Head Neck Cancer Symposium: Original Article

Prospective study of outcomes of surgically treated larynx and hypopharyngeal cancers Varghese BT, Babu S, Desai KP, Bava AS, George P1, Iype EM, Rajan B2, Sebastian P Departments of Surgical Oncology, and 1Clinical Epidemiology, Regional Cancer Centre, Trivandrum, Kerala, India, 2Department of Clinical Oncology, National Oncology Centre, Royal Hospital, Muscat, Oman Correspondence to: Dr. Bipin Thomas Varghese, E‑mail: [email protected]

Abstract

OBJECTIVE: To determine the morbidity and survival of surgically treated locally advanced carcinoma larynx and hypopharynx in a tertiary referral center in South India, a prospective cohort study was carried out. MATERIALS AND METHODS: Patients who had undergone laryngectomy or

laryngopharyngectomy from January, 2006 to January, 2011 at our institute were prospectively studied for factors affecting morbidity tumor recurrence and disease free survival (DFS). DFS was calculated for the whole group and for the larynx and hypopharynx cancer subgroups separately, using Kaplan Meir Method and the survival differences of the larynx and hypopharynx groups and between salvage and primary surgical cases were evaluated using the Cox’s regression scale. RESULTS: A total of 154 patients with ages ranging from 23 to 78 (mean 56.3 + standard deviation 9.2) were studied, which included 145 males and 9 females. Pre‑operative tracheostomy and previous radiotherapy were the most significant factors contributing to post‑operative morbidity. Survival difference between the larynx and hypopharynx cancers was statistically significant and the DFS was significantly affected by primary site wound infection, primary site margin and node positivity. CONCLUSION: The results of laryngectomy can be optimized by “proper case selection and morbidity risk assessment”. Key Words: Laryngectomy, morbidity, outcome, survival

Introduction Carcinoma of the larynx accounts for approximately 2% of all cancers. Conservative surgery or radiotherapy (RT) offers equal cure rates in its early stage although RT is more popular world‑wide. For intermediate and advanced staged tumors total laryngectomy with post‑operative RT was the standard of care until the Veterans Administration Larynx Study in 1991 and other subsequent organ preservation trials which established the role of chemo radiation in the upfront treatment of intermediate laryngeal cancers (stage III and early IV a). Hypopharyngeal cancers although managed in the same lines, are more aggressive and liable for treatment failure and low survival. The incidence of these cancers is relatively high in India (11% against 1% world‑wide, among males). [1] Surgical management of the larynx and hypopharyngeal malignancies have become increasingly challenging with the advent of on surgical organ preservation strategies. Failures of these protocols are often accompanied by post radiation sequela, which enhances post‑surgical complications when a salvage laryngectomy/ laryngopharyngectomy is undertaken. We present a 5 year prospective study of surgical management of the larynx and hypopharynx cancers at Regional Cancer Centre, Trivandrum, India, with an aim to study the survival and morbidity of the treated patients. Materials and Methods Institutional review board and local ethics committee approval was obtained for a prospective study of morbidity and survival pattern of patients undergoing laryngectomy or laryngopharyngectomy at our institute during the period of January, 2006 to January, 2011 Profoma based prospective data was entered into a computerized database (Microsoft excel software) and studied for survival Access this article online Quick Response Code:

Website: www.indianjcancer.com DOI: 10.4103/0019-509X.138140 PMID: *******

104

and factors affecting morbidity and recurrence. The site and stage distribution of the disease, type of laryngectomy, method of pharyngeal reconstruction, pathological status of primary and nodes, complications, recurrence and post laryngectomy voice rehabilitation were recorded. Morbidity factors that were analyzed included RT, previous tracheostomy, chemotherapy (CT), concomitant neck dissections, acid peptic disorders (APDs), hypertension and chronic obstructive pulmonary disease (COPD). The other morbidities recorded were chyle leak, post‑operative hemorrhage and hematomas. Disease free survival (DFS) was calculated for the whole group and for the larynx and hypopharynx cancer subgroups separately, using Kaplan Meir Method and the survival differences of the larynx and hypopharynx groups and between salvage and primary surgical cases were evaluated using the Cox’s regression scale. The follow‑up period ranged from 1 month to 59 months with a median of 20 months. Results A total of 154 patients with ages ranging from 23 to 78 (mean 56.3 + standard deviation 9.2) were studied, which included 145 males and 9 females. The site and stage distribution, the status of the patient at the time of surgery, type of laryngectomy, neck dissection and reconstruction methods used, voice rehabilitation, recurrence and complications are shown in Table 1a‑c. Total laryngectomy was done as the primary treatment modality only when the T staging was 4a or when the histopathology precluded primary RT (e.g., spindle cell carcinoma) or when the general condition of the patient was poor to tolerate CT‑RT or when there was severe laryngeal dysfunction. Immediate post‑operative wound exploration was needed in four cases of which three were for neck hematomas and one for chest hematomas. CT was the most common factor in all of them. Jugular blow out was seen in a post‑CT borderline inoperable cancer of the supraglottic larynx extending to subglottis, pyriform fossa, base of tongue and post cricoid area with bilateral lymph node involvement (T4N2cM0). The surgery was undertaken after two cycles of induction CT to downstage the disease (neo‑adjuvant CT). On the whole, 40 patients received CT either in a neo‑adjuvant setting or as a part of CT‑RT. Although the numbers were very few to Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2

Varghese, et al.: Laryngectomy and laryngopharyngectomy outcomes

Table 1a: Site and stage distribution of cases studied Site and subsite

n

T stage

Pri

Sal

Larynx Glottis Supraglottis Subglottis

42 13 4

42 7 1

Hypopharynx PF PC

26 1

12 5

0

1

PPW

T1 T2 T3 T4

n

N stage

Pri

Sal

3 5 15 13

10 20 22 16

N0 N1 N2

n Pri

Sal

43 15 28

54 12 2

Composite stage 1 2 3 4

n Pri

Sal

2 4 9 71

9 18 18 23

PC=Post cricoid; PPW=Posterior pharyngeal wall; PF=Pyriforma fossa

Table 1b: Surgical data n

Parameters Cases studied Primary Salvage Neck dissection No ND SND MRND RND Contralateral/bilateral SND Reconstruction Primary closure Stapler closure PMMC patch Tubed PMMC Gastric pull‑up Type of voice rehabilitation Conservation NTL Primary TEP Secondary TEP Electrolarynx Esophageal speech

154 86 68 60 28 2 9 55 89 35 24 3 3 7 6 13 8 7 1

Not rehabilitated

112

ND=Neck dissection; SND=Selective neck dissection; MRND=Modified radical neck dissection; RND=Radical neck dissection; PMMC=Pectoralis major myocutaneous; NTL=Near total laryngectomy; TEP=Tracheoesophageal puncture

Table 1c: Post‑surgical data Parameter Recurrence Larynx Hypopharynx Complications Pharyngeocutaneous leak Chyle leak Minimal bleeding Massive bleeding Jugular blow out

Primary

Salvage

10 7

9 7

36 5 5 2 1

draw a conclusion, CT independently or in conjunction with curative RT seems to be an important factor pre‑disposing to re‑explorations related to bleeding or hematomas (P = 0.001) in the current study. Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2

Tracheostomy was more frequent among primary surgeries and Diabetes mellitus was distributed more in the salvage group because patients with advanced cancers not suitable for non‑surgical organ preservation protocols frequently presented with airway obstruction and those with diabetes mellitus often preferred non‑surgical management even in advanced stages. Primary site wound edge infection was more in salvage cases (P = 0.010) and so was wound dehiscence (P = 0.024), drain site infection (P = 0.019), pus collection (P = 0.018), skin flap necrosis (P = 0.031) or transferred skin flap necrosis (0.021), donor site wound edge necrosis (0.004) dehiscence (0.005), drain site infection (0.011) and pus collection, 0.011) pharyngocutaneous leaks (PCL) (0.027) and readmissions for PCL. Besides RT other morbidity factors that were analyzed included previous tracheostomy and CT, concomitant neck dissections, APDs, hypertension and COPD. The other morbidities recorded were chyle leak, post‑operative hemorrhage and hematomas. Airway interventions were performed mostly on an emergency basis and tracheostomy was significantly correlated to the primary site wound infection (P = 0.006), donor site wound infection and dehiscence (P = 0.034 and 0.014) where pectoralis major myocutaneous (PMMC) flaps were used, drain site infections (P = 0.014) and pus formation (P = 0.014) in general, leak (P = 0.008) and minimal hemorrhage (P = 0.012) and hematoma (P = 0.015) post‑operatively. Table 2a shows the distribution of PCL among the different circumstances of laryngectomy and methods of neopharyngeal reconstruction. The overall PCL rate was 27%. On univariate analysis (Pearson Chi‑square) PCL showed a statistically significant correlation with RT, tracheostomy and wound infection at the primary site but on multivariate analysis, by back‑ward elimination method, this was seen only for wound infection [Table 2a]. There was no statistically significant correlation with diabetes, APD or Neck dissections either on univariate or on multivariate analysis. All leaks except 2 settled with conservative treatment. Method of closure and CT did not have a significant influence on leaks [Table 2a]. Out of the 2 established pharyngocutaneous fistulae, one was treated with the local hinge flap for lining and deltopectoral (DP) for cover and in the second case, lining and cover could be achieved with advancement of the adjacent skin. DFS by Kaplan‑Meir method and the survival 105

Varghese, et al.: Laryngectomy and laryngopharyngectomy outcomes

Table 2a: Pattern of leak distribution among different methods of neopharyngeal closure, influence of chemotherapy on leak and significant factors contributing to pharyngocutaneous fistula Type of closure/ pre‑operative chemotherapy

No.

Leak rate %

Primary surgery

Leak rate in primary surgery %

Salvage surgery

Leak rate in salvage surgery %

Primary closure Stapler closure Flap/viscera closure No chemotherapy Chemotherapy received

16 11 9 114 40

17 31 30 25 30

7 6 3 58 19

15 26 18 18 26

9 5 6 46 21

21.00 42 46.00 36 33

Univariate (P value) by Chi‑square method

Multivariate (P value) backward elimination method

Radiotherapy Tracheostomy Wound infection

0.032 0.032 0.0001

– – 0.0001 (95% CI: 3.17‑21.45)

Wound dehiscence

0.002

P value (for over all leak rates) 0.64

0.57

CI=Confidence interval

Table 2b: Survival data (survival difference between larynx and hypopharynx Total (154)

Recurrence (33)

1 year (SE) %

3 years (SE) %

5 years (SE) %

P value

Larynx

109

19

90.92 (2.89)

96.87 (5.03)

70.96 (7.34)

0.0215

Hypopharynx

45

14

83.95 (6.06)

42.93 (12.32)

42.93 (12.32)

Primary site of disease

SE=Standard error

Table 2c: Statistically significant factors affecting the DFS in the present study Factors

Univariate (P value) by Chi‑square method

Multivariate (P value) backward elimination method

Primary site wound edge infection Margin positivity

0.0297



0.0461



Node positivity

0.0013

0.002 (95% CI: 1.060‑1.281)

DFS=Disease free survival; CI=Confidence interval

difference between primary and salvage cases by Cox’s regression scale are shown in Figures 1 and 2 and Table 2b. There was a statistically significant survival difference between the larynx and hypopharynx cancers [Figure 1b] although it was not so when a comparison was made between salvage and primary surgical cases, among the whole group and among larynx and hypopharynx cases [Figure 2a and b]. DFS was significantly influenced by primary site wound edge infection, primary site margin and node positivity as shown in Table 2c. Univariate analysis by Chi‑square test showed statistically significant correlation with all the variables, but multivariate analysis by backward elimination showed node positivity alone as a significant factor. Discussion Surgery as a treatment modality for cancer of the larynx and hypopharynx has been pushed to the back seat with the advent of chemo‑radiation, in spite of the resurgence of interest in open and closed conservation surgical procedures in upfront management of early cancers.[2,3] The only situation where it is uniformly used as an upfront treatment modality is in T4a lesions of the larynx and hypopharynx where there is frank invasion of the outer cortex of the laryngeal cartilaginous frame work (penetration). The current evidence 106

however also acknowledges the chances of a high failure rate of a non‑surgical organ preservation protocol in intermediate stages of cancers of the hypopharynx and difficulty in salvaging these cases surgically.[4,5] This is the rationale for the resurgence of interest in induction CT for intermediate stage cancers of hypopharynx, whereby these cases are given a course of CT for two cycles and the response assessed. If there is more than 50% response, the treatment is consolidated with concurrent CT‑RT or else (if response less than 50%) surgery is planned (to salvage the failing situation!). An alternative here is to go ahead with concurrent CT‑RT with the caveat that an early failure of this treatment in the form of significant tumor persistence associated with immediate and intermediate chemo‑radiation related toxicities and sequelaes is extremely difficult to salvage surgically without any morbidity, increased incidence of complication and occasional mortality.[6‑8] The success rates of these salvage procedures are often commensurate with the availability of reconstructive surgical facilities in a center. When surgery is inevitable, wherever possible, a carefully executed conservation laryngectomy that preserves the voice alone (near total laryngectomy) or voice and airway (open partial laryngectomyOPL or supracricoid laryngectomySCL) is used to address cost and maintenance issues in voice rehabilitation, which is highly relevant for a low resource setting like ours.[9‑11] Wound related complications in general were found to be more in salvage surgeries which was also reflected in the fistula rates. Closed stapling was found to be a reliable alternative to suturing when the cancer is endolaryngeal. Stapling devices have gained popularity in neopharyngeal closures after laryngectomies over the past few decades.[12] Open and closed methods of closures are described in the literature. Improved operating time and lesser field contamination and chance for manual errors are the essential advantages of closed stapling in laryngecomy. Furthermore, our experience points[13] toward Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2









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Figure 1: (a) Disease free survival by status of disease, (b) Disease free survival by site of disease

the liberal usage of vascular flaps like PMMC flap to augment deficiency of pharyngeal closure and the current study further validates this observation. All the leaks after flap closures settled without leaving behind a pharyngocutaneous fistula. Our low threshold for supplementing vascularized pedicled flaps and using staplers in suitable situations is based on our published[10,13] and unpublished experience before the current study was undertaken. An interesting finding in the present study was the correlation between post‑operative wound edge infection and DFS. The plausible explanation for this would be the associated immunodeficiency in all those patients in whom the cancer recurs. We have observed that the incidence of treatment sequlae after chemo‑radiation and the therapeutic dilemma is treating them is very challenging to the surgeon. An apparently disease free patient who is on Nasogastric Tube feeds or feeding gastrostomy/jejunostomy with a tracheostomy tube for obstructed airway is a classic example of a situation where an organ preservation protocol has apparently succeeded in terms of larynx preservation and survival but not in terms of true (functional) organ preservation. [14] The ethics and justification of surgical Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2

b Figure 2:(a) Disease free survival by status of the disease among laryngeal cancers, (b) Disease free survival by status of disease among hypopharyngeal cancers

intervention in the form of laryngectomy in these circumstances have not been discussed widely.[15‑18] Prudence in executing a salvage surgical therapy is very crucial in the overall survival of the patients as it can adversely affect survival as indicated by some retrospective studies. [6,7,15,16] On the other hand, judicious selection of the most appropriate case at the appropriate time before the tumor residue or recurrence progresses is known to offer survival advantage as indicated by our present and past experience.[10] To this end, we advocate a stringent follow‑up policy for all patients subjected to organ preservation protocols or trials. Pre‑treatment or peri treatment tracheostomy also influences the outcomes of non‑surgical organ preservation. Tracheostomy enhances the predisposition to major toxicities, such as aspiration, perichondritis and chondroradionecrosis, radiodermtitis and dysphagia. The influence however depends on the circumstances of the tracheostomy, maintenance of the inserted tracheostomy tube and the care of the surgical site. Complication related to tracheostomy (for e.g.,: Low tracheostomy, infection at the 107

Varghese, et al.: Laryngectomy and laryngopharyngectomy outcomes

site of tracheostomy, dislodgment of tracheostomy tubes and false track formation) especially those done in emergency settings adversely affects the treatment outcome. The recommendations of the larynx preservation conservation panel [14] insists on comprehensive laryngopharyngeal function preservation along with survival as the primary end point and the secondary end points include duration of tracheostomy, time to laryngectomy and the time to discontinue feeding tube. The panel also encourages studies addressing outcomes and characteristics of those patients who have failed an organ preservation protocol. The current study, which is a direct continuation of a retrospective analysis completed by us in 2005[10] is one of its kind. Among the subset of tracheostomized patients in the current study we noticed that maintenance of tracheostomies done before or during radiation or CT is extremely difficult especially in the presence of complications like infections and low tracheotomy (where the skin opening is at a higher level than the tracheotomy), which is frequently accompanied by tube dislodgement and false track formation. This is partly because, very often the patients are not able to buy costly (tailor made) tracheostomy tubes designed to tackle several of these tracheostomy related problems. Decannulation of tracheostomy tubes is often not feasible due to subglottic fibrosis and granulation and retracheostomy of decannulated patients are also challenging when the initial tracheostomy was complicated by a low placement of the tracheostomy tube (which is often inevitable in short necks). An important issue in the management of larynx and hypopharynx cancers is the role of airway management and the facility available for it. Airway obstruction and its failed management as a major causative factor for impaired survival have not been documented properly in literature. Very often a survival figure for a patient is a direct effect of a successful airway intervention in the form of an emergency tracheostomy done by a surgeon in a peripheral center or by a resident in a referral center. In the current study, we have therefore documented pre‑operative tracheostomy and the circumstances that lead to it to address this issue and found that most of the tracheostomies were performed on an emergency basis. These patients showed poor quality‑of‑life due to aggravation of laryngeal dysfunction after the procedure. Conclusion Besides the potential of upfront (primary) surgery to cure locally advanced (T4) cancer of larynx and hypopharynx, a high degree of salvage can be achieved in both larynx and hypopharynx cancers with “proper case selection.” On the other hand, improper case selection and execution can adversely affect the overall outcome of anorgan preservation strategy. The role of primary surgery seems to be higher in hypopharyngeal cancers and owing to its biologically aggressive behavior, hypopharyngeal cancers require close follow‑up after an organ preservation protocol, to detect recurrence at the earliest and plan for an effective salvage surgery. Liberal usage of pedicled skin flaps have helped us to contain the pharyngeal fistula formation rate after total 108

laryngectomy and linear stapling devices have been an useful adjunct in selected cases because of its efficacy and simplicity. Acknowledgments We wish to thank Kerala State Council for Science Technology and Environment (KSCSTE) for the financial grant extended to the study and Ms. Rekha for secretarial assistance in the preparation of this manuscript.

References 1. Cervado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et al. Cancer incidence in five continents. International Agency for Research on Cancer (IARC): Scientific Publication No. 160. Vol. I ×. Lyon: IARC; 2007. 2. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685‑90. 3. Hoffman HT, Porter K, Karnell LH, Cooper JS, Weber RS, Langer CJ, et al. Laryngeal cancer in the United States: Changes in demographics, patterns of care, and survival. Laryngoscope 2006;116:1‑13. 4. NCCN. Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Vol. 2, 2011. p. 90. Available from: http://www.NCCN.org. 5. NCCN. Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Vol. 2, 2011. p. 25‑6. Available from: http://www.NCCN.org. 6. Lee SC, Shores CG, Weissler MC. Salvage surgery after failed primary concomitant chemoradiation. Curr Opin Otolaryngol Head Neck Surg 2008;16:135‑40. 7. Ganly I, Patel S, Matsuo J, Singh B, Kraus D, Boyle J, et al. Postoperative complications of salvage total laryngectomy. Cancer 2005;103:2073‑81. 8. Ganly I, Patel SG, Matsuo J, Singh B, Kraus DH, Boyle JO, et al. Results of surgical salvage after failure of definitive radiation therapy for early‑stage squamous cell carcinoma of the glottic larynx. Arch Otolaryngol Head Neck Surg 2006;132:59‑66. 9. Geraghty JA, Wenig BL, Smith BE, Portugal LG. Long‑term follow‑up of tracheoesophageal puncture results. Ann Otol Rhinol Laryngol 1996;105:501‑3. 10. Varghese BT, Sebastian P, Mathew A. Treatment outcome in patients undergoing surgery for carcinoma larynx and hypopharynx: A follow‑up study. Acta Otolaryngol 2009;129:1480‑5. 11. Varghese BT, Mathew A, Sebastian P, Iype EM, Vijay A. Comparison of quality of life between voice rehabilitated and nonrehabilitated laryngectomies in a developing world community. Acta Otolaryngol 2011;131:310‑5. 12. Gonçalves AJ, de Souza JA Jr, Menezes MB, Kavabata NK, Suehara AB, Lehn CN. Pharyngocutaneous fistulae following total laryngectomy comparison between manual and mechanical sutures. Eur Arch Otorhinolaryngol 2009;266:1793‑8. 13. Varghese BT, Sebastian P, Koshy CM, Ahammed I. Primar y laryngopharyngeal reconstruction using pectoralis major myocutaneous flaps‑Our experience. Indian J Otolaryngol Head Neck Surg 2003;55:251‑4. 14. Lefebvre JL, Ang KK, Larynx Preservation Consensus Panel. Larynx preservation clinical trial design: Key issues and recommendations – A consensus panel summary. Head Neck 2009;31:429‑41. 15. O’Brien PC. Tumour recurrence or treatment sequelae following radiotherapy for larynx cancer. J Surg Oncol 1996;63:130‑5. 16. Marioni G, Marchese‑Ragona R, Lucioni M, Staffieri A. Organ‑preservation surgery following failed radiotherapy for laryngeal cancer. Evaluation, patient selection, functional outcome and survival. Curr Opin Otolaryngol Head Neck Surg 2008;16:141‑6. 17. Varghese BT, Paul S, Elizabeth MI, Somanathan T, Elizabeth KA. Late post radiation laryngeal chondronecrosis with pharyngooesophageal fibrosis. Indian J Cancer 2004;41:81‑4. 18. Varghese BT, Ramdas K, Sebastian P, Nair MK. Salvage chemotherapy and surgery for radio recurrent carcinoma glottis. Indian J Cancer 2003;40:113‑5.

How to site this article: Varghese BT, Babu S, Desai KP, Bava AS, George P, Iype EM, et al. Prospective study of outcomes of surgically treated larynx and hypopharyngeal cancers. Indian J Cancer 2014;51:104-8. Source of Support: : Grant from Kerala State Council for Science technology and environment (India). Conflict of Interest: None declared.

Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2

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Prospective study of outcomes of surgically treated larynx and hypopharyngeal cancers.

To determine the morbidity and survival of surgically treated locally advanced carcinoma larynx and hypopharynx in a tertiary referral center in South...
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