(Chemo)radiotherapy after laser microsurgery and selective neck dissection for pN2 head and neck cancer
This study analyzed the efficacy of transoral laser microsurgery and postoperative (chemo) radiotherapy (CRT) for head and neck squamous cell carcinoma. Between 1987 and 2007, 318 patients with pN2 neck disease were included. Seventy-three patients received laser resection and neck dissection alone, 154 postoperative radiotherapy, and 91 postoperative (C)RT. Mean follow-up was 58.2 ± 51.2 months, and locoregional control was significantly better after postoperative (C)RT (surgery alone: 42 %, radiotherapy: 57 %, CRT: 59 %; p < 0.01). Postoperative (C)RT did not have a significant impact on disease-specific survival (DSS) (surgery alone: 55 %, radiotherapy alone: 60 %, CRT: 64 %; p = 0.36). Fifty-seven patients (17.92 %) developed distant metastases, and 39 patients (12.26 %) presented with secondary malignancies, with no significant differences found between the treatment groups. Postoperative (C)RT significantly improved locoregional control, but had no significant effect on DSS because of high rates of secondary malignancies and distant metastases. Reduced radicality in combination with an effective screening might improve prognosis and quality of life of these patients.
KeywordsHNSCC pN2 (Chemo)radiotherapy Transoral laser microsurgery Selective neck dissection
In patients presenting with squamous cell carcinoma (SCC) of the upper aerodigestive tract, the presence, number, and size of cervical lymph node metastases predicts an average decrease in overall survival of up to 50 % [1, 2, 3]. For clinical N2 neck disease, the need for surgical dissection of the lymph nodes is widely accepted as the standard of care. Until the late 1960s, radical neck dissection (RND) was the main surgical approach for neck nodes. However, based on anatomical observations, more conservative techniques such as modified radical neck dissection (MRND) [4, 5] and regionally limited selective neck dissection (SND)  were introduced and popularized. During recent years, it has been shown  that SND seems to be equivalent to the more radical techniques with respect to locoregional control; thus, the indications for SND were broadened to include other head and neck sites and more advanced neck disease (N2).
For a long time, postoperative radiotherapy alone was routinely administered after surgery for locally advanced HNSCC . Due to unsatisfactory locoregional control and long-term survival results, various additional chemotherapy regimens were introduced. Today, in addition to surgical treatment of the primary tumor and lymph nodes, postoperative platinum-based (chemo)radiotherapy [(C)RT] is the standard therapeutic approach in cases with a high risk of recurrence, such as residual disease after neck dissection, positive cervical lymph nodes ≥pN2, and extracapsular spread [9, 10, 11].
Against this background, the analyzed patient cohort in the present study is of particular interest due to the individual selection of the available treatment procedures: Despite the knowledge of locoregionally advanced disease of all patients and contrary to the otherwise common guidelines, 73 of the 318 patients (23 %) were intentionally not treated with additional (C)RT after curative surgery. The use of the available multimodal treatment modalities were individually selected by the attending physicians and therefore did not specifically change within the evaluated time span. Thus, the current data provide the unique opportunity to directly evaluate the impact of postoperative (C)RT on long-term survival within a patient cohort that will most likely not be available again.
We reviewed the medical records of all patients with cancer of the upper aerodigestive tract who underwent transoral CO2 laser microsurgery (TLM) and neck dissection with curative intent. All procedures were followed in accordance to the ethical standards of the responsible committee on human experimentation and with Helsinki Declaration of 1975, as revised in 2013.
We included patients (1) with SCC of the upper aerodigestive tract; (2) without simultaneous distant metastases; (3) without a previous or simultaneous second malignancy; (4) without previous treatment of the head and neck region using chemotherapy, radiation therapy, or surgery; and (5) with pN2 neck disease.
Patients with pN0/pN1 neck disease were excluded because these patients had received no postoperative (C)RT. Patients with pN3 neck metastases were excluded from the analysis because all of these patients had undergone radiation therapy.
Treatment of primary tumors
Preoperative staging examinations consisted of magnifying laryngoscopy performed on awake patients and ultrasonography of the neck for lymph node evaluation. Computed tomography (CT) or magnetic resonance imaging (MRI) of the neck was performed unless satisfactory imaging had been performed on the patient at the referring hospital. Further standard preoperative investigations included X-ray examination of the chest and ultrasonography of the abdomen.
At the commencement of the planned surgery under general anesthesia, panendoscopy was performed with the intent to diagnose any second primary tumor in the aero- or upper digestive tract prior to tumor resection. Transoral laser microsurgery was performed using a CO2 laser (C40; Lumenis, Santa Clara, CA) in the continuous superpulse mode. Resections were performed using the step-by-step technique described by Steiner , which involved cutting through the tumor under microscopic magnification. This technique enables differentiation between tumor and healthy tissue and allows the surgeon to follow the tumor while preserving as much healthy tissue as possible. If definite histological resection margins showed positive or unclear results, additional resections were conducted until an R0 resection was verified.
Diagnosis and treatment of the neck
Preoperatively, all patients were assessed for lymph node metastases by palpation of the neck, ultrasonography, CT, and/or MRI. If the patient presented with advanced primary disease and the tumor infiltration depth was >3 mm, or preoperative imaging revealed suspicious lymph nodes, a uni- or bilateral selective neck dissection was performed. Patients underwent bilateral neck dissection if imaging revealed suspicious lymph nodes bilaterally, if primary tumor had an advanced stage with midline localization, or if suspicious lymph nodes were seen only on one side, but no adjuvant (chemo)radiotherapy [(C)RT] was planned due to a small primary tumor. Follow-up consisted of ultrasound and ENT examination every 3 months for the first 3 years, every 6 months for an additional 2 years, and yearly thereafter.
From August 1987 to December 1993 (65 patients), the radiotherapy schedule was composed of two fractions per day that were separated by 6-h intervals. Each fraction consisted a maximum of 2.1 Gy (1.25 MV 60CO), with a total irradiation dose of 56 and 70 Gy to the bilateral neck and primary tumor, respectively, over 6 weeks as a split-course regimen.
From January 1994 to December 2004 (162 patients), normofractionated radiotherapy (2 Gy/day, 5 times/week) was delivered by the application of parallel, opposed lateral portals matched to a single anterior portal encompassing the primary tumor and associated nodal drainage sites up to a maximum dose of 50 Gy. To cover the lower neck and the supraclavicular nodes, one anterior portal was used, and a dose of 50 Gy at a 3-cm depth was delivered. Finally, the 3D conformal external beam radiotherapy technique was used for the boost to achieve a total dose of 60 Gy.
From January 2005 to July 2007 (18 patients), normofractionated (2 Gy/day, 5 times/week) 3D conformal external beam radiotherapy was administered from the beginning of radiotherapy. The primary tumor, involved lymph nodes, and potential drainage sites on both sides of the neck, including the supraclavicular region, were covered with a dose of 50 Gy in the first phase, followed by a boost of up to 64 Gy that included the primary tumor and involved lymph nodes.
Until December 2001, the patients were treated with radiotherapy alone (n = 127) or with a daily dose of 50 mg/m2 carboplatin i.v. on every day of radiotherapy (n = 53). Since January 2002, with the exception of patient refusal, reduced general condition, or inadequate renal function, concomitant cisplatinum-based intravenous chemotherapy was regularly applied as follows: cisplatinum 100 mg/m2/TBSA/day on days 1, 21, and 42 of radiotherapy (6 patients); cisplatinum 20 mg/m2/TBSA/day in the first and fifth weeks of radiotherapy (13 patients); or cisplatinum 6 mg/m2/TBSA/day on every day of radiotherapy (19 patients).
Age was described as the mean ± standard deviation, and categorical and ordinal parameters were described by their absolute and relative frequencies. Parameters were compared between therapy groups using either one-way analysis of variance (age) or Fisher’s exact test (categorical parameters). To study the effect of the study parameters on locoregional control and overall survival, simple Cox regression models were fitted for each parameter. Only tumor-specific deaths were regarded as events in the assessment of overall survival. The effects were described as hazard ratios and 95 % confidence intervals. The significance level was α = 5 % for all tests. All analyses were performed using the statistical software R (version 3.0, www.r-project.org). To exclude potential bias caused by differences in T categories between the groups, the T strata (i.e., T1–T4) were analyzed using a Mann–Whitney U test.
Patient characteristics and therapy
Comparison of characteristics of patients administered different therapies
None (n = 73)
RT (n = 154)
CRT (n = 91)
57.0 ± 11.5
56.6 ± 9.4
55.0 ± 8.1
63 (86 %)
125 (81 %)
84 (92 %)
10 (14 %)
29 (19 %)
7 (8 %)
18 (25 %)
41 (27 %)
22 (24 %)
18 (25 %)
28 (18 %)
12 (13 %)
12 (16 %)
24 (16 %)
16 (18 %)
25 (34 %)
61 (40 %)
41 (45 %)
Postoperative T categories of 318 patients according to tumor site and postoperative treatment
Patients who received (C)RT
Patients without (C)RT
Stratification of patients according to the treatment regimen
Locoregional control and disease-specific survival
Locoregional recurrences, distant metastases, and second primary malignancies stratified by postoperative treatment and T category
Second primary tumors
Patients who received (C)RT (n = 245)
Patients without (C)RT (n = 73)
Treatment failures after initial therapy depending on treatment regimen, trasoral laser microsurgery (TLM), radiotherapy (RT), and chemoradiotherapy (CRT)
Surgery (n = 73)
17 (39.5 %)
10 (23.3 %)
16 (37.2 %)
43 (58.9 %)
Surgery + RT (n = 154)
45 (70.3 %)
13 (20.3 %)
6 (9.4 %)
64 (41.6 %)
Surgery + CRT (n = 91)
25 (71.4 %)
7 (20.0 %)
3 (8.6 %)
35 (38.5 %)
In the group of patients not treated with adjuvant (C)RT, larynx preservation rate for patients with hypopharynx carcinoma was 100 % (18/18), and for patients with larynx carcinoma 88.9 % (16/18). Two patients with pT4a supraglottic laryngeal carcinoma needed total laryngectomy after presenting with rpT4a tumour. Within the adjuvant (C)RT group, larynx preservation rate was 98.4 % (62/63) for patients with hypopharynx carcinoma and 90.0 % (36/40) for patients with laryngeal carcinoma. All of these patients presented with rpT4 tumours after pT4 hypopharynx carcinoma, pT4 supraglottic carcinoma (n = 2), and pT3 glottis carcinoma (n = 2). There were no statistical differences between the groups.
In this study, we analyzed the medical records of 318 patients with previously untreated carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and exclusively postoperative pN2 neck disease who were treated with curative intent between August 1987 and July 2007. This patient cohort is of particular interest due to the expanded follow-up time and, more importantly, due to the unique and individual selection of the available treatment procedures throughout the time period under investigation. Thus, due to the individual decisions of the attending physicians, only 245 of the 318 patients (77 %) were treated with additional (C)RT after curative surgery, despite knowledge of existing, regionally advanced disease (pN2). Today, the omission of postoperative therapy for such patients would be a deviation from recommended treatment protocols, which are strongly based on proven strategies and continually revised guidelines . Thus, a comparable patient cohort enabling both a direct comparison between surgery alone, postoperative radiotherapy, and (C)RT and evaluation of the treatment impact on survival and local control will most likely not be available again.
One expected result of the present analysis was the significant impact of (C)RT on locoregional control rate. This effect was evident for the entire patient cohort (Fig. 2a), but especially pronounced in patients with locally advanced tumors (pT3–4) (Fig. 2c), who are characteristically known to be at higher risk for local recurrence . Accordingly, even though all patients had locoregionally advanced disease (pN2), this influence of (C)RT was not observed in patients with smaller primary tumors (pT1–2), regardless of the applied treatment.
The efficacy of additional concomitant treatment including chemotherapy combined with radiation therapy has been assessed in various meta-analyses, and a small, but unquestionable, benefit has been observed [13, 14]. In the present study, (C)RT slightly improved the local control rate in all patients, and this improvement was more pronounced in the locally advanced patient cohort. These results corroborate the conclusion that radiotherapy mainly impacts the probability of local relapse and are supported by studies demonstrating the radiosensitization provided by additional chemotherapy, especially for advanced primary tumors in the postoperative setting (pT3–4) [9, 10, 11].
Regarding DSS, we did not find a significant advantage of postoperative RT; only a trend toward better results derived from (C)RT was found in the entire cohort. Again, this effect was more pronounced in the group with locally advanced tumors, but did not reach a level of statistical significance. This finding could partially be explained by the unbalanced tumor distribution among the groups. Because the group that underwent postoperative (C)RT had more locally advanced tumors, the possible effect of this multimodal approach may be underestimated.
Furthermore, these results may have been influenced by other confounding factors that may have a similar or even greater effect on overall survival than postoperative (C)RT. In general, patients treated for HNSCC were often exposed to risk factors such as tobacco smoke, which was frequently used in combination with alcohol abuse over many years. Obviously, these patients carry a significantly increased risk of second primary malignancies, particularly tumors in other head and neck regions or the aerodigestive tract. Today, due to the improved local control rates and long-term outcomes through optimized multimodal approaches [15, 16, 17, 18, 19, 20], the incidence of these second cancers is becoming an increasingly life-limiting factor . For example, Leon et al.  retrospectively reported a 16 % second tumor rate in a cohort of 1845 patients who were treated for HNSCC. In this study, 80 % of the tumors were located in the aerodigestive tract and developed with an annual overall incidence rate of 4 %. To counter this problem, the optimal strategy is to identify patients at the highest risk for undetected secondary malignancies, followed by utilization of another curative treatment approach to obtain improved overall survival rates.
In this context, we found a high prevalence of curable second malignancies in a defined subgroup of patients with previous HNSCC: In a previous study, 118 participants underwent systematic examination for second malignancies following curative treatment for HNSCC . In all patients, CT scans, ear–nose–throat (ENT) endoscopy, and endoscopy of the esophagus and stomach were performed. Interestingly, 26 second malignancies in patients who were asymptomatic at the time of examination were detected and histologically confirmed at a very early tumor stage. Remarkably, 86 % of these affected patients were consecutively treated again with curative intent.
These high incidences and the importance of these results are clearly underlined by the data from the present cohort, with second malignancies in 39 patients (12.3 %) and distant metastases in 57 patients (17.9 %) occurring during the long-term follow-up.
Many different screening procedures were tested during the last few decades to identify patients at highest risk for the development of different tumors and distant metastases, although with limited success. As one of the most remarkable exceptions, a study by the National Lung Screening Trial research team yielded promising results in high-risk smokers without previous malignancies who were screened using CT scans compared with chest radiographs. In this study, 53,454 people, aged 55–74 years with a minimum smoking history of 30 packs/year, were randomized to receive yearly CT scans over 3 years . The analyses revealed a significant reduction of 20 % in tumor-related mortality due to a lung tumor in the group that underwent CT scanning.
As in other oncological settings, early detection and subsequent definitive treatment may also impact the initial treatment decisions in cases of locally advanced HNSCC . Due to the high mortality rates associated with second malignancies and distant metastases, initial therapy concepts involving minimally invasive surgical treatment (e.g., laser microsurgery and selective neck dissection  for organ and function preservation), as well as a less toxic (C)RT should be considered more thoroughly [27, 28, 29, 30, 31, 32]. Finally, in addition to an improvement in overall survival rates, these procedures could lead to a better quality of life with less adverse, long-term, treatment-related side effects. In particular, primary transoral laser microsurgery offers good oncologic and functional results to patients with cancer of the upper aerodigestive tract. In combination with or without selective neck dissection, this approach has considerable advantages, including lower morbidity and complication rates [33, 34, 35], a shorter duration of hospitalization, higher patient acceptability, and lower costs.
There are some limitations of the present study that should be considered. The analyzed patient cohort consisted of a heterogeneous, but representative group of patients with different HNSCCs. Thus, the analysis of prognostic factors for better locoregional control and survival may have been biased by the known diverse responses to therapy and prognoses. Although this potential bias was considered in this study, an evaluation of a larger cohort may be more informative.
Due to the long time span of this study, patients inevitably underwent treatment regimens with different chemotherapy substances and dosages. Furthermore, rapid technological development of the applied radiation techniques occurred during this period. Therefore, the effects of these factors on locoregional control and survival cannot be excluded.
Due to the retrospective character and similarity of the histology, a concluding proof of either metastases of the primary HNSCC or secondary primary malignancies as a distant failure after primary disease cannot be finally drawn.
This is an overlapping problem for all studies with HNSCC due to the same histological origin including similar known risk factors such as smoking and alcohol abuse for all SCC of the aerodigestive tract.
We confirmed the important impact of postoperative (C)RT on a unique cohort of patients with locally advanced HNSCC (pN2) compared with surgery alone. The greatest benefit of (C)RT identified in this study was the locoregional control afforded to patients with advanced primary tumors. The slight effect of (C)RT on DSS can be explained due to high rates of secondary malignancies and distant metastases.
Conflict of interest
The authors state that there are no conflicts of interest concerning this study.
- 6.Steiner W (1984) Surgical treatment of the cervical lymph node system in laryngeal carcinoma. In: Wigand ME, Steiner W, Stell PM (eds) Functional partial laryngectomy Springer, Berlin, pp 253–264Google Scholar
- 7.Hamoir M, Ferlito A, Schmitz S, Hanin FX, Thariat J, Weynand B, Machiels JP, Gregoire V, Robbins KT, Silver CE, Strojan P, Rinaldo A, Corry J, Takes RP (2012) The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. Oral Oncol 48(3):203–210. doi:10.1016/j.oraloncology.2011.10.015 CrossRefPubMedGoogle Scholar
- 9.Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350(19):1945–1952. doi:10.1056/NEJMoa032641 CrossRefPubMedGoogle Scholar
- 10.Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK (2004) Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350(19):1937–1944. doi:10.1056/NEJMoa032646 CrossRefPubMedGoogle Scholar
- 12.Steiner W (1988) Experience in endoscopic laser surgery of malignant tumours of the upper aero-digestive tract. Adv Otorhinolryngol 39:135–144Google Scholar
- 13.Pignon JP, Bourhis J, Domenge C, Designe L (2000) Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 355(9208):949–955 S0140673600900110 [pii]CrossRefPubMedGoogle Scholar
- 14.Browman GP, Hodson DI, Mackenzie RJ, Bestic N, Zuraw L (2001) 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 23(7):579–589. doi:10.1002/hed.1081 CrossRefPubMedGoogle Scholar
- 20.Rades D, Meyners T, Kazic N, Bajrovic A, Rudat V, Schild SE (2011) Comparison of radiochemotherapy alone to surgery plus radio(chemo)therapy for non-metastatic stage III/IV squamous cell carcinoma of the head and neck: a matched-pair analysis. Strahlenther Onkol 187(9):541–547. doi:10.1007/s00066-011-2262-2 CrossRefPubMedGoogle Scholar
- 23.Wolff HA, Wolff CR, Hess CF, Jung K, Sennhenn-Kirchner S, Hinterthaner M, Muller-Dornieden A, Korber W, Marten-Engelke K, Roedel R, Christiansen H, Engelke C (2013) Second primary malignancies in head and neck cancer patients: high prevalence of curable-stage disease. Strahlenther Onkol 189(10):874–880. doi:10.1007/s00066-013-0404-4 CrossRefPubMedGoogle Scholar
- 26.Ambrosch P, Kron M, Pradier O, Steiner W (2001) Efficacy of selective neck dissection: a review of 503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper aerodigestive tract. Otolaryngol Head Neck Surg 124(2):180–187. doi:10.1067/mhn.2001.111598 CrossRefPubMedGoogle Scholar
- 27.Olthoff A, Ewen A, Wolff HA, Hermann RM, Vorwerk H, Hille A, Rodel R, Hess CF, Steiner W, Pradier O, Christiansen H (2009) Organ function and quality of life after transoral laser microsurgery and adjuvant radiotherapy for locally advanced laryngeal cancer. Strahlenther Onkol 185(5):303–309. doi:10.1007/s00066-009-1967-y CrossRefPubMedGoogle Scholar
- 29.Wolff HA, Overbeck T, Roedel RM, Hermann RM, Herrmann MK, Kertesz T, Vorwerk H, Hille A, Matthias C, Hess CF, Christiansen H (2009) Toxicity of daily low dose cisplatin in radiochemotherapy for locally advanced head and neck cancer. J Cancer Res Clin Oncol 135(7):961–967. doi:10.1007/s00432-008-0532-x CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Tribius S, Sommer J, Prosch C, Bajrovic A, Muenscher A, Blessmann M, Kruell A, Petersen C, Todorovic M, Tennstedt P (2013) Xerostomia after radiotherapy : what matters-mean total dose or dose to each parotid gland? Strahlenther Onkol. doi:10.1007/s00066-012-0257-2 Epub ahead of printPubMedGoogle Scholar
- 32.Wolff HA, Bosch J, Jung K, Overbeck T, Hennies S, Matthias C, Hess CF, Roedel RM, Christiansen H (2010) High-grade acute organ toxicity as positive prognostic factor in primary radio(chemo)therapy for locally advanced, inoperable head and neck cancer. Strahlenther Onkol 186(5):262–268. doi:10.1007/s00066-010-2136-z CrossRefPubMedGoogle Scholar