Analysis of Outcomes following TORS in a Mixed Cohort of Recurrent and New T1-T2 Oropharyngeal Cancer- A Single Institution Study

Abstract

Purpose

. The transoral robotic surgery is a newer modality being used in surgical treatment of early oropharyngeal cancer. The aim of this study is to assess the outcome of these cases in terms of two year disease free survival and overall survival.

Methods

Between July 2016 and September 2018, 58 patients suffering from early oropharyngeal cancer underwent transoral robotic surgery with neck dissection at a tertiary referral centre. 43 of them have completed two years follow up and were analyzed for disease free survival and overall survival. 41 patients had HPV analysis done .

Results

The surgical margins were positive in 9/43 patients ( 6 in upfront surgery and 3 in the salvage cohort). Adjuvant therapy was administered to 16/34 patients on account of either positive margins or multiple nodal metastasis. 88% patients were found to be HPV negative. The two year disease free survival for the upfront cohort was 88.2% and salvage cohort was 55.5%. The overall survival was 86.05%.

Conclusions

The study highlights good locoregional control and two year disease free survival in HPV negative oropharyngeal cancer undergoing robotic surgery. Additionally, a positive surgical margin and recurrence were the statistically significant variables influencing 2 year disease free survival. Trans oral robotic surgery is an excellent tool for early tumors of the oropharynx. The presence of a positive surgical margin is a grim sign for survival and has a significant impact on positive outcome.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12070-022-03139-5.

Introduction

The term TORS (Trans oral robotic surgery) was first used by Weinstein et al. [1] and since then has been approved as a safe and feasible method in the treatment of early stage oropharyngeal cancers.[2, 3] The primary outcome after any surgical procedure done are the overall survival and the disease free survival.

There are many retrospective studies that have shown similar survival and control rates in patients of early stage OPSCC undergoing TORS when compared with the patients undergoing radiotherapy [4–7] The 5 year local control rates following surgery and radiotherapy in the treatment of early stage OPSCC have been reported to be in the range of 83-96% and 83-93% respectively. [8–13]

The HPV induced OPSCC having a better prognosis compared to HPV negative cohorts has led to the de-escalation strategies for the HPV positive cohort.[5, 6]. These viral induced OPSCC tend to present with a smaller primary but larger bulky nodes commonly in the younger age group often with no or limited history of any addictions.[14–16] .In comparison to the western literature that have documented a 225% increase in HPV positive OPSCC [17], the prevalence of HPV infection in Indian patients suffering from OPSCC is 15–22% [18–20]. The purpose of this article is to demonstrate the 2 years disease free survival and overall survival in North Indian patients diagnosed with an early T stage(T1-T2) OPSCC following TORS with or without adjuvant therapy .

Materials and Methods

A prospective study was conducted in patients with T1 and T2 tumors of the oropharynx who were treated with trans-oral robotic surgery(TORS)using da Vinci surgical robot.(da Vinci Sisurgical robotic system by Intuitive Surgical Inc. California) between the period of July 2016 to September 2018 in a tertiary referral center. The staging of the tumors was done as per the 8th edition AJCC which was staged HPV positive and HPV negative oropharyngeal cancer. An informed consent was obtained from all the subjects. An ethical clearance was obtained from the Institute Ethics committee. The study followed the guidelines of the Helsinki declaration in study involving human subjects. During this period, 58 patients diagnosed with early T1and T2 stage oropharyngeal carcinoma underwent Transoral robotic surgery (TORS) with ipsilateral neck dissection. After adequate exposure, en bloc excision of the tumor was performed with ipsilateral neck dissection (level II-V) in the same sitting. The surgery was performed by a single surgeon(NKP) using daVinci surgical robotic system. 43of 58 patients had completed 2 years of follow up and were analyzed. 41 of 43 patients could have their HPV P16 analysis done .

The inclusion criteria were biopsy proven T1,T2 oropharyngeal squamous cell carcinoma with(N1-N3a) or without neck nodes, but without distant metastasis who had adequate exposure for Trans oral robotic surgery, age greater than 25 years with ECOG score ranging between 0 and 2 and did not require local reconstruction. All patients were subjected to a detailed history and clinical examination. The patients underwent a contrast enhanced computed tomography and magnetic resonance imaging extending from base of skull to T4. The patients were then grouped into an upfront cohort (newly diagnosed cases) or a salvage cohort (presenting with recurrence following radiotherapy) .Distant metastatic work up was done to rule out any metastasis. A PET scan was not done during initial work up due to logistic reasons.

Treatment and Follow up

Following the surgical procedure, the patients were asked to start cold soft diet and any complication in the immediate postoperative period was assessed. The patients then attended the follow up clinic with the histopathological report. High risk features like perinodal extension, or lymphovacular invasion or the lymph node involvement and margin status (> 5 mm was defined as free) was noted . Adjuvant radiotherapy was decided based on the results of the histopathological examination. It was considered in the presence of positive margins, multiple nodal metastasis, or extra capsular invasion of the lymph nodes. In addition perineural invasion or lympho vascular invasion was also considered as indication for irradiation.

The HPV P16 expression analysis could be done in 41 out of 43 patients. In 2 patients it could not be done due to logistics. Any onset of distant metastasis warranted treatment on the basis of Tumor board meetings.

The patients were subsequently followed up every month for the first year and then 2 monthly subsequently. Recurrence was defined as histological/cytological evidence of disease at the primary site, the neck or distant metastasis. Disease free survival was defined as the time after treatment completion to the onset of recurrence. Overall survival was defined as the time from treatment completion to death from any cause.

Statistical Analysis

The demographic data has been summarized by mean ± SD and frequency and comparison was performed by using χ2 or fisher’s exact tests. Univariate and multivariate analysis was performed to identify independent prognostic factor by using cox regression model and hazard ratio (HR) with a confidence interval of 95%.

The survival analysis was done by using Kaplan –Meier method and was analyzed using the log-rank test. A p-value < 0.05 was considered significant. All the statistical analysis was performed using the SPSS 16.0 software.

Results

Demographic Profile

Out of the 43 patients 37(86%) were male and 6(14%) were females. The mean age was 52.91 ± 11.85 for the upfront cohort and 53.11 ± 10.39 years for the salvage cohort. Minimum age was 28 years and maximum age was 70 years .34out of 43(79.06%) underwent upfront surgery and 9 out of 43(20.93%) patients underwent salvage surgery. (Table 1)

Table 1.

Showing the patient profile and clinical characteristics of the patients in the two cohorts

	Salvage cohort n = 9	Upfront cohort n = 34	1p-Value
Age	53.11 ± 10.39	52.91 ± 11.85	0.937
Gender
Male	9 (100%)	28 (82.35%)	0.414
Female	0 (0.00%)	6 (17.65%)
Addictions
Smoker	8 (88.89%)	28 (82.35%)	0.637
Alcoholic	4 (44.44%)	13 (38.24%)	0.735
Tobacco Chewing	4 (44.44%)	12(35.29%)	0.885
Subsite
Tonsil	6 (66.67%)	24 (70.59%)	0.264
BOT	3 (33.33%)	5 (10.71%)
soft palate	0 (0.00%)	5 (10.71%)
Tumor Stage
1	3 (33.33%)	5 (10.71%)	0.131
2	5	16 (47.06%)
3	1 (11.11%)	1 (2.94%)
4	0 (0.00%)	12 (35.29%)
TNM Stage
T1/T2	3 (33.33%)/6 (66.67%)	8 (23.53%)/26 (76.47%)	0.887
N0/≥N1	8 (88.89%)/1 (11.11%)	21 (61.76%)/13 (38.24%)	0.253
Surgical margins free
Involved	3 (33.33%)	6 (17.65%)	0.570
Not involved	6 (66.67%)	28 (82.35%)
Adjuvant RT
Yes 0(0.00%) 16(47.06%)
No 9 18(52.94%)
Positive Lymph node status after neck dissection	n = 1	n = 13
Positive	1	12
Negative	0	1
HPV Status
Positive	2 (22.2%)	4(11.76%)	0.421
Negative	5	30
Recurrence
Yes	4 (44.44%)	4 (11.76%)	0.077
No	5 (55.56%	30 (88.24%)
Survival Status
Death	2 (22.22%	4 (11.76%)	0.792
Survive	7 (77.78%)	30 (88.24%)
Complications
Odynophagia(painful deglutition)	9	30
Ryles tube	7	8
Tracheostomy tube	0	0

Addiction Profile

36(83.72%) patients admitted to smoking and 17 (39.53%) admitted to alcohol intake which were the most common addictions. 16(37.2%) patients accepted they smoked along with alcohol intake. Only 2 patients did not indulge in any form of addictions. (Table 1)

Subsites

30 (69.76%) patients had a primary in the tonsil which was the most common subsite. 8(18.6%) patients had a primary in the base of tongue. 5(11.62%) patients had a primary in the soft palate .In the salvage cohort group the distribution of the primary site was 6 in the tonsillar fossa and 3 in the base of tongue.(Table 1).

Staging

8(18.6%) had a stage 1disease, 21(48.83%) had a stage 2 disease, 2(4.65%) had a stage 3 disease and 12(27.90%) had a stage 4 disease.Most patients were in stage 2 and stage 4 for the upfront surgical cohort. The distribution was 5 and 3 patients in stage 1, 16 and 5 patients in stage 2, 1 and 1 in stage 3 and 12 and 0 in stage 4 for upfront and salvage surgical cohort respectively. Salvage group did not have stage 4 patients. (Table 1)

T and N Status

11(25.58%) were in T1 stage and 32(74.41%) were in T2 stage. Most patients were in T2 stage in both the cohorts. The distribution of T1 was 8 and 3 patients and those of T2 were 26 and 6 in the upfront and salvage surgical cohorts respectively.

29(67.44%) had N0 neck and 14(32.55%) had N + neck. Out of the 14 N + neck 2(14.28%) were N1, 9(64.28%) were N2b, 2(14.28%) were N3a and 1 (7.14%) was N0 after final histopathological staging. (Table 1)

Surgical Margins

The surgical margins were positive in 9/43 (20.93%) patients. 6/9(66.6%) in the upfront surgical cohort and 3(33.33%) in the salvage cohort. 7/9 patients (77.77%) with positive margins had their primary lesion in the tonsillar fossa and the other 2(22.23%) in the base of tongue. (Table 1)

Neck Dissection

An ipsilateral elective neck dissection (level II-V) was the standard of care in all the patients. 14 out of 43 patients had N + disease ,13 belonging to the upfront surgical group and 1 belonged to the salvage cohort. Out of the 14, 13(92.85%) patients had nodal metastasis and 1(7.15%) was negative on final histopathological examination. (Table 1)

Adjuvant Treatment

Adjuvant treatment in the form of radiation therapy or chemotherapy was administered to 16 of the 34 patients in the upfront surgical group on account of either positive margin or multiple nodal metastases. 6 patients with positive surgical margins received concurrent chemo radiation with 60 Gy radiotherapy and Cisplatin 100 mg/m2 on day 1, 22 and 43. External radiation was delivered to the tumour bed and draining lymph nodes in a dose of 60 Gy/6 weeks/30 fractions. The treatment portals were planned using a CT simulator and the patients conformal radiation through a low energy linear accelerator. 10 patients with multiple nodal metastasis, extranodal extension, perineural invasion or lymphovascular invasion received radiation therapy only. None of the salvage cohort patient received adjuvant treatment. (Table 1). 18 patients did not receive any adjuvant therapy after TORS. Only 2 of them had recurrence. (One at the primary site and another had pulmonary metastasis.)

Complications

Local pain and odynophagia was the most common complaint post operatively. A nasogastric tube was required for 15 patients (n = 8 in upfront group and n = 7 salvage group). None of the patients required a tracheostomy or experienced oral bleeds. The duration range of NGT was 2–30 days with a mean of 6.4 days.

HPV

HPV P16 analysis was done in 41patients. 35/41 patients(85.36% ) were found to be HPV negative and 6 were positive (14.63%). (Table 1). All the patients who had recurrence or death belonged to HPV negative cohort. The difference was not significant. (p = 0.484). (Table 2)

Table 2.

Showing the comparison of overall death and recurrence based on HPV status.(n = 41)

	HPV Negative (n = 35)	HPV Positive (n = 6)	p-Value
Recurrence	8	0	0.484
Death	6	0	0.484

2 Year Disease Free Survival

A total of 8(18.6%) patients had recurrence out of which 4(50%) were in the upfront cohort and 4(50%) were in the salvage cohort.

4 patients in the upfront cohort had recurrence. 2 had local recurrence in the tonsil, one had regional recurrence and one had distant metastasis. Out of the 4 patients in the salvage cohort, all experienced recurrence at the primary site(tonsil n = 3, BOT n = 1)0.2 out of the 3 patients who had recurrence at the tonsillar fosse(margins were involved) succumbed to their disease.

The 2 year disease free survival for upfront cohort was 88.2%. In the salvage cohort,4/9 patients had recurrence. All the patients experienced recurrence at the primary site. (n = 3 Tonsil and n = 1 BOT). The 2 year disease free survival in the salvage cohort was 55.5%,

On Cox -regression model positive surgical margin and recurrence were the only statistically significant variables influencing 2 year disease free survival. (Table 3).

Table 3.

Showing the factors associated with 2-year disease-free survival in all patients (Cox regression model)

	B	SE	Wald	Sig.	Exp(B)	95.0% CI for Exp(B)
						Lower	Upper
Age	-0.864	0.867	0.993	0.319	0.422	0.077	2.305
Sex	0.443	1.099	0.162	0.687	1.557	0.181	13.415
Tobacco chewing	1.047	1.099	0.908	0.341	2.849	0.331	24.550
Smoking	-1.089	0.868	1.574	0.210	0.337	0.061	1.845
Alcohol	-0.212	0.820	0.067	0.796	0.809	0.162	4.036
Subsite	-0.124	0.683	0.033	0.855	0.883	0.231	3.370
Stage	-0.982	0.668	2.163	0.141	0.374	0.101	1.387
Margin	2.239	0.876	6.536	0.011 *	9.386	1.686	52.245
Lymph_Node	-3.366	4.314	0.609	0.435	0.035	0.000	162.41
AdjuvantRT	-0.006	0.867	0.000	0.995	0.994	0.182	5.44
Recurrence	2.924	1.096	7.114	0.008 *	18.612	2.171	159.54

^*=Significant highlighted

2 Year Overall Survival

There were 6(13.95%) deaths recorded over the period of 2 years out of which 4 occurred in the upfront surgical cohort and 2 in the salvage group(Table 1).

2 (50%) out of the 4 patients in upfront surgery had free margins and 2 had involved margins.Both patients who died in the salvage group had involved margins following resection.

5(83.66%) out of the 6 patients who expired experienced recurrence.

The 2 year overall survival in upfront cohort was 88.2% and in the salvage cohort it was 77.7%. Patients who underwent upfront surgery had a better overall survival than patients who underwent salvage surgery although the results were not statistically significant [p value 0.479, Fig. 1].

Fig. 1.

Showing the Kaplan-Meier estimates for overall survival between upfront and salvage surgery

Supplementation with adjuvant treatment did not show significant improvement in survival.(p = 0.995) [Fig. 2].

Fig. 2.

Showing the Kaplan Meier estimates for no change in survival with addition of adjuvant treatment

The patients with positive margin had reduced survival. (p < 0.001) [Fig. 3].

Fig. 3.

Showing the Kaplan Meier estimates for reduced survival in patients with positive margins

Discussion

The introduction of robotic technology for transoral surgery has rekindled interest and subsequently its use for management of oropharyngeal cancers. Robotic surgery enjoys a number of benefits like minimal scarring, fast recovery time and lesser hospital stay for the patients. Additionally use of specialized retractors and three dimensional view of surgical site allow easy access and helps in complete resection of tumors without morbidity like speech and swallowing dysfunction.

There is a paucity of prospective data from the Indian subcontinent about the outcomes of transoral robotic surgery in a mixed cohort of new and recurrent oropharyngeal carcinoma. Thakar et al. in [21]their report of oncological outcomes in HPV negative oropharyngeal squamous cell carcinoma reported significantly better overall survival and disease free survival with transoral robotic surgery compared to TORS and risk stratified adjuvant therapy and non surgical treatment. Radiation therapy with chemotherapy has been the mainstay of therapy for the management of oropharyngeal carcinoma. It is noteworthy to highlight that performing surgery upfront avoids chemo radiation. This takes care of dysphagia, one of the most important functional impairment in patients after chemoradiation therapy. Wilson et al. [22] showed in their study that dysphagia would last as long as 3 years in around 50% of the patients of oropharyngeal cancers as per SEER (Surveillance, Epidemiology end results). Though the cohort comprised of 58 patients but 43 patients of them have been followed up up to 2 years. The surgical outcome was evaluated on different variables during the follow up visits.

Men outnumbered females as was seen in our series. Patel et al. too reported predominance of male patients to develop oropharyngeal carcinoma.[23]. Majority of our patients had a history of addiction to smoking tobacco with alcohol consumption. Rosenquist et al. [24] reported that smoking tobacco and alcohol consumption are the risk factors for oropharyngeal squamous cell carcinoma. Tonsillar fossa was the most common subsite in our series. Stepnik et al. [25] have also reported the tonsil as the common sub site in their series. The resection of primary lesion either in the tonsil or base of tongue was done along with the neck dissection in the same sitting. We have been able to avoid fistula into the neck by doing only level II to IV dissection.

Weinstein et al. reported a 100% loco-regional control for T1-T3 oropharyngeal cancer [26]. Moore et al. reported a 95% 2 year disease free survival in their cases.[27] Van Loon et al. also concluded that TORS seems to be an oncologically safe and effective surgical treatment option for early stage T1-T2 oropharyngeal cancers.[28]. The 2 year overall and disease free survival in our series is 86.06% and 81.39% respectively. Lower survival rates could be attributed to the initial learning curve and secondly to a different tumor biology in our population .However our 2 year disease free survival in upfront surgery cohort is up to 88.2% which is similar to that reported in the western literature.

Paleri et al. reported 63% disease free survival in their cohort of 18 recurrent oropharyngeal cancer[29] Dabas et al. reported 57% two year disease free survival in their series[30] . Our results are also similar, though the size of our cohort is relatively smaller.

E7 mRNA expression is considered the gold standard for HPV detection due to its high sensitivity.[31]. Sannigrahi et al. reported a good correlation between HPV E7 mRNA expression and P16 nuclear positivity and increased viral load [20]. 41 of 43 patients had their P16 analysis for HPV done. 35 of them were HPV negative. The HPV prevalence in our study is consistent with the results of other Indian studies demonstrating a incidence of only 12% in T1/T2 stage OPSCC in northern India or even as low as 7%.[32, 33] The increase in prevalence of HPV in the west does not hold true for the Indian population. [34] 6 of our patients who were P16 positive did remarkably well. None of them had loco regional recurrence at 2 years follow up. Li et al. reported that HPV positive patients are less likely to experience recurrence and mortality. In a cohort of 37 patients, 2 patients were relatively younger, non smoker and had stage IV disease with neck metastasis. [35] Patients having positive margins, multiple nodes along with perineural invasion, extracapsular involvement and lympho vascular invasion were considered for adjuvant treatment in our series. The survival outcomes however were not better in patients receiving adjuvant therapy. Van Loon et al. had also reported that patients who received post operative radiotherapy had a worse outcome [28] Quon have previously described rationale and approach for post operative radiation therapy following transoral robotic surgery [36]. Weinstein et al. reported a 97% loco-regional control for 30 patients not receiving any post operative adjuvant radiotherapy [37] We too had similar results with 88.8% of our patients having a satisfactory loco regional cure.

The mortality in patients with positive margins on histopathological examination was significantly more (p value < 0.002). Even the addition of adjuvant treatment in these patients did not improve outcome [Fig. 3]. Hence ensuring free surgical margins following resection is of paramount importance in transoral robotic surgery .de Almeida et al. have reported that that negative margins after transoral robotic surgery were associated with high levels of loco regional controls[38] Gorphe et al. also proposed that a positive margin was associated with a poor control. The primary site (tonsil or tongue base) nor the HPV status had any correlation with the margin status in their series. .[39]. There is no universal agreement in defining a negative margin which accounts for a wide variation in the reported rate of positive surgical margins. [40–42]. The patients in the salvage cohort with a positive margin or recurrence did worse than those with negative margins. However the statistical significance was not observed.

It is worth mentioning that the margin positive rate in our series was observed to be on a higher side. Hanna et al. published the results of a national quality study investigating NCDB data for 2661 patients who underwent TORS in USA. The overall rate of positive margin was 17%. A slight increase in positive margin in our series can be attributed to the learning curve of the surgical team [43] The use of routine intra operative frozen section to control margins has been used in some studies [39] This could not be done in the present series due to resource crunch and logistic difficulties. Intra operative frozen section is likely to add a great deal in reducing the margin positive rate.

TORS may also be used selectively for patients with recurrence after primary radiotherapy with or without chemotherapy as in this series. White et al[44 ] compared TORS with the standard open surgery in TNM stage matched subjects undergoing salvage treatment. TORS patients had significantly low rates of tracheostomy, feeding tube dependence and hospital stay. Our results are similar to those reported by White et al. [44]. Dabas et al. in their preliminary experience of transoral robotic surgery in oropharyngeal cancers too did not report any Tracheotomy[45]. Majority of their patients had adequate swallowing. None of our patients required tracheostomy. Only one third of our patients (15/43) required naso gastric placement. There was no difference in requirement of nasogastric tube in upfront and salvage surgery group. Sinclair et al. too reported similar observations about swallowing dysfunction in patients undergoing TORS [46].

The results of our study clearly demonstrate that the disease free survival is closely related to complete surgical excision with negative margins .It therefore becomes imperative for the robotic surgeons to focus on achieving a histopathologically negative margin at the time of surgery as recurrence was also found to be associated with poor prognosis and significantly detrimental for overall survival [Fig. 4)]. One of the limitations of our study is the lack of Frozen section examination. It can be speculated that frozen section examination could have reduced the positivity rate of resected specimens.

To conclude, transoral robotic surgery in HPV negative oropharyngeal cancer is an important subject for the head and Neck surgeon. Our study highlights acceptable locoregional control and two year disease free survival in HPV negative oropharyngeal cancer undergoing robotic surgery. Additionally, a positive surgical margin is a grim sign for survival and adjuvant treatment for any other reason will not have a significant impact on the survival. The incidence of HPV positive OPSCC is seen on a lower side in the Indian population and if managed well, have an acceptable outcome. An upfront trans oral robotic surgery in early oropharyngeal carcinoma has acceptable survival outcome.

Electronic Supplementary Material

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