Nonplatinum-based chemotherapy with irinotecan plus docetaxel for advanced or metastatic olfactory neuroblastoma

A retrospective analysis of 12 cases




The efficacy and safety of chemotherapy with irinotecan plus docetaxel were retrospectively evaluated for olfactory neuroblastoma.


Twelve patients with histologically proven advanced or metastatic olfactory neuroblastoma were treated with chemotherapy with irinotecan plus docetaxel at the study institution between 2001 and 2005. Of these, 7 patients with locoregional disease and no prior radiotherapy received irinotecan plus docetaxel followed by definitive radiotherapy, 1 with photon radiotherapy and 6 with proton radiotherapy, whereas 3 patients with distant metastases and 2 with locoregional disease who had received prior radiotherapy received irinotecan plus docetaxel only.


The most common toxicities of ≥grade 3 among the 12 patients receiving irinotecan plus docetaxel were leukopenia (33%), neutropenia (50%), febrile neutropenia (8%), and diarrhea (25%), all of which were manageable. Partial response was achieved in 3 patients, giving an overall response rate of 25%. The response rate was higher in patients aged <50 years (3 of 4 patients) compared with those aged >50 years (0 of 8 patients) (P = .018). With a median follow-up period of 22.2 months, the median progression-free survival and overall survival were 13.6 months and 36.6 months, respectively. Of the 7 patients with locoregional disease also receiving definitive radiotherapy, the 2-year survival rate was 100% and 6 patients were alive at the time of last follow-up.


Chemotherapy for olfactory neuroblastoma with irinotecan plus docetaxel is safe and manageable. Patients aged <50 years may be sensitive to chemotherapy. Induction chemotherapy followed by definitive radiotherapy may represent a promising option for patients with locally advanced olfactory neuroblastoma. Cancer 2008. © 2008 American Cancer Society.

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare tumor arising from the olfactory epithelium of the upper nasal cavity.1, 2 ONB accounts for 3% of all intranasal tumors3 and its etiology is unknown. Since its first description by Berger and Luc in 1924,4 approximately 1000 cases have been reported in the literature.5 The sex distribution is roughly equal.2, 5 Although several authors have demonstrated a bimodal distribution in the age of diagnosis, with peaks in those aged 11 to 20 years and 51 to 60 years,2, 6 others have described a unimodal distribution concentrating in the fifth decade of life.7

With regard to treatment, the combination of surgery and radiotherapy is the most frequent approach and offers the highest cure rates,8–12 but definitive radiotherapy as a nonsurgical treatment is also used.2, 10, 12–14 However, despite definitive local treatment, local recurrence and distant metastases are often reported,6, 8, 12 with the latter observed in 25% to 50% of cases.15–19 Chemotherapy is therefore often also implemented in patients with recurrent or metastatic ONB. Experience at several institutions using various chemotherapeutic regimens has suggested that this tumor might be sensitive to chemotherapy,7, 8, 18, 20–22 but its rarity has prevented any clear determination of the role of chemotherapy or the optimal chemotherapy regimen.

Between 1995 and 2005, our group at the National Cancer Center Hospital East treated 20 patients with either or both advanced or metastatic ONB with chemotherapy. Results with a variety of chemotherapy regimens used before 2001, including platinum-based regimens,23 were unsatisfactory, leading us to speculate on the possibility of using irinotecan plus docetaxel (ID). In addition, in patients with locoregional disease we adopted proton radiotherapy after induction chemotherapy with ID because of its lower radiotoxicity to adjacent tissues (brain, optic nerve, eyeball, etc).24

Investigation of this regimen in 3 ONB patients in a phase 1 study of ID for solid cancer produced a good response in 2.25 The first, who had previously received platinum-based chemotherapy at our institution, was responsive to ID, with a response duration of approximately 10 months. The second, a chemotherapy-naive patient with locoregional disease, achieved a partial response with ID, and a subsequent complete response (CR) after proton radiotherapy after ID. We therefore decided to treat not only recurrent or metastatic ONB but also locoregional ONB with ID, and since 2001 have treated 12 patients with this regimen. Of these, 7 with locoregional disease and no prior radiotherapy received ID followed by definitive radiotherapy, namely, photon radiotherapy in 1 patient and proton radiotherapy in 6 patients.

In this retrospective analysis, we evaluated the efficacy and toxicity of chemotherapy with ID for ONB and the efficacy of ID followed by definitive radiotherapy for locally advanced ONB. After suggestions from several authors that the pathologic features of ONB might correlate with prognosis and response to chemotherapy,1, 10, 18, 26–28 we also analyzed the correlation between response and the histologic grading of Hyams.28


We reviewed the clinical records of the 12 patients with ONB treated with ID at the National Cancer Center Hospital East between 2001 and 2005. All 12 had histologically proven ONB and pathologic specimens were available for 10 patients. These were reviewed according to the histologic grading system of Hyams28, and the correlation between Hyams grade and response to ID was analyzed.

Response to chemotherapy was evaluated using the World Health Organization (WHO) standard response criteria.29 Chemotherapy-related toxicities were graded by the National Cancer Center Institute Common Toxicity Criteria (version 2). Overall survival time was calculated from the initiation of chemotherapy with ID to the date of death or last follow-up, whichever occurred first. Progression-free survival time was calculated from the initiation of chemotherapy with ID to the documentation of progression or death. Actuarial survival was estimated by the Kaplan-Meier method.30 Statistical analysis of categoric data was performed using a Fisher exact test. Differences were considered statistically significant at P < .05. All analyses were conducted using the statistical analysis software Stat View-J (version 5.0) for Windows (SAS Institute Inc, Cary, NC).


Patient Characteristics

Patient characteristics are summarized in Table 1. The 4 males and 8 females ranged in age from 24 to 73 years, with a median age of 58.5 years. According to the clinical staging system of Kadish and Wang,1 2 patients had stage B disease at the time of chemotherapy and 10 had stage C disease. The primary site was determined by either or both computed tomography scanning and magnetic resonance imaging. Intracranial invasion was noted in 5 patients, regional lymph node metastases in 6, and distant metastases in 3. The site of metastases in these 3 patients was the lung and liver; cervical lymph node, lung, and bone; and cervical lymph node and bone in 1 patient each. Of the 12 patients, 9 presented with locoregional disease and 3 initially presented with distant metastases. Of the 9 patients with locoregional disease, 2 had received prior radiotherapy, whereas 7 had not.

Table 1. Patient Characteristics and Treatment Course in Individual Patients
Age, yearGenderECOG PSKadish stageICILR/DMMetastatic sitePrior treatmentChemotherapyResponseSubsequent treatmentRT/PRTSurvival, monthsStatus
  1. PS indicates performance status; ICI, intercranial invasion; LR, locoregional; DM: distant metastases; RT, radiotherapy; PRT, proton radiotherapy; ECOG, Eastern Cooperative Oncology Group; +, positive; L, lung; H, liver; S, surgery; ID, irinotecan plus docetaxel; PD, progressive disease; DWD, dead with disease; −, negative; LN, lymph node; B, bone; PR, partial response; NC, no change; AWD, alive with disease; CR, complete response; ANED, alive with no evidence of disease.

65Woman1C+DML, HS, RTIDPDChemotherapy5.7DWD
24Woman0CDMLN, L, BIDPDPalliative RT6.5DWD
36Woman1C+DMLN, BS, chemotherapy, RTIDPRChemotherapy22.5DWD
54Man0CLRLNS, RT, chemotherapyIDNC16.1DWD
61Woman1C+LRLNChemotherapyIDNCPRT, chemotherapyPR63.0AWD

Of the 12 patients with histologically proven ONB, specimens for pathologic review were available for 10. Of these, 2 tumors were low grade (Hyams grade I/II) and 8 were high grade (Hyams rade III/IV).

Treatment Results

Treatment results are also listed in Table 1. All 12 patients received chemotherapy with ID, given as 3 weekly administrations of both irinotecan at a dose of 50 to 60 mg/m2 on Day 1 and docetaxel at a dose of 30 to 35 mg/m2 on Day 1, repeated every 4 weeks. The recommended dose of this regimen had been previously determined as irinotecan at a dose of 50 mg/m2 and docetaxel at a dose of 30 mg/m2 in a phase 1 study at our institution.25 Of the 12 patients, 3 had been recruited in this phase 1 study and the other 9 were treated with ID in clinical practice after the recommended dose had been determined. A median of 3 cycles of ID were given, ranging from 1 to 6 cycles. In the 7 patients with locoregional disease and no prior radiotherapy, the treatment plan called for ID followed by definitive radiotherapy. Radiotherapy was administered after a median of 3 cycles of ID (range, 1–6 cycles). One patient refused further administration of ID because his nasal bleeding was not improved after 1 cycle and he wished to receive definitive radiotherapy as soon as possible. A second patient received 6 cycles of ID because she wished to continue ID as long as a response was observed. The other 5 patients received 2 or 3 cycles of ID. Of the 7 patients, the 1 patients with Kadish stage B disease underwent definitive radiotherapy with photon radiation (total of 66 grays [Gy] in 2-Gy fractions), whereas the 6 patients with Kadish stage C disease received proton radiation (total of 65 cobalt Gray equivalents [GyE] in 2.5-GyE fractions).

All 12 patients demonstrated an assessable response to ID. Three of the 12 achieved a partial response (PR). One PR patient had distant metastatic disease and the other 2 PR patients had locoregional disease. The median progression-free survival was 13.6 months (range, 1.3–53.4 months) (Fig. 1). In the 7 patients with locoregional disease and no prior radiotherapy who received definitive radiotherapy after chemotherapy, 5 achieved a CR and 2 a PR.

Figure 1.

Progression-free survival (n = 12).

The median follow-up period in survivors was 22.2 months (range, 14.8–63 months). Estimated 1-year and 2-year survival rates were 83.3% and 53.3%, respectively. The median overall survival was 36.6 months (Fig. 2). The median survival of the 6 of 12 patients with recurrent or distant metastatic disease was 16.1 months (Fig. 3). Of the 7 of 12 patients with locoregional disease who had received no prior radiotherapy, 1 received ID followed by photon radiation and 6 received ID followed by proton radiation. Among them, the 2-year survival rate was 100% and 6 patients were alive at the time of last follow-up (Fig. 4). Of the 5 CR patients who received definitive radiotherapy (1 with photon radiation and 4 with proton radiation), 4 patients were alive at the time of last follow-up with no evidence of disease. Toxicity of definitive photon or proton radiotherapy was mild and manageable. None of the 7 patients experienced treatment-related death or severe late toxicity due to irradiation, including vision impairment, brain necrosis, or others. Nevertheless, ongoing follow-up to ensure safety is required.

Figure 2.

Overall survival (n = 12).

Figure 3.

Survival in patients with recurrent or metastatic disease (n = 6).

Figure 4.

Survival in patients treated with irinotecan plus docetaxel followed by definitive radiation therapy (n = 7).

The most common grade 3 or 4 chemotherapy-related toxicities were leukopenia (33%), neutropenia (50%), febrile neutropenia (8%), and diarrhea (25%), all of which were manageable.

The correlation between response to chemotherapy and clinical and histologic variables is summarized in Table 2. The response rate to ID was 75% (3 of 4 patients) in the group aged <50 years, but was 0% (0 of 8 patients) in those aged >50 years (P = .018). Furthermore, the response rate was 60% (3 of 5 patients) in patients with intracranial invasion, but was 0% (0 of 7 patients) in those without (P = .045). Although the sample size was small, no response was observed (0 of 2 patients) in the Hyams low-grade (grade I/II) patients, whereas 3 responses were observed (3 of 8 patients) in the Hyams high-grade (grade III/IV) patients. No significant correlations between response to chemotherapy and other clinical variables were identified.

Table 2. Response According to Patient Characteristics
CharacteristicNo.No. of patients respondingP
Age <50 y43.018
Age ≥50 y80 
Distant metastasis  >.99
Kadish stage B20>.99
Kadish stage C103 
Intracranial invasion  .045
Low Hyam grade (I/II)20>.99
High Hyam grade (III/IV)83 


As ONB is a rare tumor, and to our knowledge no consensus exists regarding treatment, particularly for advanced cases. Review of the literature suggests that ONB is a surgical disease; the advent of craniofacial resection has clearly improved disease-free survival6, 15 and many authors recommend surgery as the initial treatment.8, 12, 31, 32 To improve locoregional control and survival, several authors recommend surgery followed by adjuvant radiotherapy.10, 12, 31–33 Together, these reports suggest that the optimal treatment for surgically resectable cases is surgery followed by adjuvant radiotherapy.

Of our 12 patients with ONB, 5 had recurrent disease, 3 had intracranial invasion, 1 each had cervical lymph node metastases and distant metastases, and 2 were staged as Kadish B. Because these Kadish stage B patients declined surgery, treatment was initiated with chemotherapy and, if the disease was locoregional, continued with definitive radiotherapy after chemotherapy with ID.

Many authors have commented on the effectiveness of chemotherapy in the treatment of ONB.7, 12, 14, 18, 19, 34–37 Notwithstanding that these previous reports were based on single-institution experience with relatively small sample sizes, platinum-based chemotherapy was well regarded and considered effective.14, 36, 37 We previously reported that 2 of 8 ONB patients responded to chemotherapy with mainly platinum-based regimens.23 In our present analysis in 12 patients treated with ID, the response was also 25% (3 of 12 patients), but toxicities were mild and manageable. The median survival in the setting of recurrent or metastatic disease was approximately 12 months in previous reports,22, 31 but was 16.1 months in the current study. Although our sample size was small (n = 6), this result might indicate that chemotherapy for recurrent or metastatic ONB contributes to improving survival.

On univariate analysis, response rates to ID were significantly higher in patients aged <50 years and those with intracranial invasion. Rates for high-grade (Hyams grade III/IV) and low-grade (Hyams grade I/II) ONB were 37.5% (3 of 8 patients) and 0% (0 of 2 patients), respectively, but this difference was not statistically significant. Several authors have reported that the pathologic features of ONB correlate with its prognosis and response to chemotherapy,1, 10, 18, 26–28 whereas McElroy et al.18 suggested that high-grade ONB (Hyams grade III/IV) may be sensitive to chemotherapy. Data from the current study may also suggest that ONB in younger patients and in those with aggressive disease extension may be sensitive to chemotherapy. The question of which subset of ONB patients will respond to chemotherapy is important but remains to be answered. The ability to predict response will allow the identification of those patients who should receive chemotherapy before definitive radiotherapy. Our present and previous reports may suggest that younger patients, those with aggressive disease extension, and those with high-grade histology (Hyams grade III/IV) may be sensitive to chemotherapy.1, 10, 18, 26–28 ONB is a rare disease, and identification of the clinical determinants of a response to chemotherapy will require the further accumulation of patients.

Although craniofacial resection is effective in controlling ONB, it is not without substantial risk and morbidity. Levine et al.38 reported that of 27 patients undergoing this treatment, 20% experienced cerebrospinal fluid leakage and 12% had symptomatic postoperative pneumocephalus. Similarly, Richtsmeier et al.39 reported 1 death and 9 major intracranial complications among a total of 26 patients. Radiotherapy as the initial treatment has been proposed as 1 means of obviating these complications. Elkon et al.2 found that radiotherapy and surgery provided equivalent results in patients with early-stage disease. Similarly, a review from the Mayo Clinic indicated no significant difference in survival between patients receiving either radiotherapy or surgery alone.10 However, recurrence with radiotherapy alone was approximately 60%.2, 33 Bhattacharyya et al.13 reported excellent results in 9 cases of esthesioneuroblastoma (olfactory neuroblastoma) or neuroendocrine carcinoma treated using induction chemotherapy with cisplatin and etoposide followed by proton radiotherapy, with 8 of 9 patients exhibiting a dramatic response to therapy and remission of their tumor, which obviated the need for resection. Fitzek et al.14 also reported promising results with the combination of induction chemotherapy and proton-photon radiotherapy for patients with advanced ONB. Nineteen patients with a sinonasal tumor (10 olfactory neuroblastoma and 9 neuroendocrine carcinoma) received chemotherapy with 2 courses of cisplatin and etoposide, followed by high-dose proton-photon radiotherapy to 69.2 GyE. Thirteen of the 19 responded to chemotherapy, with a 5-year survival rate of 74% and 5-year local control rate from the time of initial treatment of 88%. These findings demonstrated the possibility of nonsurgical treatment for ONB.

Nevertheless, radiotherapy for ONB is challenging because of the surrounding critical organs, including the optic pathway, brain, and brainstem. Thanks to its physical characteristics, proton radiotherapy provides better dose distribution than photon radiotherapy, and is deemed a feasible and effective treatment modality for curative high-dose irradiation to the tumor volume without any increase in normal tissue toxicity.24 We therefore used proton radiotherapy in cases in which the potential for damage to surrounding critical organs with photon radiotherapy could not be ruled out. To facilitate prevention to surrounding critical organs, we adopted induction chemotherapy with ID for locoregional ONB. Thus, ID was followed by photon radiation therapy of 66 Gy in 2-Gy fractions in 1 of 7 locoregional ONB patients and by proton radiotherapy of 65 GyE in 2.5-GyE fractions in 6 patients. The patient receiving photon radiation achieved a CR, as did 4 of the 6 patients receiving proton radiotherapy, with the other 2 achieving PRs. At a median follow-up of 22.2 months, 6 of these 7 patients with locoregional ONB who received ID followed by definitive radiotherapy were still alive and the 2-year survival rate was 100%. These findings suggest that induction chemotherapy followed by definitive radiotherapy may be a promising nonsurgical treatment option for patients with locally advanced ONB.

In conclusion, chemotherapy with ID for both advanced and/or metastatic ONB was found to be safe and manageable. The response to ID was no better than expected, however, indicating that ONB requires a more active chemotherapy regimen. Induction chemotherapy followed by proton radiotherapy may be a promising treatment option for patients with locally advanced ONB and warrants further investigation.