Squamous Cell Carcinoma, Undifferentiated Carcinoma, and Adenocarcinoma
Squamous cell carcinoma is the most common histology seen in nasal cavity and paranasal sinus tumors, accounting
for approximately 80% of cases; undifferentiated carcinoma (UC) and ACA are less common.
Typically, SCC and ACA are subclassified on the basis of the histologic grading from well to poorly differentiated, or even undifferentiated. The prognosis is worse for SCC and, in particular, for UC. In general, lymphatic spread to subdigastric, submandibular, and retropharyngeal nodes is infrequent and related to tumor location, histologic grade, and clinical stage. Lymph node involvement is more common (up to 30%) for undifferentiated and maxillary sinus carcinomas, as well as stage IV tumors. Distant metastases were infrequently seen in the past when local control of the primary tumor was uncommon; with the higher rates of local control with more modern surgical and RT techniques, more distant metastases are now being reported.
The treatment strategy for SCC, UC, and ACA depends greatly upon anatomic site and local disease extent. Surgery, when feasible, followed by postoperative RT is the treatment of choice. Invasion of surrounding structures such as dura, brain, orbit, and nasopharynx are usually considered as contraindications for surgery. For these nonoperable cases, definitive RT alone or in combination with chemotherapy is the usual approach.
A 5-year survival rate of 60% to 70% has been reported for ethmoid tumors treated by craniofacial resection and postoperative RT. Orbital exenteration may be avoided in cases of isolated bony orbital extension but it should be performed in cases of frank intraorbital involvement. With intracranial extension or involvement of the nasopharynx or base of skull, there appears to be no survival advantage for surgical debulking. In such cases, primary RT with photons results in 5-year local control rates of approximately 20%.
Surgery and postoperative RT yield the best results in early stage maxillary sinus carcinoma limited to the infrastructure with 5-year local control rates of 50% to 70% and 5- year survival figures of 40% to 65%; primary RT results in approximately 20% local control and 40% 5-year survival. Maxillary sinus tumors involving the suprastructure should be managed by aggressive surgery and postoperative RT. With this combined approach, local control rates for T3 and operable T4 tumors are 40% to 50%. Chemotherapy can be employed as neoadjuvant treatment with using a combination of different active drugs including cisplatin, 5-fluorouracil, gemcitabine, doxorubicin, methotrexate, cyclophosphamide, vincristine, and etoposide. For aggressive SCC and UC tumors, concomitant chemoradiation can be employed, typically using cisplatin and/or gemcitabine. The use of targetted therapies such as cetuximab is under evaluation in clinical studies.
Since the major oncologic risk after surgery is local relapse, postoperative RT with highly conformal techniques is recommended for most patients. Radiation doses in the postoperative setting typically range from 54 Gy to 70 Gy with conventional fractionation. Elective neck RT is often employed for T3-T4 SCC and UC. Definitive RT is adopted in cases where surgery is contraindicated using the same techniques described for postoperative RT but possibly to doses as high as 70 to 75 Gy depending on the dose to critical structures.
The use of protons for epithelial paranasal sinus tumors was studied in PROG protocol 92-15.17
All patients, >
90% stage IV, were treated with hyperfractionated, accelerated proton/photon RT to a dose of 76.5 Gy. The treatment paradigm for this paranasal sinus protocol, first initiated at MGH in 1991 and supported by Loma Linda University Medical Centre (LLUMC), was concomitant boost RT to the primary tumor with protons, complementing a larger photon field incorporating both the GTV and adjuvant treatment volumes. The investigators expended significant effort to limit the total daily dose to the visual system to 180 cGy, while also respecting a total optic chiasm dose limit of 54 Gy. This often required proton treatment to a GTV volume in close (1 to 2 mm) juxtaposition to the chiasm. Dose was delivered with a mixture of photons and protons. Neuro-ophthalmologic and endocrine evaluations were performed before RT and at regular intervals during follow-up.
Primary sites were the maxillary sinus (13), ethmoid sinus (12), sphenoid sinus (3) and nasal cavity (2). The study enrolled advanced cases with a primary stage distribution of T3 in 2 cases and T4 in 23 cases. The five cases without AJCC staging were of T4-equivalent stage when classified along the guidelines for maxillary sinus and ethmoid sinus cancer. Only 4 patients had a gross total resection, with the majority having a biopsy (7) or subtotal resection (19). For the first 20 treatment days, the CTV was treated to 66 Gy (RBE) with b.i.d. fractionation. The 80% 3-year LC rate in the first 30 patients (SCC, ACC, mucoepidermoid, ACA, and sinonasal undifferentiated carcinoma) reported by Thornton in 1998 was updated by Yonemoto in 200440
reporting on the results on the first 36 patients. The 5-year local control rate was maintained in excess of 80% (including esthesioneuroblastoma subtypes) with an overall actuarial 5-year survival rate of 56%. Of particular interest was the lack of visual morbidity, despite the aggressive b.i.d. fractionation and proximity of the optic apparatus.
Reported light ion therapy series only included patients with advanced stage disease; the clinical data are still limited. Lawrence Berkeley Laboratory LBL reported on 12 patients of various histologic types treated by neon ions and noted a 5-year survival rate of 69%.19
The NIRS phase I study of carbon ions included ten patients (five with SCC) in whom the 5-year local control rate was 49%.21
In the phase II study, the 5-year local control was 66% (see subsequent text).29
Adenoid Cystic Carcinoma
ACC is a rare tumor, accounting for 5% to 10% of all salivary gland tumors and 1% of all head and neck malignancies.
These most frequently arise from the minor salivary glands in the head and neck region and especially in the sinonasal tract. The sinonasal tract may also be invaded by lesions arising from the hard palate. ACC are characterized by having an indolent, slow-growing but often relentless, aggressive clinical course, with early perineural invasion and spread along major nerves, as well as along periosteal planes and a high rate (˜50%) of late distant metastasis to the lungs, liver, brain, and bones. On the other hand, nodal metastases are uncommon at presentation or as a late event (5%). In the MGH series, the median duration between the onset of symptoms and diagnosis of the primary tumor was 12 months. Owing to the slow-growing progression of the metastases, aggressive treatment of the primary tumor in patients with distant metastases is often warranted. ACC is considered to be relatively insensitive to chemotherapy and requires high RT doses for local tumor control. Hence, complete surgical removal of the tumor is attempted whenever possible. Adjuvant RT is generally employed as R0 resection is difficult to achieve in most paranasal sinus cancers.
Several series in the literature report the treatment results in patients with paranasal sinus ACC. Rhee et al. reported a 5-year survival figure of 85%, in spite of 5-year local recurrence and distant metastasis rates of 30% and 57% respectively (40% and 70% for T3-T4 lesions) and 10-year figures of 25% and 43% respectively.41
In patients with ACC, advanced T stage (T4), perineural invasion, major nerve involvement, omission of postoperative RT, and RT dose <
60 Gy have been described as independent predictors of local recurrence.42
Inoperable tumors with infiltration of the skull base are considered particularly unfavorable because gross residual tumor requires high target doses rarely achievable with conventional photon RT.44
Twenty-four patients with newly diagnosed locally advanced ACC of skull base, unresectable or with a macroscopically incomplete resection, were treated between 1999 and 2002 at the MGH.46
A high-dose accelerated, b.i.d. fractionated photon/proton protocol was used to deliver 70 to 76.8 (mean 75.9) Gy (RBE) to the GTV or the high-risk volume. The local control rate at 5 years was 93% (two local recurrences). The main site of failure was distant metastasis (38% at 5 years). The 5-year disease-free and OS rates were 56% and 77%, respectively. In multivariate analysis, significant adverse factors predictive for survival were change in vision (p
02) and sphenoid or clivus involvement (p
Carbon Ion Therapy
The rationale to use carbon ions in ACC paranasal tumors is based on the relatively high RBE values of up to 8 reported for high linear energy transfer (LET) RT47
and on favorable results obtained with neutrons compared with photons for unresectable or recurrent salivary gland cancers. The Radiation Therapy Oncology Group (RTOG)-Medical Research Council (MRC), randomized clinical phase III trial showed significantly better locoregional control (LRC) for fast neutron RT as compared to photon RT (56% versus 17% at 10 years).48
At GSI, locally advanced paranasal sinus ACC has been treated with carbon ion RT in a clinical phase I/II trial. Through September 2003, a total of 29 patients with ACC had been treated with a combination of photon IMRT to the CTV and a carbon ion boost to the macroscopic tumor. Only patients with histologically proven, inoperable, incompletely resected or recurrent ACC were included. The CTV, treated to a median dose of 54 Gy in 30 fractions of 1.8 Gy, covered the course of the involved cranial nerves up to their entry into the skull base; regional lymph nodes were not irradiated. The GTV included the macroscopic tumor with a safety margin of 1 to 2 mm. Figure 16A.4
shows a composite IMRT/carbon dose distribution. A dose of 18 Gy (RBE) carbon ion RT was delivered in six fractions of 3.0 Gy (RBE) to the GTV. With median follow-up of 16 months, the 4-year LRC and OS rates were 77% and 75.8%, respectively.49
Severe grade 4 late toxicity was observed in one patient only, who developed recurrent bacterial infections after partial resection including stabilization with metal implants and postoperative photon/carbon RT.
Similar results have been obtained with carbon ion RT at the NIRS in Japan. Between 1994 and 1997, nine patients with locally advanced ACC were treated within a dose escalation trial with carbon ions. Doses of 52.8 to 70.2 Gy (RBE) were given in 16 or 18 fractions over 4 to 6 weeks. The 5-year local control rate with carbon ion RT was 50%.21
In a phase II study of 62 patients treated with
64.0 or 57.6 Gy (RBE) in 16 fractions over 4 weeks, the 5-year local control was 74% and survival was 69%.29
Figure 16A.4 Dose distribution (GSI, Darmstadt, Germany) for a composite plan consisting of a photon intensity-modulated radiotherapy (IMRT) component of 54 Gy and a carbon ion component of 18 Gy (RBE) in a patient with locally advanced adenoid cystic carcinoma. Maximum dose in the composite plan is 82.8 Gy (RBE), the percent isodoses relate to this maximum dose. Orange line = 90% isodose line, yellow line = 80% isodose line, green line = 50% isodose line, and blue line = 30% isodose line. The dotted yellow line represents the 60 Gy (RBE) isodose line. Dose distributions are shown in the axial, coronal, and sagittal planes.
Olfactory neuroblastoma or esthesioneuroblastoma (ENB) is a rare tumor arising from the olfactory epithelium, representing 5% of all malignancies of the sinonasal tract.50
ENB can have variable behavior; some tumors can grow slowly whereas others are aggressive with early spread along the olfactory phyla into the anterior cranial fossa, regional cervical nodes (synchronous and metachronous node involvement has been described in >
20% of patients), and distant metastases in bone, lung, pleura, liver, and the spinal epidural space. Several specific staging classifications have been proposed, including the Kadish et al.4
and the UCLA Dulguerov and Calcaterra.5
T-stage, lymph involvement, Hyams histopathologic grade, postoperative RT, and shrinkage after chemotherapy have been reported as prognostic factors for local control and survival.50
In a meta-analysis and review of publications between 1990 and 2000 conducted by Duguerov et al., mean values (with standard deviation [SD]) for 5-year OS and disease-free survival were 45% (22%) and 41% (21%), respectively.50
OS was different according to the treatment modalities, recognizing however that these were not randomized results and that there were low patient numbers in each treatment group. The mean (with SD) 5-year OS was 37% (33%); 48% (40%); 65% (25%); 51% (45%) and 47% (37%) respectively for RT only, surgery alone, surgery/RT, RT/chemotherapy, and surgery/RT/chemotherapy. Craniofacial resection has been associated with better local control than less extensive surgical approaches.5
The standard photon technique employs three fields (anterior and wedged lateral fields) with dose ranges from 55 to 65 Gy. The role of adjuvant RT after surgery has been reported in several series.52
The role of cervical RT in N0 patients is still a matter of debate.54
The use of neoadjuvant and adjuvant chemotherapy has also been advocated for this pathology.
The role of protons for ENB has been assessed by the MGH group. The treatment schedule was first published in 1997:55
two cycles of cisplatinum and etoposide chemotherapy, followed for responders by combined photon/proton RT of 68 Gy (RBE) to the primary site, or for poor responders by surgical resection followed by RT. In both cases, two additional cycles of adjuvant chemotherapy were added. The b.i.d. RT protocol was based on the same concomitant irradiation strategy as was employed for the more common sinus histologies (1.8 Gy photons in the AM + 1.5 Gy [RBE] protons in the PM), albeit to a lower cumulative dose. Fitzek et al. published the results of 19 patients so treated from 1992 to 1998 (pure ENB in 10 and neuroendocrine or mixed tumors in 9).56
Seventy-nine percent of the patients had Kadish stage C tumors and 74% had base of skull involvement. The median dose to the macroscopic tumor ranged from 67.2 to 72.6 (median 69.2) Gy (RBE) in 38 to 43 (median 40) fractions (range 38-43) over 29 to 49 (median 38) days. The proton component was variable because of scheduling constraints at the HCL—the median proton dose was 22.8 Gy (RBE) until 1996; thereafter it was 43.1 Gy (RBE). The neck was irradiated in all patients (45 Gy in 1.8 Gy/fraction, 5 days a week with photons).56
With a median follow-up of 45 months (range, 20-92), the actuarial 5-year survival, progression-free survival and local control were 74% (SD 48% to 99%), 78.9% (SD 54% to 94%) and 88% (SD 68% to 99%), respectively. Four patients died of metastases (liver, bone, meninges, and spine). Two patients experienced local failure, both salvaged with surgery. The 5-year local control rate with the initial treatment was 88% and was 100% with surgical salvage. Four patients developed frontal/temporal lobe damage; this was grade 2 in three patients who received short-term steroid treatment and grade 3 in one patient. This series was updated in 2004, and included 34 patients at that time.16
With 45 months’ mean follow-up, local control at 3 years was 91%. The principal cause of failure was metastatic disease.
Preliminary data from 13 patients treated with protons ± surgery in Kashiwa, Japan were recently presented.18
The dose was 65 Gy (RBE) in 26 fractions over 6 to 7 weeks. With a median follow-up of 24 months (range 2 to 53), 3-year local control and OS rates were 71% and 90%, respectively. Regional lymph nodes metastases developed in one patient whereas distant metastasis was noted in another.
Mucosal melanoma (MM) of the paranasal sinuses and nasal cavity is rare, representing <
2% of all melanoma cases and approximately 3% to 4% of all sinonasal tumors; nevertheless, it is the most common site of melanoma in the respiratory tract. The most common anatomic sites of involvement are the nasal septum, turbinates, lateral wall of the nasal fossae, and maxillary and ethmoid sinuses.57
Angioinvasiveness appears to predispose to metastases. Advanced disease stage, tumor invasion deeper than 5 to 7 mm, and multicentricity are also associated with a worse prognosis. Amelanotic lesions seem to have a worse prognosis whereas tumors arising on melanotic macules can be less aggressive.
Surgery is the standard treatment of MM of the upper aerodigestive tract. Patients undergoing radical surgical resection fare better than those treated with nonradical surgery or nonoperatively.58
Resection should be performed with wide excision of the primary tumor and regional lymph node dissection when node-positive. Postoperative RT is recommended for macroscopic or microscopic residual disease or as a definitive treatment
when surgery is not feasible;59
in this latter situation, consideration should also be given to adding systemic therapy. While large doses per fraction (>
4 Gy) have been advocated by some to overcome the relative radioresistance of melanoma cells, there is no documented clinical advantage to date for hypofractionation for MM.58
High-LET particles for MM can be justified by the relative radioresistance of some melanoma cells as demonstrated by in vitro
studies that show a broad shoulder on survival curves in some melanoma cell lines.62
Neutrons were tested in skin and mucosal melanoma with quite favorable results at Hammersmith Hospital.63
More recently a series of 76 cases of mucosal melanoma, 61 of them (80%) from the paranasal sinus and nasal cavity, was reported from NIRS.22
No patient underwent surgical resection. Carbon ion therapy was performed to a total dose of 57.6-64.0 Gy (RBE) in fractions of 3.6 to 4.0 Gy (RBE). The local control results from the whole series were very encouraging with a 5-year local control rate of 77%; 5-year OS, however, was only 26% due to the very high incidence of distant metastases. This prompted a phase II study of carbon ion RT for malignant melanoma (44 cases) with concomitant chemotherapy consisting of DAV—day 1: DTIC (dacarbazine) 120 mg/m2
, ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3-nitrosourea) 70 mg/m2
, and vincristine 0.7 mg/m2
; days 2 to 5: DTIC 120 mg/m2
. Cycles were given at 4-week intervals for five courses. The 4-year local control and survival rates were 85% and 44%, respectively. When the GTV was <50 mL, the 4-year survival was 62%.29
These data show carbon ions are very effective in obtaining local tumor control. Further investigational studies with systemic therapy are needed to improve long-term survival.
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