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 Table of Contents  
Year : 2019  |  Volume : 7  |  Issue : 2  |  Page : 52-61

Induction chemotherapy in sinonasal malignancies: A review of literature

1 Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
2 Department of Otorhinolaryngology, University of Genoa, Genoa, Italy
3 Department of Head and Neck Oncology and Plastic and Reconstructive Surgery, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

Date of Submission27-Jan-2020
Date of Acceptance02-Feb-2020
Date of Web Publication21-Feb-2020

Correspondence Address:
Deepak Balasubramanian
Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_6_20

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Sinonasal cancers form a distinct subset of head-and-neck tumors. They exhibit varied histologies with different clinical outcomes. These tumors are rare, and there exists no randomized trial identifying the ideal treatment for these patients. Induction chemotherapy (CT) has been tried with varying success for different purposes such as bioselection, improving outcomes, orbital preservation, and reduction in the extent of surgery. The purpose of this review is to examine and present the literature regarding the use of induction CT in sinonasal cancers and their outcomes.

Keywords: Chemoselection, induction chemotherapy, sinonasal cancer

How to cite this article:
Subramanian N, Marchi F, Camillo Carobbio AL, Missale F, Balasubramanian D, Thankappan K, Iyer S. Induction chemotherapy in sinonasal malignancies: A review of literature. J Head Neck Physicians Surg 2019;7:52-61

How to cite this URL:
Subramanian N, Marchi F, Camillo Carobbio AL, Missale F, Balasubramanian D, Thankappan K, Iyer S. Induction chemotherapy in sinonasal malignancies: A review of literature. J Head Neck Physicians Surg [serial online] 2019 [cited 2022 Nov 29];7:52-61. Available from: https://www.jhnps.org/text.asp?2019/7/2/52/278891

  Introduction Top

Sinonasal tumors are a distinct subset in head-and-neck cancers. Unlike the oral cavity and laryngopharynx, there is a wide spectrum of tumor histologies that can affect this site. Surgery remains the mainstay in the treatment of these tumors. The close proximity to the skull base and the orbit makes the surgical management challenging. Certain attempts have been made to use an alternative strategy namely the use of induction chemotherapy (CT) in the management of these tumors. The purpose of this review is to study the effects of induction CT in the management of sinonasal malignancies of varied histologies (as summarized in [Table 1]).
Table 1: Summary of literature

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  Squamous Cell Carcinoma Top

Squamous cell carcinoma (SCC) is the most common type of tumor affecting the skull base. The therapeutic approach for early-stage sinonasal SCC (SNSCC) tends to be unimodal. In advanced tumors, multimodality treatment is advocated. The extent of the primary surgery is varied, however, in certain instances, primary surgery would include orbital exenteration. Advanced lesions tend to have poor prognosis in spite of multimodal treatment. In Stage III–IV SNSCC, to achieve better disease control and reduce treatment-related morbidity with regard to the orbit, the incorporation of neoadjuvant CT had been advocated by some authors.[1],[2] The use of induction CT has been tried for two reasons, i.e., to improve tumor control and for orbital preservation.

Hanna et al. studied the effects of induction CT for disease control.[2] Their population of 46 previously untreated patients affected by locally advanced (Stages III–IV) SNSCC received induction CT. The treatment regimen was a combination of a taxane and platinum in 80% of patients, by themselves (14 patients) or in combination with a third agent, such as ifosfamide (14 patients) or 5-fluorouracil (9 patients). The combination of a taxane and 5-fluorouracil was used in the remaining nine patients. They observed a high rate of partial response (67% of the cohort): 9% had stable disease and 24% had progressed. Subsequent treatment consisted of surgery (22 patients), usually followed by postoperative radiation (n = 15) or chemoradiation (n = 5) or with definitive radiation (n = 14) or definitive chemoradiation (n = 8), with planned surgical resection for any residual disease (n = 2). Two patients that showed progression after induction CT refused further therapy. The selection criteria for subsequent therapeutic strategy were not mentioned. The disease-free survival (DFS) was 85%; in most of the cases, recurrences observed were local. The disease-specific survival (DSS) improved in one-third of patients who had response or stable disease with induction CT compared with those who had progressive disease (P = 0.008) and interestingly, the observed improved survival in patients who responded to induction CT seems to be independent of their subsequent definitive local therapy. In contrast, only 1 of the 11 patients with progressive disease after induction CT was alive at last contact, regardless of subsequent local therapy. The survival benefit in responders is supported even by previous studies. Similar outcome was reported in an earlier series from the same institution, using intra-arterial route of administration of CT; the main concern was the substantial toxicity, especially of the neurological toxicity seen in 10% of the study population.[3]

In other studies, the most frequent inclusion criteria to enroll patient for induction were the requirement of major craniofacial resection/orbital exenteration as an upfront treatment. In a French series, the study population was divided into three groups according to treatment strategy: 25 patients underwent nonsurgical therapy (CT or radiotherapy [RT] or chemoradiotherapy [CTRT]); 40 patients had induction treatment with CT (34) or RT (1) or concurrent CTRT (5) followed by surgery; and 8 patients underwent primary surgery. Among the surgical group, 51 had postoperative RT or CTRT. CT was administered in a subgroup of selected patients with locally advanced disease, with a combination of cisplatin and 5-fluorouracil and taxol. Enrollment criteria for upfront nonsurgical therapy were internal carotid artery invasion, cavernous sinus involvement, massive intracranial invasion, distant metastasis, and poor general status. In case of very good response to the induction, surgery and 64 Gy of postoperative RT or postoperative CTRT were attempted in selected cases of young patients without comorbidities. Among the surgical group, patients that received neoadjuvant CT performed better. Tumors treated without surgery showed a 3-year survival rate of 19%, whereas it was 65% for patients treated with surgery; local control (LC) was achieved in 48% for the group treated without surgery and 72% for the group treated with surgery (P < 0.05), and the 5-year survival rates were 10% and 58%, respectively. It is clear that these results could reflect a selection bias as patients treated without surgery present a more advanced disease than patients treated with surgery.[4]

A study from Korea, on the basis of MD Anderson series, evaluated the role of induction CT in locally advanced (T3-T4a-T4b) SNSCC in terms of survival and organ preservation (eye preservation). Tumors invading the orbital floor, or the orbital contents, or the orbital apex, were selected; in this group, orbital exenteration would have been indicated. The use of induction CT was attempted to preserve the orbit.

All the patients enrolled received a full regimen of induction CT every 3 weeks with docetaxel, cisplatin, and fluorouracil. Majority (76.2%) of the patients tolerated full dose of induction CT. After induction, patients received definitive treatment with CCRT, RT alone, or surgery. CCRT regimens consisted of conventional standard fractionated RT of more than 60 Gy for primary tumor and regional lymph nodes, with concurrent CT with weekly administration of cisplatin 35 mg/m 2. Responses were evaluated according to RECIST. All patients who achieved a partial response also achieved downstaging of the T stage, a longer 5-year overall survival (OS) (64%), and eyeball preservation (100%). This is in contrast to nonresponders where eyeball preservation was seen in only 62% of the cases, with an OS of 16.7% (P = 0.027).[5]

Chen et al. investigated the efficacy of induction CT followed by CCRT in patients with T4b tumors (16 cases of maxillary SCC, 10 cases of ethmoid SCC, and 1 case of nasal cavity SCC) assessing the impact of the strategy on organ preservation rate and quality of life. In this cohort, 27 patients completed the therapeutic protocol. Patients were candidates for one to two courses of induction therapy. The number of induction courses was determined using imaging with magnetic resonance imaging contrast enhancement: if the tumor was significantly reduced after one cycle of therapy, with clearance of the orbital apex, the rear of the eyeball, and the craniocerebral area, the patient was treated with CCRT ± epidermal growth factor receptor inhibitor. Otherwise, a second cycle of induction was applied. A regimen of taxane with cisplatin or taxane, cisplatin, and 5-fluorouracil combination was administrated. RT dosage ranged from 60 to 70 Gy. Ninety-six percent of the cohort completed the scheduled therapy. All patients were able to tolerate the adverse reactions of the treatment, classified mostly as moderate. In the cited article, 1 month after treatment, reduction of the primary tumor >80% was achieved in 100% of the patients. The 3-year OS, LC, and organ preservation were 59.2%, 80.2%, and 78.8%, respectively. However, the addition of targeted therapy did not show any survival improvement.[6]

Given the heterogeneity and paucity in published data, no definite conclusions can be ascertained with regard to the role of induction CT in SCC of the sinonasal area. Tumor response after induction could be a predictor of prognosis; the response rate ranges from 60% to 70%. The main issue is to determine who would benefit from induction CT as clinicopathologic characteristics do not differ between patients who achieved a partial response and patients with stable or progressive disease.

  Intestinal-Type Adenocarcinoma Top

The age-standardized incidence per 100,000 person-years of intestinal-type adenocarcinoma (ITAC) has been reported to be 0.26–0.04 (male–female) in Europe and 0.058–0.034 (male–female) in the USA.[7] Five pathological types of ITAC have been described: papillary (18%) and colonic (40%), both classified as “low-grade” tumors (G1–G2), and solid (20%), mucinous, and mixed (22%), classified as “high-grade” tumors (G3). Papillary are well differentiated (G1). Colonic-type ITAC consists of moderately differentiated cells (G2) with a mixed tubulopapillary pattern and an increased mitotic rate. Solid- type ITACs are poorly differentiated and can be characterized by a solid growth pattern (G3). Mucinous-type ITACs generally show a diffuse pattern formed by alveolar goblet or signet ring cells and mucin lakes and are the most aggressive subtype.[8],[9] It is mandatory to discern among those subgroups because the treatment strategies are different. In head-and-neck SCC, the functional status of p53 is a predictor of response to induction CT.[10] Licitra et al. demonstrated the importance of the mutation of the TP53 gene and the functional status of p53 protein in ITAC.[11] The combination of these data is of paramount importance because TP53 nonsense or silent mutations could transcript for a functional p53 protein.[12] In the Italian cohort, patients affected by biopsy-proven ITAC were submitted to induction CT. The CT regimen consisted of primary leucovorin, fluorouracil, and cisplatin (PFL) for five cycles followed by anterior craniofacial resection and postoperative RT. Each cycle was repeated every 21 days for five courses. Clinically responding patients received three or more cycles, whereas nonresponders received two or fewer cycles. A complete pathologic remission (pCR) was defined as absence of any viable tumor cells in the surgical specimen.

Twelve patients achieved a pCR, whereas 18 patients did not (overall response rate, 40%). In patients with wild-type TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively, and in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P < 0.0001). At a median 55-month follow-up, all pCR patients were disease free; 44% of the nonresponding patients experienced relapse.[11]

The same Italian group reviewed 100 consecutive patients with untreated ITAC, of whom 74 patients were evaluable for TP53 analysis. The authors divided this cohort into two groups: Group A received craniofacial resection followed by RT and Group B received PFL induction CT followed by standard treatment. Five-year OS in Groups A and B was 41.8% versus 70.4% (P = 0.04), and 5-year DFS in Groups A and B was 40.0% versus 65.9% (P = 0.009). Both OS and DFS according to p53 functional status were in favor of patients carrying p53 functional tumor; nonfunctional p53 was associated with worse OS (P = 0.024), with a hazard ratio (HR) of 2.32. One of the most interesting findings was that nonfunctional p53 was associated with a significantly worse outcome in the induction CT group. On the contrary, in the group not receiving CT, no significant prognostic role for p53 functionality was highlighted. These observations point to a predictive role for induction CT rather than a prognostic role of functional p53: in fact, no prognostic role could be identified when CT was not administered. These results could guide the treatment strategy whether or not to perform induction PFL CT. Remarkably, the induction CT prognostic effect was maintained at multivariable analysis, taking into account possible inhomogeneity between the groups in postoperative RT and tumor stage.[13] Neoadjuvant CT with a platinum-based regimen can provide a survival benefit in selected ITACs with functional p53. In addition, recent advances in understanding the carcinogenetic mechanisms and genetic alterations involved in the tumor may contribute to defining a role for biotherapy.[7]

  Olfactory Neuroblastoma Top

Olfactory neuroblastoma (ONB) is a rare entity, comprising under 5% of sinonasal tract malignancies, arising from the olfactory neuroepithelium.[14] These tumors can show a range of biological behavior, ranging from an indolent slow-growing tumors to aggressive disease with a high metastatic potential.[15] This would explain why chemosensitivity could vary significantly; patients with a high Hyam's histological grade (based on the preservation of lobular architecture, mitotic index, nuclear pleomorphism, fibrillary matrix, and presence of rosettes and necrosis) would, in theory, respond better to CT.

The approach to this tumor is dependent on the Kadish staging system (which was modified by Dulguerov), where Group A includes tumors limited to the nasal fossa, Group B include tumors involving the paranasal sinuses, Group C involves extension beyond the paranasal sinuses (to the skull base, dura, brain parenchyma, and orbit), and Group D includes lymph node and distant metastases. Induction CT was first advocated for Kadish Group C disease by the group from the University of Virginia, who treated these patients with VAC regimen (two cycles of cyclophosphamide 300–650 mg/m 2 and vincristine 1–2 mg with or without adriamycin 40–50 mg/m 2 intravenously), followed by 50 Gy of RT and then craniofacial resection.[16] With this regimen, they were able to achieve excellent success; the OS at 10 years was 60%.

Apart from the University of Virginia protocol, most centers preferred cisplatin-based regimens, with certain institutions using a combination of cisplatin and etoposide.[17],[18] Fitzek et al. used two cycles of cisplatin (33 mg/m 2) and etoposide (100 mg/m 2) in 19 Kadish Group B and C patients, followed by a radical resection and proton beam RT.[19] The response rate was favorable with a 5-year OS of 88%. Kim et al. used a different induction CT regimen of cisplatin (20 mg/m 2), etoposide (75 mg/m 2), and ifosfamide (1000 mg/m 2) for a median of 4 cycles in 11 patients. Nearly 82% of these patients experienced a tumor size reduction by >50%. In this series, patients went on to receive surgery with adjuvant RT, radical RT, or no further treatment, depending on the response and subsequent performance status.[20]

Induction CT has the potential to be used to decide the choice of radical therapy. Patil et al. described their experience of administering induction CT in 25 patients with locally advanced (resectable and nonresectable) nonsquamous sinonasal tumors, of which 12 had ONB and 13 had tumors with neuroendocrine differentiation.[21] They were treated with two cycles of cisplatin (33 mg/m 2) and etoposide (100 mg/m 2), following which they were assessed for response on cross-sectional imaging (computed tomography [CT] or positron emission tomography-CT). Those who were candidates for complete surgical resection were offered radical surgery with adjuvant CTRT, while those in whom gross total resection was not possible were offered radical CTRT or palliative RT, depending on the patients' preference and the tumor volume. The overall response rate to induction CT was good, at 80%, with an OS of 78.5%.

The current indication for induction CT in ONBs is in locally advanced tumors, where significant downstaging can help achieve better surgical resection margins and possibly lower postoperative complication rates. It is crucial to note that, however, all the data presented are retrospective, and it is unclear how the surgeons altered their resection margins after induction CT. There is no Level I evidence that shows that resection margins based on the postinduction CT imaging are adequate; this needs to be factored in treatment planning. It is also unclear if induction CT is beneficial in upfront resectable disease, or in patients planned for radical concurrent CTRT.

  Sinonasal Undifferentiated Carcinoma Top

The use of CT in sinonasal undifferentiated carcinoma (SNUC) is common place, with the National Cancer Database review by Kuo et al. showing that almost 73% of patients received some form of CT as part of their treatment.[22] Some of the agents that have been described for use are cisplatin (most common), etoposide, 5-fluorouracil, docetaxel, and paclitaxel. As it is an aggressive cancer with a propensity for distant metastases, CT is a definite consideration for any patient who can tolerate it. Some of the first reports of the use of CTRT in SNUC were from the University of Virginia Health Sciences Centre, where twenty patients were treated according to a policy of induction CT with vincristine (1–2 mg), adriamycin (40–50 mg/m 2), and cyclophosphamide (300–650 mg/m 2) (VAC regimen), followed by radical RT of 50–63 Gy and craniofacial resection. The 2-year OS for the entire cohort was 47%; survival in the groups treated with and without surgery after initial CTRT was 64% and 25%, respectively.[23]

Rischin et al. showed the results of ten patients with SNUC treated with concurrent CTRT, seven of whom received induction CT with two cycles of cisplatin (100 mg/m 2) and 5-fluorouracil (1000 mg/m 2 given as a continuous infusion for 5 days) followed by RT with two cycles of concurrent cisplatin. None of the patients who received induction CT had distant metastases at follow-up (range 8–62 months). The 2-year OS and DFS were 64% and 43%, respectively.[24]

Mourad et al. published their experience of 18 patients with SNUC where patients received surgery alone (three Stage II patients), surgery followed by adjuvant CTRT (12 Stage III–IVA patients), or radical concurrent CTRT (three Stage IVB patients).[25] All the Stage IVB patients received induction CT with TPF (docetaxel 75 mg/m 2, cisplatin 75 mg/m 2, and 5-fluorouracil at 750 mg/m 2) for 2–3 cycles. The results of the whole cohort were favorable; the 2-year LC, DFS, and OS were 78%, 72%, and 56%, respectively. However, both the patients in the cohort who developed distant metastases had received induction CT.

Al-Mamgani et al. described their experience on treating 21 consecutive patients with SNUC who were treated with surgery and adjuvant RT (n = 5), surgery and adjuvant CTRT (n = 2), radical CTRT (n = 7), and induction CT followed by surgery and adjuvant RT (n = 7).[26] The protocol used was four cycles of cisplatin (80 mg/m 2 on day 1) and etoposide (100 mg/m 2 on days 1–3). Patients who received induction CT were clinically Stage T4b (intracranial or intradural spread, optic pathway involvement, invasion of cavernous sinus, or carotid encasement). They noted that all those receiving induction CT who went on to receive surgery had a much better LC than those who did not (85% vs. 25% at 5 years; hence, they suggested that induction CT had an important role in treating patients for whom adequate surgical clearance was doubtful).

A constant debate has been whether treatment with two modalities (radical concurrent CTRT with or without induction CT) is inferior to treatment with three modalities (surgery followed by adjuvant concurrent CTRT); this is yet to be resolved. The largest systematic review and meta-analysis was published by Morand et al. on 390 patients; they found that treatment with two modalities was superior to treatment with one modality, but not superior to treatment with three.[27]

Another potential role for induction CT, although not yet well established, is chemoselection, using treatment response to decide between surgical and nonsurgical radical therapy. Moran et al. published their experience of 95 patients with SNUC who received induction CT followed by surgical or nonsurgical definitive treatment.[28] Their regimen for induction CT was cisplatin (60–80 mg/m 2) on day 1 and etoposide (100–120 mg/m 2) or docetaxel (75 mg/m 2) on days 1–3, administered intravenously once every 21 days. The median number of CT cycles administered was three (range 1–5). Following induction CT, the patients received definitive locoregional therapy in the form of concurrent CTRT or surgery with adjuvant radio/CTRT. The response rate to induction CT was 67%. Interestingly, they noticed that among those who responded to induction CT, 5-year DSS in those treated with radical CTRT was significantly better than those treated with radical surgery and RT. It is to be noticed, however, that the choice of local therapy after induction CT was left to the treating physician, without any objective decision-making criteria. None of the patients who had no response to induction CT were alive at 5 years.

Although robust evidence is lacking, the current indications for induction CT in SNUC are to reduce tumor volume for favorable resections (borderline resectable or unresectable), as part of an organ preservation strategy by following up with chemoradiation and more controversially, to downstage disease from requiring an open resection to an endoscopic approach.[29] Cisplatin-based CT has better response rates than the traditional VAC regimens and should be preferred.[23] Although induction CT may play a role in choosing local therapy, it is unclear if induction CT adds any benefit to those patients otherwise planned for radical CTRT.

  Sinonasal Neuroendocrine Carcinoma Top

Sinonasal tumors with neuroendocrine differentiation are a rare group of neoplasms that account for only 5% of all sinonasal malignancies. Frequently, an ambiguous nomenclature is maintained regarding the undifferentiated carcinoma, the poorly differentiated large cell or small cell neuroendocrine carcinoma (SNEC), the well-differentiated neuroendocrine carcinoma (carcinoid tumor), and moderately differentiated neuroendocrine carcinoma (atypical carcinoid tumor).[30]

In a study reporting the outcome of neoadjuvant CT in various SNECs, 13 patients affected by SNEC were included. CT used was cisplatin and etoposide based, and it was well tolerated. SNEC had a 2-year OS and progression-free survival (PFS) of 64% and 57.0%, respectively. In this series, neuroendocrine carcinomas were reported to be chemosensitive because 80% of the patients were considered responders; however, the stage of disease and response to CT were not found significantly associated with median PFS, and in SNEC patients, the benefit of neoadjuvant CT was less prominent. The authors concluded that neoadjuvant CT followed by local treatment is associated with improvement in outcomes, but without distinguishing which population of neuroendocrine carcinoma benefits from CT.[21]

In 2017, an Italian multi-institutional study demonstrated the protective effect of induction CT in 22 patients affected by poorly differentiated SNEC. This regimen consists of cisplatin and etoposide delivered up to a maximum of five cycles. In the multivariate analysis, induction CT emerged as the only statistically significant prognostic factor for OS (HR = 16.8, P= 0.01) and DFS (HR = 4, P= 0.04). Sixty-three percent of the population experienced distant metastasis and 54% died of the disease. These findings underline the aggressiveness of poorly differentiated SNEC with the need of multimodal treatment, combining local and systemic therapy.[31] A recent feature regarding SNEC that emerged is the association in some patients with high-risk HPV positivity. Unlike SCC, neuroendocrine carcinomas are very rare, and the HPV-positive subgroup is even rarer. Most importantly, in contrast to the excellent clinical behavior typically associated with HPV-positive oropharyngeal squamous carcinoma, HPV-positive SNEC does not correlate with improved patient outcome. The prevalence and clinical significance of HPV in SNEC is unclear and needs further study. This entity has not been deeply investigated and could represent a different disease, previously unnoticed and considered the same as HPV-negative SNEC.[32]

In a meta-analysis which evaluated 127 patients treated for SNEC, the authors attempted to identify the best treatment combination. While there was a trend favoring surgery in SNEC, no statistically significant difference could be observed (P = 0.077). RT did not yield better results in these patients (P = 0.199), while the application of CT was associated with a significantly unfavorable outcome. Patients with SNEC treated without surgery had a significantly higher chance of dying of disease. For SNEC, surgery as monotherapy produced the most favorable results (5-year DSS 83.3%). Due to the nature of the study, care should be taken in interpreting the resulting analyses. Moreover, decoupling the combination of treatment modalities introduces an obvious bias.[33]

Two aspects emerge from the literature: SNEC represents a broad variety of disease that overlap histologically, each with a peculiar behavior; for this reason, conflicting results are reported. Second, the role of induction is controversial and an ideal treatment strategy is elusive because of the rarity of cases and the heterogeneity of treatment approaches.[34] Well-differentiated SNEC does not appear to benefit from induction CT and surgery represents the mainstay, unlike poorly differentiated SNEC in which 4–5 cycles of cisplatin and etoposide seem to offer a survival improvement. In contrast to other head-and-neck cancers, tumor staging appears of limited value in predicting survival or deciding on a treatment strategy, whereas tumor grading plays a pivotal role.[30] Lastly, given the heterogeneity in the types of SNEC and its nomenclature, referral of these cases to high-volume centers may lead to a more accurate pathological diagnosis. Obtaining abundant biological specimen under general anesthesia may reduce the risk of diagnostic error and inadequate treatment.[35],[36]

  Sinonasal Mucosal Melanoma Top

Ranging from 4% to 8% of the sinonasal malignancies, mucosal melanoma represents one of the most aggressive entities affecting the sinonasal region. Surgery is considered the mainstay.[37] Data regarding induction CT in sinonasal mucosal melanoma (SNMM) are very rare, and there is no prospective trial published in this regard. Indications for CT are less well defined in nonmetastatic (M0) patients, and the role of induction CT in locally advanced disease is under evaluation in ongoing clinical trials. Outcomes are extrapolated from heterogeneous cohorts with different treatment regimen and subsequent therapy.[38] The only data available in the English literature are reported by Hanna et al.[39] They divided their population into four subgroups according to the treatment strategy (surgery with no adjuvant therapy; postoperative radiotherapy [PORT]; postoperative chemoradiotherapy; induction CT; and PORT). Their data did not suggest any survival benefits in patients treated with either of the four protocols. The induction CT regimen consisted of cisplatin, vinblastine, and dacarbazine, however dosage was not reported. Most of the patients enrolled (67%) in the induction group had SNMM arising from the paranasal sinus. The reported OS and DSS were 27% and 43%, respectively, and distant metastasis failure rate in this subgroup was not reported due to low OS rates. From these results, we can presume that death occurred due to local failure. None of the parameters namely OS, DSS, and DFS were affected by the treatment strategy.

There is no other evidence published in the English literature assessing the role of induction in SNMM. Male gender, positive surgical margins, and paranasal sinus origin are the most important factors affecting the prognosis, despite treatment strategies. PORT does not affect survival, but marginally improves the LC. This comes with the cost of increased morbidity, and its use should be carefully balanced. Induction with standard chemotherapeutic agents does not seem to be effective in SNMM. BRAF mutations in mucosal melanomas are very rare, unlike in cutaneous melanomas, thus, the usefulness of target therapies is limited. Targeting RAS and KIT mutations or inhibiting PI3K-Akt-mTOR pathway is emerging as a newer treatment option according to recent findings.[40]

  Sarcomas Top

Sarcomas are tumors that arise from cells of mesenchymal origin. Thus, malignant lesions made up of cancellous bone, cartilage, fat, muscle, vascular, or hematopoietic tissues are, by definition, considered sarcomas, which therefore represent a heterogeneous group of tumors, reflecting a different natural behavior and clinical approach.

Ewing's sarcoma (ES) is a malignant neuroectodermal tumor that generally arises in the long bones or pelvis and less frequently in the soft tissue of the trunk and extremities, Primary head-and-neck ES is uncommon, accounting for 1%–9% of all cases.[41] Lombardi et al. reported a 70-month OS of 80% in a case series of five patients affected by ES with a long-term follow-up that is crucial as there is a risk of long-term relapse of this disease.[42] All patients underwent neoadjuvant CT with the following schemes: vincristine, adriamycin, and cyclophosphamide in two patients; mitomycin C, ifosfamide, and adriamycin in one patient; and vincristine, adriamycin, and ifosfamide in two patients. Subsequent treatment was cranioendoscopic resection and ten cycles of adjuvant CT with vincristine, adriamycin, and ifosfamide in one patient due to minimal response and RT (60–70 Gy) in four patients. In ES, a good response rate (50% used as cutoff from the author) to neoadjuvant CT is a prominent prognostic factor; in fact, the only poor responder died. These results are slightly better compared to those of ES from other human body subsites. Medical therapy represents a milestone in ES since the high tendency to metastasize. Chemotherapeutic schemes include adriamycin, actinomycin D, cyclophosphamide, and vincristine. The subsequent introduction of ifosfamide has shown remarkable results in different studies.[43] In a recent review, summarizing previous case series papers, the authors affirm that 81 patients (87%) received systemic treatment in the form of CT, but only one-third of the patients received CT in the neoadjuvant setting (29 patients, 35.8%). Sixty-eight patients (86%) were disease free, with nine death and two recurrences. The authors underline the need of a multidisciplinary approach as the decision-making process could vary along the local extension of the disease.[44] In a French multicentric analysis, from a large sarcoma database, 48 patients who were affected by sinonasal sarcoma were identified. The most frequent type with the worst prognosis was rhabdomyosarcoma. Fifteen patients received neoadjuvant CT (regimen was not reported), and the remaining cohort received multimodal treatment with upfront surgery or RT. No specific data regarding each type of treatment strategy were reported; for the entire population, the OS rates at 3, 5, and 10 years were 67.1%, 62.3%, and 44.5%, respectively. In this report, the only factors affecting the outcome were the histological type (rhabdomyosarcoma vs. others) and the grading (G1–G2 vs. G3).[45] It is important to distinguish the exact histology of sarcoma because for some of them, surgery and RT are of a paramount importance for LC. However, some sarcomas such as rhabdomyosarcoma and ES are reported to have an excellent response to CT. They classified rhabdomyosarcoma and ES as chemosensitive and chondrosarcoma and undifferentiated/unclassified sarcoma as chemo-resistant sarcomas. The following therapeutic strategies were applied: patients with chemo-sensitive sarcomas underwent four cycles of induction with vincristine, dactinomycin, and cyclophosphamide (for rhabdomyosarcoma) and four courses of vincristine, doxorubicin, and cyclophosphamide/ifosfamide and etoposide (for ES). In case of poor response, patients underwent extensive skull base resections, and in case of good response, patients experienced more limited surgery. All of them had postoperative RT. The cohort with chemo-resistant sarcomas had upfront radical resection and postoperative RT was administered in case of positive surgical margin. Patients with good response to induction had an increased 3-year LC (100% vs. 63%, P= 0.048) even when a more conservative resection was performed. Moreover, as a result of postoperative treatment, patients with microscopic-positive margins had better LC (83%); in contrast, 75% of the patients with macroscopic-positive margins developed local recurrence, despite postoperative treatment (P = 0.014).[46] An international collaborative study reported that positive margins were the only predictor of DSS and decreased DSS of 43%.[47] Induction, therefore, has several aims especially in those cases, when the mutilation brought by surgery seems unacceptably high or complete surgical excision is technically impossible. It also increases the chance to obtain negative margins. In the event that surgery is not performed, radiation therapy may be equally successful. It may prove to be similarly efficacious for achieving good LC without compromising long-term survival.[48]

  Conclusions Top

With this article, we tried to assess the role of induction CT in sinonasal cancer treatment. Sinonasal cancers include a large variety of histological subtypes with different biological behaviors. Histology and tumor grading appear the most relevant prognostic factors and should lead the surgeon in deciding on a treatment strategy, while tumor staging revealed of more limited value. In general, in most cases of advanced sinonasal cancer, a multimodal treatment approach with the contribution of systemic therapy may provide the greatest chance at successful outcome, improving survival with a possible role in organ preservation, sometimes reducing the need for orbital exenteration. Instead, the role played by induction CT in patients' chemo selection is still controversial. An exception to this seems to be the mucosal melanoma, whose survival rates are not improved by any induction CT and where a target therapy may play a more significant role. However, sinonasal cancers may be generally considered chemo-sensitive tumors, and induction CT should at least be taken into consideration as a valid option to offer to patients as part of their multimodality therapy. Unfortunately, due to the rarity of their presentation, what is known about sinonasal cancers' response to therapies comes only from systematic reviews and meta-analysis with the risk of nonhomogeneous data. Prospective randomized trials on large cohorts of patients affected by sinonasal cancer are still lacking in literature, but they can only come from the combined efforts of multiple institutions.

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The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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