- © 2007 by American Society of Clinical Oncology
Successful Treatment of leptomeningeal disease in Colorectal Cancer With a Regimen of Bevacizumab, Temozolomide, and Irinotecan
To the Editor:
CNS metastases from colorectal cancer are an uncommon occurrence, with an estimated incidence of 1% to 3%.1-3 Similarly, the presence of leptomeningeal disease (LMD) is also distinctly uncommon, although there are no precise estimates of its incidence.4 The development of CNS metastases from colorectal cancer usually occurs late in the clinical course5 and carries a very poor prognosis.3,6 In our experience, LMD from colorectal cancer in particular is associated with a sharp decline in clinical status and a dismal short-term prognosis.
The treatment of LMD in solid tumors comprises a combination of focal irradiation of symptomatic areas or areas of bulky disease with intrathecal chemotherapy and/or systemic chemotherapy to control active systemic disease. To date, the optimal regimen has not been defined and therapeutic outcomes remain poor.4,7,8
Here, we present a case report of a patient treated for LMD with bevacizumab, temozolomide, and irinotecan. He was a 49-year-old man who underwent initial treatment for rectal cancer between 1997 and mid-1999. He underwent surgical resection for a T2N0 lesion, with rapid recurrence of the primary tumor. He was treated with subsequent preoperative fluorouracil (FU), radiotherapy, and re-resection, and intraoperative brachytherapy and adjuvant bolus FU and leucovorin. He then remained free of disease until October 2005, when he underwent resection of a right cerebellar mass, which revealed metastatic rectal cancer. At that time, he was also found to have biopsy proven metastatic rectal cancer to mediastinal lymph nodes.
In December 2005, he was treated with the FOLFIRI regimen (irinotecan 180 mg/m2, FU 400 mg/m2, and leucovorin 400 mg/m2 on day 1, continuous infusion of FU 1,200 mg/m2 day 1 through 2) administered every 14 days.
After two cycles of FOLFIRI therapy, repeat imaging demonstrated slight improvement in mediastinal lymphadenopathy. However, further imaging revealed recurrent disease at the surgical site as well as new LMD, without focal bulky areas, throughout the brain and spinal cord. He was treated with whole-brain radiation therapy down to the C2 vertebrae for a total of 30 Gy over 10 fractions.
Preliminary data provided by Friedman (H.S. Friedman, personal communication, January 2006) and subsequently presented in abstract form9 suggested that bevacizumab could be safely administered in the setting of primary brain tumors. Furthermore, temozolomide was known to have modest activity in brain metastases from solid malignancies.10-13 The patient's systemic disease had also responded to initial irinotecan-based therapy and there were additional data that the combination of temozolomide and irinotecan was both safe and effective.14-16
In February 2006, we initiated a treatment regimen of temozolomide 200 mg/m2 on days 1 through 5, irinotecan 180 mg/m2 on days 1 and 15, and bevacizumab 5 mg/kg on days 1 and 15, administered every 28 days.
Imaging after one cycle of therapy demonstrated stable LMD with decreasing mediastinal lymphadenopathy. Imaging after two cycles demonstrated response both systemically and also with LMD. Imaging after four complete cycles of treatment demonstrated stability of his brain parenchymal metastasis, marked improvement of his LMD, and further decrease in mediastinal lymph nodes. Representative images are shown in Figure 1.
Magnetic resonance imaging of the spine (A) after one cycle of treatment and (B) follow-up study 3 months later after four treatment cycles. Sagittal T1-weighted sequences reveal almost complete resolution of linear and nodular enhancement around the (arrows) conus medullaris and roots of cauda equina.
Clinically, he remained fully ambulatory with an Eastern Cooperative Oncology Group performance status of 0. Prior complaints of nausea, headache, back pain, and fatigue completely resolved within the first 2 weeks of therapy.
He continued on treatment for more than 6 months until July 2006, when he was hospitalized locally after several days of intractable headache and nausea. While hospitalized, he suffered a respiratory arrest and died after vomiting while eating. At autopsy, he was found to have extensive LMD as well as aspirated material in the main bronchi. There was no evidence of metastatic disease in his lungs or lymph nodes.
Although we cannot attribute response in the recurrent brain metastases to chemotherapy or bevacizumab given the prior administration of whole-brain radiation therapy, observation of a response to systemic therapy in LMD is remarkable. To our knowledge, effective therapy for LMD in colorectal cancer has not been previously reported.
The combination of temozolomide and irinotecan has previously been evaluated in phase I studies.14-16 It has been found to be tolerable in a number of dosing schedules and also has activity in several tumor types, including colorectal cancer. Because phase I and II studies with bevacizumab suggested an increased incidence of bleeding17,18, patients with known CNS metastases were excluded from the phase III colorectal cancer trial that led to its US Food and Drug Administration approval.19 As such, the broad safety of administering bevacizumab in this setting is unknown. However, recent data from a phase II study of 32 patients with progressive malignant glioma indicated an impressive response rate of 63% (with 19 partial responses and one complete response) for the combination of bevacizumab and irinotecan.9 In the study, no CNS hemorrhages or more than grade 1 systemic hemorrhages were observed.
The encouraging clinical response reported here suggests that the combination of bevacizumab, temozolomide, and irinotecan may be safe and may have significant activity in the treatment of CNS metastases from colorectal cancer. Because of the pressing need for well-tolerated and effective regimens, further evaluation of these agents in this disease setting and in CNS metastases and LMD from other solid malignancies may be warranted.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: David H. Ilson, Pfizer, Sanofi-Aventis, Genentech, Bristol-Myers Squibb Testimony: N/A Other: N/A
