Abstract
Background: Prognosis of metastatic malignant peripheral nerve sheath tumor (MPNST) is poor and the role of chemotherapy is controversial. There has been no report of metastatic MPNST with a good prognosis without surgery for metastases. Case Report: A 40-year-old man with neurofibromatosis type 1 (NF1)-related MPNST on his shoulder with multiple lung metastases visited our hospital. After two cycles of chemotherapy with ifosfamide, carboplatin and etoposide (ICE), the primary lesion and lung metastases had shrunk. The primary lesion was resected with negative margins. Subsequently, ‘gradual subtraction’ ICE was administered, wherein the dose was reduced and the treatment interval was increased. After 14 courses of ICE over a period of 2 years, the lung metastases disappeared; there has been no recurrence for over 12 years. Conclusion: ICE can be an excellent, inexpensive treatment for NF1-related MPNST. ‘Gradual subtraction’ chemotherapy allowed us to maintain long-term efficacy, induce tumor dormancy, and reduce side-effects.
Malignant peripheral nerve sheath tumors (MPNSTs) are malignant neoplasms arising in a peripheral nerve from a pre-existing benign nerve sheath tumor (usually neurofibroma) or in a patient with neurofibromatosis type 1 (NF1). MPNSTs account for 5–10% of soft-tissue sarcomas (1), and up to 50% of MPNSTs are reportedly NF1-related (2). The incidence of NF1 is estimated to be about one in 3,000 (3), and 8-13% of patients with NF1 develop MPNST (4, 5). The 5-year survival rate of patients with MPNST is 33-51%, but patients with NF1-related MPNST have a 5-year survival of only 16-32% (2, 5, 6). The prognosis of metastatic, recurrent, or unresectable MPNST is worse, and, according to Valentin et al.'s report, 1-year overall survival is only 53.73% and the median progression-free survival is only 4.3 months with doxorubicin-based chemotherapy (7).
Here we report a case of multiple metastatic NF1-related MPNST with a fungating primary lesion at the first visit. Combination chemotherapy with ifosfamide, carboplatin, and etoposide, known as ICE chemotherapy, enabled resection of the primary lesion and elimination of multiple lung metastases. This case illustrates good prognosis after ICE chemotherapy without surgery for metastases.
The patient provided informed consent to the use of his case for publication. The study protocol adhered to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by our Institutional Review Board (J2019-14-2019-1).
Case Report
A 40-year-old man noticed a mass in his right shoulder that progressed over 21 months. He had visited three clinics and had not improved significantly, so he was referred to our hospital. He had a history of NF1 and had been followed-up at a nearby hospital from childhood to 30 years of age. He also had a history of surgery for neurofibroma on the right side of his back. However, the follow-up had been discontinued 10 years prior to referral. There were no other cases of NF1 in his family.
At the first visit, the tumor was about 8×8 cm in size with a perimeter of 25 cm (Figure 1A). There were bleeding ulcers on the surface of the tumor. Computed tomography (CT) revealed multiple lung metastases (Figure 2A). Skin biopsy showed atypical spindle and polygonal tumor cells with pleomorphism proliferating in the dermis. Mitotic figures were frequent. Immunohistochemically, the tumor cells were positive for S-100 but negative for cytokeratin AE1/AE3, epithelial membrane antigen (EMA), α smooth muscle actin (αSMA), CD34, and CD31. The features were compatible with MPNST, and he was diagnosed with MPNST (Figure 3).
Considering the large size of the tumor and multiple lung metastases, two cycles of chemotherapy with mid-dose ICE regimen (ifosfamide at 1.5 g/m2 on days 1-3, carboplatin at 400 mg/m2 on day 3, and etoposide at 100 mg/m2 on days 1-3) were administered (8). The patient's symptoms gradually improved after chemotherapy, and 6 weeks from the start of chemotherapy, the ulcers had healed. Magnetic resonance imaging indicated that the mass had shrunk to 5×6.6 cm (Figure 1B), and the diameters of the two target lesions in the lung were also significantly reduced (Figure 2B). The chemotherapy effect was evaluated as partial response, since the sum of the maximum diameters of the primary lesion and the two lung lesions decreased from 13.1 cm to 8 cm after chemotherapy.
Resection of the primary tumor in the right shoulder was performed 2 months after the start of chemotherapy. Pathological examination of the resected specimen revealed that there were still viable spindle or pleomorphic malignant cells but the surgical margin was negative.
Three weeks after the surgery, postoperative chemotherapy with another 12 courses of the ICE regimen was started. The last chemotherapy administration was 24 months from his first visit. We wanted to continue ICE chemotherapy as long as possible but a cumulative dose of etoposide in excess of 2,000 mg/m2 increases the risk of secondary leukemia (9). Therefore, we reduced the etoposide dosage from 100 mg/m2/day to 60 mg/m2/day beginning with the 4th course of chemotherapy. In the last two cycles of chemotherapy, only ifosfamide and carboplatin were administered. In addition, the interval of chemotherapy was gradually extended from 4 weeks to 5 weeks, then 6 weeks, and finally 10 weeks. The lung metastases continued to shrink, and 10 months after the first visit, they became like scars and eventually disappeared (Figure 2C).
Initially, we planned to continue ICE for at least 2 years, but 1 month after the last course, the patient developed a fever and low back pain. Magnetic resonance imaging revealed narrowing of the L4/5 disc space and erosion of the end plate (Figure 4). Two separate blood cultures were positive for Staphylococcus epidermidis, and a diagnosis of pyogenic discitis was established. Intravenous therapy with cefepime dihydrochloride hydrate and vancomycin was administered for 2 weeks, after which oral antibacterial therapy with clindamycin was administered for 15 months. The pyogenic discitis healed uneventfully and the patient had no more back pain. It has been 12 years since his first visit and he continues to be disease-free, enjoying a normal life at home.
Discussion
Some studies suggest that the prognosis of NF1-related MPNST is worse than that of non-NF1-related MPNST (2, 5, 6). In contrast, others suggest no significant difference between NF1-related and non-NF1-related MPNST (1, 10). Kolberg et al. performed a meta-analysis of survival involving more than 1,800 patients with MPNST and reported that this discrepancy is due to the increased survival rate of patients with NF1-related MPNST in the previous decade (11). Although the prognosis of NF1-related MPNST may have improved in recent years, the outcome of patients with metastatic MPNST is still poor. For patients with MPNST with multiple metastases, the 5-year survival rate is only about 13%, and the 10-year survival rate is zero (12).
Surgery is the most important curative method of therapy for MPNST. The most common prognostic factors, such as the tumor site, size, and margin status, all relate to whether complete resection can be achieved. The goal of surgery is to completely remove the tumor and achieve negative margins (13). In a 10-year institutional review of 21 cases of NF1-related MPNST, the R0 resection rate was only 5%, and the 5-year survival rate was as low as 14% (14). The main reasons for this disappointing result were the large tumor diameters and difficulty in achieving R0 resection in that study. In recent years, due to regular prophylactic follow-up of patients with NF1 and use of positron-emission tomography–CT, malignant transformations are being detected earlier, and surgery with adequate margins is more feasible (12, 15).
Although non-surgical treatment options have been explored, few have a satisfactory effect on survival. Radiotherapy can only be used as an adjuvant therapy to improve local control. Adjuvant chemotherapy is also part of comprehensive treatment, and it aims to improve systemic control (1). Kroep et al. compared chemotherapy for MPNST and other types of sarcomas and reported that their clinical outcomes were similar. However, a better outcome was observed for patients with MPNST treated with combination chemotherapy using doxorubicin and ifosfamide (AI) (16). At present, AI would be the most common chemotherapy for MPNST but no large-scale studies have confirmed the effect of this chemotherapy on the recurrence, metastasis, and survival of patients with MPNST. Stucky et al. (1) and Yuan et al. (10) reported that chemotherapy did not affect prognosis. In addition, there has been no breakthrough in the research into new targeted drugs. Clinical trials have examined various drugs in NF1-related MPNST, including erlotinib, sorafenib, imatinib, dasatinib, alisertib, bevacizumab, ganetespib, and sirolimus, but there is no evidence that these targeted drugs are effective (17).
Regarding treatment other than AI, Hirbe et al. studied five patients treated with ifosfamide and etoposide. The response rate was 60% and the clinical benefit rate was 100%, including two out of three patients with NF1-related MPNST who responded (18). There are two case reports wherein complete response was achieved with other chemotherapy regimens after AI failed, including one NF1-related MPNST (19, 20). These reports suggest that chemotherapy may be effective for MPNST. However, these patients were treated with chemotherapy regimens other than ICE.
There have been many reports of ICE chemotherapy for other neoplasms since the 1990s, but the doses varied (8). This regimen is often used as a second-line treatment for recurrent and refractory soft-tissue tumors, especially in children (8, 21). There are two studies regarding ICE chemotherapy in recurrent and refractory non-small round cell sarcomas. The effective rate of chemotherapy and the 2-year survival rate were satisfactory (8, 21). Lafay-Cousin et al. reported on the treatment of primary intracranial sarcoma with ICE and radiotherapy in eight children. R0 resection was not achieved due to specific tumor location. However, after combined radiotherapy and mid-dose ICE, the prognosis was good (22). ICE for NF1-related MPNST has been reported in only two studies involving six NF1-related pediatric cases (22, 23). Two out of the six patients were lost to follow-up, one patient died after 2 years, and one patient was followed up for 3.4 years and survived without disease. The other two patients with non-metastatic disease survived for around 10 years even without a perfect surgical margin. In spite of the small number of cases, the results of ICE chemotherapy are still promising.
Doxorubicin and the AI regimen, which are currently considered standard chemotherapy for advanced soft-tissue sarcomas, have a dose-dependent effect. However, with higher dose, toxicity can be less tolerable, and treatments cannot be continued for a long period. The ICE regimen also has a cumulative dose limit because the risk of developing secondary leukemia increases if the total dose of etoposide is over 2,000 mg/m2. Fortunately, mid-dose ICE is not inferior to high-dose ICE with regard to the response rate (8). Therefore, we started with mid-dose ICE and once the tumor responded well, we gradually extended the treatment interval from 4 weeks to 10 weeks and reduced the dose of etoposide. This made the toxicity tolerable, enabled more courses of chemotherapy, and extended the total treatment period up to 2 years. We believe this modification enabled curing of this case of metastatic NF1-related MPNST. This treatment was a combination of intermittent and metronomic treatment. Extending the interval and reducing the dose enabled us to maintain the efficacy for the longest possible period and to induce tumor dormancy while reducing side-effects. This unique method can be called ‘gradual subtraction’ chemotherapy.
In this patient with multiple lung metastases, ‘gradual subtraction’ ICE achieved a progression-free survival of more than 12 years. Some patients may have NF1-related MPNST which is sensitive to ICE and therefore may be candidates for this treatment. ICE is an excellent and inexpensive treatment for patients with NF1-related MPNST as neoadjuvant chemotherapy for resectable cases or palliative chemotherapy for metastatic cases.
Footnotes
Authors' Contributions
Study conception and design: H. Katagiri and Y. Wang. Acquisition of data: H. Katagiri, H. Murata, J. Wasa, M. Miyagi, Y Kakuda and M. Takahashi. Analysis and interpretation of data: Y. Wang, H. Katagiri, H. Murata, J. Wasa, M. Miyagi, Y. Kakuda and M. Takahashi. Drafting of manuscript: Y. Wang and H. Katagiri. Critical revision: H. Katagiri.
Conflicts of Interest
The Authors did not receive and will not receive any benefits or funding from any commercial party related either directly or indirectly to the subject of this article.
- Received December 28, 2019.
- Revision received February 4, 2020.
- Accepted February 6, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved