METASTATIC Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

METASTATIC COLORECTAL CANCER

Executive Summary

Metastatic colorectal cancer is, with a few exceptions, an incurable illness. Palliative significantly improves survival and provides relief of symptoms in settings that have sufficient resources to administer and handle the toxicities of treatment. Multiple chemotherapy regimens are effective. The least costly regimen shown to increase survival is 5- FU/leucovorin. The efficacy of 5-FU/Leucovorin is improved, in an usually cost-effective manner, by combining it with (FOLFOX regimen) or (FOLFIRI). It is also thought that first and second lines of treatment should be seen as complimentary to reach maximum benefit from currently available palliative chemotherapy agents. Survival can be further improved, albeit to a small degree, with the use of biological agents such as , , or in first-line, followed subsequently by other newer agents such as ziv- or regorafenib. These agents are not usually considered cost-effective.

Public Health Relevance

Colorectal cancer is one of the most common, and deadly, malignancies; it has been estimated that worldwide there are 1.2 million new cases a year [1]. Globally, colorectal cancer is the fourth most common cause of cancer-related deaths in men and third in women, killing an estimated 320,600 men and 288,100 women annually [1].

In the developed world, the death rate from colorectal cancer has been decreasing, largely due to colonoscopy screening, that enable both the removal of precancerous polyps and the detection of early stage, curable disease. Because 90% of colon cancers occur in patients who are at least 50 years-old, in countries that are able to afford colonoscopy screening the recommendation for the general population is to begin at age 50[2].

Because of the expense of colonoscopy, population based screening programs are usually not feasible in many parts of the world. With poor access to health care added to that, colorectal cancer patients in low- and middle-income countries often present with more advanced stages of the disease.

In the United States, 40% of colorectal cancer patients have localized disease (stage I and II) [3], 36% are regionally advanced (stage III) and 20% have metastases at presentation [3].

Requirements for diagnosis, treatment, and monitoring

Diagnostics and testing: Localized colorectal cancer often presents with one of the following symptoms: change in bowel habits, blood in the stools, abdominal discomfort, and weight loss. 1

METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

The symptoms of metastatic colorectal cancer depend on the site of metastasis depending on the site of metastasis (liver: RUQ abdominal pain, jaundice; bone: bone pain; lungs: chest pain, shortness of breath).

The primary mass in colorectal cancer can be diagnosed with a rectal exam, sigmoidoscopy or colonoscopy. During endoscopy a biopsy can be performed so that the diagnosis of cancer is confirmed pathologically.

A critical aspect of the evaluation of a colorectal cancer patient is establishing whether she has metastatic disease. In high resource health systems, computed tomography scan of the Chest, Abdomen and Pelvis is performed routinely. In resource-constrained settings systemic evaluation with abdominal and pelvic ultrasound and a chest x-ray is a less costly commonly employed option. Preoperative rectal cancer staging, which evaluates the T and N stage of the tumor, is also important in establishing the degree of loco-regional invasiveness of the tumor. Where available, it is performed by either rectal MRI or endoscopic ultrasound, complex and highly specialized have limited availability in resource-constrained settings.

When chemotherapy is employed, laboratory evaluations play an important role in monitoring patient safety. A complete blood count (CBC) with differential assesses whether patients are myelosuppressed and neutropenic. A comprehensive metabolic panel monitors renal and hepatic function as well as electrolyte imbalances.

Treatment: Palliative chemotherapy for metastatic colorectal cancer has improved in a stepwise fashion over the past several decades. 5-FU is a thymidylate synthase inhibitor that functions by disrupting the synthesis of the pyrimidine thymine. 5-FU was the first cytotoxic chemotherapeutic agent shown to be effective in metastatic colorectal cancer and arguably is still the most efficacious and cost- effective drug against colorectal cancer. One early trial demonstrated that a regimen of 5- FU//leucovorin, when compared to best supportive care, increases survival in metastatic colorectal cancer from 5 months to 11 months [4]. Subsequent trials demonstrated that cisplatin is an inactive agent in colorectal cancer and hence 5-FU/Leucovorin became the regimen of choice [5]. Several clinical trials have tested the importance of combining leucovorin, a reduced form of folate, with 5-FU. A meta-analysis showed that 5-FU/Leucovorin doubles the response rate of single agent 5-FU (21% for 5-FU/Leucovorin versus 11% for 5-FU) and also increases survival (11.7 versus 10.5 months) [6].

Two subsequent cytotoxic , irinotecan and oxaliplatin, showed considerable efficacy when added to the 5-FU/Leucovorin backbone. Irinotecan, a type I inhibitor, is combined with 5-FU/Leucovorin in the FOLFIRI regimen. Oxaliplatin, a third- generation platinum chemotherapy, is combined with 5-FU/Leucovorin in the FOLFOX, infusional, or FLOX, bolus, regimens or with in the CAPOX scheme, also known as XELOX. Multiple clinical trials have shown that the FOLFIRI and FOLFOX or CAPOX regimens are equivalent in terms of efficacy [7,8]. Oncologists typically use one regimen in the first line and then utilize the other regimen in second line therapy. Demonstrative of the equivalence of the two regimens, a randomized phase III GERCOR trial showed survival was

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

21.5 months in patients treated with FOLFIRI followed by FOLFOX; and survival was 20.6 months in patients treated with FOLFOX and then FOLFIRI [7]. For first line therapy, oncologists choose between FOLFOX and FOLFIRI based on the side effect profile of both regimens. FOLFOX can causes significant neuropathy and approximately 18% of patients develop grade 3 neuropathy [9]. On the other hand, FOLFIRI can cause severe diarrhea and approximately 13% of patients develop grade 3-4 diarrhea [10]. Notably, both the FOLFOX and FOLFIRI regimens cause increased myelosuppression and nausea compared to 5-FU/Leucovorin alone.

It is important to emphasize that systemic chemotherapy in metastatic colorectal cancer is usually not curative. In countries that do not have sufficient resources to administer and handle the toxicities of chemotherapy, it is appropriate to forego chemotherapy and instead to focus on palliative care. It must also be noted that where available, multidisciplinary treatment and resection of oligometastatic disease associated with systemic treatment may cure some patients with metastatic colorectal cancer.

Administration and Care of Patients: Administration requires intravenous infusion capacity, and requires that patients have regular access to clinical care. In developed countries administration is usually performed in out-patient facilities, though in other settings, patients may be treated in in-patient facilities. Antiemetics need to be available. Monitoring requires that clinicians have access to laboratory facilities, as well as the ability to recognize and address potential adverse events caused by the treatment itself. Importantly, in-patient facilities capable of supporting patients with severe infections and dehydration need to be readily available. Social and financial wellbeing can be impacted by treatment side effects and should be monitored and addressed as well.

Standard Regimens

Modified de-Gramont regimen of adjuvant chemotherapy with 12 cycle of 5-FU and Leucovorin Leucovorin 400 mg/m2 IV on Day 1 of each 14 day cycle (5-FU) 400 mg/m2 IV bolus on Day 1 of each 14 day cycle Fluorouracil (5-FU) 1200mg/m2 daily; continuous infusion over 46 hours (day 1 and 2 of each 14 day cycle)

FOLFOX-6 Regimen Leucovorin 400 mg/m2 IV on Day 1 of each 14 day cycle Fluorouracil (5-FU) 400 mg/m2 IV bolus on Day 1 of each 14 day cycle Fluorouracil (5-FU) 1200mg/m2 daily; continuous infusion over 46 hours (day 1 and 2 of each 14 day cycle) Oxaliplatin 85mg/m2 IV on Day 1 of each 14 day cycle

FOLFIRI Regimen Leucovorin 400 mg/m2 IV on Day 1 of each 14 day cycle

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

Fluorouracil (5-FU) 400 mg/m2 IV bolus on Day 1 of each 14 day cycle Fluorouracil (5-FU) 1200mg/m2 daily; continuous infusion over 46 hours (day 1 and 2 of each 14 day cycle) Irinotecan180mg/m2 IV on Day 1 of each 14 day cycle

CAPEOX Regimen (3 week cycle; 8 cycles) Capecitabine 850-1,000 mg/m2 PO BID twice daily on Days 1-14 of each 21-day cycle Oxaliplatin 130 mg/m2 over 2 hours on Day 1 of each 21-day cycle

Where the ability of administering 5FU by continuous infusion or oral capecitabine is not feasible, many centers have established the following standard: first line FLOX [a regimen that includes bolus instead of infusional 5FU, see below] followed by irinotecan on a bi-weekly or three-weekly basis in second line.

FLOX Regimen (8 week cycle; continuous until toxicity or progression) Fluorouracil 400 mg/m2 IV bolus weekly for first 6 weeks of 8-week cycle Leucovorin 500 mg/m2 IV (acceptable to use low-dose leucovorin i.e. 20 mg/m2)

Irinotecan Single Agent Schedule 1: 135 mg/m2 on Days 1 and 8 every 21 days Schedule 2: 180 mg/m2 on Day 1 every 14 days Schedule 3: 300-350 mg/m2 on Day 1 every 21 days (*least preferred due to toxicity)

Review of Benefits and Harms

Benefits

Fluoropyrimidines alone Similar to the adjuvant setting, fluoropyrimidines form the cornerstone of chemotherapy for advanced disease. Bolus regimens of the Mayo and RPMI regimens have been compared in several trials, showing comparable efficacy. Response rates of about 20% are reported, with median overall survival of 9–12 months. Many clinicians slightly prefer RPMI over the Mayo regimen because of its toxicity profile. The Mayo regimen has been compared with the infusional de Gramont regimen ( and fluorouracil) done every 2 weeks. The de Gramont regimen is associated with superior response rates (32% vs. 14%; p=0·0004) and median progression-free survival (28 vs 22 weeks; p=0·0012); median overall survival is increased slightly (62 vs 57 weeks; p=0·067). Furthermore, grade 3–4 toxic effects were less frequent with the de Gramont regimen (11% vs 24%; p=0·0004). Similarly, oral fluoropyrimidines such as capecitabine, have been compared with fluorouracil regimens in several trials, most of which show non-inferiority of oral fluoropyrimidines and, typically, a superior toxicity profile.

As in the adjuvant setting, choice of fluoropyrimidine (fluorouracil bolus or infusion or oral capecitabine) should be based on local practice, experience and the availability of infusional

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines capabilities and other supportive treatment. In general, a fluoropyrimidine alone as initial treatment for advanced colon cancer should be reserved only for patients who are not candidates for more intensive therapy. If a fluoropyrimidine alone is selected, infusional fluorouracil or an oral fluoropyrimidine are preferred over bolus fluorouracil regimens because of reduced toxic effects and possibly slightly superior outcomes.

Fluoropyrimidine doublets For 40 years, fluorouracil was the only agent available to treat advanced colon cancer. In the early 2000s, the US Food and Drug Administration (FDA) approved two other chemotherapy drugs: oxaliplatin and irinotecan. These agents are typically combined with a fluoropyrimidine (irinotecan has single-agent activity, oxaliplatin does not). To date, three phase 3 trials have compared a fluoropyrimidine backbone with or without irinotecan. In two, infusional fluorouracil backbones were used (the FOLFIRI regimen), and in the third, a bolus fluorouracil and folinic acid regimen was administered (the IFL regimen). Overall, improvements were noted in response rates (about 45–50% with irinotecan based regimens) and median overall survival (about 15–20 months) compared with fluorouracil and folinic acid alone. In the Douillard trial for instance, the response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p<0.001 for evaluable patients, 35 vs 22%, p<0.005 by intention to treat); time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6.7 vs 4.4 months, p<0.001); and overall survival was higher (median 17.4 vs 14.1 months, p=0.031). Subsequent researcher investigating the IFL regimen did note an increase in toxic effects (including treatment-related deaths). In a trial from the USA, in which patients were randomly allocated to one of three irinotecan-based regimens (FOLFIRI, IFL, or capecitabine plus irinotecan [CapeIri]) in addition to and, later, bevacizumab, superiority of FOLFIRI over the IFL regimen was reported, in terms of both efficacy and tolerability. As such, the IFL regimen should no longer be used.

The FOLFOX regimen also improves response rates, median progression-free and overall survival in patients with advanced colon cancer. In the US Intergroup 9741 study, superiority of FOLFOX over the IFL regimen was noted. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively, for OS: P = .0001; hazard ratio, 0.66) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin.

Comparisons of FOLFIRI and FOLFOX showed similar results with either regimen in the GOIM 9901 and CALGB 80405 studies. Substitution of capecitabine for fluorouracil has been assessed for regimens containing either irinotecan or oxaliplatin. Non-inferiority of CapeOx over FOLFOX has been noted,53 with a comparable but different toxicity profile. FOLFOX is associated with more grade 3–4 neutropenia and neutropenic fever, whereas CapeOx causes more grade 3 diarrhoea and hand-foot syndrome. Conversely, in a comparison of the CapeIri regimen and FOLFIRI in North American patients, CapeIri was associated with inferior

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines progression-free survival and more toxic effects, a finding that has been criticized because of poor tolerance of capecitabine, which persisted even when patients who discontinued treatment because of toxic eff ects were excluded. European trials in which CapeIri has been tolerated generally used lower doses of irinotecan (190–200 mg/m² vs 250 mg/m²) and capecitabine (800 mg/m² vs 1000 mg/m² twice a day). No direct comparison has been done of dose-reduced CapeIri regimens and either FOLFIRI or full-dose CapeIri. Therefore, patients treated with an irinotecan- containing regimen should preferentially receive FOLFIRI over CapeIri because of the noted concerns about inferior outcomes and increased toxic effects with the capecitabine based regimen. Patients treated with an oxaliplatin-containing regimen can receive either FOLFOX or Capeox. FLOX is also often used in settings where capecitabine and the ability to administer infusional fluoruracil are not available, even though it has not been assessed in phase III trials outside the adjuvant setting. Survival is comparable between FOLFIRI and FOLFOX. Most clinicians select the starting regimen on the basis of competing toxicity profiles: FOLFIRI is associated with more grade 3–4 febrile neutropenia, nausea and vomiting, mucositis, and fatigue, whereas FOLFOX is associated with dose-limiting peripheral neuropathy that is related to the cumulative oxaliplatin dose. The neuropathy associated with continuous oxaliplatin treatment has led to development of intermittent oxaliplatin strategies, but these studies are beyond the scope of this Review.

Triplet regimen A triplet regimen of infusional fluorouracil and folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) has been compared with infusional fluorouracil, folinic acid, and irinotecan in two phase 3 studies from Italy and Greece. In the Italian study, all outcomes were improved with FOLFOXIRI, but in the Greek study no differences were noted.

Chemotherapy and targeted treatments Targeted treatments have been investigated extensively in advanced colon cancer. Currently, five targeted agents are approved in different jurisdictions for advanced disease: bevacizumab, ziv- aflibercept and regorafenib, which target angiogenesis; and cetuximab and panitumumab, which target the epidermal growth factor receptor [EGFR]. All of these agents have shown a small increase in overall survival but have not usually been considered cost-effective and are not being recommended. One set of resource-stratified guidelines for instance suggests that fluoruracil costs less than US$ 1,000 per life-year saved, oxaliplatin or irinotecan can cost up to US$ 40,000 – likely less nowadays with the use of generics, and the targeted agents often cost more than US$ 200,000. As such, the task force suggests the maintenance of fluoruracil and calcium folinate and the inclusion of irinotecan, oxaliplatin and capecitabine to the essential medicines list.

Harms and Toxicity Considerations

Common Frequent adverse effects of Flourouracil (5-FU)/Leucovorin combination therapy are diarrhea and associated dehydration, neutropenia (uncommonly leading to infection in <2% of patients), anemia, nausea and vomiting, and mucositis.[14] Notably, both the FOLFOX and FOLFIRI regimens cause increased myelosuppression and nausea compared to 5-FU/Leucovorin alone.

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

Palmar-plantar erythrodysesthesia (hand-foot) syndrome is also common with 5-FU and capecitabine regimens, with an increased incidence of up to 60% fin patients treated with capecitabine. This adverse effect typically resolves following treatment interruption.[15] Irinotecan can cause asthenia or weakness and is associated with a cholinergic syndrome characterized by rhinitis, increased salivation, lacrimation, diaphoresis and flushing, although symptoms are typically low-grade.

Serious Oxaliplatin-containing regimens can cause significant neuropathy, approximately 18% of patients develop grade 3 neuropathy.[9] Irinotecan may cause severe diarrhea, with approximately 13% of patients developing grade 3-4 events. [10] Diarrhea can be severe with any of the above regimens and may require hospital admission for IV fluid replacement. It can be early or late-onset and is often dose-limiting. [10,14,16]

Systematic Reviews

Cancer TM-AGi. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: An updated meta-analysis. Journal of Clinical Oncology 2004;22:3766-3775.

Purpose: The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials. Patients and Methods: Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons. Results: Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms. Conclusion: This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer; 1993.

Objectives: To compare the length of survival and quality of life in patients given combination chemotherapy in addition to supportive care and in patients given only supportive care. DESIGN: Randomised study. Setting: Gastrointestinal oncology departments. Patients: 40 previously untreated patients with histologically confirmed, measurable colorectal cancer that was locally recurrent or metastatic. Interventions: Patients were allocated randomly to receive chemotherapy or only supportive care in a ratio of 2:1 according to performance status, metastatic disease of the liver, and weight loss in the six months before entering the study. Chemotherapy consisted of four week cycles of intravenous leucovorin (200 mg/m2/day) followed by 5-fluorouracil (550 mg/m2/day) and cisplatin (20 mg/m2/day), each drug being given on the first four days of the cycle. Main Outcomes Measures: Length of survival and quality of life score with an optimised functional living index-cancer scale. Results: Overall survival was significantly longer for patients given chemotherapy (11.0 months) than for those receiving supportive care alone (5.0 months; p = 0.006). Despite common association of chemotherapy with mild to moderate gastrointestinal symptoms, there was no significant difference between the two groups in global or subgroup quality of life scores. In patients with abnormal scores before treatment, quality of life seemed better in the chemotherapy arm. Conclusions: In this sample of patients with disseminated colorectal cancer the was an effective form of palliative treatment.

Ku G, Tan IB, Yau T, Boku N, Laohavinij S, Cheng AL, Kang YK, Lopes G. Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012. The Lancet Oncology - 1 November 2012 ( Vol. 13, Issue 11, Pages e470-e481 ).

This review summarizes all of the available evidence on metastatic colorectal cancer using a resource-stratification approach.

Recommendations

The reviewers recommend the incorporation of metastatic colorectal cancer treatment options into the WHO Model List of Essential Medicines, and recommend specifically that oxaliplatin, irinotecan, and capecitabine be added to the core Essential Medicines List.

Oxaliplatin Irinotecan Capecitabine

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METASTATIC COLORECTAL CANCER Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

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6. Cancer TM-AGi. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: An updated meta-analysis. Journal of Clinical Oncology 2004;22:3766-3775.

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11. Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, Waterkamp D, Tabernero J. Efficacy and safety of bevacizumab in metastatic colorectal cancer: Pooled analysis from seven randomized controlled trials. Oncologist 2013;18:1004-1012.

12. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P. Kras mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-3995.

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17. Ku G, Tan IB, Yau T, Boku N, Laohavinij S, Cheng AL, Kang YK, Lopes G. Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012 The Lancet Oncology - 1 November 2012 ( Vol. 13, Issue 11, Pages e470-e481 ).

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