Japanese Journal of Clinical Oncology Advance Access originally published online on June 20, 2008
Japanese Journal of Clinical Oncology 2008 38(7):493-496; doi:10.1093/jjco/hyn046
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© The Author (2008). Published by Oxford University Press. All rights reserved
Metastatic Rectal Cancer Responding to Third-line Therapy Employing Bevacizumab After Failure of Oxaliplatin and Irinotecan: Case Report
Department of Medical Oncology, Misawa City Hospital, Misawa, Aomori, Japan
For reprints and all correspondence: Kohei Shitara, Department of Clinical Oncology, Aichi Cancer Center, 1-1 Kanakoden, Chikusa-ku Nagoya 464-8581, Japan. E-mail: kouheis0824{at}yahoo.co.jp
Received February 12, 2008; accepted May 18, 2008
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Abstract |
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A 61-year-old female with surgically treated rectal cancer that had metastasized to lung and lymph nodes was treated with bevacizumab (BV) plus 5-fluorouracil (5-FU) and leucovorin (LV) as third-line chemotherapy after treatment failures with infusional 5-FU, LV and oxaliplatin (FOLFOX regimen); and infusional 5-FU, LV and irinotecan (FOLFIRI regimen). After four cycles of treatment, a computed tomography scan revealed reduced sizes of the lung and lymph node metastases. Tumor response has still been maintained after six cycles of treatment, and the chemotherapeutic response was evaluated as partial response according to the Response Evaluation Criteria In Solid Tumor guidelines. Manageable toxicity included grade 2 hypertension, grade 1 epistaxis and grade 1 stomatitis. Although there are no clinical trial results supporting the use of BV-containing therapy as third-line chemotherapy for advanced colorectal cancer, BV plus 5-FU and LV was effective and feasible in our patient with colon cancer that had progressed after treatment with 5-FU, irinotecan and oxaliplatin.
Key Words: bevacizumab • third-line • colorectal cancer
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INTRODUCTION |
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Bevacizumab (BV), a humanized monoclonal antibody targeting vascular endothelial growth factor, was recently approved for treatment of advanced colorectal cancer (ACC) in Japan. In a phase III trial of patients with previously untreated ACC, BV in combination with chemotherapy consisting of irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV), resulted in a significant increase in median survival time (MST, 20.3 vs. 15.6 months) and in progression-free survival (PFS, 10.6 vs. 6.2 months) compared with the treatment arm consisting of chemotherapy alone (1). Other studies have shown similar beneficial results when BV was combined with 5-FU and LV or infusional 5-FU, LV and oxaliplatin (FOLFOX regimen) (2,3). In the second-line treatment setting for ACC, BV (10 mg/kg) biweekly plus FOLFOX significantly extended survival compared with FOLFOX alone, while maintaining a safety profile consistent with BV (5 mg/kg) biweekly administered as first-line treatment (3). But, until now there have been no clinical trial results supporting the use of BV as third-line therapy for ACC.
Here, we report on a patient with rectal cancer with lung and lymph node metastasis, progressing after 5-FU, irinotecan and oxaliplatin. BV plus 5-FU and LV was an effective and feasible treatment in this case.
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CASE REPORT |
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A 61-year-old female was diagnosed with rectal cancer in February 2005. She underwent lower anterior resection with lymph node dissection on February 14, and lymph node metastases were identified by histopathological examination (Stage IIIa according to the American Joint Committee on Cancer Staging System). She received adjuvant chemotherapy consisting of bolus 5-FU and LV, but therapy was discontinued after 2 weeks because of rash and stomatitis.
In March 2006, a follow-up computed tomography (CT) scan revealed multiple lung metastases. FOLFOX4 was started as first-line chemotherapy. After three cycles of FOLFOX, a CT scan showed reduced size of multiple metastases, but they progressed after 13 cycles.
In April 2007, combination chemotherapy consisting of infusional 5-FU, LV and irinotecan (FOLFIRI regimen) was started as second-line chemotherapy. After three cycles of FOLFIRI, the lung metastases appeared stable, with no apparent enlargement (stable disease), but they progressed after six cycles. In November 2007, the patient was referred to our hospital for further treatment. She had a 10-year history of hypertension that was controlled well by oral amlodipine (5 mg). A CT scan showed multiple lung metastases with a maximum diameter of 30 mm, and multiple mediastinal lymph node metastases (Fig. 1A–C). Because cetuximab has not been approved in Japan as of November 2007, BV-containing chemotherapy was considered for third-line treatment. Our patient strongly hoped to receive BV, although clinical trial results reported a low possibility of response. Combination therapy consisting of BV plus 5-FU and LV was thus initiated as third-line therapy. The initial dose and administration schedule were as follows: BV (5 mg/kg) was administered in 90 min followed by l-LV (200 mg/m2) in 2 h, bolus 5-FU (400 mg/m2) and infusional 5-FU (2400 mg/m2) in 46 h (simplified de Gramont regimen). This treatment was repeated every 2 weeks. The infusion time of BV was shortened to 60 min in the second cycle and 30 min after the third cycle. Toxicity was tolerable, although grade 2 hypertension (after three cycles), grade 1 epistaxis and grade 1 stomatitis were noted. After four cycles of treatment, a CT scan showed multiple lung and lymph node metastases, reduced in size (Fig. 1D–F). Tumor response has still been maintained after six cycles (3 months), and the response to treatment was determined to be a partial response, according to the Response Evaluation Criteria in Solid Tumor guidelines. No regrowth of metastases was seen as of June 2008.
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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Until recently, the standard therapy for patients with ACC was chemotherapy with 5-FU, usually modulated by LV and the MST was <1 year (4). After the introduction of irinotecan and oxaliplatin, the prognosis of ACC was improved significantly, and the MST of patients with ACC who received all three drugs is expected to be more than 20 months (5,6). However, there are few data on salvage chemotherapy in patients who have progressed after irinotecan- or oxaliplatin-based chemotherapy.
Two molecular targeting agents, BV and cetuximab, were recently introduced for the treatment of ACC. As mentioned previously, BV combined with chemotherapy in first- and second-line settings significantly prolongs the survival of ACC patients (1–3). Because of these results, BV-containing chemotherapy is recommended as a first-line treatment for ACC patients, unless there are contraindications for the use of BV (7). However, in the salvage setting, a large non-randomized study (NCI Treatment Referral Center Trial TRC-0301) has shown that the combination of BV and a bolus or infusional 5-FU/LV (Roswell Park regimen or de Gramont regimen) is not sufficiently active in irinotecan- and oxaliplatin-pretreated patients. In that trial, the response rate was reported to be 1% based on an independent review (8). Although the PFS and MST of 3.7 and 9.1 months, respectively, were not as short as conventional salvage therapy, the survival benefit is unknown because this was a non-randomized study (8). Consequently, BV is currently not recommended in the third-line setting.
Cetuximab is a chimeric human-murine monoclonal antibody that targets the epidermal growth factor receptor (EGFR) (9). Unlike BV, which was investigated largely in the front-line setting, cetuximab was studied primarily as a salvage therapy. In the phase III trial (BOND-1 study) for patients progressing after irinotecan-based chemotherapy (60% of patients also received prior oxaliplatin), cetuximab monotherapy and cetuximab plus irinotecan resulted in response rates of 10.8 and 22.9%, respectively; PFSs of 1.5 and 4.1 months, respectively; and MSTs of 6.9 and 8.6 months, respectively (10). In addition, subset analysis revealed that previous oxaliplatin treatment did not diminish any benefit from cetuximab. Because of these results, cetuximab plus irinotecan was approved for use in the treatment of EGFR-expressing ACC in patients who are refractory to irinotecan-based chemotherapy. Cetuximab was also granted approval for use as a single agent in the treatment of EGFR-expressing ACC in patients who are intolerant to irinotecan-based chemotherapy. Another phase III study of cetuximab in combination with chemotherapy for first- and second-line settings has also shown promising results (11,12).
Although direct comparison was difficult in the TRC-0301 trial, the response rate of BV plus 5-FU/LV was relatively lower than the rates seen with cetuximab or cetuximab plus irinotecan; however, the PFS of 3.7 months and MST of 9.1 months did not seem to be lower in the salvage setting after irinotecan- or oxaliplatin-based chemotherapy (8,10). Also, according to a retrospective analysis, the objective response did not predict the magnitude of PFS or OS benefit from chemotherapy for ACC (13).
Recently, in a small randomized phase II trial (BOND-2 study), promising data have shown that BV added to cetuximab or to cetuximab plus irinotecan has high activity in chemotherapy-refractory and molecular targeting-agent naive ACC (14). In that trial, the response rate, PFS and MST were relatively better in the three drug arm (20 vs. 37%, 4.9 vs. 7.3 months, 11.4 vs. 14.5 months, respectively). This result suggests that it may be important to use all five drugs (5-FU/LV, irinotecan, oxaliplatin, BV and cetuximab) to prolong survival in ACC. Additional results of that ongoing trial are needed before deciding on the optimal therapeutic strategy for ACC.
After Japanese approval of BV in June 2007, increasing numbers of patients have received BV in combination with chemotherapy as a first-line treatment for ACC. But there remain many ACC patients progressing after treatment with irinotecan- or oxaliplatin-based regimens that did not include BV, because their initial treatment had been started prior BV approval. There is no established effective chemotherapy for these patients, since, as of February 2008, cetuximab had not been approved in Japan.
Although it is strongly hoped for early Japanese approval of cetuximab, the results seen in our patient indicate that BV in combination with chemotherapy may be one treatment option in the era prior to approval of cetuximab for patients progressing after receiving irinotecan- and oxaliplatin-based chemotherapy.
Conflict of interest statement
None declared.
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Footnotes |
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* Present Address: Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
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References |
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