Systemic options for third-line treatment

From Cancer Guidelines Wiki

Background

In the situation of disease progression in mCRC after patients have received two lines of therapy, the survival is poor at approximately 4-6 months with best supportive care alone.[1] Patients in the third-line setting have limited therapeutic options and typically have reduced quality of life; therefore physicians must carefully balance any efficacy benefit associated with therapy with its toxicity profile.

However, many patients retain adequate performance status to be considered for further systemic therapy and a number of systemic agents have been shown to modestly improve survival in this situation. This remains an area where further clinical trials are needed to determine the best therapeutic approach. Decisions regarding the choice of therapy depend on previously utilised therapies, tumour biology, patient comorbidities, performance status and patient preference.

After failure of all conventional agents/combinations, if performance status is adequate and a tumour-directed therapeutic approach is still warranted, enrolment into a clinical trial testing novel agents/combinations should be considered.

The benefits of palliative care involvement on quality of life for cancer patients and their families have been widely demonstrated.[2] Both Australian and international data show patients with metastatic CRC experience significant symptoms throughout the course of their disease.[3] Integration of palliative care in the management of patients with advanced malignancy improves symptom control and quality of life for patients and their families[2] and as such represents an important component of the continuum of care for patients with mCRC.

Overview of evidence (non-systematic literature review)

No systematic reviews were undertaken for this topic. Practice points were based on selected reviews, primary studies, and other clinical practice guidelines (see Guideline development process).

Patients who maintain adequate performance status should be considered for third-line therapy.

Cetuximab and panitumumab

In patients with RAS wild-type metastatic colorectal cancer, both cetuximab and panitumumab have shown efficacy in the third-line/salvage-therapy setting,[4][5] and are equally active as single agents.[6] Combination therapy with cetuximab and irinotecan appears more active than cetuximab alone in patients with irinotecan-refractory tumours.

See eviQ protocols:


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Regorafenib

Regorafenib is an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3), as well as other receptor and intracellular kinases. It has reported activity versus placebo plus best supportive care in two phase III trials.[7][8]

Based on these data, regorafenib may be considered for patients with refractory metastatic colorectal cancer after treatment with all available cytotoxic agents, bevacizumab and EGFR antibodies (in RAS wild-type tumours) . The CORRECT trial[9] compared best supportive care plus regorafenib (160 mg orally once daily for three of every four weeks) or placebo in 760 patients with chemotherapy refractory disease. It demonstrated a significant survival benefit for regorafenib (median 6.4 versus 5 months, Hazard Ratio 0.77), albeit with little objective antitumor response, but with maintained quality of life over time.[9]

The dosing regimen has been questioned by many clinicians; many start with a lower dose and then increase the dose to the approved dose if no toxicity is observed. Frequent and close monitoring for regorafenib toxicity is recommended. See eviQ protocol: Colorectal Metastatic Regorafenib

Regorafenib is approved in Australia by the Therapeutic Goods Administration (TGA).

Trifluridine-tipiracil

Recently, trifluridine-tipiracil (Lonsurf ®), an oral cytotoxic agent that consists of the nucleoside analogue trifluridine and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well has been shown to be effective in patients with refractory metastatic colorectal cancer.[10]

In the phase III trial (RECOURSE) 800 patients who were refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and anti-EGFR agents (if wild-type KRAS) were randomly assigned to trifluridine-tipiracil (35 mg/m2 orally twice daily on days 1 through 5, and 8 to 12 of each 28-day cycle) or placebo.[9]

The final survival results of the RECOURSE phase III trial were presented at 2016 ASCO meeting. The updated survival analysis confirmed that OS benefit with trifluridine-tipiracil was maintained and increased to a full 2 months - improvement in 1-year survival surpassed 10% in these heavily pre-treated patients. OS benefit appears to be maintained for all patients in the trial regardless of prognostic status at trial entry.[11]

The benefit of this agent is similar to that of regorafenib, but with a better toxicity profile.

Trifluridine-tipiracil is not registered in Australia by the TGA as of May 2017.


Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Patients with mCRC considering treatment in the third-line setting have limited therapeutic options and typically have reduced quality of life; therefore physicians must carefully balance any efficacy benefit associated with therapy with its toxicity profile.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Cetuximab or panitumumab treatment should be considered in patients with RAS wild-type and BRAF wild-type metastatic colorectal cancer not previously treated with these agents, taking into account the following:

  • Cetuximab and Panitumumab are equally effective as single agents.
  • Cetuximab in combination with irinotecan is more active than cetuximab alone in patients refractory to irinotecan with adequate performance status to receive combination therapy.
Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

If available, regorafenib or trifluridine/tipiracil can be considered for patients with metastatic colorectal cancer refractory to all standard available therapies.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Patients receiving third-line therapy should be offered participation in clinical trials, wherever available.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Symptom burden is often high in patients with mCRC especially as the disease progresses. Early palliative care intervention should be considered for all patients with mCRC as they can improve the quality of life of patients with cancer.

Next: Supportive care options for patients with non resectable metastatic CRC

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References

  1. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007 Nov 15;357(20):2040-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18003960.
  2. 2.02.1 Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015 May;16(5):499-508 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25877855.
  3. El-Jawahri A, Greer JA, Temel JS. Does palliative care improve outcomes for patients with incurable illness? A review of the evidence. J Support Oncol 2011 May;9(3):87-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21702398.
  4. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004 Jul 22;351(4):337-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15269313.
  5. Hecht JR, Patnaik A, Berlin J, Venook A, Malik I, Tchekmedyian S, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007 Sep 1;110(5):980-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17671985.
  6. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014 May;15(6):569-79 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24739896.
  7. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004 Apr 1;22(7):1209-14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15051767.
  8. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015 Jun;16(6):619-29 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25981818.
  9. 9.09.19.2 Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015 May 14;372(20):1909-19 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25970050.
  10. Matsushita S, Nitanda T, Furukawa T, Sumizawa T, Tani A, Nishimoto K, et al. The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors. Cancer Res 1999 Apr 15;59(8):1911-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10213500.
  11. Mayer R, Ohtsu A, Yoshino T, et al.. TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial. J Clin Oncol 2016;34:Abstr 634.
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