VOLUME 32 䡠 NUMBER 33 䡠 NOVEMBER 20 2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
Case Report A 23-year-old white woman was diagnosed with stage IIB melanoma of the upper extremity after wide resection and sentinel lymph node biopsy. Ten months later, metastatic disease developed, requiring palliative resection of a large chest wall mass and axillary lymph node dissection. A positron emission tomography scan demonstrated bilateral pulmonary nodules and bilateral hilar adenopathy. Magnetic resonance imaging (MRI) of the brain showed multiple enhancing lesions. Palliative whole-brain radiation was given, followed by two courses of high-dose IL-2 systemic therapy. A restaging positron emission tomography scan demonstrated an excellent partial response of the lung disease. Five months later, lower extremity neurologic deficits developed. MRI of the thoracic and lumbar spine showed multiple intramedullary masses and significant spinal cord edema from the fourth through eleventh thoracic vertebral levels (T4 through T11). Radiation therapy (RT; 30 Gy) was administered to T3 to T12 over 2 weeks. Immediately after finishing RT, temozolomide (200 mg/m2 per day for 5 days) was begun; however, during the last day of RT and the first few days of
Intrathecal Interleukin-2 for Melanomatous Meningitis Introduction One person dies as a result of melanoma every 64 minutes in the United States; it is the most common cancer killer in women age 30 to 35 years.1,2 Melanoma is among the three cancers most likely to spread to the leptomeninges, with a 23% rate of meningeal spread.3 In a retrospective review of 110 patients with melanomatous meningitis (MM), median overall survival from time of diagnosis of MM was 10 weeks.4 The majority of patients with MM and leptomeningeal disease from other solid tumors are frequently treated with intrathecal methotrexate, cytarabine, thiotepa, or topotecan, but published reports of treatment with intrathecal interleukin (IT IL-2) are rare. This report describes a patient with MM who was treated with IT IL-2 and experienced subsequent extended survival.
A
I N
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 33 (November 20), 2014: pp e111-e113
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e111
Shonka, Kessinger, and Aizenberg
Table 1. Intrathecal Therapy With IL-2 for Melanomatous Meningitis No. of Patients
IT IL-2 Dose
Outcome
Moser et al, 19915
9
12 ⫻ 106 IU
Samlowski et al, 19936
1
3-6 ⫻ 106 IU
12
6 ⫻ 106 IU
1
1.2 ⫻ 106 IU
46
1.2 ⫻ 106 IU
1
1.2 ⫻ 106 IU
CSF clearance in 6 of 9 patients (insufficient data in 3 patients) No CSF clearance, but minor improvement of neurologic deficits CSF clearance and resolution of clinical symptoms in 3 of 12 patients, no MRI changes CSF clearance, stability of symptoms, MRI progression CSF clearance in 12 of 46 patients (11 patients not evaluable); MRI progression despite response CSF clearance, no clinical improvement, no MRI changes
Report
Papadopoulos et al, 19957
Fathallah-Shaykh, 19968 Papadopoulos et al, 20029
Our patient
TTP NR — 6-42 weeks
— NR
CSF clear at time of death
Median OS All patients, 150 days (range, 10-582 days) 1 month NR
15 months (alive at time of report) Responders, 11.5 months (range, 7-90 months); nonresponders, 3.5 months (range, 1.5-11 months) 170 days
Abbreviations: IL-2, interleukin-2; IT IL-2, intrathecal IL-2; IU, international units; MRI, magnetic resonance imaging; NR, not recorded; OS, overall survival; TTP, time to progression.
temozolomide administration, right lower extremity paresthesias, weakness, and urinary retention developed. Imaging revealed diffuse leptomeningeal tumor in the thoracic and lumbar regions, as noted in Figures 1A and 1B. The sagittal T1 image with contrast (Fig 1A) shows the classic diffuse enhancement of the pial surface of the cord and conus medullaris, which is indicative of MM, as well as medullary deposits in the cord. The sagittal T2 image (Fig 1B) shows diffuse cord edema secondary to these deposits. Emergent radiation was given at 20 Gy in five fractions to L1 to S4. Spinal fluid contained malignant cells that were consistent with melanoma. IT IL-2 (1.2 million U) was initially administered through an external ventricular drain (EVD) that had been placed secondary to a malfunctioning Ommaya reservoir. The patient received once-per-day administration of IT IL-2 for 4 consecutive days. Intracranial pressure (ICP) readings were measured hourly, before and after each dose, and were continuously transduced by the EVD. ICP measurements taken from the EVD ranged from 4 to 19 cm H2O. Before administration of IL-2, a volume of CSF was removed that was equivalent to the volume of IL-2 to be administered or to reach a goal ICP of 10 to 15 cm H2O, if needed. Low-grade fevers were noted after each dose and were accompanied by moderate headaches. By the end of the induction period, CSF analysis revealed only rare atypical cells that were consistent with inflammation. IT IL-2 was continued every second and then every third day for a total of 4 weeks of inpatient therapy. The patient’s EVD was converted back to an Ommaya reservoir during this time, and ICP measurements taken from the Ommaya ranged from 11 to 25 cm H2O. The ICP of 25 cm H2O was the initial measurement on the day after EVD removal. Thereafter, IT IL-2 was given once per week, and the time between treatments was gradually lengthened over the next several months, until administration occurred every 3 weeks. Neither imaging response nor clinical response was achieved; however, CSF cytology remained negative throughout therapy. Death was attributed to systemic disease rather than MM and occurred 170 days after the start of treatment with IT IL-2 for MM.
were no differences in survival between patients with or without concurrent parenchymal CNS metastases and MM. On multivariate analysis, IT chemotherapy was significantly associated with improved survival, with a hazard ratio of 0.5 (P ⫽ .0036).4 Published reports of using IT IL-2 to treat MM are rare (Table 1).5-9 In 2002, Papadopoulos et al presented an abstract wherein 46 patients received IT IL-2 for MM. Of those evaluable, 12 patients (34%) responded as defined by negative cytology that persisted for 4 weeks or longer. Responders had an overall survival of 11.5 months compared with nonresponders, who had an overall survival of 3.5 months. Adverse effects included fevers, chills, and signs of elevated ICP that were managed with medications, CSF withdrawal, and low-dose dexamethasone. Three patients had a sustained remission with survival of 13⫹, 32⫹, and 90⫹ months. Discontinuation of IT IL-2 resulted in relapses that were reversed with the resumption of therapy.9 A 2008 review by Harstad et al4 indicated that one of these long-term responders was alive at 11.2 years and continued to receive IL-2 maintenance therapy, although the required frequency of treatment for this patient was not noted. Despite cytologic response, patients in the MD Anderson Cancer Center experience had progression of parenchymal disease on MRI.7,9 Our patient experienced intramedullary spinal lesion stability, which may be attributed to radiation therapy. At the time of death from progressive systemic melanoma, which occurred 24.3 weeks after the diagnosis of MM, CSF cytology remained negative, comparing favorably with the median survival of 10 weeks. This patient case illustrates the feasibility and efficacy of using IT IL-2 for MM in carefully selected and monitored patients. This case is presented to heighten the awareness of IT IL-2 as an effective agent against leptomeningeal disease from melanoma.
Nicole A. Shonka, Anne M. Kessinger, and Michele R. Aizenberg University of Nebraska Medical Center, Omaha, NE
Discussion This patient presented with spinal cord metastases that were concurrent with MM. In the review of 110 patients with MM,4 there e112
© 2014 by American Society of Clinical Oncology
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
REFERENCES 1. American Cancer Society: Cancer facts and figures 2010. Atlanta, GA, American Cancer Society, 2010. http://www.cancer.org/acs/groups/content/ @epidemiologysurveilance/documents/document/acspc-026238.pdf 2. Howlader N, Noone AM, Krapcho M, et al (eds): SEER cancer statistics review. Bethesda, MD, National Cancer Institute, 1997-2009 3. Amer MH, Al-Sarraf M, Baker LH, et al: Malignant melanoma and central nervous system metastases: Incidence, diagnosis, treatment and survival. Cancer 42:660-668, 1978 4. Harstad L, Hess KR, Groves MD: Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol 10:1010-1018, 2008 5. Moser RP, Bruner JM, Grimm EA: Biological therapy of brain tumors. Cancer Bull 43:117-126, 1991 6. Samlowski WE, Park KJ, Galinsky RE, et al: Intrathecal administration of interleukin-2 for meningeal carcinomatosis due to malignant melanoma: Sequen-
tial evaluation of intracranial pressure, cerebrospinal fluid cytology, and cytokine induction. J Immunother Emphasis Tumor Immunol 13:49-54, 1993 7. Papadopoulos NE, Moser RP, Grimm E, et al: Intrathecal use of recombinant interleukin-2 (rIL-2) in the treatment of leptomeningeal disease (LMD) from metastatic melanoma. Proc Am Soc Clin Oncol 14, 1995 (abstr 1307) 8. Fathallah-Shaykh HM, Zimmerman C, Morgan H, et al: Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2: A case report. Cancer 77:1544-1550, 1996 9. Papadopoulos NE, Gerber DL, Eton O, et al: The role of intrathecal (IT) use of interleukin-2 (IL-2) in the treatment of leptomeningeal disease (LMD) in patients (pts) with melanoma. Proc Am Soc Clin Oncol 21, 2002 (abstr 1408)
DOI: 10.1200/JCO.2013.49.1100; published online ahead of print at www.jco.org on February 18, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e113
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
Case Report A 23-year-old white woman was diagnosed with stage IIB melanoma of the upper extremity after wide resection and sentinel lymph node biopsy. Ten months later, metastatic disease developed, requiring palliative resection of a large chest wall mass and axillary lymph node dissection. A positron emission tomography scan demonstrated bilateral pulmonary nodules and bilateral hilar adenopathy. Magnetic resonance imaging (MRI) of the brain showed multiple enhancing lesions. Palliative whole-brain radiation was given, followed by two courses of high-dose IL-2 systemic therapy. A restaging positron emission tomography scan demonstrated an excellent partial response of the lung disease. Five months later, lower extremity neurologic deficits developed. MRI of the thoracic and lumbar spine showed multiple intramedullary masses and significant spinal cord edema from the fourth through eleventh thoracic vertebral levels (T4 through T11). Radiation therapy (RT; 30 Gy) was administered to T3 to T12 over 2 weeks. Immediately after finishing RT, temozolomide (200 mg/m2 per day for 5 days) was begun; however, during the last day of RT and the first few days of
Intrathecal Interleukin-2 for Melanomatous Meningitis Introduction One person dies as a result of melanoma every 64 minutes in the United States; it is the most common cancer killer in women age 30 to 35 years.1,2 Melanoma is among the three cancers most likely to spread to the leptomeninges, with a 23% rate of meningeal spread.3 In a retrospective review of 110 patients with melanomatous meningitis (MM), median overall survival from time of diagnosis of MM was 10 weeks.4 The majority of patients with MM and leptomeningeal disease from other solid tumors are frequently treated with intrathecal methotrexate, cytarabine, thiotepa, or topotecan, but published reports of treatment with intrathecal interleukin (IT IL-2) are rare. This report describes a patient with MM who was treated with IT IL-2 and experienced subsequent extended survival.
A
I N
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 33 (November 20), 2014: pp e111-e113
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e111
Shonka, Kessinger, and Aizenberg
Table 1. Intrathecal Therapy With IL-2 for Melanomatous Meningitis No. of Patients
IT IL-2 Dose
Outcome
Moser et al, 19915
9
12 ⫻ 106 IU
Samlowski et al, 19936
1
3-6 ⫻ 106 IU
12
6 ⫻ 106 IU
1
1.2 ⫻ 106 IU
46
1.2 ⫻ 106 IU
1
1.2 ⫻ 106 IU
CSF clearance in 6 of 9 patients (insufficient data in 3 patients) No CSF clearance, but minor improvement of neurologic deficits CSF clearance and resolution of clinical symptoms in 3 of 12 patients, no MRI changes CSF clearance, stability of symptoms, MRI progression CSF clearance in 12 of 46 patients (11 patients not evaluable); MRI progression despite response CSF clearance, no clinical improvement, no MRI changes
Report
Papadopoulos et al, 19957
Fathallah-Shaykh, 19968 Papadopoulos et al, 20029
Our patient
TTP NR — 6-42 weeks
— NR
CSF clear at time of death
Median OS All patients, 150 days (range, 10-582 days) 1 month NR
15 months (alive at time of report) Responders, 11.5 months (range, 7-90 months); nonresponders, 3.5 months (range, 1.5-11 months) 170 days
Abbreviations: IL-2, interleukin-2; IT IL-2, intrathecal IL-2; IU, international units; MRI, magnetic resonance imaging; NR, not recorded; OS, overall survival; TTP, time to progression.
temozolomide administration, right lower extremity paresthesias, weakness, and urinary retention developed. Imaging revealed diffuse leptomeningeal tumor in the thoracic and lumbar regions, as noted in Figures 1A and 1B. The sagittal T1 image with contrast (Fig 1A) shows the classic diffuse enhancement of the pial surface of the cord and conus medullaris, which is indicative of MM, as well as medullary deposits in the cord. The sagittal T2 image (Fig 1B) shows diffuse cord edema secondary to these deposits. Emergent radiation was given at 20 Gy in five fractions to L1 to S4. Spinal fluid contained malignant cells that were consistent with melanoma. IT IL-2 (1.2 million U) was initially administered through an external ventricular drain (EVD) that had been placed secondary to a malfunctioning Ommaya reservoir. The patient received once-per-day administration of IT IL-2 for 4 consecutive days. Intracranial pressure (ICP) readings were measured hourly, before and after each dose, and were continuously transduced by the EVD. ICP measurements taken from the EVD ranged from 4 to 19 cm H2O. Before administration of IL-2, a volume of CSF was removed that was equivalent to the volume of IL-2 to be administered or to reach a goal ICP of 10 to 15 cm H2O, if needed. Low-grade fevers were noted after each dose and were accompanied by moderate headaches. By the end of the induction period, CSF analysis revealed only rare atypical cells that were consistent with inflammation. IT IL-2 was continued every second and then every third day for a total of 4 weeks of inpatient therapy. The patient’s EVD was converted back to an Ommaya reservoir during this time, and ICP measurements taken from the Ommaya ranged from 11 to 25 cm H2O. The ICP of 25 cm H2O was the initial measurement on the day after EVD removal. Thereafter, IT IL-2 was given once per week, and the time between treatments was gradually lengthened over the next several months, until administration occurred every 3 weeks. Neither imaging response nor clinical response was achieved; however, CSF cytology remained negative throughout therapy. Death was attributed to systemic disease rather than MM and occurred 170 days after the start of treatment with IT IL-2 for MM.
were no differences in survival between patients with or without concurrent parenchymal CNS metastases and MM. On multivariate analysis, IT chemotherapy was significantly associated with improved survival, with a hazard ratio of 0.5 (P ⫽ .0036).4 Published reports of using IT IL-2 to treat MM are rare (Table 1).5-9 In 2002, Papadopoulos et al presented an abstract wherein 46 patients received IT IL-2 for MM. Of those evaluable, 12 patients (34%) responded as defined by negative cytology that persisted for 4 weeks or longer. Responders had an overall survival of 11.5 months compared with nonresponders, who had an overall survival of 3.5 months. Adverse effects included fevers, chills, and signs of elevated ICP that were managed with medications, CSF withdrawal, and low-dose dexamethasone. Three patients had a sustained remission with survival of 13⫹, 32⫹, and 90⫹ months. Discontinuation of IT IL-2 resulted in relapses that were reversed with the resumption of therapy.9 A 2008 review by Harstad et al4 indicated that one of these long-term responders was alive at 11.2 years and continued to receive IL-2 maintenance therapy, although the required frequency of treatment for this patient was not noted. Despite cytologic response, patients in the MD Anderson Cancer Center experience had progression of parenchymal disease on MRI.7,9 Our patient experienced intramedullary spinal lesion stability, which may be attributed to radiation therapy. At the time of death from progressive systemic melanoma, which occurred 24.3 weeks after the diagnosis of MM, CSF cytology remained negative, comparing favorably with the median survival of 10 weeks. This patient case illustrates the feasibility and efficacy of using IT IL-2 for MM in carefully selected and monitored patients. This case is presented to heighten the awareness of IT IL-2 as an effective agent against leptomeningeal disease from melanoma.
Nicole A. Shonka, Anne M. Kessinger, and Michele R. Aizenberg University of Nebraska Medical Center, Omaha, NE
Discussion This patient presented with spinal cord metastases that were concurrent with MM. In the review of 110 patients with MM,4 there e112
© 2014 by American Society of Clinical Oncology
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
REFERENCES 1. American Cancer Society: Cancer facts and figures 2010. Atlanta, GA, American Cancer Society, 2010. http://www.cancer.org/acs/groups/content/ @epidemiologysurveilance/documents/document/acspc-026238.pdf 2. Howlader N, Noone AM, Krapcho M, et al (eds): SEER cancer statistics review. Bethesda, MD, National Cancer Institute, 1997-2009 3. Amer MH, Al-Sarraf M, Baker LH, et al: Malignant melanoma and central nervous system metastases: Incidence, diagnosis, treatment and survival. Cancer 42:660-668, 1978 4. Harstad L, Hess KR, Groves MD: Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol 10:1010-1018, 2008 5. Moser RP, Bruner JM, Grimm EA: Biological therapy of brain tumors. Cancer Bull 43:117-126, 1991 6. Samlowski WE, Park KJ, Galinsky RE, et al: Intrathecal administration of interleukin-2 for meningeal carcinomatosis due to malignant melanoma: Sequen-
tial evaluation of intracranial pressure, cerebrospinal fluid cytology, and cytokine induction. J Immunother Emphasis Tumor Immunol 13:49-54, 1993 7. Papadopoulos NE, Moser RP, Grimm E, et al: Intrathecal use of recombinant interleukin-2 (rIL-2) in the treatment of leptomeningeal disease (LMD) from metastatic melanoma. Proc Am Soc Clin Oncol 14, 1995 (abstr 1307) 8. Fathallah-Shaykh HM, Zimmerman C, Morgan H, et al: Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2: A case report. Cancer 77:1544-1550, 1996 9. Papadopoulos NE, Gerber DL, Eton O, et al: The role of intrathecal (IT) use of interleukin-2 (IL-2) in the treatment of leptomeningeal disease (LMD) in patients (pts) with melanoma. Proc Am Soc Clin Oncol 21, 2002 (abstr 1408)
DOI: 10.1200/JCO.2013.49.1100; published online ahead of print at www.jco.org on February 18, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e113
