survival outcome measures (local control in neck [LCn]; locoregional control [LRC]; progression-free survival [PFS]; and overall survival [OS]), and patterns of failure in patients with CUP-HN.
Statistical Analysis
Statistical Package for the Social Sciences (SPSS version 24) and R software were used for analysis. Descriptive analysis of demographic data, tumor characteristics, response to DRT, and patterns of failure was done and described in rates and percentages. Comparison of baseline variables between the DRT and Sx + ART cohort (including NACT/CCT in treatment for the abovementioned indications in either cohort) was done using the chi-square or Mann–Whitney tests as per their parametricity. All time to event outcomes were estimated from completion of RT. Death was not included as an event for LCn and LRC in the analysis. The Kaplan–Meier method was used to estimate the survival outcomes (LCn, LRC, PFS, and OS). The survival outcomes of the DRT and Sx + ART cohorts were compared using the log-rank test. Propensity score matching (PSM) was performed to balance the covariates between the two cohorts and compared.
Results
Of 165 patients screened, 108 were eligible for the study. Seventy-five patients (69.4%) were treated with DRT (±chemotherapy) while 33 patients (30.6%) were treated with Sx + ART (±chemotherapy). Table 1 depicts the sociodemographic and clinicoradiological parameters. Majority (81 patients, 75%) chewed or smoked tobacco. The most common presentation was level II cervical adenopathy (74 patients, 68.6%). The staging investigation was PET-CT in majority (102 patients, 94.4%). When comparing the various clinicoradiological parameters between DRT and ART cohorts, clinical LN size was the only factor that differed significantly (median: 5 vs. 3.5 cm, p = 0.001). Table 2 describes the treatment details. IMRT was used in majority of patients (54.6%). CMI was performed in 64 patients, of which 44 received the same by virtue of having been treated with conventional techniques (anterolateral or B/L portals). Seventeen patients received NACT and the most common regimen was a combination of taxane, platinum, and 5-flurouracil. Injection cisplatinum was the most commonly used drug for CCT (Table 2). Response PET-CT showed complete metabolic response in 41 (54.7%) of the 75 patients treated with DRT, while the rest had either residual ± progressive and/or metastatic disease (Table 2). Salvage neck dissection was performed in four patients with residual disease.
|
Variables |
All patients n = 108 |
Definitive RT n = 75 |
Adjuvant RT n = 33 |
p-Value |
|---|---|---|---|---|
|
n (%) |
n (%) |
n (%) |
||
|
Age in years (mean ± SD) |
55.1 ± 11.1 |
54.4 ± 10.4 |
56.7 ± 12.9 |
0.1 |
|
Gender (Male:Female) |
90 (83.3):18 (16.7) |
62 (82.3):13 (17.3) |
25 (75.7):8 (24.3) |
0.8 |
|
Tobacco use |
81 (75) |
54 (72) |
27 (81.8) |
0.3 |
|
Clinical LN size (median, range) |
4 (1–14) |
5 (1–14) |
3.5 (1–7) |
0.001 |
|
Clinical fixity |
59 (54.6) |
44 (58.7) |
15 (45.4) |
0.2 |
|
Radiological investigation CECT HN PET-CECT NK |
2 (1.9) 102 (94.4) 4 (3.7) |
0 (0) 73 (97.3) 2 (2.7) |
2 (6.1) 29 (87.8) 2 (6.1) |
0.06
|
|
Radiological LN size |
3.5 (0.8–13.7) |
3.7 (0.8–13.7) |
3 (0.9–6.4) |
0.3 |
|
Radiological LN levels involved Single Multiple Not known |
43 (39.8) 63 (58.3) 2 (1.9) |
30 (40) 44 (58.7) 1 (1.3) |
13 (39.4) 19 (57.5) 1 (3.1) |
0.9
|
|
Radiological LN levels Single Level I Level II Level III Level IV Level V Multiple Level II + others Others NK |
13 (12) 27 (25) 1 (0.9) 3 (2.8) 2 (1.9)
46 (42.6) 15 (13.9) 1 (0.9) |
5 (6.7) 22 (29.3) 1 (1.3) 2 (2.7) 2 (2.7)
32 (42.7) 10 (13.3) 1 (1.3) |
8 (24.3) 5 (15.2) 0 1 (3) 0
14 (42.3) 5 (15.2) 0 |
0.3
|
|
Radiological LN laterality Left Right Bilateral NK |
44 (40.7) 57 (52.8) 6 (5.6) 1 (0.9) |
34 (44.3) 36 (48.1) 4 (5.3) 1 (1.3) |
10 (30.3) 21 (63.6) 2 (6.1) 0 (0) |
0.2
|
|
N stage (cN) cN1 cN2a cN2b cN2c cN3 NK |
19 (17.6) 12 (11.1) 16 (14.8) 3 (2.8) 57 (52.8) 1 (0.9) |
12 (16) 8 (10.7) 9 (12) 3 (4) 42 (56) 1 (1.3) |
7 (21.2) 4 (12.1) 7 (21.2) 0 (0) 15 (45.5) 0 (0) |
0.5
|
|
Histology Squamous Ca Adeno Ca Poorly differentiated Ca Others |
96 (88.9) 1 (0.9) 8 (7.4) 3 (2.8) |
69 (92) 0 (0) 1 (1.3) 5 (6.7) |
27 (81.8) 1 (3) 2 (6.1) 3 (9.1) |
0.2
|
|
p16 positivea |
6/30 (20) |
6/22 (27.2) |
0/6 (0) |
0.003 |
|
EBV positiveb |
0/22 (0) |
0/18 (0) |
0/4 (0) |
0.34 |
Abbreviations: Ca, carcinoma; CECT, contrast-enhanced computed tomography; EBV, Epstein–Barr virus; HN, head and neck; LN, lymph node; NK, not known; PET-CT, positron emission tomography with computed tomography; RT, radiotherapy; SD, standard deviation.
Test done in 30 patients.
Test done in 22 patients.
|
Radiotherapy details (n = 108) |
n (%) |
|
|---|---|---|
|
Dose (Gy) < 64 66–70 |
34 (31.5) 74 (68.5) |
|
|
RT volume Ipsilateral neck Bilateral neck NK |
14 (13) 87 (80.6) 7 (6.5) |
|
|
Mucosal irradiation (n = 64, 59.2%) NPX NPX + OPX OPX + LNX NPX + OPX + LNX Unintentional (OPX + LNX ± partial NPX)a |
3 (4.7) 5 (7.8) 2 (3.1) 10 (15.6) 44 (68.8) |
|
|
RT technique 2DRT 3DCRT IMRT NK |
45 (41.7) 3 (2.8) 59 (54.6) 1 (0.9) |
|
|
RT duration (d) |
47 (32–101) |
|
|
Concurrent chemotherapy (n = 86, 79.6%) With definitive RT With adjuvant RT |
64 (74.4%) 22 (25.6%) |
|
|
Number of concurrent chemotherapy cycles (median) |
6 |
|
|
Response to radiotherapy (n = 75, 69.4%) CMR PR Progression Local Distant Local + Distant Not evaluable |
41 (54.7) 16 (21.4)
7 (9.3) 6 (8) 2 (2.6) 3 (4) |
|
|
Surgery details (n = 33) |
n (%) |
|
|
Pathological N stage (pN) pN1 pN2b pN3 ypN0 ypN2b ypN3 NK |
2 (6.1) 4 (12.1) 23 (69.7) 1 (3) 2 (6.1) 1 (3) 0 (0) |
|
|
Clinical-radiological staging correlation (n = 29)a
cN1 cN2a cN2b cN3 |
Retained (16, 55.2%) |
Upstaged (13, 44.8%) |
|
2 - 2 12 |
5 (pN2b-2, pN3-3) 4 (pN3) 4 (pN3) - |
|
|
Number of nodes dissected (mean ± SD) |
26.2 ± 2.1 |
|
|
Pathological PNE Positive |
22 (66.7) |
|
Abbreviations: 2DRT, two-dimensional radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; c, clinical; CMR, complete metabolic response; IMRT, intensity-modulated radiotherapy; LNX, larynx; NK, not known; NPX, nasopharynx; OPX, oropharynx; PNE, perinodal extension; PR, partial response; RT, radiotherapy; SD, standard deviation.
By virtue of the conventional portals (bilateral or anterolateral).
At a median follow-up (surviving patients) of 60 (41.5–91) months, 38 patients (35.1%) had a neck nodal failure (within treatment portal: 37, outside portal: 1). The index local treatment for these patients was DRT in 36 patients (including 25 with residual disease + progression post-DRT) and Sx + ART in two patients. Eight and two patients were salvaged with Sx ± adjuvant treatment and reirradiation, respectively, while 15 patients received palliative chemotherapy. SMP occurred in 9 patients (8.3%) at 10 sites. Table 3 shows details of SMP. Of the nine, one patient developed a HN mucosal primary (alveolus) after 5 years of treatment on the C/L side of the initial LN disease. The incidence of SMP was not compared between CMI versus non-CMI cohorts as all SMPs occurred outside the sites covered by CMI. Six of the nine (67%) patients were successfully salvaged.
|
No: |
Index treatment |
CMI |
HPV/EBV |
Site of primary |
Lateralitya |
TI |
Salvage treatment |
|---|---|---|---|---|---|---|---|
|
1. |
DRT + CCT |
+ |
NP/NP |
BM |
I/L |
2.7 |
Palliation |
|
2. |
NACT→DRT + CCT |
− |
-/NP |
FOM |
I/L |
3.3 |
Palliative CT |
|
3. |
NACT→DRT |
+ |
NP/NP |
BM |
I/L |
7.8 |
Palliation |
|
4. |
Sx→ART + CCT |
− |
NP/NP |
BM→lip |
I/L |
11.6, 12 |
Sx (BM)→Sx (lip) |
|
5. |
Sx→ART + CCT |
+ |
NP/NP |
HP |
I/L |
19.4 |
Sx→ART + CT |
|
6. |
DRT + CCT |
+ |
-/NP |
Tongue |
I/L |
22.7 |
DRT + CT |
|
7. |
DRT + CCT |
− |
−/− |
BM |
I/L |
36 |
Sx |
|
8. |
Sx→ART + CCT |
+ |
NP/NP |
RMT |
I/L |
54.9 |
Sx |
|
9. |
NACT→Sx→ART + CCT |
+ |
NP/NP |
Alveolus |
C/L |
83.5 |
Sx→ART + CT |
Abbreviations: ART, adjuvant radiotherapy; BM, buccal mucosa; C/L, contralateral; CMI, comprehensive mucosal irradiation including nasopharynx, oropharynx, and larynx; CCT, concurrent chemotherapy; CT, chemotherapy; DRT, definitive radiotherapy; EBV, Epstein–Barr virus; FOM, floor of mouth; HP, hard palate; HPV, human papillomavirus; I/L, ipsilateral; NACT, neoadjuvant chemotherapy; NP, not performed; RMT, retromolar trigone; Sx, surgery; TI, time interval (in months) between completion of radiotherapy and detection of mucosal primary.
Compared to initial presentation of cervical lymph nodal disease.
The 3-year LCn, LRC, PFS, and OS of the overall cohort were 65.5 ± 4.8, 61.8 ± 5, 52 ± 5.1, and 49.9 ± 5.1%, respectively. Survival outcome measures were significantly better with ART when compared with DRT directly (Fig. 1). The 3-year LCn, LRC, PFS, and OS of DRT and ART were 50.6 ± 6.2 versus 96.8 ± 3.2 (p < 0.001), 48.6 ± 6.3 versus 89.7 ± 5.7 (p < 0.001), 38.7 ± 6 versus 80.7 ± 7.1 (p < 0.001), and 41.9 ± 6.2 versus 67.2 ± 8.5 (p = 0.01), respectively. PSM was done to negate the negative selection bias toward DRT. Clinical size, nodal stage, radiological LN levels involved, and NACT were identified as covariates. The nearest-neighbor matching method without replacement was used with 1:1 matching ratio and the caliper size as 0.2. Forty-six patients were matched successfully with good covariate balance, depicted as plots (Supplementary Figs. 1 and 2 available in online version only). All survival outcome measures continued to be better with ART, except OS. The 3-year LCn, LRC, PFS, and OS of DRT and ART after matching were 49.2 ± 10.8% versus 95.2 ± 4.6% (p = 0.002), 49.2 ± 10.8% versus 85.27.9% (p = 0.03), 38.3 ± 10.9% versus 77 ± 9% (p = 0.04), and 54.5 ± 11.5% versus 57.6 ± 10.8% (p = 0.79), respectively (Fig. 2). The LCn was also compared between RT to the I/L versus B/L neck and no difference was found (p = 0.64). Acute toxicities (Radiation Therapy Oncology Group grading system) of treatment were available in 68 patients and were as follows—skin grade I: 42.7%, II: 38.2%, III: 17.7%, and IV: 1.4%; mucosa grade I: 32.3%, II: 60.3%, and III: 7.4%; and pharynx grade I: 43.1%, II: 50.7%, and III: 6.2%.
![Kaplan–Meir curves (definitive radiotherapy [DRT] vs. surgery [Sx] + adjuvant radiotherapy [ART]) without matching. (A) Local control in the neck (LCn). (B) Locoregional control (LRC). (C) Progression-free survival (PFS). (D) Overall survival (OS). Patterns of subsequent mucosal primary (SMP).](/content/199/2025/14/02/img/10-1055-s-0045-1806744-i2512229-1.jpg)
![Kaplan–Meir curves (definitive radiotherapy [DRT] vs. surgery [Sx] + adjuvant radiotherapy [ART]) after propensity score matching. (A) Local control in the neck (LCn). (B) Locoregional control (LRC). (C) Progression-free survival (PFS). (D) Overall survival (OS).](/content/199/2025/14/02/img/10-1055-s-0045-1806744-i2512229-2.jpg)
Discussion
We report patterns of failure and survival outcomes in CUP-HN with a high prevalence of tobacco use. We observed a neck failure in 35.1%, SMP in 8.3%, and distant metastases (DM) in 20% of the patients. Interestingly, all the SMPs were located in the oral cavity, irrespective of the delivery of CMI. Sx + ART imparted better local control and PFS when compared with DRT, which was maintained after matching as well.
HPV is a key etiological factor in CUP-HN, with a 50 to 70% prevalence in developed countries and 5-year OS and LC rates of 16 to 86% and 37 to 91% as compared to 20 to 30% prevalence in developing countries and a 5-year OS of 50 to 55%, which is similar to the present study, respectively.35678910111213 PET-CT has good sensitivity (80–90%) and specificity (60–70%) in detecting a hidden primary.21415161718 In the current study, 94.4% of the cohort had undergone PET-CT.
Despite consensus guidelines, management of CUP-HN is still a clinical conundrum. Whether the optimal treatment is neck dissection (Sx) followed by ART or DRT ± CCT or DRT ± CCT followed by salvage Sx (in case of PET positive residual disease) is debatable.19 The current study reveals better outcomes in Sx + ART with a statistically significant difference in the median clinical size of LNs between the Sx + ART and DRT groups. Patients with a bulky LN mass are more likely to receive DRT as local treatment, while a patient with smaller node(s) with ENE could be considered for either treatment (stage matched as N3), thus causing a potential negative bias for DRT. Conflicting results in this context may stem from the varying HPV prevalence and nodal stage distribution; and most importantly the evolving American Joint Committee on Cancer definitions of N3 disease (small LN with ENE vs. large bulky LN mass > 6 cm with or without ENE).102021
RT is crucial for treating CUP-HN, but there is no clear consensus on defining the clinical target volume, particularly the inclusion of uninvolved C/L neck (B/L neck irradiation) and CMI (irradiating the seemingly uninvolved mucosa of nasopharynx [NPX], oropharynx [OPX], and pharynx). There was no difference in survival noted between the U/L and B/L neck RT in the current study. Like HPV's link to OPX primary, EBV positivity predicts NPX primary and may be considered to be included electively in CMI. Given the global prevalence of these infections (HPV > EBV), CMI has shown to reduce SMP emergence.11 This may be a fairly reasonable strategy for a young nonsmoker, whereas a smoker with CUP-HN would be quite likely to harbor an occult HN primary in other sites as well. With a high proportion of tobacco users in our study, all SMPs were detected in the oral cavity. The biology of tobacco-induced oral cavity cancers is considered to be more radioresistant than HPV-related oropharyngeal cancers, which could possibly be the explanation for a superior local control with ART over DRT in our cohort.2223 It is noteworthy that the occurrence of SMPs was not influenced by the local treatment (surgical vs. nonsurgical) or the delivery of CMI (Table 3). This finding alludes to the questionable relevance of the potential HN subsites irradiated in CMI as per guidelines in tobacco-induced HN cancers. Alternatively, inclusion of oral cavity in CMI may have to be weighed with caution in such cancers. Also, Grupo Español de Oncologia Radioterapia para Cancer Cabeza y Cuello (GEORCC) recommends exclusion of level Ib LNs in the RT volume when not involved with disease as it is seldom the drainage area for the OPX.1 However, owing to high number of SMPs occurring in the oral cavity (current study), the inclusion of level Ib LNs may be a potential consideration.
Despite being the largest series from India, our study has certain limitations. Our study is retrospective and hence, prone to inherent biases. The cohorts compared (Sx + ART vs. DRT) are heterogeneous in several aspects; however, we have attempted to match these variables to minimize bias. HPV and EBV biomarkers had been performed only in a small proportion of patients, thus limiting the complete analysis of the etiological factors of CUP-HN in our cohort. The inadvertent mucosal irradiation due to the use of conventional techniques (59%) does not allow us to accurately comment on the role of CMI in our study.
In conclusion, SMPs occurred majorly in the oral cavity, irrespective of the delivery of CMI. Tobacco-induced CUP-HN is a unique disease with regards to its biology and patterns of failure, which mandates a nuanced understanding from the treating physician. Direct adoption of existing recommendations in this scenario may not be appropriate. Inclusion of oral cavity for CMI may also have to be weighed with caution.
Note
As this is a retrospective audit on the evolving multidisciplinary treatment practices of a relatively rare cancer over > 15 years, we have included authors who have contributed to the same.
Highlights
Tobacco use was present in majority of the patients.
Neck nodal failure was the most common pattern of failure in CUP-HN.
All SMPs occurred in the oral cavity in this tobacco-driven population.
Supplementary Material
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