Chemotherapy Research and Practice

Chemotherapy Research and Practice / 2014 / Article

Clinical Study | Open Access

Volume 2014 |Article ID 487872 | https://doi.org/10.1155/2014/487872

Vanita Noronha, Vijay Maruti Patil, Amit Joshi, Muddu Vamshi Krishna, Sachin Dhumal, Shashikant Juvekar, P. Pai, Pankaj Chatturvedi, Devendra Arvind Chaukar, Jai Prakash Agarwal, Sarbani Ghosh, Vedang Murthy, Anil D’cruz, Kumar Prabhash, "Induction Chemotherapy in Technically Unresectable Locally Advanced Carcinoma of Maxillary Sinus", Chemotherapy Research and Practice, vol. 2014, Article ID 487872, 6 pages, 2014. https://doi.org/10.1155/2014/487872

Induction Chemotherapy in Technically Unresectable Locally Advanced Carcinoma of Maxillary Sinus

Academic Editor: Enzo Bonmassar
Received25 Nov 2013
Revised23 Mar 2014
Accepted03 Apr 2014
Published11 May 2014

Abstract

Background. Locally advanced carcinoma of maxillary sinus has been historically reported to have poor prognosis. We evaluated the role of NACT in improving the outcome in these patients. Methods. 41 patients with locally advanced technically unresectable (stage IVa) or unresectable maxillary carcinoma (stage IVb) were treated with induction chemotherapy between 2008 and 2011. The demographic profile, response and toxicity of chemotherapy, definitive treatment received, progression free survival (PFS), and overall survival (OS) were analyzed. Univariate and multivariate analysis were performed to determine factors associated with PFS and OS. Results. The chemotherapy included two drugs (platinum and taxane) in 34 patients (82.9%) and three drugs (platinum, taxane, and 5 FU) in 7 (17.1%). There was no complete response seen in any of the patients, stable disease in 18 (43.9%), partial response in 16 (39%), and progression in 7 (17.1%) patients. After induction, the treatment planned included surgery in 12 (29.3%), CT-RT in 24 (58.5%), radical RT in 1 (2.4%), palliative RT in 1 (2.4%), and palliative chemotherapy in 3 (7.3%) patients. Overall, the median PFS was 10.0 months. The OS at 24 months and 36 months was 41% and 35%, respectively. Conclusion. In unresectable maxillary carcinoma, induction chemotherapy has clinically significant benefit with acceptable toxicity.

1. Introduction

Carcinoma of maxillary sinus is a rare entity [1]. It represents less than 1% of the tumours in the head and neck. Consequently, there is limited high-level evidence to define the ideal therapy in patients with maxillary tumours [16]. Epidemiologically, most of the cancers arising in this location are squamous cell carcinoma and are seen in advanced stage [1]. These tumours typically require extensive and morbid surgeries followed by adjuvant radiation. Though these procedures have been shown to improve outcomes, the long-term results are far from satisfactory [511].

Nearly 25–35% of patients have locally advanced unresectable disease [5, 11]. These patients have traditionally been treated with radical radiotherapy, with or without concurrent chemotherapy. The 5-year overall survival in this subgroup of patients is dismal, around 9–25% [7, 9, 12]. Considering such results, there is an urgent need for a new treatment paradigm for patients with maxillary carcinomas, especially in patents with unresectable disease or those who will require morbid resections.

Induction or neoadjuvant chemotherapy (NACT) prior to definitive local treatment has been used in carcinoma of maxillary sinus and response rates in the region of 60–70% have been reported. The survival with this approach was 77% at 2 years, as reported by Hanna et al. [3]. Since we had several patients with locally advanced and unresectable carcinoma we started using induction chemotherapy before definitive local treatment. The primary aim of NACT was to reduce the size of the tumour sufficiently to make them resectable. We present our results in locally advanced technically unresectable maxillary sinus tumours that were treated at our institute with NACT followed by reassessment for local treatment.

2. Material and Methods

All patients with squamous cell carcinoma of the maxillary sinus seen in the Head and Neck Medical Oncology Outpatient Department between January 2008 and December 2011 were evaluated. The patients treated with NACT were included in the present analysis. Data was collected on the demographics, baseline investigations, stage of the disease, indication of NACT, details of chemotherapy, chemotoxicity, response, post-NACT treatment details, failure pattern, and overall survival. The treatment for all patients at presentation was discussed in a multidisciplinary clinic. After clinical examination and radiological investigations, the tumour was considered either unresectable in advanced T stage (T4b) or technically unresectable when upfront surgery was likely to be associated with positive margins or result in an extremely morbid resection (Figure 1). These patients subsequently received 2 cycles of chemotherapy, either a 2-drug combination of platinum and taxane or a 3-drug combination of docetaxel, cisplatin, and 5 FU. The choice of chemotherapy depended upon the performance status, logistic issues, and financial status. Our personal experience had shown that the 3-drug regimen required a longer period of hospitalisation, prophylactic growth factors and was generally more expensive than the 2-drug regimens [13]. The platinum used depended on the serum creatinine clearance calculated in accordance with the modified Cockcroft Gault formula. If the creatinine clearance was above 60 mL/min, cisplatin was used. Carboplatin was the preferred agent when the creatinine clearance was below 60 mL/min. Standard doses of chemotherapy as previously established were used [13]. All the patients completed 2 cycles of chemotherapy and underwent axial imaging (either a contrast-enhanced computerised tomography or magnetic resonance imaging of the paranasal sinuses and cervical region) within 2–4 weeks. The response to therapy was quantified in terms of the RECIST criteria (response evaluation criteria in solid tumours). Further treatment was decided in the multidisciplinary clinic. In patients with stable disease or any response, patients either underwent definitive surgery followed by chemoradiation or definitive radiotherapy. Patients with progressive disease were treated with palliative intent. After the completion of therapy, patients were followed up with regular clinical examination and imaging whenever appropriate to document relapse and the pattern of relapse. All patients were followed up till death.

SPSS version 16 was used for statistical analysis. The demographic details, the response to induction chemotherapy, toxicity of induction, progression frees survival (PFS), and overall survival (OS) have been reported. Kaplan Meier analysis was used for estimation of time to event data.

PFS was calculated from date of first chemotherapy cycle to either date of progression or date of death whichever occurred earlier. The OS was calculated from date of first chemotherapy cycle to the date of death. Log-rank test was used for initial univariate analysis of factors affecting PFS and OS. The variables tested include age, gender, serum albumin, serum haemoglobin, body mass index, grade of tumour, response to NACT, drug regimen, dose intensity, and local treatment. Since multiple tests were used, Bonferroni correction was applied [14]. The value was taken as significant if it was below 0.005.

3. Results

Forty-one patients were included in the analysis. Two patients had T4b disease. The remaining patients with T4a tumours were considered technically unresectable due to involvement of pterygoid plates in 6 patients, infratemporal fossa involvement in 20, and orbital involvement up to the anterior cranial fossa in 13 patients.

The disease related details are presented in Table 1. All patients had squamous cell cancer. The grade of the tumour was well differentiated in 23 (56%), moderately differentiated in 10 (24.5%), and poorly differentiated in 8 (19.5%). The median age was 48 years (22–71 years). The sex ratio was 33 : 8. The median haemoglobin, albumin, and body mass index of these patients were 12.2 g/dL, 4 mg/dL, and 21.3 Kg/m2, respectively.


Number (%)

T stage
 T32 (5%)
 T4a37 (90%)
 T4b2 (5%)
N stage
 N023 (56%)
 N16 (14%)
 N212 (30%)
 N30
Stage grouping
 Stage IVA39 (95%)
 Stage IVB2 (5%)
Grade of the tumour
 Grade 123 (56%)
 Grade 210 (24.5%)
 Grade 38 (19.5%)

3.1. Chemotherapy Details

The median number of cycles of chemotherapy received was 2 (range 2-3). 34 patients (82.9%) were treated with 2-drug protocol. The chemotherapy given was docetaxel and cisplatin in 10 patients, docetaxel and carboplatin in 5, paclitaxel and cisplatin in 15, and paclitaxel and carboplatin in 4 patients. Seven patients (17.1%) were treated with a 3-drug regimen of docetaxel, cisplatin, and 5-fluorouracil. All patients completed at least 2 cycles of chemotherapy. The 20th quartile dose intensity was 85.4%.

The toxicity profile after chemotherapy was available for 38 patients and is depicted in Table 2. There were no deaths related to NACT. Serious adverse effects were febrile neutropenia in 8 patients (21.05%) and hyponatremia. All grades of hyponatremia were seen in 24 patients (63.16%) while grades 3-4 hyponatremia were seen in 11 patients (28.95%).


Grade 0Grade 1Grade 2Grade 3Grade 4

Anemia7211010
Neutropenia199136
Thrombocytopenia275513
Vomiting1781120
Loose motions1741142
Mucositis244910
Fatigue209810
Hyponatremia1613NA74
Hypokalemia287NA30
Febrile neutropeniaNANANA35

3.2. Response Evaluation Postchemotherapy

As per the RECIST criteria, complete response was seen in none, partial response in 16 (39%) patients, stable disease in 18 (43.9%), and progressive diseases in 7 patients (17.1%). The median decrement in size of the lesion was 20%. The waterfall plot of decrement in size of the lesion is given in Figure 2.

3.3. Post-NACT Definitive Treatment

After reassessment in the multidisciplinary clinic, the definitive treatment planned was surgery in 12 patients (29.3%), CT-RT in 24 (58.5%), radical RT in 1 (2.4%), palliative RT in 1 (2.4%), and palliative chemotherapy in 3 (7.3%) patients. However, 9 patients defaulted further treatment and 4 patients could not complete planned therapy due to logistical issues. Hence, the final therapy was surgery followed by postoperative chemoradiation in 8 patients, chemoradiation in 21, radical radiation in 1, palliative radiation in 1, palliative chemotherapy in 4, and no local treatment in 6 patients. Among the patients undergoing definitive surgery, 7 underwent total maxillectomy and one underwent suprastructure maxillectomy. The resection achieved was R0 in all patients. The margin status was close (2 mm or less of soft tissue margin) in 1 patient and was adequate in 7 patients. Pathological CR was achieved in 1 patient.

Among the patients receiving radiation, radical chemoradiation was given to 21 patients, radical radiation alone to 1 patient, adjuvant chemoradiation to 8, and palliative radiation to one patient. The median equivalent dose received by the tumour in these patients was 66 Gy (20–70 Gy). The median fraction time was 33 (10–33). The radiation techniques utilized were 3DCRT (3-dimensional conformal radiation technique) in 8 patients, IMRT (intensity modulated radiotherapy) in 8, and conventional planning in the remaining patients. Planned radiation course was completed by 27 patients.

3.4. Failure Pattern

At a median followup of 36 months, 27 patients had failed. Local failure was the predominant type seen in 26 patients (96.3%). One patient had both local and distant failure. The local control rate was 34.1% at 3 years. The median PFS was 10 months. The OS at 24 months and 36 months was 41% and 35%, respectively. The variables evaluated included age, gender, serum albumin, haemoglobin, body mass index, grade of tumour, response to NACT, drug regimen, dose intensity, and local treatment. None of the variables affected the PFS and the only factor affecting OS was baseline serum albumin level (Figures 2 and 3).

4. Discussion

Carcinoma maxillary sinus is a challenging tumour to treat. The anatomical proximity to vital structures, locally advanced nature at presentation, and the biological aggressiveness have resulted in inferior outcomes compared to other head and neck subsites. There is a paucity of well-designed, large, and randomised studies specifically addressing maxillary cancers. As seen in Table 3, the studies are mostly retrospective case series which have low numbers, patients treated over decades, and both early and late stage carcinoma maxilla and include patients with malignancy of other paranasal sinuses [47, 9, 12, 1522]. The available data suggests that in locally advanced tumours, surgery followed by radiation leads to better outcomes than radical radiation alone [58, 12]. There have been some studies on concurrent chemoradiation too that have shown benefit [4]. Overall, the reported survival in these studies has been between 34 and 40% at 5 years [2, 4, 23]. A previously published study from our centre by Qureshi et al. also reported a 3-year survival rate of 38% [9].


StudyNumberProportion of T4Local controlOS

Paulino et al. [5]4850% Sx + RT 3 years —65.2%
RT 3 years —22.7%
NR
Jansen et al.* [6]7359% Sx + RT 5 years —65.0%
RT 5 years —47%
Sx+RT 5 years —60.0%
RT 5 years —9%
Waldron et al. [15]11071% Five years—42%Cause specific survival (5 years)—43%
Hayashi et al. [7]6248% CT-RT + Sx 5 years —84%
RT 5 years —18.2%
CT-RT + Sx 5 years —68.5%
RT 5 years —9.1%
Myers*et al. [16]14188% 51% median 336 days Five years disease specific survival—52%
Duthoy* et al. [17]3944% Two years—73%
Cribriform plate invasion: 7 months
Two years—68%
Dirix et al. [18]127Five years: 53%Five years 54%
Hoppe et al. [20]8552% Five years local progression free: 62%Five years overall survival: 67%
Gabriele* et al. [12]31Sx + RT 5 years —74.0%
RT 5 years —20%
Sx + RT 5 years —72.0%
RT 5 years —25%
Hoppe et al. [20]3939 Five years: 21%Five years: 15%
Ramalingam et al. [22]2412 Five years: 25%Five years: 25%
Qureshi et al. [9]7336 Three years: 54.8%Three years: 38%
Jang et al. [4]3022 Five years: 29%Five years: 34%

These studies which have included paranasal sinus patients rest are restricted to maxillary sinus carcinomas.

In the present study, we evaluated the role of induction chemotherapy followed by local therapy. We specifically wanted to assess the feasibility and effectiveness of surgery in patients following induction therapy whenever feasible. The primary reason for using NACT has been the discouraging results with radical radiation alone. In our study, all patients had squamous cell carcinoma, T4 disease, and around (2/3)rd of the patients (28 patients) had tumour invasion of the base of skull. All these have been documented to be poor risk factors in the literature [6, 19]. Despite this, our 3-year OS of 35% is comparable to our own published literature [9]. Significantly, in our previous study, 37.5% of patients had positive margins after surgery while in the present analysis, there was no margin positivity despite all the patients having upfront technically unresectable tumour (Table 4). Induction chemotherapy resulted in successful surgery in 12 patients out of 43 patients (27.9%) with technically unresectable patients.


Present seriesOld series [9]

Number of patients4162
Time period2008–20111994–1999
Stage IV100.00%58.50%
Induction chemotherapy100.00%0.00%
Radically treated100.00%100.00%
Margin positive rate0.00%37.50%
Three-year OS35.00%38.00%

Another factor which may have improved outcomes in our series is the use of advanced conformal radiotherapy techniques. Dirix et al. have previously reported on the use of 3D CRT (3-dimensional conformal radiotherapy) and IMRT (intensity modulated radiotherapy) at this site [18]. In their report, 2-year local control of 76% and OS of 89% were achieved. IMRT improved disease free survival from 60% to 72% compared to 3 DCRT ().

We used induction chemotherapy primarily consisting of 2 drugs with a taxane and platinum. The results with a similar regimen have been previously reported from Texas by Hanna et al. [3]. The response rate in our study is lower than the 67% reported in that study. The difference might be explained by the advanced stage of tumours in our study and the inclusion of other paranasal sinus malignancies in the study from Texas. The regimen was well tolerated, with an average relative dose intensity of more than 0.85 maintained by 80% of subjects and no treatment related mortality. The 2-drug protocol is easier to administer and needs fewer days of hospitalisation, which is an important consideration in resource-constrained countries. Though the numbers are small, the use of 3 drugs did not improve outcomes in terms of response rate, OS, and PFS.

The failure rate is significant and the majority occur in the first year. This pattern of early locoregional failure is consistent with previous literature [9, 12, 22]. By reducing the bulk of the tumour, induction chemotherapy facilitates surgery and also reduces the area of high risk CTV (critical tumour volume) in radiation planning.

5. Conclusion

Induction chemotherapy may be effective in locally advanced technically unresectable maxillary cancers and leads to successful surgery in a significant proportion of patients. Our protocol of 2-drug regimen of taxane and platinum is effective and well tolerated. These findings are preliminary and require fsurther studies for confirmation.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. B. Ansa, M. Goodman, K. Ward et al., “Paranasal sinus squamous cell carcinoma incidence and survival based on Surveillance, Epidemiology, and End Results data, 1973 to 2009,” Cancer, vol. 119, no. 14, pp. 2602–2610, 2013. View at: Google Scholar
  2. J. H. Kang, S. H. Cho, J. Pyeong-Kim 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,” Journal of Oral and Maxillofacial Surgery, vol. 70, no. 7, pp. 1717–1723, 2012. View at: Publisher Site | Google Scholar
  3. E. Y. Hanna, A. D. Cardenas, F. DeMonte et al., “Induction chemotherapy for advanced squamous cell carcinoma of the paranasal sinuses,” Archives of Otolaryngology: Head and Neck Surgery, vol. 137, no. 1, pp. 78–81, 2011. View at: Publisher Site | Google Scholar
  4. N. Y. Jang, H.-G. Wu, C. Park II et al., “Definitive radiotherapy with or without chemotherapy for T3-4N0 squamous cell carcinoma of the maxillary sinus and nasal cavity,” Japanese Journal of Clinical Oncology, vol. 40, no. 6, pp. 542–548, 2010. View at: Publisher Site | Google Scholar
  5. A. C. Paulino, J. E. Marks, P. Bricker, E. Melian, S. P. Reddy, and B. Emami, “Results of treatment of patients with maxillary sinus carcinoma,” Cancer, vol. 83, no. 3, pp. 457–465, 1998. View at: Google Scholar
  6. E. P. M. Jansen, R. B. Keus, F. J. M. Hilgers, R. L. M. Haas, I. B. Tan, and H. Bartelink, “Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma?” International Journal of Radiation Oncology Biology Physics, vol. 48, no. 1, pp. 27–35, 2000. View at: Publisher Site | Google Scholar
  7. T. Hayashi, S. Nonaka, N. Bandoh, Y. Kobayashi, M. Imada, and Y. Harabuchi, “Treatment outcome of maxillary sinus squamous cell carcinoma,” Cancer, vol. 92, no. 6, pp. 1495–1503, 2001. View at: Google Scholar
  8. S. Porceddu, J. Martin, G. Shanker et al., “Paranasal sinus tumors: Peter MacCallum Cancer Institute experience,” Head and Neck, vol. 26, no. 4, pp. 322–330, 2004. View at: Publisher Site | Google Scholar
  9. S. S. Qureshi, D. A. Chaukar, S. D. Talole, and A. K. D’Cruz, “Squamous cell carcinoma of the maxillary sinus: a Tata Memorial Hospital experience,” Indian Journal of Cancer, vol. 43, no. 1, pp. 26–29, 2006. View at: Google Scholar
  10. H. S. Won, S. H. Chun, B. S. Kim et al., “Treatment outcome of maxillary sinus cancer,” Rare Tumors, vol. 1, no. 2, article e36, 2009. View at: Google Scholar
  11. M. Ashraf, J. Biswas, A. Dam et al., “Results of treatment of squamous cell carcinoma of maxillary sinus: a 26-year experience,” World Journal of Oncology, vol. 1, no. 1, pp. 28–34, 2010. View at: Google Scholar
  12. A. M. Gabriele, M. Airoldi, M. Garzaro et al., “Stage III-IV sinonasal and nasal cavity carcinoma treated with three-dimensional conformal radiotherapy,” Tumori, vol. 94, no. 3, pp. 320–326, 2008. View at: Google Scholar
  13. V. M. Patil, V. Noronha, V. K. Muddu et al., “Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: does it make a difference?” Indian Journal of Cancer, vol. 50, no. 1, pp. 1–8, 2013. View at: Google Scholar
  14. Q. Shi, E. S. Pavey, and R. E. Carter, “Bonferroni-based correction factor for multiple, correlated endpoints,” Pharmaceutical Statistics, vol. 11, no. 4, pp. 300–309, 2012. View at: Google Scholar
  15. J. N. Waldron, O. ’Sullivan B, P. Gullane et al., “Carcinoma of the maxillary antrum: a retrospective analysis of 110 cases,” Radiotherapy and Oncology, vol. 57, no. 2, pp. 167–173, 2000. View at: Google Scholar
  16. L. L. Myers, B. Nussenbaum, C. R. Bradford, T. N. Teknos, R. M. Esclamado, and G. T. Wolf, “Paranasal sinus malignancies: an 18-year single institution experience,” The Laryngoscope, vol. 112, no. 11, pp. 1964–1969, 2002. View at: Google Scholar
  17. W. Duthoy, T. Boterberg, F. Claus et al., “Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients,” Cancer, vol. 104, no. 1, pp. 71–82, 2005. View at: Publisher Site | Google Scholar
  18. P. Dirix, B. Vanstraelen, M. Jorissen, V. Vander Poorten, and S. Nuyts, “Intensity-modulated radiotherapy for sinonasal cancer: improved outcome compared to conventional radiotherapy,” International Journal of Radiation Oncology Biology Physics, vol. 78, no. 4, pp. 998–1004, 2010. View at: Publisher Site | Google Scholar
  19. P. Dirix, S. Nuyts, Y. Geussens et al., “Malignancies of the nasal cavity and paranasal sinuses: long-term outcome with conventional or three-dimensional conformal radiotherapy,” International Journal of Radiation Oncology Biology Physics, vol. 69, no. 4, pp. 1042–1050, 2007. View at: Publisher Site | Google Scholar
  20. B. S. Hoppe, C. J. Nelson, D. R. Gomez et al., “Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities,” International Journal of Radiation Oncology Biology Physics, vol. 72, no. 3, pp. 763–769, 2008. View at: Publisher Site | Google Scholar
  21. B. S. Hoppe, L. D. Stegman, M. J. Zelefsky et al., “Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting-the MSKCC experience,” International Journal of Radiation Oncology Biology Physics, vol. 67, no. 3, pp. 691–702, 2007. View at: Publisher Site | Google Scholar
  22. B. Ramalingam and V. Ebenezer, “Retrospective analysis of survival of patients with squamous cell carcinoma of the maxilla after primary resection and elective bilateral neck dissection: an institutional experience,” Annals of Maxillofacial Surgery, vol. 1, no. 1, pp. 42–47, 2011. View at: Google Scholar
  23. K. Freier, M. Engel, K. Lindel et al., “Neoadjuvant concurrent radiochemotherapy followed by surgery in advanced Oral Squamous Cell Carcinoma (OSCC): a retrospective analysis of 207 patients,” Oral Oncology, vol. 44, no. 2, pp. 116–123, 2008. View at: Publisher Site | Google Scholar

Copyright © 2014 Vanita Noronha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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