- Email: [email protected]
Correlation Between Rash and a Positive Drug Response Associated with Bevacizumab in a Patient with Advanced Colorectal Cancer
Case
Report Correlation Between Rash and a Positive Drug Response Associated with Bevacizumab in a Patient with Advanced Colorectal Cancer M. Wasif Saif,1 Walter L. Longo,2 Gary Israel3 Abstract Bevacizumab is the first vascular endothelial growth factor-targeted agent shown to increase survival in patients receiving first- and second-line intravenous 5-FU–based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is typically well tolerated and its major side effects include hypertension, proteinuria, bleeding, gastrointestinal perforation and arterial thrombotic events. Although exfoliative dermatitis has been described as a side effect in 19% of patients, skin rash (type unspecified) has rarely been described in patients following infusion of bevacizumab. We recently reported the first patient with colon cancer manifesting a correlation between rash and a positive drug response with bevacizumab. A 49-year old male with T3 N1 M1 rectal carcinoma received modified FOLFOX-6/bevacizumab, which he tolerated very well except for grade 2 skin rash related to bevacizumab. The rash continued to progress as the serum carcinoembryonic antigen decreased significantly. Computed tomography and positron emission tomography scan confirmed response to FOLFOX/bevacizumab. We therefore believe that this rash was linked to bevacizumab administration and correlated with response to therapy. Grade 1/2 rash has been described in patients after infusion of bevacizumab in initial phase I and II studies. Skin rash was observed in 34% and 46% of patients in the Kabbinavar’s study receiving 5 mg/kg dose and 10 mg/kg respectively but no patient developed > grade 3 rash. This toxicity was not well described in pivotal phase III studies. On the other hand, acneiform rash occurs in > 90% patients who receive cetuximab and panitumumab, severity of which appears to be predictive of response. To our knowledge, this case report is the second report of possible correlation between rash and a positive drug response associated with bevacizumab and warrants further investigation of similar observation. Clinical Colorectal Cancer, Vol. 7, No. 2, 144-148, 2008 Key words: Cetuximab, Epidermal growth factor receptor, Vascular endothelial growth factor
Case Report Bevacizumab in combination with intravenous 5-fluorouracil (5-FU)–based regimens is an accepted standard of care for the treatment of metastatic colorectal cancer (mCRC) in the first-line and second-line setting.1-4 In the pivotal phase III study in the first-line setting, bevacizumab provided a 30% increase in median overall survival (OS; 20.3 months vs. 15.6 months; P < .001) and a 71% increase in progression1Division
of Medical Onclogy of Surgical Oncology 3Division of Radiology Yale University School of Medicine, New Haven, CT 2Division
Submitted: Oct 17, 2007; Revised: Dec 18, 2007; Accepted: Jan 17, 2008 Address for correspondence: M. Wasif Saif, MD, Division of Medical Oncology, 333 Cedar Street, FMP 116, New Haven, CT 06520 Fax: 203-785-3788; e-mail: [email protected]
free survival (PFS; 10.6 months vs. 6.2 months; P < .001) when combined with irinotecan/5-FU/leucovorin (LV; IFL) verses IFL alone.2 Clinical benefit, as measured by OS, was observed across all patient subgroups analyzed. Increased survival and PFS with bevacizumab added to chemotherapy has also been observed in other trials in the first-line setting using oxaliplatin-based regimens and 5-FU/LV.1,2 The ECOG E3200 trial confirmed the increased efficacy of FOLFOX4 plus bevacizumab among patients who had progressed on first-line therapy.4 Patients were randomized to FOLFOX4, FOLFOX4 plus bevacizumab 10 mg/kg every 2 weeks, or bevacizumab alone. Accrual to the bevacizumab monotherapy arm was discontinued after an interim analysis showed less clinical activity compared with FOLFOX alone, but there was a significant improvement in median OS with FOLFOX plus bevacizumab (12.9 months) versus FOLFOX alone (10.7 months). This study confirmed the activity of bevacizumab in the second-line setting when combined with
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
144 • Clinical Colorectal Cancer March 2008
Figure 1
Figure 2
Image from a Contrast-Enhanced Computed Tomography Examination Demonstrating a 1.4 cm Metastasis in the Dome of the Liver
Figure 3
Rash on the Forehead after 6 Weeks of Therapy with Bevacizumab
Figure 4
Progression of Rash on the Face and Neck Area After 10 Weeks of Bevacizumab Therapy
Axial Image from a PET Scan Demonstrating Increased Uptake in the Liver Metastasis*
*Standard uptake value = 4.5.
FOLFOX, and it provided data about the safety profile at a 10 mg/kg (every 2 weeks) dose of bevacizumab. Combination of bevacizumab with cetuximab, a chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR) has been evaluated in the BOND-2 study.5 The results showed an improvement in time to progression and response rates compared with historical data from the BOND-1 trial. This study proved that combining biologic agents is feasible and safe, with no unexpected toxicities. Bevacizumab does not have any overlapping hematologic or gastrointestinal toxicities with chemotherapeutic agents. Trials of bevacizumab in mCRC have identified proteinuria (all grades 1%-28%), hypertension (all grades 3-25%), wound healing complications (1%-2%), hemorrhage (2%9.3%), arterial thromboembolism (0-3.8%), and gastrointestinal perforation (1.5%) as bevacizumab-associated adverse
effects.1-6 Skin rash (type unspecified) has been described in some patients after bevacizumab infusion.1,7-9 On the other hand, acneiform rash occurs in > 90% of patients who receive cetuximab, the severity of which appearing to be predictive of response.10 We recently reported a patient with mCRC who developed a rash secondary to bevacizumab.11
Case Report The patient is a 48-year-old Hispanic man with no significant past medical history who presented with 1 month complaints of intermittent constipation and abdominal pain. Colonoscopy revealed a near-obstructing mass approximately 6 cm to 8 cm from the anal verge, biopsy of which was consistent with moderately differentiated invasive adenocarcinoma. A computed tomography (CT) scan of chest, abdomen, and pelvis showed an infiltrating mass within the Clinical Colorectal Cancer March 2008 • 145
Rash Associated with Bevacizumab Figure 5
Bevacizumab-Associated Rash on the Neck and Chest After 10 Weeks of Therapy
Figure 7
Axial Image from a PET Scan Obtained 7 Weeks After the Computed Tomography Scan in Figure 3
Demonstrates complete resolution of the liver metastasis.
Table 1 Figure 6
Axial Image from a Contrast-Enhanced CT Examination 5 Months After the CT Scan in Figure 1
Relation of Rash and Response to Serum CEA Level
Cycle of FOLFOX Plus Bevacizumab
CEA Level
Rash
Baseline (Pre-Therapy)
97.3 ng/mL
No rash
After 2 Cycles
44.1 ng/mL
No rash
After 6 Cycles
4.7 ng/mL
Appearance of rash on forehead
After 8 Cycles
3.5 ng/mL
Progression of rash
After 10 Cycles
3.3 ng/mL
Progression of rash
After 12 Cycles
2.8 ng/mL (normal)
Stable rash
2 ng/mL (normal)
Rash resolved
6 Weeks After Stopping Bevacizumab
Demonstrates interval decrease in size of the liver metastasis, which now measures 0.4 cm.
rectosigmoid colon with extra colonic extension and perirectal adenopathy. The largest perirectal lymph node measured 1.3 cm. There was no evidence of bowel obstruction. Also noted were 3 small lesions within the liver; the largest was a 1.4 cm × 1.3 cm lesion in the dome of the liver, and was suspicious for metastatic disease (Figure 1). A positron emission tomography (PET) scan further confirmed these lesions to be metastatic in nature (Figure 2). He subsequently underwent a diverting loop colostomy. The patient was not taking any medications nor is he allergic to any medications. Physical examination at the time of start of chemotherapy was normal except for the rectal mass. The baseline carcinoembryonic antigen (CEA) level was 97.3 ng/mL. Chemotherapy consisting of modified FOLFOX-6 regimen with bevacizumab was initiated. Oxaliplatin was administered on day 1 at a dose of 85 mg/m2 as a 2-hour infusion concur-
146 • Clinical Colorectal Cancer March 2008
rently with LV 200 mg/m2 every day, followed by bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2. Bevacizumab was given as 5 mg/kg intravenously. The treatment was repeated every 2 weeks. The patient tolerated the therapy very well except for grade 1 peripheral neuropathy related to oxaliplatin and grade 1 nausea (NCI-CTC version 3.0). In addition, he had grade 1 epistaxis related to bevacizumab. He developed a papular erythematous rash (grade 1) on the forehead at the end of the third cycle (6 weeks; Figure 3). He was not taking any medications, including over-the-counter medications. An emphasis on keeping his skin moist and appling skin screen was made. His CEA level was noticed to be decreased to 44.1 ng/mL and then 4.1 ng/ mL during this period. After 10 weeks of therapy, his red papillary rash progressed to his face, neck, and upper part of his chest (Figure 4,5). A repeat CT scan at that time showed a partial response to therapy. The previously identified metastasis in the dome of the liver decreased in size from 1.4 cm × 1.3 cm to 4 mm × 6 mm (Figure 6). In addition, the previously identified large retroperitoneal nodes have decreased further in
M. Wasif Saif et al Table 2
Table 3
Incidence of Rash in Studies of Bevacizumab
Study
Dose
Number of Patients
Grade 1/2 Rash
Grade 3/4 Rash
Gordon et al (2001)7
0.1 to 10 mg/kg
25
9
0
Kabbinavar et al (2003)1
5 mg/kg
35
16
1
10 mg/kg
32
11
0
Differences Between Rash Associated with Bevacizumab Versus Cetuximab or Panitumumab Bevacizumab
Cetuximab/Panitumumab
< 1%
a 15%
Skin rash (type unspecified), exfoliative dermatitis
Acneiform rash, skin drying, and fissuring
+*
+++†
Associated Skin and Nail Changes
Not reported
Nail disorder
Infectious Complications
Not reported
Sepsis, septic death, and abscesses requiring incisions and drainage have been reported
Rash Incidence of Grade 3/4 Characteristics Relation to Response
size to normal. Perirectal stranding of the rectosigmoid junction has also decreased. Body PET scan after an intravenous (I.V.) administration of 18-fluoro-2-deoxyglucose (FDG) revealed that the previously noted hypermetabolic primary rectosigmoid lesion, left perirectal soft tissue density, and the left para-aortic nodes are no longer visualized in PET images without corresponding definite CT findings (Figure 7). The previous hypermetabolic focus in the dome of the liver has also resolved. Serum CEA is now within normal limits (3.1 ng/mL; Table 1). The patient has now received 12 cycles of FOLFOX/bevacizumab, and his rash continues to parallel his response: CEA has normalized, and CT and PET scans continue to show improvement. Magnetic resonance imaging (MRI) and PET scan ruled out liver metastases. Therefore, it was decided to administer radiation therapy with concomitant capecitabine. Bevacizumab was stopped. The rash associated with bevacizumab was fully resolved when the patient was evaluated at the end of chemoradiation therapy. He is now scheduled for surgical resection. We therefore believe that this rash emergence was linked to bevacizumab administration.
Discussion Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), inhibiting angiogenesis. Bevacizumab is the first antiangiogenic agent clinically proven to extend survival, and in combination with 5-FU–based chemotherapy, is approved by the FDA for the first-line or second-line treatment of mCRC.2,4 In addition, the FDA recently approved bevacizumab in metastatic non–small-cell lung cancer.12 The main toxicities of bevacizumab include hypertension, proteinuria, bleeding, gastrointestinal perforation, and arterial thrombotic events.1-6 Although exfoliative dermatitis was also described as a side effect in 19% of patients,13 skin rash (type unspecified) has been rarely described in some patients after infusion of bevacizumab.7-9 In Kabbinavar’s study, 16 patients (68%) developed a rash with only 1 patient with > grade 3 rash at a 5 mg/kg dose of bevacizumab. On the other hand, only 11 patients (34%) developed a rash at 10 mg/kg bevacizumab with no patient developing > grade 3 rash (Table 2).1 Also, no correlation between rash development and a positive drug response was previously reported in these pivotal trials.1-5 Skin rashes are most commonly associated with EGFR antagonists, including antibodies such as cetuximab, panitumumab, and tyrosine kinase inhibitors such as erlo-
*Indicates a weak relation. †Indicates a strong relation.
tinib.10,14,15 This toxicity usually occurs in the first 2 weeks of treatment and affects the face, trunk and extremities.16 Epidermal growth factor receptor antagonist–induced skin rashes are characterized by clusters of monomorphic pustular lesions with a histologic examination revealing neutrophilic infiltration of the dermis. The skin rashes are dose dependent and can improve or resolve spontaneously. On the other hand, the most common adverse reactions of 5-FU, an antimetabolite, are acute gastrointestinal effects and bone marrow suppression while neurologic, ocular and dermatologic toxicities are unusual. Several cutaneous manifestations can be found and might include hyperpigmentation, maculo-papular eruption, and palmar-plantar erythrodysesthesia (PPE) that promptly reverse with discontinuation of 5-FU. However, facial rash such as appears in our patient is not a common occurrence.17 It can be hypothesized that the functional similarity of EGFR and VEGFR points to a possibility of correlation between skin rash development and bevacizumab therapy. Rash is not unknown to drugs targeting the VEGF pathway. The toxic effects of BAY 43-9006, another anti-VEGF, also include rash in addition to hypertension, edema, diarrhea, PPE, and hair loss wherein the rash involves the scalp.18 It is important to recognize a few differences in the rash associated with bevacizumab versus anti-EGFR agents, because newer regimens are assessing 2 targeted agents combined together (Table 3). We previously described a case of such an association with bevacizumab.11 We believe the current patient is the second report of such an association between rash and response to bevacizumab in a patient with mCRC. It is possible that our previous experience of recognizing such an association helped this case, but it is also possible that this might be an underreported toxicity of bevacizumab as a result of its mildness (mostly grade 1/2). We hope that this case report will incite interest in further investigation of similar cases to support this observation. We would be interested in finding out if any oncologists Clinical Colorectal Cancer March 2008 • 147
Rash Associated with Bevacizumab have experienced the similar coincidence of a remarkable response to the therapy and dermatologic side effects.
8.
References 1. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21:60-5. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Eng J Med 2004; 350:2335-42. 3. Hochster HS, Welles L, Hart L et al. Bevacizumab (B) with oxaliplatin (O)-based chemotherapy in the first-line therapy of metastatic colorectal cancer (mCRC): preliminary results of the randomized “TREE-2” trial. Presented at: the 2005 American Society of Clinical Gastrointestinal Cancers Symposium; January 27-29, 2005; Hollywood, FL. Abstract 241. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at: the 2005 American Society of Clinical Gastrointestinal Cancers Symposium; January 27-29, 2005; Hollywood, FL. Abstract 169a. 5. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007; 25:4557-61. 6. Saif MW, Mehra R. Incidence and management of bevacizumabrelated toxicities in colorectal cancer. Expert Opin Drug Saf 2006; 5:553-66. 7. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharma-
148 • Clinical Colorectal Cancer March 2008
9.
10.
11.
12.
13. 14.
15. 16. 17. 18.
cokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19:843-50. Chen HX, Gore-Langton RE, Cheson BD. Clinical trials: referral resource: current clinical trials of the anti-VEGF monoclonal antibody bevacizumab. Oncology 2001; 15:1019-26. Pegram MD, Reese DM. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 2002; 29(suppl 11):29-37. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. Gotlib V, Khaled S, Lapko I, et al. Skin rash secondary to bevacizumab in a patient with advanced colorectal cancer and relation to response. Anticancer Drugs 2006; 17:1227-9. Azim HA, Jr, Ganti AK. Targeted therapy in advanced non-small cell lung cancer (NSCLC): where do we stand? Cancer Treat Rev 2006; 32:630-6. Motl, S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health Syst Pharm 2005; 62:1241. Meyerhardt JA, Zhu AX, Enzinger PC, et al. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 2006; 20:1892-7 Saif MW, Cohenuram M. Role of panitumumab in the management of metastatic colorectal cancer. Clin Colorectal Cancer 2006; 6:118-24. Saif MW, Kim R. Incidence and management of cutaneous toxicities associated with cetuximab. Expert Opin Drug Saf 2007; 6:175-82. Leo S, Tatulli C, Taveri R, et al. Dermatological toxicity from chemotherapy containing 5-fluorouracil. J Chemother 1994; 6:423-6. Ratain MJ, Eisen T, Stadler WM, et al. Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2006; 24:2505-12.
Report Correlation Between Rash and a Positive Drug Response Associated with Bevacizumab in a Patient with Advanced Colorectal Cancer M. Wasif Saif,1 Walter L. Longo,2 Gary Israel3 Abstract Bevacizumab is the first vascular endothelial growth factor-targeted agent shown to increase survival in patients receiving first- and second-line intravenous 5-FU–based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is typically well tolerated and its major side effects include hypertension, proteinuria, bleeding, gastrointestinal perforation and arterial thrombotic events. Although exfoliative dermatitis has been described as a side effect in 19% of patients, skin rash (type unspecified) has rarely been described in patients following infusion of bevacizumab. We recently reported the first patient with colon cancer manifesting a correlation between rash and a positive drug response with bevacizumab. A 49-year old male with T3 N1 M1 rectal carcinoma received modified FOLFOX-6/bevacizumab, which he tolerated very well except for grade 2 skin rash related to bevacizumab. The rash continued to progress as the serum carcinoembryonic antigen decreased significantly. Computed tomography and positron emission tomography scan confirmed response to FOLFOX/bevacizumab. We therefore believe that this rash was linked to bevacizumab administration and correlated with response to therapy. Grade 1/2 rash has been described in patients after infusion of bevacizumab in initial phase I and II studies. Skin rash was observed in 34% and 46% of patients in the Kabbinavar’s study receiving 5 mg/kg dose and 10 mg/kg respectively but no patient developed > grade 3 rash. This toxicity was not well described in pivotal phase III studies. On the other hand, acneiform rash occurs in > 90% patients who receive cetuximab and panitumumab, severity of which appears to be predictive of response. To our knowledge, this case report is the second report of possible correlation between rash and a positive drug response associated with bevacizumab and warrants further investigation of similar observation. Clinical Colorectal Cancer, Vol. 7, No. 2, 144-148, 2008 Key words: Cetuximab, Epidermal growth factor receptor, Vascular endothelial growth factor
Case Report Bevacizumab in combination with intravenous 5-fluorouracil (5-FU)–based regimens is an accepted standard of care for the treatment of metastatic colorectal cancer (mCRC) in the first-line and second-line setting.1-4 In the pivotal phase III study in the first-line setting, bevacizumab provided a 30% increase in median overall survival (OS; 20.3 months vs. 15.6 months; P < .001) and a 71% increase in progression1Division
of Medical Onclogy of Surgical Oncology 3Division of Radiology Yale University School of Medicine, New Haven, CT 2Division
Submitted: Oct 17, 2007; Revised: Dec 18, 2007; Accepted: Jan 17, 2008 Address for correspondence: M. Wasif Saif, MD, Division of Medical Oncology, 333 Cedar Street, FMP 116, New Haven, CT 06520 Fax: 203-785-3788; e-mail: [email protected]
free survival (PFS; 10.6 months vs. 6.2 months; P < .001) when combined with irinotecan/5-FU/leucovorin (LV; IFL) verses IFL alone.2 Clinical benefit, as measured by OS, was observed across all patient subgroups analyzed. Increased survival and PFS with bevacizumab added to chemotherapy has also been observed in other trials in the first-line setting using oxaliplatin-based regimens and 5-FU/LV.1,2 The ECOG E3200 trial confirmed the increased efficacy of FOLFOX4 plus bevacizumab among patients who had progressed on first-line therapy.4 Patients were randomized to FOLFOX4, FOLFOX4 plus bevacizumab 10 mg/kg every 2 weeks, or bevacizumab alone. Accrual to the bevacizumab monotherapy arm was discontinued after an interim analysis showed less clinical activity compared with FOLFOX alone, but there was a significant improvement in median OS with FOLFOX plus bevacizumab (12.9 months) versus FOLFOX alone (10.7 months). This study confirmed the activity of bevacizumab in the second-line setting when combined with
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
144 • Clinical Colorectal Cancer March 2008
Figure 1
Figure 2
Image from a Contrast-Enhanced Computed Tomography Examination Demonstrating a 1.4 cm Metastasis in the Dome of the Liver
Figure 3
Rash on the Forehead after 6 Weeks of Therapy with Bevacizumab
Figure 4
Progression of Rash on the Face and Neck Area After 10 Weeks of Bevacizumab Therapy
Axial Image from a PET Scan Demonstrating Increased Uptake in the Liver Metastasis*
*Standard uptake value = 4.5.
FOLFOX, and it provided data about the safety profile at a 10 mg/kg (every 2 weeks) dose of bevacizumab. Combination of bevacizumab with cetuximab, a chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR) has been evaluated in the BOND-2 study.5 The results showed an improvement in time to progression and response rates compared with historical data from the BOND-1 trial. This study proved that combining biologic agents is feasible and safe, with no unexpected toxicities. Bevacizumab does not have any overlapping hematologic or gastrointestinal toxicities with chemotherapeutic agents. Trials of bevacizumab in mCRC have identified proteinuria (all grades 1%-28%), hypertension (all grades 3-25%), wound healing complications (1%-2%), hemorrhage (2%9.3%), arterial thromboembolism (0-3.8%), and gastrointestinal perforation (1.5%) as bevacizumab-associated adverse
effects.1-6 Skin rash (type unspecified) has been described in some patients after bevacizumab infusion.1,7-9 On the other hand, acneiform rash occurs in > 90% of patients who receive cetuximab, the severity of which appearing to be predictive of response.10 We recently reported a patient with mCRC who developed a rash secondary to bevacizumab.11
Case Report The patient is a 48-year-old Hispanic man with no significant past medical history who presented with 1 month complaints of intermittent constipation and abdominal pain. Colonoscopy revealed a near-obstructing mass approximately 6 cm to 8 cm from the anal verge, biopsy of which was consistent with moderately differentiated invasive adenocarcinoma. A computed tomography (CT) scan of chest, abdomen, and pelvis showed an infiltrating mass within the Clinical Colorectal Cancer March 2008 • 145
Rash Associated with Bevacizumab Figure 5
Bevacizumab-Associated Rash on the Neck and Chest After 10 Weeks of Therapy
Figure 7
Axial Image from a PET Scan Obtained 7 Weeks After the Computed Tomography Scan in Figure 3
Demonstrates complete resolution of the liver metastasis.
Table 1 Figure 6
Axial Image from a Contrast-Enhanced CT Examination 5 Months After the CT Scan in Figure 1
Relation of Rash and Response to Serum CEA Level
Cycle of FOLFOX Plus Bevacizumab
CEA Level
Rash
Baseline (Pre-Therapy)
97.3 ng/mL
No rash
After 2 Cycles
44.1 ng/mL
No rash
After 6 Cycles
4.7 ng/mL
Appearance of rash on forehead
After 8 Cycles
3.5 ng/mL
Progression of rash
After 10 Cycles
3.3 ng/mL
Progression of rash
After 12 Cycles
2.8 ng/mL (normal)
Stable rash
2 ng/mL (normal)
Rash resolved
6 Weeks After Stopping Bevacizumab
Demonstrates interval decrease in size of the liver metastasis, which now measures 0.4 cm.
rectosigmoid colon with extra colonic extension and perirectal adenopathy. The largest perirectal lymph node measured 1.3 cm. There was no evidence of bowel obstruction. Also noted were 3 small lesions within the liver; the largest was a 1.4 cm × 1.3 cm lesion in the dome of the liver, and was suspicious for metastatic disease (Figure 1). A positron emission tomography (PET) scan further confirmed these lesions to be metastatic in nature (Figure 2). He subsequently underwent a diverting loop colostomy. The patient was not taking any medications nor is he allergic to any medications. Physical examination at the time of start of chemotherapy was normal except for the rectal mass. The baseline carcinoembryonic antigen (CEA) level was 97.3 ng/mL. Chemotherapy consisting of modified FOLFOX-6 regimen with bevacizumab was initiated. Oxaliplatin was administered on day 1 at a dose of 85 mg/m2 as a 2-hour infusion concur-
146 • Clinical Colorectal Cancer March 2008
rently with LV 200 mg/m2 every day, followed by bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2. Bevacizumab was given as 5 mg/kg intravenously. The treatment was repeated every 2 weeks. The patient tolerated the therapy very well except for grade 1 peripheral neuropathy related to oxaliplatin and grade 1 nausea (NCI-CTC version 3.0). In addition, he had grade 1 epistaxis related to bevacizumab. He developed a papular erythematous rash (grade 1) on the forehead at the end of the third cycle (6 weeks; Figure 3). He was not taking any medications, including over-the-counter medications. An emphasis on keeping his skin moist and appling skin screen was made. His CEA level was noticed to be decreased to 44.1 ng/mL and then 4.1 ng/ mL during this period. After 10 weeks of therapy, his red papillary rash progressed to his face, neck, and upper part of his chest (Figure 4,5). A repeat CT scan at that time showed a partial response to therapy. The previously identified metastasis in the dome of the liver decreased in size from 1.4 cm × 1.3 cm to 4 mm × 6 mm (Figure 6). In addition, the previously identified large retroperitoneal nodes have decreased further in
M. Wasif Saif et al Table 2
Table 3
Incidence of Rash in Studies of Bevacizumab
Study
Dose
Number of Patients
Grade 1/2 Rash
Grade 3/4 Rash
Gordon et al (2001)7
0.1 to 10 mg/kg
25
9
0
Kabbinavar et al (2003)1
5 mg/kg
35
16
1
10 mg/kg
32
11
0
Differences Between Rash Associated with Bevacizumab Versus Cetuximab or Panitumumab Bevacizumab
Cetuximab/Panitumumab
< 1%
a 15%
Skin rash (type unspecified), exfoliative dermatitis
Acneiform rash, skin drying, and fissuring
+*
+++†
Associated Skin and Nail Changes
Not reported
Nail disorder
Infectious Complications
Not reported
Sepsis, septic death, and abscesses requiring incisions and drainage have been reported
Rash Incidence of Grade 3/4 Characteristics Relation to Response
size to normal. Perirectal stranding of the rectosigmoid junction has also decreased. Body PET scan after an intravenous (I.V.) administration of 18-fluoro-2-deoxyglucose (FDG) revealed that the previously noted hypermetabolic primary rectosigmoid lesion, left perirectal soft tissue density, and the left para-aortic nodes are no longer visualized in PET images without corresponding definite CT findings (Figure 7). The previous hypermetabolic focus in the dome of the liver has also resolved. Serum CEA is now within normal limits (3.1 ng/mL; Table 1). The patient has now received 12 cycles of FOLFOX/bevacizumab, and his rash continues to parallel his response: CEA has normalized, and CT and PET scans continue to show improvement. Magnetic resonance imaging (MRI) and PET scan ruled out liver metastases. Therefore, it was decided to administer radiation therapy with concomitant capecitabine. Bevacizumab was stopped. The rash associated with bevacizumab was fully resolved when the patient was evaluated at the end of chemoradiation therapy. He is now scheduled for surgical resection. We therefore believe that this rash emergence was linked to bevacizumab administration.
Discussion Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), inhibiting angiogenesis. Bevacizumab is the first antiangiogenic agent clinically proven to extend survival, and in combination with 5-FU–based chemotherapy, is approved by the FDA for the first-line or second-line treatment of mCRC.2,4 In addition, the FDA recently approved bevacizumab in metastatic non–small-cell lung cancer.12 The main toxicities of bevacizumab include hypertension, proteinuria, bleeding, gastrointestinal perforation, and arterial thrombotic events.1-6 Although exfoliative dermatitis was also described as a side effect in 19% of patients,13 skin rash (type unspecified) has been rarely described in some patients after infusion of bevacizumab.7-9 In Kabbinavar’s study, 16 patients (68%) developed a rash with only 1 patient with > grade 3 rash at a 5 mg/kg dose of bevacizumab. On the other hand, only 11 patients (34%) developed a rash at 10 mg/kg bevacizumab with no patient developing > grade 3 rash (Table 2).1 Also, no correlation between rash development and a positive drug response was previously reported in these pivotal trials.1-5 Skin rashes are most commonly associated with EGFR antagonists, including antibodies such as cetuximab, panitumumab, and tyrosine kinase inhibitors such as erlo-
*Indicates a weak relation. †Indicates a strong relation.
tinib.10,14,15 This toxicity usually occurs in the first 2 weeks of treatment and affects the face, trunk and extremities.16 Epidermal growth factor receptor antagonist–induced skin rashes are characterized by clusters of monomorphic pustular lesions with a histologic examination revealing neutrophilic infiltration of the dermis. The skin rashes are dose dependent and can improve or resolve spontaneously. On the other hand, the most common adverse reactions of 5-FU, an antimetabolite, are acute gastrointestinal effects and bone marrow suppression while neurologic, ocular and dermatologic toxicities are unusual. Several cutaneous manifestations can be found and might include hyperpigmentation, maculo-papular eruption, and palmar-plantar erythrodysesthesia (PPE) that promptly reverse with discontinuation of 5-FU. However, facial rash such as appears in our patient is not a common occurrence.17 It can be hypothesized that the functional similarity of EGFR and VEGFR points to a possibility of correlation between skin rash development and bevacizumab therapy. Rash is not unknown to drugs targeting the VEGF pathway. The toxic effects of BAY 43-9006, another anti-VEGF, also include rash in addition to hypertension, edema, diarrhea, PPE, and hair loss wherein the rash involves the scalp.18 It is important to recognize a few differences in the rash associated with bevacizumab versus anti-EGFR agents, because newer regimens are assessing 2 targeted agents combined together (Table 3). We previously described a case of such an association with bevacizumab.11 We believe the current patient is the second report of such an association between rash and response to bevacizumab in a patient with mCRC. It is possible that our previous experience of recognizing such an association helped this case, but it is also possible that this might be an underreported toxicity of bevacizumab as a result of its mildness (mostly grade 1/2). We hope that this case report will incite interest in further investigation of similar cases to support this observation. We would be interested in finding out if any oncologists Clinical Colorectal Cancer March 2008 • 147
Rash Associated with Bevacizumab have experienced the similar coincidence of a remarkable response to the therapy and dermatologic side effects.
8.
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