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Progress in the management of chemorefractory colorectal cancer
ejc supplements 10, no. 3 (2012) 7–9
Progress in the management of chemorefractory colorectal cancer Eric Van Cutsem* Digestive Oncology, University Hospitals Leuven, Belgium
article info Keywords: Radioembolisation Selective Internal Radiation Therapy 90 Y Yttrium-90 Liver-directed therapy Advanced colorectal cancer Liver metastases
1. Introduction A multidisciplinary approach, combining advances in systemic chemotherapy, targeted agents and aided by better surgical and imaging techniques has significantly enhanced the outcome for patients with metastatic colorectal cancer (mCRC) over the last two decades (Fig. 1). 1 Advancements in the management of unresectable mCRC have been characterised by small incremental improvements in overall survival which now extends beyond 2 years with the addition of biological agents to standard fluoropyrimidine-based chemotherapy regimens. Today, a whole host of newly identified targeted therapeutic agents inhibiting one or more key pathways are being evaluated in phase III clinical trials (including aflibercept and regorafenib) 2,3 as potential new treatments for mCRC. Our understanding of the benefits of targeted agents has been aided by large well-designed multicentre studies in patients with proven chemorefractory mCRC. While cetuximab initially showed only modest benefits * Correspondence: Eric Van Cutsem, MD, PhD, University Hospital Gasthuisberg, Digestive Oncology Unit, Herestraat 49, 3000 Leuven, Belgium. E-mail address: [email protected]; [email protected] (E. Van Cutsem).
in overall survival in unselected patients (Hazard ratio [HR], 0.77, 95% CI: 0.64–0.92), 4 a subsequent study of patients with wild-type K-ras tumours revealed that cetuximab plus best supportive care (BSC) was associated with a doubling overall survival (median, 9.5 vs. 4.8 months for BSC alone; HR for death, 0.55; P < 0.001) in chemorefractory disease. 5 In the same way, the recent evaluation of regorafenib plus BSC showed only a modest improvement in overall survival (median, 6.4 vs. 5.0 months for placebo plus BSC; HR, 0.77 [95% CI: 0.63–0.94; 1-sided P = 0.0051]) in patients with mCRC who progressed after standard therapies, 3 but there is early evidence to suggest that some patients do benefit more than others. 3 Like locoregional treatments, the challenge with targeted agents is to select the cohorts of patients who will benefit most. For targeted agents such as regorafenib, the decision to treat is likely to be based on the identification of a combination of molecular biomarkers (angiogenic signatures) for regorafenib activity.
2. Locoregional treatment with SIRT The published evidence suggests that locoregional treatments may play a complementary role to systemic
1359-6349/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
8
ejc supplements 10, no. 3 (2012) 7–9
(a)
(b)
Fig. 1 – (a) Overall survival of mCRC increasing over the decades, with (b) progressively more complex regimens combined with biologicals. Reproduced from Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27:3677−83 with permission from American Society of Clinical Oncology. Table 1 – Comparative or prospective studies of selective internal radiation therapy with in chemorefractory colorectal cancer liver metastases
90
Y resin microspheres
Investigators
n
Treatment
ORR
SD
TTP/PFS*
Survival
P value
HR
Hendlisz et al. 7 (cross-over at progression)
21
SIRT+ 5-FU
10%
76%
5.5/4.5 months
10.0 months
0.80
0.92
23
5-FU + salvage with SIRT at PD
0%
35%
2.1 months
7.3 months <0.001
0.26
0.001
0.50
Seidensticker et al. 8 (matched-pairs)
Bester et al. 9 (retrospective comparison)
Cosimelli et al. 10 SIRT with
90Y
29
SIRT
41%
17%
5.5 months*
8.3 months
29
Best supportive care
nr
nr
2.1 months*
3.5 months
224
SIR-Spheres
nr
nr
nr
11.9 months
29
Best supportive care
nr
nr
nr
6.6 months
50
SIRT
24%
24%
4 months*
12.6 months
resin microspheres; nr: not reported; PFS: Progression-free survival; TTP: Time to progression.
treatment by improving the local control of metastases in the liver. Comparisons between these two treatment modalities cannot be made because the locoregional treatments are used to manage liver-limited or liverpredominant disease while clinical trials of systemic agents include a much broader group of patients including those with disease that has progressed beyond the liver to the lungs and peritoneum. Early evidence for selective internal radiation therapy (SIRT) in mCRC was largely based on small case series. In review of the evidence in 2009, the Cochrane group concluded that there was a need for well-designed, adequately powered phase III trials to assess the effect of SIRT combined with modern chemotherapy regimens. 6 Further studies with SIRT were also needed in chemorefractory disease, with a particular focus on the impact on quality of life. 6 Since this review, four comparative or prospective studies have been published on SIRT in chemorefractory patients (Table 1). 7−10 One such study at the University Hospitals Leuven in collaboration with other Belgian sites evaluated 44 patients with liver-limited mCRC for whom all other evidence-based treatments had failed. 7 Patients
were randomised to receive either protracted IV infusion of 5-FU (300 mg/m2 day 1−14 every 3 weeks) or SIRT using 90 Y resin microspheres plus 5-FU (225 mg/m2 [cycle 1] then 300 mg/m2 day 1−14 every 3 weeks, thereafter) until documented hepatic progression. Most patients had a good performance status (ECOG 0 or 1). The burden of liver metastases was similar in both treatment arms. The study found that median time to liver progression was significantly prolonged with the addition of SIRT compared to 5-FU alone (5.5 vs. 2.1 months; hazard ratio [HR] 0.38; p = 0.003). The median time to progression at any site was also increased in the SIRT arm (4.5 vs. 2.1 months; HR 0.51; p = 0.03), as was the disease control rate (86% vs. 35%; p = 0.001). After 10 of 23 patients on 5-FU monotherapy crossed over to receive SIRT following progression, median overall survival was 7.3 and 10.0 months in the 5-FU and SIRT plus 5-FU arms, respectively (HR = 0.92 95% CI 0.47–1.78; p = 0.80). Grade 3 or 4 toxicities were recorded in 6 patients following 5-FU monotherapy and in 1 patient following SIRT plus 5-FU treatment (p = 0.10). Adverse events associated with SIRT are generally mild and transient, including nausea, fever and abdominal pain (Table 2).
9
ejc supplements 10, no. 3 (2012) 7–9
Table 2 – Adverse events profile with SIRT using cancer liver metastases
90
Y resin microspheres in chemorefractory colorectal
AE
Incidence
Characteristics
Prevention/Action
Fever
>50%
Mild (grade 1*) onset on day of treatment for up to 1 week
None normally required
Abdominal pain
~50% (~10% grade 3−4)
Acute onset during treatment; self-limiting (normally <24 h)
May require narcotic (>oral analgesia)
Nausea
~40% (<5% grade 3−4)
Highest in treatment-experienced; self-limiting (normally <24 h)
Prophylactic anti-emetics
Fatigue
~40% (<5% grade 3−4)
Onset in 1st month post-SIRT, normally subsides within 2 weeks
Adequate nutrition and hydration; prophylactic oral steroids
Abnormal Liver Function Tests
~20−40% (1−6% grade 3−4)
Particularly in combination with chemotherapy; transient: resolves in days (ALT, AST), weeks (bilirubin) or months (albumin)
None normally required
More rarely, radiation-associated gastrointestinal ulcers can occur and these are more difficult to treat. 11 Patients should be carefully monitored with a low threshold of suspicion for evidence of gastrointestinal ulcer to ensure early and effective treatment, especially if subsequent treatment with antiangiogenics such as bevacizumab is being considered. In summary, SIRT is likely to play an important complementary role to systemic therapies for the control of colorectal liver metastases. Ongoing randomised controlled clinical trials with conventional chemotherapies with or without SIRT (in the first-line setting and in chemorefractory disease) will further define the role of this treatment modality in the management of liverdominant mCRC.
Conflict of interest statement The author receives research funding from Merck Serono, Roche and Sanofi.
References
1. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27:3677−83. 2. Tabernero J. Results from VELOUR, a phase III study of aflibercept (A) versus placebo (pbo) in combination with FOLFIRI for the treatment of patients (pt) with previously treated metastatic colorectal cancer (MCRC). In: Program and abstracts of the European Multidisciplinary Cancer Congress; September 23−27, 2011; Stockholm, Sweden. Abstract LBA6.
3. Grothey A, Sobrero AF, Siena S, Falcone A, et al. Results of a randomized phase 3 trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with mCRC who have progressed after standard therapies. Gastrointestinal Cancers Symposium; January 19−21, 2012. San Francisco, CA. J Clin Oncol 2012; 30(Suppl 4):abstr LBA385. 4. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040−8. 5. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757−65. 6. Townsend A, Price T, Karapetis C. Selective internal radiation therapy for liver metastases from CRC. Cochrane Database Syst Rev 2009;(4):CD007045. 7. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol 2010;28:3687−94. 8. Seidensticker R, Seidensticker M, Damm R, et al. Hepatic toxicity after radioembolization of the liver using 90Y-microspheres: Sequential lobar versus whole liver approach. Cardiovasc Interven Radiol 2011 Oct 26; ePub doi: 10.1007/s00270–011−0295−7. 9. Bester L, Meteling B, Pocock N, et al. Radioembolization versus standard care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse events in salvage patients. J Vasc Interven Radiol 2011 Nov 11; ePub doi: 10.1016/ j.jvir.2011.09.028. 10. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Can 2010;103:324−31. 11. Collins J, Salem R. Hepatic radioembolization complicated by gastrointestinal ulceration. Semin Interven Radiol 2011;28:240−5.
Progress in the management of chemorefractory colorectal cancer Eric Van Cutsem* Digestive Oncology, University Hospitals Leuven, Belgium
article info Keywords: Radioembolisation Selective Internal Radiation Therapy 90 Y Yttrium-90 Liver-directed therapy Advanced colorectal cancer Liver metastases
1. Introduction A multidisciplinary approach, combining advances in systemic chemotherapy, targeted agents and aided by better surgical and imaging techniques has significantly enhanced the outcome for patients with metastatic colorectal cancer (mCRC) over the last two decades (Fig. 1). 1 Advancements in the management of unresectable mCRC have been characterised by small incremental improvements in overall survival which now extends beyond 2 years with the addition of biological agents to standard fluoropyrimidine-based chemotherapy regimens. Today, a whole host of newly identified targeted therapeutic agents inhibiting one or more key pathways are being evaluated in phase III clinical trials (including aflibercept and regorafenib) 2,3 as potential new treatments for mCRC. Our understanding of the benefits of targeted agents has been aided by large well-designed multicentre studies in patients with proven chemorefractory mCRC. While cetuximab initially showed only modest benefits * Correspondence: Eric Van Cutsem, MD, PhD, University Hospital Gasthuisberg, Digestive Oncology Unit, Herestraat 49, 3000 Leuven, Belgium. E-mail address: [email protected]; [email protected] (E. Van Cutsem).
in overall survival in unselected patients (Hazard ratio [HR], 0.77, 95% CI: 0.64–0.92), 4 a subsequent study of patients with wild-type K-ras tumours revealed that cetuximab plus best supportive care (BSC) was associated with a doubling overall survival (median, 9.5 vs. 4.8 months for BSC alone; HR for death, 0.55; P < 0.001) in chemorefractory disease. 5 In the same way, the recent evaluation of regorafenib plus BSC showed only a modest improvement in overall survival (median, 6.4 vs. 5.0 months for placebo plus BSC; HR, 0.77 [95% CI: 0.63–0.94; 1-sided P = 0.0051]) in patients with mCRC who progressed after standard therapies, 3 but there is early evidence to suggest that some patients do benefit more than others. 3 Like locoregional treatments, the challenge with targeted agents is to select the cohorts of patients who will benefit most. For targeted agents such as regorafenib, the decision to treat is likely to be based on the identification of a combination of molecular biomarkers (angiogenic signatures) for regorafenib activity.
2. Locoregional treatment with SIRT The published evidence suggests that locoregional treatments may play a complementary role to systemic
1359-6349/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
8
ejc supplements 10, no. 3 (2012) 7–9
(a)
(b)
Fig. 1 – (a) Overall survival of mCRC increasing over the decades, with (b) progressively more complex regimens combined with biologicals. Reproduced from Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27:3677−83 with permission from American Society of Clinical Oncology. Table 1 – Comparative or prospective studies of selective internal radiation therapy with in chemorefractory colorectal cancer liver metastases
90
Y resin microspheres
Investigators
n
Treatment
ORR
SD
TTP/PFS*
Survival
P value
HR
Hendlisz et al. 7 (cross-over at progression)
21
SIRT+ 5-FU
10%
76%
5.5/4.5 months
10.0 months
0.80
0.92
23
5-FU + salvage with SIRT at PD
0%
35%
2.1 months
7.3 months <0.001
0.26
0.001
0.50
Seidensticker et al. 8 (matched-pairs)
Bester et al. 9 (retrospective comparison)
Cosimelli et al. 10 SIRT with
90Y
29
SIRT
41%
17%
5.5 months*
8.3 months
29
Best supportive care
nr
nr
2.1 months*
3.5 months
224
SIR-Spheres
nr
nr
nr
11.9 months
29
Best supportive care
nr
nr
nr
6.6 months
50
SIRT
24%
24%
4 months*
12.6 months
resin microspheres; nr: not reported; PFS: Progression-free survival; TTP: Time to progression.
treatment by improving the local control of metastases in the liver. Comparisons between these two treatment modalities cannot be made because the locoregional treatments are used to manage liver-limited or liverpredominant disease while clinical trials of systemic agents include a much broader group of patients including those with disease that has progressed beyond the liver to the lungs and peritoneum. Early evidence for selective internal radiation therapy (SIRT) in mCRC was largely based on small case series. In review of the evidence in 2009, the Cochrane group concluded that there was a need for well-designed, adequately powered phase III trials to assess the effect of SIRT combined with modern chemotherapy regimens. 6 Further studies with SIRT were also needed in chemorefractory disease, with a particular focus on the impact on quality of life. 6 Since this review, four comparative or prospective studies have been published on SIRT in chemorefractory patients (Table 1). 7−10 One such study at the University Hospitals Leuven in collaboration with other Belgian sites evaluated 44 patients with liver-limited mCRC for whom all other evidence-based treatments had failed. 7 Patients
were randomised to receive either protracted IV infusion of 5-FU (300 mg/m2 day 1−14 every 3 weeks) or SIRT using 90 Y resin microspheres plus 5-FU (225 mg/m2 [cycle 1] then 300 mg/m2 day 1−14 every 3 weeks, thereafter) until documented hepatic progression. Most patients had a good performance status (ECOG 0 or 1). The burden of liver metastases was similar in both treatment arms. The study found that median time to liver progression was significantly prolonged with the addition of SIRT compared to 5-FU alone (5.5 vs. 2.1 months; hazard ratio [HR] 0.38; p = 0.003). The median time to progression at any site was also increased in the SIRT arm (4.5 vs. 2.1 months; HR 0.51; p = 0.03), as was the disease control rate (86% vs. 35%; p = 0.001). After 10 of 23 patients on 5-FU monotherapy crossed over to receive SIRT following progression, median overall survival was 7.3 and 10.0 months in the 5-FU and SIRT plus 5-FU arms, respectively (HR = 0.92 95% CI 0.47–1.78; p = 0.80). Grade 3 or 4 toxicities were recorded in 6 patients following 5-FU monotherapy and in 1 patient following SIRT plus 5-FU treatment (p = 0.10). Adverse events associated with SIRT are generally mild and transient, including nausea, fever and abdominal pain (Table 2).
9
ejc supplements 10, no. 3 (2012) 7–9
Table 2 – Adverse events profile with SIRT using cancer liver metastases
90
Y resin microspheres in chemorefractory colorectal
AE
Incidence
Characteristics
Prevention/Action
Fever
>50%
Mild (grade 1*) onset on day of treatment for up to 1 week
None normally required
Abdominal pain
~50% (~10% grade 3−4)
Acute onset during treatment; self-limiting (normally <24 h)
May require narcotic (>oral analgesia)
Nausea
~40% (<5% grade 3−4)
Highest in treatment-experienced; self-limiting (normally <24 h)
Prophylactic anti-emetics
Fatigue
~40% (<5% grade 3−4)
Onset in 1st month post-SIRT, normally subsides within 2 weeks
Adequate nutrition and hydration; prophylactic oral steroids
Abnormal Liver Function Tests
~20−40% (1−6% grade 3−4)
Particularly in combination with chemotherapy; transient: resolves in days (ALT, AST), weeks (bilirubin) or months (albumin)
None normally required
More rarely, radiation-associated gastrointestinal ulcers can occur and these are more difficult to treat. 11 Patients should be carefully monitored with a low threshold of suspicion for evidence of gastrointestinal ulcer to ensure early and effective treatment, especially if subsequent treatment with antiangiogenics such as bevacizumab is being considered. In summary, SIRT is likely to play an important complementary role to systemic therapies for the control of colorectal liver metastases. Ongoing randomised controlled clinical trials with conventional chemotherapies with or without SIRT (in the first-line setting and in chemorefractory disease) will further define the role of this treatment modality in the management of liverdominant mCRC.
Conflict of interest statement The author receives research funding from Merck Serono, Roche and Sanofi.
References
1. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27:3677−83. 2. Tabernero J. Results from VELOUR, a phase III study of aflibercept (A) versus placebo (pbo) in combination with FOLFIRI for the treatment of patients (pt) with previously treated metastatic colorectal cancer (MCRC). In: Program and abstracts of the European Multidisciplinary Cancer Congress; September 23−27, 2011; Stockholm, Sweden. Abstract LBA6.
3. Grothey A, Sobrero AF, Siena S, Falcone A, et al. Results of a randomized phase 3 trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with mCRC who have progressed after standard therapies. Gastrointestinal Cancers Symposium; January 19−21, 2012. San Francisco, CA. J Clin Oncol 2012; 30(Suppl 4):abstr LBA385. 4. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040−8. 5. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757−65. 6. Townsend A, Price T, Karapetis C. Selective internal radiation therapy for liver metastases from CRC. Cochrane Database Syst Rev 2009;(4):CD007045. 7. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol 2010;28:3687−94. 8. Seidensticker R, Seidensticker M, Damm R, et al. Hepatic toxicity after radioembolization of the liver using 90Y-microspheres: Sequential lobar versus whole liver approach. Cardiovasc Interven Radiol 2011 Oct 26; ePub doi: 10.1007/s00270–011−0295−7. 9. Bester L, Meteling B, Pocock N, et al. Radioembolization versus standard care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse events in salvage patients. J Vasc Interven Radiol 2011 Nov 11; ePub doi: 10.1016/ j.jvir.2011.09.028. 10. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Can 2010;103:324−31. 11. Collins J, Salem R. Hepatic radioembolization complicated by gastrointestinal ulceration. Semin Interven Radiol 2011;28:240−5.