Head Neck Cancer Symposium: Original Article
Referral pattern for neoadjuvant chemotherapy in the head and neck cancers in a tertiary care center Patil VM, Noronha V, Joshi A, Krishna VM, Dhumal S, Chaudhary V, Juvekar S1, Pai PS2, Pankaj C2, Chaukar D2, Dcruz AK2, Prabhash K Departments of Medical Oncology, 1Radiodiagnosis, and 2Head and Neck Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India Correspondence to: Dr. Kumar Prabhash, E‑mail: [email protected]
Abstract
BACKGROUND: Use of any treatment modality in cancer depends not only on the effectiveness of the modality, but also on other factors such as
local expertise, tolerance of the modality, cost and prevalence of the disease. Oropharyngeal and laryngeal cancer are the major subsites in which majority of neoadjuvant chemotherapy (NACT) literature in the head and neck cancers is available. However, oral cancers form a major subsite in India. MATERIALS AND METHODS: This is an analysis of a prospectively maintained data on NACT in the head and neck cancers from 2008 to 2012. All these patients were referred for NACT for various indications from a multidisciplinary clinic. Descriptive analysis of indications for NACT in this data base is presented. RESULTS: A total of 862 patients received NACT within the stipulated time period. The sites where oral cavity 721 patients (83.6%), maxilla 41 patients (4.8%), larynx 33 patients (3.8%), laryngopharynx 8 patients (0.9%) and hypopharynx 59 patients (8.2%). Out of oral cancers, the major indication for NACT was to make the cancer resectable in all (100%) patients. The indication in carcinoma of maxilla was to make the disease resectable in 29 patients (70.7% of maxillary cancers) and in 12 patients (29.3% of maxillary cancers) it was given as an attempt to preserve the eyeball. The indication for NACT in laryngeal cancers was organ preservation in 14 patients (42.4% of larnyngeal cancer) and to achieve resectability in 19 patients (57.6% of larnyngeal cancer). The group with laryngopharynx is a cohort of eight patients in whom NACT was given to prevent tracheostomy, these patients had presented with early stridor (common terminology criteria for adverse events Version 4.02). The reason for NACT in hypopharyngeal cancers was for organ preservation in 24 patients (40.7% of hypopharyngeal cancer) and for achievement of resectability in 35 patients (59.3% of hypopharyngeal cancer). CONCLUSION: The major indication for NACT is to make disease resectable at our center while cases for organ preservation are few. Key Words: Borderline resectable, neoadjuvant chemotherapy, oral cancers, unresectable
Introduction Treatment of cancer is determined by the standard guidelines laid down by professional bodies. The use of chemotherapeutic agents is further governed by regulatory organizations in each country. By and large, the treatment strategies are developed on the basis of large, well‑designed randomized controlled trials. However, such guidelines may not adequately address local influences such as prevalent epidemiology, socio‑economic conditions, resource availability and infrastructure.[1] In India, head and neck cancer is the most common malignancy among males.[2,3] Due to the limited number of trained head and neck surgeons and delay in seeking treatment, patients often present with locally advanced disease. The standard treatment in such patients is radical chemoradiotherapy. [4,5] However, the outcomes are not optimal. One option is giving induction chemotherapy followed by definitive surgery or radiation. Though neoadjuvant chemotherapy (NACT) has been evaluated in multiple studies, there is no consensus regarding the actual benefit and optimal situations where it may be beneficial.[6‑15] In the majority of NACT trials, the indication of chemotherapy has been either organ preservation or its use has been followed by chemoradiation in unresectable cancer settings.[6‑8,13‑15] NACT followed by surgery has been evaluated in a few studies, nearly always in operable cancers.[16,17] At our center, NACT is given to patients based on discussions in a multidisciplinary clinic. In the present paper, Access this article online Quick Response Code:
Website: www.indianjcancer.com DOI: 10.4103/0019-509X.137956 PMID: *******
100
we have attempted to analyze the patterns of use of NACT in our center. Materials and Methods We maintain a prospective database of all patients how are referred for NACT in our Head and Neck Cancer Medical Oncology Out‑patient Department. This was a retrospective analysis of patients undergoing NACT from 2009 to 2012. At our center, every case of head and neck cancer is discussed in a multidisciplinary joint clinic and a decision regarding the treatment is taken. For this analysis, only patients with squamous cell carcinoma and primary in the oral cavity, maxilla, larynx and hypopharynx were selected. There were 862 patients, fitting within the above criteria who had been referred for NACT during this period. The site distribution, stage distribution and the indication for NACT were recorded. The database, the hospital electronic medical record and the case papers of each patient were sought for the exact reason why the patient was considered for NACT. Indication for NACT was divided in to two broad categories either organ preservation or to achieve resectability. In addition, objective reasons as far as possible were sought for NACT referral. These reasons were objective involvement of anatomical landmarks, important spaces, proximity to important vital structures or extensive involvement of soft‑tissue or skin, which would have required a morbid surgery. The statistical analysis was performed by SPSS version 16. Descriptive analysis has been presented. Results During the above mentioned period, 862 patients received NACT. Out of the 862 patient, oral cavity primary was seen in 721 patients (83.64%), maxillary primary in 41 patients (4.75%), laryngeal primary in 33 patients (3.83%), laryngopharyngeal primary in 8 patients (0.93%) Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
Patil, et al.: Pattern of use of NACT in the head and neck cancers
and hypopharyngeal primary in 59 patients (8.18%). The subsite distribution has been depicted in Table 1. The stage grouping was Stage III in one patient and rest all where Stage IV. The details of T staging N staging according to major site are depicted in Table 2. Referral pattern for NACT
Overall the referral for NACT was for organ preservation in 76 patients (8.82%) and for achievement of resectability in patients in 786 patients (91.18%). The detailed referral pattern for each site and the reasons for NACT are described below at each site in detail. Oral cavity cancer
• The referral for NACT was to make the cancer resectable in 721 patients (100.0% of oral cancers). The reasons for referral for NACT [Figure 1] were: Extensive skin infiltration, which would have necessitate extensive skin resection: 255 (35.36% of oral cancers) • Peritumoral edema reaching up to or above zygoma: 260 (36.06% of oral cancers) • Peritumoral edema reaching up to hyoid bone or below it: 82 (11.37% of oral cancers) • Infratemporal fossa (ITF) involvement: 76 (10.54% of oral cancers) • Borderline resectability: 39 (5.27% of oral cancers) • Extensive involvement of the floor of mouth: 9 (1.25% of oral cancers).
Table 1: The subsite distribution of primaries in major site Tumor site
Frequency (%)
Oral cavity (n=721 patients) Buccal mucosa Anterior 2/3 of tongue Floor of mouth Others Larynx (n=33 patients) Supraglootic larynx Glottic larynx Subglottic larynx Hypopharynx (n=59 patients) Pyriform sinus
496 (68.80) 157 (21.80) 29 (4.02) 39 (5.38) 27 (81.81) 5 (15.15) 1 (3.04) 49 (83.05)
Posterior pharyngeal wall
7 (11.86)
Table 2: Stage wise distribution according to site of primary. N0 nodal status is not depicted Site Oral cavity Maxilla Larynx Hypopharynx Larngo‑pharynx
T staging
N staging
T3
T4a
T4b
N1
N2
N3
101 2 7 24*
427 37 22 31
193 2 4 4
27 6 3 9
406 12 15 25
49 0 5 8
5
3
0
1
3
1
*Four patients had T2 disease
Carcinoma of maxillary sinus
The indication was to make the disease resectable in 29 patients (70.73%). Among these patients two patients had intracranial extension, six had involvement of pterygoid plates and 20 had ITF involvement. In 12 patients (29.27%), it was given so that eyeball could be attempted to be preserved. Carcinoma of larynx
The indication for NACT was organ preservation in 14 patients (42.42% of laryngeal cancer) and to achieve resectability in 19 patients (57.58% of laryngeal cancer). Among those for organ preservation, the need was due to exolaryngeal spread in 6 patients (18.18% of laryngeal cancer) and superficial cartilage invasion in 8 patients (24.24% of larnyngeal cancer). In those with unresectable disease, the reasons were carotid encasement in 3 patients (9.09% of larnyngeal cancer), mucosal extension of disease until tonsil in 10 patients (30.30% of larnyngeal cancer), N3 lymph node in 4 patients (12.12% of larnyngeal cancer) while prevertebral muscle extension and extension to the esophagus in one patient each (3.03%).
Figure 1: Depiction of reasons in stage IV a tumors for neoadjuvant chemotherapy because of which these tumors were considered borderline resectable. In the buccal mucosa primary if the tumor or edema related to it extends above the level of zygoma. In case of floor of mouth or anterior two‑third of tongue primary if the tumor extents up to the level of hyoid bone or if the tumor extends into the vallecula or base of tongue. In case of primaries in larynx or hypopharynx if the tumor is extending up to oropharynx
The group with laryngopharynx is a cohort of eight patients in whom NACT was given to prevent tracheostomy (included in organ preservation), these patients had presented with early stridor (common terminology criteria for adverse events version 4.02). This was done to avoid deleterious effects of tracheostomy.
of hypopharyngeal cancer). The need for NACT in organ preservation was exolaryngeal spread without cartilage erosion in 4 patients (6.78% of hypopharyngeal cancer) and minor thyroid cartilage invasion in 20 patients (33.90% of hypopharyngeal cancer). In group for achievement of resectability the reasons were N3 node in 8 patients (13.56% of hypopharyngeal cancer), oropharyngeal involvement in 24 patients (40.68% of hypopharyngeal cancer) or extensive disease with cartilage erosion in 3 patients (5.08% of hypopharyngeal cancer).
Carcinoma of hypopharynx
Discussion
Carcinoma of laryngopharynx
The reason for NACT was for organ preservation in 24 patients (40.68% of hypopharyngeal cancer) and for achievement of resectability in 35 patients (59.32% Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
The aim of surgery in the head and neck cancers is R0 resection. [18‑20] The factors determining achievement of 101
Patil, et al.: Pattern of use of NACT in the head and neck cancers
R0 resection includes tumor stage, surgeon’s experience and skill and rehabilitative facilities. As such, it may be difficult to define strict objective criteria for resectability of a particular tumor and the surgical outcome will depend on myriad factors. This is especially true in case of tumors that are borderline resectable or which require morbid surgeries. In India and the developing countries, a major proportion of patients present with locally advanced and very locally advanced head and neck cancers. In such patients, achievement of R0 resection remains a challenge.[18] Down‑staging of tumor by preoperative chemotherapy may help by down‑staging tumors and allow R0 resections in such technically challenging tumors with acceptable morbidity.[21] As can be seen in our analysis, this forms the major indication of our patients referred for NACT. This in contrast to the trials reported mainly from the western countries where the indication for use of NACT been mainly for organ preservation strategies or for improvement in local control. [6‑8,13,15,16] The use of NACT for organ preservation has been typically described in the larynx and hypopharynx.[14,15,22,23] Several trials (RTOG 91‑11, DeCIDE and PARADIGM) showed that NACT prior to concurrent chemoradiation (CT‑RT) did not result in any improvement in the measured endpoints.[13,15] Even at our center, few patients have received NACT for organ preservation. Licitra et al. have previously reported that NACT in operable oral cavity cancers can increase the rate of mandibular preservation. However, other studies have shown that NACT followed by surgery in operable oral cancers is not associated with any improvement in disease free survival or overall survival.[16,17] We have mainly utilized NACT in the setting of locally advanced tumors of the oral cavity, which were considered unresectable or borderline unresectable. The decision was made in a multidisciplinary clinic, which included radiologists, surgical oncologists, radiotherapists and medical oncologists. The anatomical landmarks used for specifying resectability have been highlighted earlier in publications by Pradhan [18] and Patil et al. [21] These landmarks have been explained in Figure 1. Mostly, these are anatomical landmarks, spaces or boundaries, which when involved hamper the ability of the surgeon to achieve R0 resection. We believe that our approach might help improve outcomes especially in patients with cancers of the oral cavity, maxillary sinus and hypopharynnx.[18,23‑34] These sites have traditionally had poor outcomes with chemoradiation alone. Recent reports from major centers in India appear to show benefit with NACT.[21,35] Theoretically, NACT followed by surgery might have more favorable outcomes compared with CT‑RT due to the excision of chemoresistant and radioresistant tumor tissues. Figure 2 shows a hypothetical diagrammatic representation of a cross‑sectional view of locally advanced head and neck cancers. The tumor tissue can be postulated to consist of three types of cell populations. The peripheral cells are well oxygenated; the intermediate zone cells are hypoxic while the center has necrotic cells and negligible oxygen supply. Since the oxygen enhancement ratio is high for 102
Figure 2: The saggital profile of locally advanced tumor showing the population of well‑ oxygenated, hypoxic and necrotic tumors
low linear energy transfer radiation, the use of radiation or chemoradiation will be associated with suboptimal outcomes. [36‑39] However, when such patients receive NACT, even a minimal shrinkage in the areas depicted can make these technically unresectable tumors resectable. Consequently, the tumor with the resistant clones can be completely excised. This is a biologically plausible explanation, which has to be confirmed by experimental and laboratory work. The clinical relevance of this approach needs to be confirmed in a well‑conducted randomized trial in technically unresectable tumors where one arm should consist of NACT followed by CT/RT and the other arm CT/RT alone. Conclusions To conclude, our data shows that NACT referral pattern is different from that seen in western trials. The major indication for NACT in our setting is to achieve resectability. A detailed analysis in future would provide us with the results of this approach and A in the subsequent period would through further light on this approach. References 1. André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low‑income and middle‑income countries? Lancet Oncol 2013;14:e239‑48. 2. Sankaranarayanan R. Oral cancer in India: An epidemiologic and clinical review. Oral Surg Oral Med Oral Pathol 1990;69:325‑30. 3. Gupta PC. Mouth cancer in India: A new epidemic? J Indian Med Assoc 1999;97:370‑3. 4. Grégoire V, Lefebvre JL, Licitra L, Felip E, EHNS‑ESMO‑ESTRO guidelines working group. Squamous cell carcinoma of the head and neck: EHNS‑ESMO‑ESTRO clinical practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol 2010;21 Suppl 5:v184‑6. 5. Baxi S, Fury M, Ganly I, Rao S, Pfister DG. Ten years of progress in head and neck cancers. J Natl Compr Canc Netw 2012;10:806‑10. 6. Paccagnella A, Orlando A, Marchiori C, Zorat PL, Cavaniglia G, Sileni VC, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the gruppo di studio sui tumori della testa e del collo. J Natl Cancer Inst 1994;86:265‑72. 7. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705‑15. 8. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
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Degardin M, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695‑704. Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, et al. Randomized trial of induction chemotherapy with cisplatin and 5‑fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498‑506. Hitt R, Grau JJ, Lopez‑Pousa A, Berrocal A, Garcia‑Giron C, Irigoyen A, et al. Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5‑FU or docetaxel/cisplatin/5‑FU follow by chemoradiotherapy (CRT) versus CRT alone as first‑line treatment of unresectable locally advanced head and neck cancer (LAHNC). J Clin Oncol Meet Abstr 2009;27:6009. Haddad RI, Posner MR. Induction chemotherapy in head and neck cancer. J Clin Oncol 2009;27:e52‑3. Fury MG, Shah JP. Induction chemotherapy in the management of head and neck cancer. J Surg Oncol 2010;101:292‑8. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet Oncol 2013;14:257‑64. Lefebvre JL, Pointreau Y, Rolland F, Alfonsi M, Baudoux A, Sire C, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: The TREMPLIN randomized phase II study. J Clin Oncol 2013;31:853‑9. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. Long‑term results of RTOG 91‑11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845‑52. Available from: http://www.jco.ascopubs.org/content/early/2012/11/26/ JCO.2012.43.6097. [Cited on 2013 Jan 24]. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up‑front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 2013;31:744‑51. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: A randomized controlled trial. J Clin Oncol 2003;21:327‑33. Pradhan SA. Surgery for cancer of the buccal mucosa. Semin Surg Oncol 1989;5:318‑21. Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol 2007;43:780‑4. Shah JP, Gil Z. Current concepts in management of oral cancer – surgery. Oral Oncol 2009;45:394‑401. Patil VM, Noronha V, Muddu VK, Gulia S, Bhosale B, Arya S, et al. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference? Indian J Cancer 2013;50:1‑8. 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. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: Preliminary results of a European organization for research and treatment of cancer phase III trial. EORTC head and neck cancer cooperative group. J Natl Cancer Inst 1996;88:890‑9.
24. Kang JH, Cho SH, Kim JP, Kang KM, Cho KS, Kim W, et al. Treatment outcomes between concurrent chemoradiotherapy and combination of surgery, radiotherapy, and/or chemotherapy in stage III and IV maxillary sinus cancer: Multi‑institutional retrospective analysis. J Oral Maxillofac Surg 2012;70:1717‑23. Available from: http://www.sciencedirect.com/ science/article/pii/S0278239111011529. [Cited on 2011 Dec 8]. 25. Gabriele AM, Airoldi M, Garzaro M, Zeverino M, Amerio S, Condello C, et al. Stage III‑IV sinonasal and nasal cavity carcinoma treated with three‑dimensional conformal radiotherapy. Tumori 2008;94:320‑6. 26. Jang NY, Wu HG, Park CI, Heo DS, Kim DW, Lee SH, et al. Definitive radiotherapy with or without chemotherapy for T3‑4N0 squamous cell carcinoma of the maxillary sinus and nasal cavity. Jpn J Clin Oncol 2010;40:542‑8. 27. Hayashi T, Nonaka S, Bandoh N, Kobayashi Y, Imada M, Harabuchi Y. Treatment outcome of maxillary sinus squamous cell carcinoma. Cancer 2001;92:1495‑503. 28. Waldron JN, O’Sullivan B, Gullane P, Witterick IJ, Liu FF, Payne D, et al. Carcinoma of the maxillary antrum: A retrospective analysis of 110 cases. Radiother Oncol 2000;57:167‑73. 29. Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45:301‑8. 30. Nair MK, Sankaranarayanan R, Padmanabhan TK. Evaluation of the role of radiotherapy in the management of carcinoma of the buccal mucosa. Cancer 1988;61:1326‑31. 31. Chaudhary AJ, Pande SC, Sharma V, Bhalavat RL, Shrivastava SK, Gonsalves MA, et al. Radiotherapy of carcinoma of the buccal mucosa. Semin Surg Oncol 1989;5:322‑6. 32. Pathak KA, Nason RW, Talole SD, Abdoh AA. Are buccal cancers in India and Canada any different? J Surg Oncol 2008;97:529‑32. 33. Scully C, Bagan JV. Recent advances in Oral Oncology 2007: Imaging, treatment and treatment outcomes. Oral Oncol 2008;44:211‑5. 34. Misra S, Chaturvedi A, Misra NC. Management of gingivobuccal complex cancer. Ann R Coll Surg Engl 2008;90:546‑53. 35. Joshi P, Patil V, Joshi A, Norohna V, Chaturvedi P, Chaukar D, et al. Neo‑adjuvant chemotherapy in advanced hypopharyngeal carcinoma. Indian J Cancer 2013;50:25‑30. 36. Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev 1994;13:139‑68. 37. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285‑9. 38. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437‑47. 39. Rajendran JG, Schwartz DL, O’Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with F‑18 fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 2006;12:5435‑41.
How to site this article: Patil VM, Noronha V, Joshi A, Krishna VM, Dhumal S, Chaudhary V, et al. Referral pattern for neoadjuvant chemotherapy in the head and neck cancers in a tertiary care center. Indian J Cancer 2014;51:100-3. Source of Support: Nil. Conflict of Interest: None declared.
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Referral pattern for neoadjuvant chemotherapy in the head and neck cancers in a tertiary care center Patil VM, Noronha V, Joshi A, Krishna VM, Dhumal S, Chaudhary V, Juvekar S1, Pai PS2, Pankaj C2, Chaukar D2, Dcruz AK2, Prabhash K Departments of Medical Oncology, 1Radiodiagnosis, and 2Head and Neck Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India Correspondence to: Dr. Kumar Prabhash, E‑mail: [email protected]
Abstract
BACKGROUND: Use of any treatment modality in cancer depends not only on the effectiveness of the modality, but also on other factors such as
local expertise, tolerance of the modality, cost and prevalence of the disease. Oropharyngeal and laryngeal cancer are the major subsites in which majority of neoadjuvant chemotherapy (NACT) literature in the head and neck cancers is available. However, oral cancers form a major subsite in India. MATERIALS AND METHODS: This is an analysis of a prospectively maintained data on NACT in the head and neck cancers from 2008 to 2012. All these patients were referred for NACT for various indications from a multidisciplinary clinic. Descriptive analysis of indications for NACT in this data base is presented. RESULTS: A total of 862 patients received NACT within the stipulated time period. The sites where oral cavity 721 patients (83.6%), maxilla 41 patients (4.8%), larynx 33 patients (3.8%), laryngopharynx 8 patients (0.9%) and hypopharynx 59 patients (8.2%). Out of oral cancers, the major indication for NACT was to make the cancer resectable in all (100%) patients. The indication in carcinoma of maxilla was to make the disease resectable in 29 patients (70.7% of maxillary cancers) and in 12 patients (29.3% of maxillary cancers) it was given as an attempt to preserve the eyeball. The indication for NACT in laryngeal cancers was organ preservation in 14 patients (42.4% of larnyngeal cancer) and to achieve resectability in 19 patients (57.6% of larnyngeal cancer). The group with laryngopharynx is a cohort of eight patients in whom NACT was given to prevent tracheostomy, these patients had presented with early stridor (common terminology criteria for adverse events Version 4.02). The reason for NACT in hypopharyngeal cancers was for organ preservation in 24 patients (40.7% of hypopharyngeal cancer) and for achievement of resectability in 35 patients (59.3% of hypopharyngeal cancer). CONCLUSION: The major indication for NACT is to make disease resectable at our center while cases for organ preservation are few. Key Words: Borderline resectable, neoadjuvant chemotherapy, oral cancers, unresectable
Introduction Treatment of cancer is determined by the standard guidelines laid down by professional bodies. The use of chemotherapeutic agents is further governed by regulatory organizations in each country. By and large, the treatment strategies are developed on the basis of large, well‑designed randomized controlled trials. However, such guidelines may not adequately address local influences such as prevalent epidemiology, socio‑economic conditions, resource availability and infrastructure.[1] In India, head and neck cancer is the most common malignancy among males.[2,3] Due to the limited number of trained head and neck surgeons and delay in seeking treatment, patients often present with locally advanced disease. The standard treatment in such patients is radical chemoradiotherapy. [4,5] However, the outcomes are not optimal. One option is giving induction chemotherapy followed by definitive surgery or radiation. Though neoadjuvant chemotherapy (NACT) has been evaluated in multiple studies, there is no consensus regarding the actual benefit and optimal situations where it may be beneficial.[6‑15] In the majority of NACT trials, the indication of chemotherapy has been either organ preservation or its use has been followed by chemoradiation in unresectable cancer settings.[6‑8,13‑15] NACT followed by surgery has been evaluated in a few studies, nearly always in operable cancers.[16,17] At our center, NACT is given to patients based on discussions in a multidisciplinary clinic. In the present paper, Access this article online Quick Response Code:
Website: www.indianjcancer.com DOI: 10.4103/0019-509X.137956 PMID: *******
100
we have attempted to analyze the patterns of use of NACT in our center. Materials and Methods We maintain a prospective database of all patients how are referred for NACT in our Head and Neck Cancer Medical Oncology Out‑patient Department. This was a retrospective analysis of patients undergoing NACT from 2009 to 2012. At our center, every case of head and neck cancer is discussed in a multidisciplinary joint clinic and a decision regarding the treatment is taken. For this analysis, only patients with squamous cell carcinoma and primary in the oral cavity, maxilla, larynx and hypopharynx were selected. There were 862 patients, fitting within the above criteria who had been referred for NACT during this period. The site distribution, stage distribution and the indication for NACT were recorded. The database, the hospital electronic medical record and the case papers of each patient were sought for the exact reason why the patient was considered for NACT. Indication for NACT was divided in to two broad categories either organ preservation or to achieve resectability. In addition, objective reasons as far as possible were sought for NACT referral. These reasons were objective involvement of anatomical landmarks, important spaces, proximity to important vital structures or extensive involvement of soft‑tissue or skin, which would have required a morbid surgery. The statistical analysis was performed by SPSS version 16. Descriptive analysis has been presented. Results During the above mentioned period, 862 patients received NACT. Out of the 862 patient, oral cavity primary was seen in 721 patients (83.64%), maxillary primary in 41 patients (4.75%), laryngeal primary in 33 patients (3.83%), laryngopharyngeal primary in 8 patients (0.93%) Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
Patil, et al.: Pattern of use of NACT in the head and neck cancers
and hypopharyngeal primary in 59 patients (8.18%). The subsite distribution has been depicted in Table 1. The stage grouping was Stage III in one patient and rest all where Stage IV. The details of T staging N staging according to major site are depicted in Table 2. Referral pattern for NACT
Overall the referral for NACT was for organ preservation in 76 patients (8.82%) and for achievement of resectability in patients in 786 patients (91.18%). The detailed referral pattern for each site and the reasons for NACT are described below at each site in detail. Oral cavity cancer
• The referral for NACT was to make the cancer resectable in 721 patients (100.0% of oral cancers). The reasons for referral for NACT [Figure 1] were: Extensive skin infiltration, which would have necessitate extensive skin resection: 255 (35.36% of oral cancers) • Peritumoral edema reaching up to or above zygoma: 260 (36.06% of oral cancers) • Peritumoral edema reaching up to hyoid bone or below it: 82 (11.37% of oral cancers) • Infratemporal fossa (ITF) involvement: 76 (10.54% of oral cancers) • Borderline resectability: 39 (5.27% of oral cancers) • Extensive involvement of the floor of mouth: 9 (1.25% of oral cancers).
Table 1: The subsite distribution of primaries in major site Tumor site
Frequency (%)
Oral cavity (n=721 patients) Buccal mucosa Anterior 2/3 of tongue Floor of mouth Others Larynx (n=33 patients) Supraglootic larynx Glottic larynx Subglottic larynx Hypopharynx (n=59 patients) Pyriform sinus
496 (68.80) 157 (21.80) 29 (4.02) 39 (5.38) 27 (81.81) 5 (15.15) 1 (3.04) 49 (83.05)
Posterior pharyngeal wall
7 (11.86)
Table 2: Stage wise distribution according to site of primary. N0 nodal status is not depicted Site Oral cavity Maxilla Larynx Hypopharynx Larngo‑pharynx
T staging
N staging
T3
T4a
T4b
N1
N2
N3
101 2 7 24*
427 37 22 31
193 2 4 4
27 6 3 9
406 12 15 25
49 0 5 8
5
3
0
1
3
1
*Four patients had T2 disease
Carcinoma of maxillary sinus
The indication was to make the disease resectable in 29 patients (70.73%). Among these patients two patients had intracranial extension, six had involvement of pterygoid plates and 20 had ITF involvement. In 12 patients (29.27%), it was given so that eyeball could be attempted to be preserved. Carcinoma of larynx
The indication for NACT was organ preservation in 14 patients (42.42% of laryngeal cancer) and to achieve resectability in 19 patients (57.58% of laryngeal cancer). Among those for organ preservation, the need was due to exolaryngeal spread in 6 patients (18.18% of laryngeal cancer) and superficial cartilage invasion in 8 patients (24.24% of larnyngeal cancer). In those with unresectable disease, the reasons were carotid encasement in 3 patients (9.09% of larnyngeal cancer), mucosal extension of disease until tonsil in 10 patients (30.30% of larnyngeal cancer), N3 lymph node in 4 patients (12.12% of larnyngeal cancer) while prevertebral muscle extension and extension to the esophagus in one patient each (3.03%).
Figure 1: Depiction of reasons in stage IV a tumors for neoadjuvant chemotherapy because of which these tumors were considered borderline resectable. In the buccal mucosa primary if the tumor or edema related to it extends above the level of zygoma. In case of floor of mouth or anterior two‑third of tongue primary if the tumor extents up to the level of hyoid bone or if the tumor extends into the vallecula or base of tongue. In case of primaries in larynx or hypopharynx if the tumor is extending up to oropharynx
The group with laryngopharynx is a cohort of eight patients in whom NACT was given to prevent tracheostomy (included in organ preservation), these patients had presented with early stridor (common terminology criteria for adverse events version 4.02). This was done to avoid deleterious effects of tracheostomy.
of hypopharyngeal cancer). The need for NACT in organ preservation was exolaryngeal spread without cartilage erosion in 4 patients (6.78% of hypopharyngeal cancer) and minor thyroid cartilage invasion in 20 patients (33.90% of hypopharyngeal cancer). In group for achievement of resectability the reasons were N3 node in 8 patients (13.56% of hypopharyngeal cancer), oropharyngeal involvement in 24 patients (40.68% of hypopharyngeal cancer) or extensive disease with cartilage erosion in 3 patients (5.08% of hypopharyngeal cancer).
Carcinoma of hypopharynx
Discussion
Carcinoma of laryngopharynx
The reason for NACT was for organ preservation in 24 patients (40.68% of hypopharyngeal cancer) and for achievement of resectability in 35 patients (59.32% Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
The aim of surgery in the head and neck cancers is R0 resection. [18‑20] The factors determining achievement of 101
Patil, et al.: Pattern of use of NACT in the head and neck cancers
R0 resection includes tumor stage, surgeon’s experience and skill and rehabilitative facilities. As such, it may be difficult to define strict objective criteria for resectability of a particular tumor and the surgical outcome will depend on myriad factors. This is especially true in case of tumors that are borderline resectable or which require morbid surgeries. In India and the developing countries, a major proportion of patients present with locally advanced and very locally advanced head and neck cancers. In such patients, achievement of R0 resection remains a challenge.[18] Down‑staging of tumor by preoperative chemotherapy may help by down‑staging tumors and allow R0 resections in such technically challenging tumors with acceptable morbidity.[21] As can be seen in our analysis, this forms the major indication of our patients referred for NACT. This in contrast to the trials reported mainly from the western countries where the indication for use of NACT been mainly for organ preservation strategies or for improvement in local control. [6‑8,13,15,16] The use of NACT for organ preservation has been typically described in the larynx and hypopharynx.[14,15,22,23] Several trials (RTOG 91‑11, DeCIDE and PARADIGM) showed that NACT prior to concurrent chemoradiation (CT‑RT) did not result in any improvement in the measured endpoints.[13,15] Even at our center, few patients have received NACT for organ preservation. Licitra et al. have previously reported that NACT in operable oral cavity cancers can increase the rate of mandibular preservation. However, other studies have shown that NACT followed by surgery in operable oral cancers is not associated with any improvement in disease free survival or overall survival.[16,17] We have mainly utilized NACT in the setting of locally advanced tumors of the oral cavity, which were considered unresectable or borderline unresectable. The decision was made in a multidisciplinary clinic, which included radiologists, surgical oncologists, radiotherapists and medical oncologists. The anatomical landmarks used for specifying resectability have been highlighted earlier in publications by Pradhan [18] and Patil et al. [21] These landmarks have been explained in Figure 1. Mostly, these are anatomical landmarks, spaces or boundaries, which when involved hamper the ability of the surgeon to achieve R0 resection. We believe that our approach might help improve outcomes especially in patients with cancers of the oral cavity, maxillary sinus and hypopharynnx.[18,23‑34] These sites have traditionally had poor outcomes with chemoradiation alone. Recent reports from major centers in India appear to show benefit with NACT.[21,35] Theoretically, NACT followed by surgery might have more favorable outcomes compared with CT‑RT due to the excision of chemoresistant and radioresistant tumor tissues. Figure 2 shows a hypothetical diagrammatic representation of a cross‑sectional view of locally advanced head and neck cancers. The tumor tissue can be postulated to consist of three types of cell populations. The peripheral cells are well oxygenated; the intermediate zone cells are hypoxic while the center has necrotic cells and negligible oxygen supply. Since the oxygen enhancement ratio is high for 102
Figure 2: The saggital profile of locally advanced tumor showing the population of well‑ oxygenated, hypoxic and necrotic tumors
low linear energy transfer radiation, the use of radiation or chemoradiation will be associated with suboptimal outcomes. [36‑39] However, when such patients receive NACT, even a minimal shrinkage in the areas depicted can make these technically unresectable tumors resectable. Consequently, the tumor with the resistant clones can be completely excised. This is a biologically plausible explanation, which has to be confirmed by experimental and laboratory work. The clinical relevance of this approach needs to be confirmed in a well‑conducted randomized trial in technically unresectable tumors where one arm should consist of NACT followed by CT/RT and the other arm CT/RT alone. Conclusions To conclude, our data shows that NACT referral pattern is different from that seen in western trials. The major indication for NACT in our setting is to achieve resectability. A detailed analysis in future would provide us with the results of this approach and A in the subsequent period would through further light on this approach. References 1. André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low‑income and middle‑income countries? Lancet Oncol 2013;14:e239‑48. 2. Sankaranarayanan R. Oral cancer in India: An epidemiologic and clinical review. Oral Surg Oral Med Oral Pathol 1990;69:325‑30. 3. Gupta PC. Mouth cancer in India: A new epidemic? J Indian Med Assoc 1999;97:370‑3. 4. Grégoire V, Lefebvre JL, Licitra L, Felip E, EHNS‑ESMO‑ESTRO guidelines working group. Squamous cell carcinoma of the head and neck: EHNS‑ESMO‑ESTRO clinical practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol 2010;21 Suppl 5:v184‑6. 5. Baxi S, Fury M, Ganly I, Rao S, Pfister DG. Ten years of progress in head and neck cancers. J Natl Compr Canc Netw 2012;10:806‑10. 6. Paccagnella A, Orlando A, Marchiori C, Zorat PL, Cavaniglia G, Sileni VC, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the gruppo di studio sui tumori della testa e del collo. J Natl Cancer Inst 1994;86:265‑72. 7. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705‑15. 8. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
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How to site this article: Patil VM, Noronha V, Joshi A, Krishna VM, Dhumal S, Chaudhary V, et al. Referral pattern for neoadjuvant chemotherapy in the head and neck cancers in a tertiary care center. Indian J Cancer 2014;51:100-3. Source of Support: Nil. Conflict of Interest: None declared.
News Next APLCC meeting will be held in Kuala Lumpur from 6-8 November 2014. The deadline for abstract submission is 1 July 2014. Conference Secretariat of 2014 IASLC Asia Pacific Lung Cancer Conference (APLCC2014): 19-5, Dutaria, Jalan Dutamas Raya, 51200 Kuala Lumpur, MALAYSIA Tel: +60 3 6241 3850 Mobile: +60 17 2215 123 Email: [email protected] Website: www.aplcc2014.com News 31st ICON Conference. Organizing Secretary : Dr. T. P. Sahoo, 12th - 14th September, 2014 Web: www.iconconferences.com Mail: [email protected] Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
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