Practical Radiation Oncology (2012) 2, e129–e132

www.practicalradonc.org

Teaching Case

Nelfinavir treatment of adenoid cystic carcinoma: A case report Gabriel O. de la Garza MD a , Ameera F. Ismail MD b , Carryn M. Anderson MD c , Werner W. Wilke MD, PhD c , Mohammed M. Milhem MD d,⁎, Henry T. Hoffman MD a , John M. Buatti MD c a

Department of Otolaryngology–Head and Neck Surgery, University of Iowa, Iowa City, Iowa Department of Radiology, University of Iowa, Iowa City, Iowa c Department of Radiation Oncology, University of Iowa, Iowa City, Iowa d Department of Internal Medicine, University of Iowa, Iowa City, Iowa b

Received 7 July 2011; revised 19 September 2011; accepted 20 September 2011

Introduction Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck cancers and most commonly arises from the major and minor salivary glands, but may also develop in other sites. 1 Complete resection with negative margins, the recommended surgical treatment, is commonly compromised by extensive perineural spread. Anatomic constraints such as extension to or through the skull base may also preclude meaningful resection, in which case the standard postoperative radiation therapy may serve as primary therapy instead. Despite displaying an indolent behavior, ACC is highly lethal. Disease-free survival at 5 years is around 50% and decreases to 30% to 40% at 15 years. 2,3 Management options for recurrence are usually limited by the location and extent of the cancer (which is often metastatic), precluding further surgery or reirradation. Systemic treatment has been limited to toxic chemotherapy regimens with low efficacy. As a result, management of recurrent disease warrants further investigation.

Conflicts of interest: None. ⁎ Corresponding author. Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242. E-mail address: [email protected] (M.M. Milhem).

To identify possible therapeutic targets we analyzed the molecular characteristics of ACC from pathologic samples at our hospital. We found that ACC tumors highly express markers of the PI3K-Akt and MAPK signaling pathways. Treatment with nelfinavir, a protease inhibitor approved for use in human immunodeficiency virus, down regulates signaling through the AKT and MAPK pathways. This in turn results in clonogenic cell death and growth inhibition in a cell line with ACC characteristics at clinically relevant concentrations. 4 Nelfinavir inhibits the proteasome, resulting in accumulation of misfolded cellular proteins, induction of cellular arrest, and a signaling cascade that results in inactivation of Akt by dephosphorylation. 5 Based on this evidence, we applied nelfinavir to manage a patient with progressive ACC of the skull base that was recurrent after primary radiotherapy and progressive in nature despite subsequent treatment with vinorelbine and cisplatin.

Case presentation This report is a retrospective chart review at a tertiary care academic medical center. All imaging was reviewed by a board-certified neuroradiologist, whose findings confirmed the interpretations in the original radiology report.

1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2011.09.003

e130

G.O. de la Garza et al

Practical Radiation Oncology: October-December 2012

Figure 1 Contrast-enhanced, T1 weighted, magnetic resonance imaging with fat saturation at the time diagnosis (A, B) and after radiation therapy (C, D). (A) Axial cut showing the tumor centered in the sphenoid sinus with extension into the posterior ethmoid sinus and nasal cavity, with involvement of the cavernous sinuses and the right Meckel’s cave; (B) Coronal cut showing the tumor elevating the planum sphenoidale and involving the medial orbital walls. There is extension into the posterior nasal cavity and the right maxillary sinus and involvement of the maxillary alveolar ridge; (C) Axial cut showing necrosis and decreased bulk of the tumor in the right maxillary sinus (arrow); (D) Coronal cut showing decreased tumor mass in the right maxillary sinus, posterior nasal cavity (arrowheads), and skull base (arrow).

At the time of diagnosis, 10 years prior to starting nelfinavir, the patient was a 69-year-old woman with a 1-year history of congestion and 6 months of visual loss associated with headaches. Physical exam revealed afferent papillary defect and vision loss in both eyes with nearly complete loss of vision in the right eye. A magnetic resonance imaging study revealed a 4.5 × 5.5 × 5.5-cm mass centered in the sphenoid extending into the posterior nasal cavity, right maxillary sinus, and alveolar ridge, involving the cavernous sinuses bilaterally, and extending to the right pterygopalatine fossa and the right Meckel's cave (Fig 1 A, B). Intranasal biopsy revealed ACC and the tumor was staged as T4N0M0. Medical history included insulin-dependent diabetes mellitus, with the most recent hemoglobin A1C of 6.8%. Family history was strongly positive for cancer. The patient was treated with intensity modulated radiation therapy to a dose of 63 Gy in 35 fractions over 7 weeks without any immediate complication. At 3 months

after finishing radiotherapy, the tumor size was reduced to 3.5 × 3.5 × 3.5 cm with necrosis and regression of the tumor from the right Meckel's cave, and decreased mass in the right maxillary sinus, posterior nasal cavity, and skull base (Fig 1 C, D). The patient had significant symptomatic progression at 61/2 years after radiotherapy, including paresthesia and intermittent numbness in the right V1 distribution. Seven years after radiotherapy, surveillance imaging confirmed progression of the intracranial and orbital extensions of the tumor, and physical exam revealed nearly complete numbness in the V1 distribution. Eight years after radiotherapy, after further observation and with no viable surgical options, the patient was offered a palliative chemotherapy regimen of cisplatin and vinorelbine based on a promising phase II trial; cisplatin 80 mg/m 2 on days 1 and 8, with vinorelbine 25 mg/m 2 on day 8, and cycles occurring every 3 weeks. 6 She was able to tolerate only 2 cycles of this treatment and

Practical Radiation Oncology: October-December 2012

Nelfinavir treatment of ACC

e131

Figure 2 Contrast-enhanced, T1 weighted magnetic resonance imaging with fat saturation and T2 with fat saturation 9 years after diagnosis showing the tumor prior to treatment (A)-(C), and after 1 year of nelfinavir treatment (D)-(F), showing stable tumor burden with increased necrosis. (A) Axial T1 with fat saturation showing interval increase of the tumor in the right maxillary sinus; (B) Coronal T1 with fat saturation showing interval increase of the tumor size in the right maxillary sinus and increased extension through the medial orbital walls; (C) Coronal T2 with fat saturation showing interval increase in size of the tumor, which is of low signal intensity, in the right maxillary sinus and increased extension through the medial orbital walls; (D) Axial T1 with fat saturation showing grossly stable size of the tumor in the right maxillary sinus, however, with increased necrotic changes (arrowhead); (E) Coronal T1 with fat saturation showing grossly stable size of the tumor in the right maxillary sinus with increased necrotic changes (arrowhead); (F) Coronal T2 with fat saturation showing grossly stable size of the tumor in the right maxillary sinus and stable involvement of the medial orbital walls, however, there are small areas of high T2 signal intensity indicating increased necrosis of the tumor (arrowhead).

there was no evidence of tumor necrosis or reduction in tumor size based on magnetic resonance imaging, and no symptomatic reprieve. By 9 years after diagnosis the tumor continued to grow, particularly in the right maxillary sinus, medial orbital wall, and posterior nasal cavity (Fig 2 A-C), and there was still no evidence of distant disease based on chest computed tomographic imaging. Because of the progression of disease radiographically, and with ongoing facial numbness, the patient opted to begin treatment with nelfinavir at 1250 mg by mouth twice daily, with symptomatic reprieve the focus of palliative care. The patient's facial numbness improved after 3 months, but the patient also experienced known side effects of nelfinavir, including fatigue, somnolence, and leg discomfort. The frequency of dosing was reduced to once daily after 4 months due to hyperglycemia requiring a single hospitalization. The extension of the tumor remained stable and central necrosis became prominent, most noticeably in the right maxillary sinus and posterior nasal cavity (Fig 2

D-F). The overall tumor size has not progressed for 11/2 years on this regimen and there were no further admissions to the hospital. During this period the patient's improvement in facial numbness and her remaining vision was stable.

Discussion Recurrent ACC is a disease with limited treatment options. Surgery and radiotherapy are often not curative, yet the durable local control, illustrated more than 6 years after initial treatment, attests to its' role as standard initial therapy. In addition, chemotherapy is generally not used for primary, metastatic, or recurrent tumors due to low response rates and difficulties in completing treatment, as in this case. Other groups are currently searching for more targeted therapies for ACC, 7,8 and the need for additional therapeutic options remains (Table 1).

e132 Table 1

G.O. de la Garza et al

Practical Radiation Oncology: October-December 2012

Recent phase I-II clinical trials, which include treatment of adenoid cystic carcinoma of the head and neck

Year

Molecular target

Targeted drug

Radiation

2010

EGFR

Cetuximab

2010

PI3-K/AKT/mTOR

RAD001

2010

Histone deacetylase

Vorinostat

2009

(c-kit?)

2009 2008

EGFR VEGFR2, c-kit, and PDGFR/unknown (antiautophagy)

Dasatinib (BMS 354825 Erlotinib Sunitinib/ hydroxychloroquine

IMRT + Heavy I and II University of carbon (C12) Boost Heidelberg None II Seoul National University Hospital None II Barbara Ann Karmanos Cancer Institute None II University of Chicago

2010

Microtubule spindle/folate

Combined traditional chemotherapy Docletaxel and pemetrexed

None None

Phase

I

Sponsor

Clinicaltrials.gov ID NCT01192087 NCT01152840 NCT01175980 NCT00859937

Northwestern University NCT01013831 University of Medicine NCT00813423 and Dentistry New Jersey

I None

I

University of Arizona

NCT01172028

EGFR, epidermal growth factor receptor; IMRT, intensity-modulated radiation therapy; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor.

Monitoring for side effects of nelfinavir treatment was uncomplicated, as the side effect profile of nelfinavir has been extensively reviewed 9 and genetic variation in its metabolism has been studied. Insulin resistance, dyslipidemia, and lipoatrophy commonly occur, 10 and this patient required admission for severe hyperglycemia after using nelfinavir for 4 months despite being an educated and long-term insulin user. The molecular pathway shown to be affected by nelfinavir is the PI3K-AKT pathway, which is commonly activated in malignancies and confers resistance to radiotherapy, while reduction of Akt signaling confers sensitivity to radiotherapy. 11 Because Akt and MAPK are thought to be downstream effectors of EGFR (epidermal growth factor receptor) or IGF1 (insulin-like growth factor 1)-R, 12 and because the ACC tumors we examined do not express EGFR, 5 it is possible that the direct therapeutic target of nelfinavir is IGF1-R. However, phase I-II studies have shown poor efficacy when targeting signaling pathways upstream of Akt and MAPK. 7 The potential of combining nelfinavir with other therapies remains a possibility.

Conclusions To our knowledge, this case is the first known report of nelfinavir use in any head and neck tumor and this case illustrates a promising stabilization of known progressive ACC for 11/2 years in a patient who had no other reasonable therapeutic options. We have opened a phase II trial to examine the efficacy of nelfinavir treatment for recurrences of ACC (see http://clinicaltrials.gov/ct2/show/ NCT01065844). Further study is ongoing.

References 1. Spiro RH, Huvos AG, Strong EW. Adenoid cystic carcinoma of salivary origin. A clinicopathologic study of 242 cases. Am J Surg. 1974;128:512-520. 2. Iseli TA, Karnell LH, Graham SM, et al. Role of radiotherapy in adenoid cystic carcinoma of the head and neck. J Laryngol Otol. 2009;123:1137-1144. 3. Rapidis AD, Givalos N, Gakiopoulou H, et al. Adenoid cystic carcinoma of the head and neck. Clinicopathological analysis of 23 patients and review of the literature. Oral Oncol. 2005;41:328-335. 4. Gupta AK, Wilke WW, Taylor EN, et al. Signaling pathways in adenoid cystic cancers: implications for treatment. Cancer Biol Ther. 2009;8:1947-1951. 5. Gupta AK, Li B, Cerniglia GJ, Ahmed MS, Hahn SM, Maity A. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia. 2007;9:271-278. 6. Airoldi M, Pedani F, Succo G, et al. Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer. 2001;91:541-547. 7. Papaspyrou G, Hoch S, Rinaldo A, et al. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review. Head Neck. 2011;33:905-911. 8. Dodd RL, Slevin NJ. Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. Oral Oncol. 2006;42:759-769. 9. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62. 10. Evans WE, McLeod HL. Pharmacogenomics — drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538-549. 11. Rudner J, Ruiner CE, Handrick R, Eibl HJ, Belka C, Jendrossek V. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation. Radiat Oncol. 2010;5:108. 12. Gills JJ, Lopiccolo J, Tsurutani J, et al. Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res. 2007;13:5183-5194.

Nelfinavir treatment of adenoid cystic carcinoma: A case report.

Nelfinavir treatment of adenoid cystic carcinoma: A case report. - PDF Download Free
625KB Sizes 0 Downloads 5 Views