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Adjuvant Chemotherapy for Stage III Colon Cancer

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Adjuvant Chemotherapy for Stage III Colon Cancer cancers Review Adjuvant Chemotherapy for Stage III Colon Cancer Julien Taieb 1,2,* and Claire Gallois 1,2 1 Sorbonne Paris cite, University of Paris, 75006 Paris, France; [email protected] 2 Siric CARPEM, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, 75015 Paris, France * Correspondence: [email protected] or [email protected]; Tel.: +33-156093551 Received: 15 August 2020; Accepted: 9 September 2020; Published: 19 September 2020 Simple Summary: In patients with stage III colon cancer, adjuvant chemotherapy with a fluoropyrimidine combined with oxaliplatin reduces the risk of recurrence and mortality, with a treatment duration that may be shortened from 6 to 3 months in certain situations allowing to limit toxicities, especially cumulative sensitive neuropathy. However, it is difficult to effectively predict the risk of recurrence individually for each patient. It is indeed necessary not to over-treat patients with potential toxicities of chemotherapy and, conversely, not to under-treat patients at high risk of recurrence, and also to find new treatment approaches for specific subgroups. Though no single biomarker have sufficient predictive value to adapt the therapeutic strategy, we have considerably improved our knowledge of these biomarkers predictive of recurrence in localized colon cancer and many trials testing their ability to guide treatment are ongoing. Abstract: In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC. Keywords: colon cancer; adjuvant chemotherapy; prognosis 1. Introduction Colon cancer (CC) is the third most common cancer and the second leading cause of cancer death worldwide [1]. In localized CC, lymph node invasion is a major prognostic factor, with a 5 year-overall survival (OS) of 99% and 70% for patients with stage I and II CC, respectively, versus only 45 to 65% for stage III patients [2], representing about 35% of CC at diagnosis. In stage III CC patients, adjuvant fluoropyrimidine-based chemotherapy is a standard of care since the 90s based on the Moertel trial [3]. In 2004, the MOSAIC trial set up the combination of oxapliplatin to a fluoropyrimidine (FOLFOX regimen) for 6 months (12 cycles) as a new standard of care for stage III CC, by improving disease-free survival (DFS) [4] but also long-term overall survival (OS) [5] with the use of this doublet chemotherapy. However, our capacity to identify patients that do really need this Cancers 2020, 12, 2679; doi:10.3390/cancers12092679 www.mdpi.com/journal/cancers Cancers 2020, 12, 2679 2 of 17 doublet adjuvant treatment remains limited. It is accepted that for 100 stage III CC patients receiving fluoropyrimidine + oxaliplatin, only 30 patients at the most will benefit from this adjuvant treatment, 50 patients being already cured by the surgical removal of their tumor and 20 patients experiencing disease recurrence despite the adjuvant treatment [6]. Though adjuvant therapy benefits a limited number of treated patients, all of them will be exposed to short- and long-term toxicities induced by these chemotherapeutic agents, including long lasting cumulative sensitive neuropathy induced by oxaliplatin. Waiting to be able to personalize adjuvant treatment and give the right therapeutic approach to the right patient, strategies aiming at reducing treatment toxicities were tested and the reduction in treatment duration from 6 to 3 months proposed by the International Duration Evaluation of Adjuvant (IDEA) international collaboration allowed to reduce significantly treatment-induced toxicities [7]. In this review, we will first discuss the recommendations for adjuvant chemotherapy in stage III CC (timing of initiation, different regimens, treatment duration, specific situations such as elderly patients or locally advanced tumors). We will then discuss the different biomarkers described in this situation and the future perspectives for the management of stage III CC. 2. Timing of Adjuvant Chemotherapy A meta-analysis in stage III CC showed that delay in initiation of adjuvant chemotherapy beyond 8 weeks after curative surgery decreased OS (RR: 1.20; 95% Confidence Interval (CI) 1.15–1.26), probably also in part due to post-operative complications and a poor general condition [8]. However, patients could still benefit from adjuvant chemotherapy with a longer delay, up to 5–6 months, but the effectiveness of chemotherapy decreases with a time elapsed of 8 weeks [9,10]. Thus, chemotherapy should be initiated 6–8 weeks after curative surgery to have the greatest benefit, and has no role beyond 6 months after surgery. 3. Chemotherapy Regimens The first adjuvant chemotherapy regimen to demonstrate its efficacy in localized CC compared to surgery alone was the FULV regimen: fluorouracil (370–400 mg/m2) plus L-folinic acid (175–200 mg or 25 mg) daily for 5 days every month for 6 cycles [11–14] with a reduction of around 15% in the risk of death at 5 years. The semimonthly LV5FU2 regimen and capecitabine (oral fluoropyrimidine) have been shown to be as effective and better tolerated than FULV [15,16]. Then, the addition of oxaliplatin with FOLFOX or CAPOX regimens for 6 months has been validated with an increase in 6-year DFS and OS to 73.3% and 78.5%, respectively, as compared to 67.4% and 76% for fluoropyrimidine alone in the MOSAIC trial [4], confirmed by the NSABP C-07 [17,18] and XELOXA trials [19], with similar outcomes in improving DFS. Updated 10-year OS data of the MOSAIC trial in stage III CC confirmed these results with a 10-year OS rate of 59.0% for patients treated with LV5FU2 and 67.1% for patients treated with FOLFOX (HR, 0.80; p = 0.016) [5]. Compared to the FOLFOX4 regimen, modified FOLFOX6 regimen (biweekly courses of oxaliplatin 85 mg/m2, with leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 bolus, then 46-hour intravenous fluorouracil 2400 mg/m2) seems more convenient and cost-effective because the patient only comes once in a day hospital, with similar DFS rates in the two adjuvant phase 3 trials using FOLFOX6m: NSABPC-08 [20] and NCCTG NO147 [21] in cross-study comparisons with the MOSAIC (using FOLFOX4) [4] and NSABPC-07 (using FLOX) trials [17]. Although they are effective in the metastatic setting, FOLFIRI, IFL and FOLFOX combined to VEGF- or EGFR-targeted therapies, did not improved outcomes in stage III CC [21–27]. Interestingly, we showed in the PETACC-8 trial that in the subgroup of patients with full RAS and BRAF wild-type tumors, there was a trend to a better DFS when cetuximab was added to FOLFOX with a clinically relevant adjusted HR of 0.76 (p = 0.11) but not sufficient to change practices [28]. Likewise, a phase 3 trial comparing raltitrexed to 5-FU in stage III CC was closed prematurely due to raltitrexed-induced overmortality and failed to demonstrate non-inferiority of raltitrexed on 5-FU [29]. Cancers 2020, 12, 2679 3 of 17 Thus, the only regimens validated in stage III CC are the oxaliplatin-based chemotherapy FOLFOX or CAPOX, when patients are eligible to a doublet treatment, and LV5FU2 or capecitabine without oxaliplatin in the others. Compared to FOLFOX, the CAPOX regimen has the advantages of not necessarily requiring the insertion of a central venous access device [30] and reducing the number of injections of oxaliplatin (every 3 weeks) which may be more convenient for the patient and cost-effective. However, in a significant proportion of patients, capecitabine may be contraindicated (renal insufficiency) or poorly tolerated (ileostomy, elderly patients) and leads generally to more frequent and severe diarrhea and hand-foot syndrome. In fragile patients, a tailored-dose escalation strategy for capecitabine prescription could be proposed with an initial dose of 2000 mg/m2/d increased if well tolerated to the standard dose of 2500mg /m2/d for the second cycle [31]. Finally, dihydropyrimidine dehydrogenase (DPD) deficiency, present in approximately 0.3% of the general population in western countries, has to be tested before adjuvant chemotherapy with fluoropyrimidines, to prevent severe toxicity and possible toxic death in deficient patients [32]. DPD phenotype (assessed by dosing uracilemia) should be preferred to genotyping to detect deficient patients. In case of uracilemia greater than or equal to 150 ng/mL (suggestive of a complete deficit in DPD), treatment with fluoropyrimidines is contraindicated, and their dosage should be substantially reduced in case of uracilemia between 16 and 150 ng/mL. 4. Duration of Adjuvant Chemotherapy: IDEA Collaboration Cumulative sensory neuropathy is one of the major toxicities of oxaliplatin-based adjuvant chemotherapy and can affect the long-term quality of life of patients. Considering adjuvant treatment duration, the international collaboration IDEA [7] is a pooled analysis of six phase 3 randomised trials across 12 countries, including 12934 patients with stage III CC, and comparing 6 months versus 3 months of FOLFOX/CAPOX (investigators’ choice for chemotherapy regimen) with a primary end point of 3-year DFS.
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