American Journal of Clinical Oncology:
Original Article: Soft Tissue
Early Outcomes for Malignant Peripheral Nerve Sheath Tumor Treated With Chemotherapy
Moretti, Vincent M. MD*; Crawford, Eileen A. MD*; Staddon, Arthur P. MD†; Lackman, Richard D. MD*; Ogilvie, Christian M. MD‡
From the *Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA; †Department of Hematology and Oncology, Pennsylvania Hospital, Philadelphia, PA; and ‡Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN.
Supported by Stryker Orthopaedics (to V.M.M. and E.A.C.).
One or more authors (R.D.L.) is a consultant for Stryker Orthopaedics.
The other authors declare no conflicts of interest.
Each author certifies that his or her institution has approved or waived approval for the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
Reprints: Vincent M. Moretti, MD, University of Pennsylvania, 301 S. 8th St, Suite 2C, Philadelphia, PA 19106. E-mail: email@example.com.
Objectives: Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue sarcomas with a tendency for recurrence and metastasis. Treatment using chemotherapy is controversial, but benefit with some agents has been described. This study aimed to analyze early survival outcomes using doxorubicin and ifosfamide chemotherapy for MPNST.
Methods: Pathology records at our musculoskeletal tumor center were searched for patients with a new diagnosis of MPNST between 2003 and 2008. Treatment involved surgical resection, radiation, and chemotherapy with doxorubicin and ifosfamide. Ten patients met inclusion criteria, with mean age 40 years (range, 20–70). Four patients had metastatic disease on presentation. Four patients had neurofibromatosis type I (NF1).
Results: Of 6 patients with nonmetastatic disease on presentation, 5 had no evidence of disease post-treatment. The sixth had positive margins after surgery and initially received no further treatment due to noncompliance. Three from this subgroup developed local recurrence, but none developed distant metastases and 1 died of disease at last follow-up. One- and 2-year disease-free survival (DFS) for this subgroup was 80% and 60%, respectively. One- and 2-year overall survival (OS) for the subgroup was 100%. Of 4 patients with metastatic disease on presentation, 2 had no evidence of disease post-treatment. One of these 2 developed local recurrence, but none from the subgroup developed new metastatic disease. Two of these 4 died of disease at last follow-up. One- and 2-year DFS for this subgroup was 100% and 50%, respectively. One- and 2-year OS was 75% and 50%, respectively. Two of the 4 patients presenting with metastatic disease had NF1. All 3 local recurrences and 2 of the 3 deaths in this study occurred in NF1 patients.
Conclusions: For all patients, when combined with surgery and radiation, chemotherapy using doxorubicin and ifosfamide yielded 57% DFS and 80% OS at 2 years. NF1 patients appeared to have worse outcomes, with a statistically significantly lower DFS than non-NF1 patients. Limitations of this study include a small sample size, retrospective design, and use of different chemotherapy regimens.
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive soft-tissue sarcoma arising from cells of the nerve sheath, most notably the Schwann cells or perineural cells.1 It can develop de novo from peripheral nerves or from preexisting benign neurofibromas.2,3 MPNST are relatively rare, with a reported incidence of 1 per 106 people per year.1,4 Neurofibromatosis type 1 (NF1) and radiation exposure are the most important risk factors, with 50% to 60% of MPNST occurring in patients with NF1 and 10% of MPNST occurring in patients with prior radiation exposure.1,2,5,6
The rates of successful treatment of MPNST are generally low, and the available literature provides only limited guidance regarding the management of this disease. As with most soft-tissue sarcomas, surgical resection is typically the primary treatment modality for MPNST.1 Depending on the tumor's location though, anywhere from 5% to 80% of MPNST will be unresectable because of involvement of critical neurovascular structures.1,7 Complete wide resection can therefore be a serious challenge, and can carry the additional risk of significant functional loss. Radiotherapy is generally recommended for all MPNST, but the role of chemotherapy remains controversial as a result of the rarity of the disease and subsequent paucity of data.1,8 Several chemotherapeutic agents have been used against MPNST, but the clinical benefits have been variable and inconclusive.2,3,7,9–25 Part of this inconsistency, no doubt, arises from the fact that most large studies on MPNST span long periods and use a variety of chemotherapeutic agents sporadically in their series.1,2,11,12,14,16–18,20–22,25 There have been no controlled studies looking at the effect of chemotherapy on MPNST alone.
To contribute additional information on the clinical management of MPNST, we therefore report a series of patients seen at our musculoskeletal tumor center over 5 consecutive years and treated with a similar chemotherapeutic regimen. Specifically, this study investigates short-term outcomes in MPNST patients treated with aggressive surgical intervention, radiation therapy, and chemotherapy using doxorubicin and ifosfamide. It aims to test the hypothesis that multimodality therapy including doxorubicin and ifosfamide leads to improved disease-free survival (DFS) and overall survival (OS) in patients with MPNST, versus comparative rates currently published in the literature.
MATERIALS AND METHODS
Pathology records at our musculoskeletal tumor center were searched for all patients with a new diagnosis of MPNST between 2003 and 2008. Inclusion criteria for this study were confirmed pathologic diagnosis of MPNST, primary treatment involving doxorubicin and ifosfamide chemotherapy, complete clinical records, and minimum follow-up of 12 months or until death of the patient.
Eighteen patients were identified from pathology records. Four patients were excluded because they did not receive doxorubicin and ifosfamide chemotherapy. Two patients were excluded because doxorubicin and ifosfamide were only given as secondary treatment for recurrent disease. Two patients were excluded because they were primarily treated elsewhere and/or had incomplete clinical records. The remaining 10 patients (6 male, 4 female) are the subjects of this study. The clinical data for these patients are listed in Table 1.
The mean age at presentation was 40 years (range, 20–70). Four patients had known NF1. The MPNST were located in the hip/pelvis (3 patients), upper arm (2 patients), thigh (2 patients), ankle (1 patient), jaw (1 patient), and chest wall (1 patient). Nine of the 10 tumors were described as high-grade and 9 were at least 5 cm in largest dimension. Six patients had only local disease at presentation. Four patients had metastatic disease at presentation. The lungs were the most common site of metastasis (3 patients), but regional nodes were involved in 1 patient.
Patients were treated mainly using multimodality therapeutic approaches, including surgery, chemotherapy, and radiotherapy. Overall strategies did not change substantially during the study period, although decisions about neoadjuvant versus adjuvant chemotherapy, total cycles of chemotherapy, and use of radiotherapy were customized depending on the patient's and physician's preferences. All patients were treated with surgical excision of resectable disease. Five patients received at least 1 cycle of neoadjuvant chemotherapy. All patients in this study received doxorubicin and ifosfamide as part of their primary treatment. Etoposide was added in 4 patients and camptothecin added for 1 additional patient. Seven patients received radiation therapy.
Outcome measures were disease status at last follow-up, DFS, and OS. DFS was measured from the date of definitive surgery or disease remission to the date of local recurrence or metastasis. If the patient did not have local recurrence or metastasis, DFS was measured to the date of last follow-up. OS was measured from the date of diagnosis to the date of last follow-up or patient death. One- and 2-year DFS and OS rates were calculated using Kaplan-Meier methodology. Survival distributions were statistically compared using the Mantel-Cox log-rank test.
Full treatment details for each patient can be found in Table 1. A summary of subgroup results can be found in Table 2. Average follow-up was 25.4 months (range, 6.4–40.8).
The outcomes were largely positive for the 6 patients with only local disease at presentation. Five of these patients were disease free after surgery, although 4 required a wound bed excision after initial surgery to reach disease-free status. The sixth patient from this subgroup (Patient 5) was never free of disease. She had positive margins after surgery and subsequently refused recommended radiotherapy and chemotherapy. Her tumor regrew 14.2 months later. She recently underwent amputation for the regrowth, again resulting in positive margins. Higher amputation, radiotherapy, and/or additional chemotherapy have now been offered. Two patients from this subgroup (Patients 1 and 2) developed local recurrences. Recurrence in Patient 1 was treated symptomatically and he subsequently died because of complications from the local recurrence. Patient 2 received radiation therapy for the recurrence but the tumor continued to increase in size. He is currently considering other treatment options.
For the 6 patients with only local disease on presentation, the 1- and 2-year DFS rates were 80% and 60%, respectively. The 1- and 2-year OS rates were both 100%.
Outcomes for the 4 patients with metastatic disease on presentation were more variable, but the longer term survivors had all their disease successfully resected. Only 2 patients from this subgroup (Patients 7 and 10) reached disease-free status. Patient 10 remains free of all disease after surgical resection of both her primary and metastatic lesions. Patient 7 was free of disease after resection of both his primary and metastatic lesions, but the tumor later recurred locally. This recurrence was treated by resection, with positive margins, and subsequent radiation therapy. Two patients from this subgroup (Patients 8 and 9) were never disease-free. After a debulking surgery, Patient 9 received chemotherapy and radiotherapy but his tumor continued to progress despite these treatments. He eventually died of disease before a second definitive resection could be attempted. Patient 8 was without local disease after surgery but later died of her metastatic disease. For these 4 patients with metastatic disease on presentation, the 1- and 2-year DFS rates were 100% and 50%, respectively. The 1- and 2-year OS rates were 75% and 50%, respectively. Neither DFS (P = 0.813) nor OS (P = 0.176) were significantly different between those with and without metastatic disease on presentation.
Patients with NF1 were statistically more likely to recur and appeared more likely to die compared with those without NF1. Two of the 4 NF1 patients had metastatic disease on presentation, accounting for half the patients with metastatic disease in this study. Although 3 of these 4 patients had no evidence of malignant disease following treatment, all 3 subsequently developed a local recurrence. These recurrences in NF1 patients accounted for all recurrences in this study. In addition, 2 of the 4 NF1 patients had died at last follow-up, accounting for 67% of the deaths in this study. For these NF1 patients, the 1- and 2-year DFS rates were 67% and 0%, respectively. The 1- and 2-year OS rates were 100% and 75%, respectively. In comparison for the non-NF1 patients, their 1- and 2-year DFS rates were both 100%. Their 1-year and 2-year OS rates were both 83%. This difference in DFS between NF1 patients and non-NF1 patients was statistically significant (P = 0.010), but the difference in OS was not (P = 0.235).
For all patients with MPNST treated by doxorubicin and ifosfamide regimens, despite metastatic or NF1 status, the 1- and 2-year OS rates were 90% and 80%, respectively. For all patients who appeared disease-free at some point during the study, the 1- and 2-year DFS rates were 86% and 57%.
MPNST are rare soft-tissue sarcomas with a high tendency for local recurrence and metastasis.1 The rates of successful treatment of MPNST are generally low, and the available published data provides only limited guidance regarding their management. MPNST are typically treated surgically, identical to other soft-tissue tumors, with success dependent on complete excision of the lesion.1,9 Radiotherapy is generally recommended for all intermediate- to high-grade lesions, and for low-grade tumors after a marginal excision.8 The use of chemotherapy in MPNST is acknowledged to be controversial though.1,8 Several agents with at least some activity against MPNST have been reported in the literature, including gemcitabine, docetaxel, carboplatin, etoposide, dactinomycin, cisplatinum, vincristine, cyclophosphamide, imidazole carboxamide, doxorubicin, and ifosfamide, but the clinical benefits with each have been variable and inconclusive.2,3,7,9–25 Assessing the effect of these chemotherapy agents and determining the best combination for MPNST is primarily complicated by the rarity of the disease. To assemble a substantial study population, most large series in the literature have had to span multiple decades and institutions, consequently covering an array of treatment methods.1,2,11,12,14,16–18,20–22,25 To minimize this variability, we herein sought to solely review the effects of 1 chemotherapy protocol used at 1 institution within a period lasting less than 5 years. We hypothesized that multimodality therapy which included chemotherapy with specifically doxorubicin and ifosfamide would lead to improved DFS and OS in patients with MPNST, when compared with currently published rates in the literature
Limitations present in this study included the small sample size, retrospective design, and use of additional chemotherapeutic agents. Addition of etoposide and camptothecin may have had an affect on the outcomes in those patients. With multiagent therapy, it is difficult to attribute responses and adverse events to specific drugs, unless there is clear evidence for specific correlations in the literature. Etoposide has been reported to have at least some activity in treating MPNSTs, and camptothecin has had reported activity against other soft-tissue sarcomas.23,26–29
In this study we used doxorubicin and ifosfamide as the primary chemotherapy regimen for a group of patients with primarily large- and high-grade MPNSTs. Our study also had a relatively high proportion of patients presenting with metastatic disease and NF1. Older age, size >5 cm, higher grade, metastatic disease, and NF1 are all generally considered to be poor prognostic factors,2,9,12,15,20,21 and so our series represents a high-risk group. Despite elevated risk in our study population though, our 2-year survival of 80% was slightly higher than rates from larger studies in the literature on predominantly nonchemotherapeutic treatments. Two-year OS rates from these studies ranged from 54.6% to 73.4%.2,11–13,18,20,21,25 Although several of these larger studies found no significant survival benefit based on their handful of patients receiving systemic chemotherapy, this may be an artifact of patient selection. For instance, Wong et al12 point out in their review of 134 MPNST cases that 75% of patients who received chemotherapy in their study had grade 3 or grade 4 tumors. Only 52% of patients in their nonchemotherapy group had grade 3 or grade 4 tumors though, so the nonchemotherapy group in their study would be expected to do better regardless of intervention.
Our study had a higher percentage of patients presenting with metastatic disease compared with the 5% to 25% in the literature.9,20–22,25,30 This again suggests our study population was particularly high-risk. Hematogenous spread is the most frequent method of metastases in MPSNT.11,20 The predominant location for metastases is the lungs, accounting for 70% to 100% of sites.1,2,12,13,31 The lymph nodes, bone, liver, peritoneum, brain, and other soft tissues are additional sites for metastatic disease, although these are reported far less commonly.1,2,18,20 A similar distribution of metastases was seen in our study, with the lungs accounting for 3 (75%) of 4 sites. More reflective of the disease's aggressiveness and resilience though is the high frequency with which MPNST spread after presentation. 28.7% to 60.5% of patients from several large studies in the literature eventually developed metastases despite treatment.2,12,13,18,19,25 The median time to development of metastatic disease ranged from 13 to 20.6 months.12,19–21 However, chemotherapy was used sparingly in those large series, and very little was discussed regarding the effect of chemotherapeutic regimens on development of metastatic disease. In the series by Sordillo et al,18 none of the 9 patients who received chemotherapy developed distant metastasis. Similarly, no patient from our study using doxorubicin and ifosfamide developed new metastatic disease through 25.4 months (range, 6.4–40.8) of follow-up. Although these results are encouraging, they require longer follow-up.
Chemotherapy was not able to eliminate local recurrence. Three (42.9%) of the 7 patients in our study who were free of all disease eventually experienced local recurrence. These occurred at 11.1, 16.7, and 20.9 months, respectively. This rate of local recurrence of MPNST after resection is in line with those published in the literature on predominantly nonchemotherapeutic treatments, which ranged from 28.8% to 53.9%.2,12,18,20,21,25 Our follow-up duration is admittedly shorter than these other studies though, so our rate could conceivably increase in the future. The median time to development of a local recurrence in several published studies has ranged from 9 to 22 months, but local recurrences have been reported as far as 25 years after definitive treatment.7,12,20,21,25 Several of these larger studies found no significant local control benefit based on their handful of patients receiving systemic chemotherapy, but this again may be an artifact of patient selection.2,12,20 In the study of Sordillo et al,18 53.9% of 165 patients in the study experienced a local recurrence, whereas only 2 (22%) of the 9 patients that received chemotherapy experienced a local recurrence. Ducatman et al2 in his study found less impressive results, with a 42% local recurrence rate in the general study population of 120 patients and a 39% local recurrence rate in the 18 patients receiving chemotherapy. Our DFS rates with doxorubicin and ifosfamide similarly showed no major advantage over predominantly nonchemotherapeutic approaches. Our 2-year DFS rate was 57%, in comparison to the 2-year DFS rates of approximately 42% to 57% in the literature for predominantly nonchemotherapeutic treatments.11,15,16 The high rate of recurrence and our number of positive margins may be related to the surgical challenges of obtaining wide margins on large nerve tumors and/or the ability of the tumor to seed surrounding tissues.
The prognosis after recurrence is particularly poor,20 and so the initial treatment should be aggressive, complete, and performed at an experienced center. Aggressive treatment carries its own risks though. In addition to the immediate complications that can occur with surgery, radiation therapy, and chemotherapy, long-term survivors may be faced with delayed complications of their treatment. Although no patients from this study have experienced any significant chemotherapy side effects, there are numerous reports in the literature of adverse events associated with doxorubicin and ifosfamide therapy.32–39 Doxorubicin has been linked to serious complications such as arrhythmias, pericarditis/myocarditis, and myelosuppression, as well other delayed events such as congestive heart failure, thromboembolism, secondary leukemia, and infertility.32,37–39 Ifosfamide has similarly been linked to serious complications such as arrhythmias, heart failure, myelosuppression, encephalopathy, and hemorrhagic cystitis, as well as delayed events such as pulmonary fibrosis, proximal tubular damage, and infertility.33–36
In summary, when combined with surgery and radiation therapy, the regimen of doxorubicin and ifosfamide resulted in 57% DFS and 80% OS at 2-years. These short-term results are similar or slightly better than rates from predominantly nonchemotherapeutic studies in the literature, despite our patient population being higher risk. The outcomes for our patients without metastatic disease on presentation or without NF1 were generally better than those with metastases or with NF1, but the sample size in this study is too small to draw firm conclusions. Even this short-term study illustrates the perils of metastatic disease, resectability, and recurrence. Longer follow-up and a larger cohort are needed though to determine whether the survival for patients receiving this regimen approaches results of longer-term studies on MPNST.
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malignant peripheral nerve sheath tumor; MPNST; chemotherapy; doxorubicin; ifosfamide; neurofibromatosis; malignant schwannoma
© 2011 Lippincott Williams & Wilkins, Inc.
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