Should FOLFOXIRI Plus Bevacizumab Be the Standard First-Line Therapy in Metastatic Colorectal Cancer?

The TRIBE trial compared the FOLFOXIRI regimen plus bevacizumab with FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. FOLFOXIRI plus bevacizumab is an acceptable therapeutic option, but the results of the TRIBE trial do not establish this regimen as the best treatment option for patients with metastatic colorectal cancer.Colorectal cancer is the third leading cause of cancer death in the U.S. [1]. With the advent of irinotecan, oxaliplatin, anti-EGFR, and anti-VEGF treatments, patients diagnosed with metastatic colorectal cancer can expect to live for 2 years after diagnosis, with 20% of patients alive at 5 years [2]. Most patients initially receive chemotherapy with 5-fluorouracil (5-FU), leucovorin, and either oxaliplatin (FOLFOX regimen) or irinotecan (FOLFIRI regimen) [3]. FOLFOX and FOLFIRI have equivalent efficacy in the metastatic setting, provided that patients eventually receive the alternate regimen following disease progression [3, 4]. The addition of VEGF-targeting agents to either FOLFOX or FOLFIRI can improve overall survival (OS) [5–7], and patients with KRAS wild-type (wt) tumors benefit from the addition of anti-EGFR antibody therapy [8, 9]. More than 20% of patients have metastatic disease at the time of diagnosis, and more than one-third of patients with colorectal cancer eventually develop metastases [10]. The majority of patients with metastatic colorectal cancer cannot be cured and receive palliative treatments; however, 10%–20% of patients with metastatic disease (specifically those with metastases limited to the liver) may be candidates for potentially curative surgical resection either at presentation or after a favorable response to chemotherapy [11].In an attempt to improve response rates, to convert patients into candidates for surgical resection, and to increase survival, Italian investigators compared the regimen of 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI) with FOLFIRI in patients with unresectable metastatic colorectal cancer [12]. FOLFOXIRI consists of 5-FU administered as a 48-hour continuous infusion to a total dose of 3,200 mg/m² without a bolus, leucovorin 200 mg/m², irinotecan 165 mg/m², and oxaliplatin 85 mg/m² (5]. Consequently, the same Italian investigators recently compared FOLFOXIRI plus bevacizumab with FOLFIRI plus bevacizumab (the Treating Patients with Metastatic Colorectal Cancer [TRIBE] trial) [13]. FOLFOXIRI plus bevacizumab, compared with FOLFIRI plus bevacizumab, resulted in significantly higher RRs (65% vs. 53%) and PFS (median: 12.1 vs. 9.7 months). Initially, the survival advantage failed to meet statistical significance (median: 31.0 vs. 25.8 months), but updated results demonstrate a significant survival advantage (median: 29.8 vs. 25.8 months) for the TRIBE regimen [14]. Notably, secondary complete (R0) liver resection rates (15% vs. 12%) did not differ between treatment groups. Additionally, patients who received FOLFOXIRI/bevacizumab experienced higher rates of neutropenia, diarrhea, stomatitis, and peripheral neuropathy. Given these findings, should physicians caring for patients with metastatic colorectal cancer adopt the FOLFOXIRI/bevacizumab regimen as a standard first line therapy?

Table 1.

Dosing of FOLFOXIRI compared with FOLFIRINOXOpen in a separate windowWhen considering whether FOLFOXIRI/bevacizumab is the optimal regimen for patients with metastatic colorectal cancer, the following concerns with the TRIBE trial merit discussion: (a) OS and PFS benefits in clinical trials of first line therapies are difficult to interpret, considering that other, unmeasured factors after the initial progression may influence OS; (b) the lack of genotyping and imbalance in right-sided colon cancers; and (c) the general applicability of the results to all patients with metastatic colorectal cancer. Using PFS as the primary endpoint in metastatic colorectal cancer trials seemed to be appropriate in the first-line setting when this study was started, but it is becoming evident that the PFS endpoint is problematic. Longer PFS does not always correspond with improved survival or quality of life (QOL) [15]. Furthermore, PFS is an imprecise endpoint, subject to clinical judgment, monitoring frequency, and measurement bias. And most importantly, patients’ underlying disease biology and the subsequent treatment they receive may ultimately determine their OS [16–18]. Multiple factors in the setting of metastatic colorectal cancer can influence survival after progression on first-line therapy, such as (a) continued use of bevacizumab or aflibercept in second line, (b) use of anti-EGFR antibodies in patients with KRAS wt disease, (c) the use of regorafenib, and (d) the toxicity of first-line therapy preventing the delivery of subsequent lines of therapy. As is often standard practice, the TRIBE trial investigators did not control for therapy after progression on first-line treatment. Additionally, they did not systematically collect data on patients’ subsequent lines of therapy, and did not collect QOL data. All of these questions raise the possibility that even OS cannot be trusted as a reliable endpoint for determining the best first-line therapy in patients with metastatic colorectal cancer.A second concern is the lack of data regarding tumor mutational status, particularly in a study in which the arms were not well balanced regarding the site of primary tumor. Tumors with BRAF mutations are usually right-sided and can behave more aggressively than BRAF wt tumors. Notably, more patients in the experimental arm had right-sided tumors. In addition, the lack of knowledge regarding KRAS status draws into question whether subsequent anti-EGFR antibody therapy was used appropriately. The phase III FIRE-3 trial compared FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab as first-line treatment in patients with KRAS wt colorectal cancer [17]. Although RR and PFS did not differ between treatment groups, patients treated with FOLFIRI plus cetuximab experienced longer median OS (28.7 vs. 25.0 months). In contrast, results from the US Intergroup trial 80405 demonstrated no advantage for first-line cetuximab over bevacizumab when added to either FOLFOX or FOLFIRI (oncologist’s choice) [18]. Nevertheless, both groups experienced median survival of more than 29 months and PFS of more than 10 months, demonstrating the importance of anti-EGFR antibody therapy in appropriately selected patients. Thus, knowledge of tumor mutational status and subsequent use of anti-EGFR antibody therapy is critically important when evaluating trials involving patients with metastatic colorectal cancer.Finally, the TRIBE trial excluded patients over age 75 and only allowed patients over age 70 who did not have performance status limitations. These restrictions reflect concerns about the tolerability of this regimen because the investigators did not want to compromise the feasibility of using FOLFOXIRI plus bevacizumab. Elderly patients are commonly underrepresented in clinical trials [19], and by excluding these patients, investigators limit the generalizability of the data to a large proportion of colorectal cancer patients, given that the median age at diagnosis is 68 years [20].Interestingly, FOLFOXIRI/bevacizumab did not benefit patients who received prior adjuvant treatments or those seeking a surgical resection. While the TRIBE trial was not specifically designed to answer the question of whether more patients with metastatic disease could be brought to a potentially curative resection, it remains the most compelling indication for this more aggressive regimen. Without an improvement in R0 liver resection rates, the results of the TRIBE trial do not support the use of FOLFOXIRI/bevacizumab as a means of converting patients to resection candidates. Additionally, FOLFOXIRI/bevacizumab did not benefit patients who received prior adjuvant chemotherapy, perhaps related to the development of chemoresistance [23, 24].The TRIBE trial demonstrates several emerging principles in clinical trial design for initial treatment of metastatic colorectal cancer. First, the challenge of interpreting PFS and OS benefits with first-line therapy makes drug approval and the establishment of a “standard” in the first-line setting increasingly difficult. Second, mutational analysis is critical for understanding efficacy results in colorectal cancer clinical trials and this should be incorporated into all future clinical trials. Lastly, our ability to influence surgical resectability is limited and may have more to do with the underlying biology of the cancer and the presence of multi-organ metastases than any response to a specific therapy. FOLFOXIRI plus bevacizumab is an acceptable therapeutic option, but whether it is the best choice for our patients is still a matter of debate.     

A Review on the Scope of Photothermal Therapy–Based Nanomedicines in Preclinical Models of Colorectal Cancer

Oncologic thermal ablation involves the use of hyperthermic temperatures to damage and treat solid cancers. Thermal ablation is being investigated as a method of treatment in colorectal cancers and has the potential to complement conventional anticancer treatments in managing local recurrence and metastatic disease. Photothermal therapy utilizes photosensitive agents to generate local heat and induce thermal ablation. There is growing interest in developing nanotechnology platforms to deliver such photosensitive agents. An advantage of nanomedicines is their multifunctionality, with the capability to deliver combinations of chemotherapeutics and cancer-imaging agents. To date, there have been no clinical studies evaluating photothermal therapy–based nanomedicines in colorectal cancers. This review presents the current scope of preclinical studies, investigating nanomedicines that have been developed for delivering multimodal photothermal therapy to colorectal cancers, with an emphasis on potential clinical applications.     

Localization of PKCη in Cell Membranes as a Predictor for Breast Cancer Response to Treatment

Background: Successful treatment of breast cancer is frequently limited by the resistance of tumors to chemotherapy. Recent studies suggested a role for protein kinase C (PKC) in the resistance to chemotherapy. Here we used retrospective analysis of breast cancer biopsies of neoadjuvantly treated patients to investigate the correlation of PKC expression with aggressiveness and resistance to chemotherapy. Patients and Methods: Our cohort (n = 25) included patients with advanced and aggressive breast cancers, who underwent neoadjuvant therapy with the CAF regimen (cyclophosphamide, doxorubicin, fluorouracil). Core biopsies (pre-chemotherapy) and surgical biopsies of primary tumors and lymph node metastases (post-chemotherapy) were scored for PKCeta (PKCh) and PKCepsilon (PKCe) expression in the cytoplasm, cell membrane, nuclear membrane, and the nucleus. Results: Our results showed increased expression of PKCh (not PKCe) in the cytoplasm and cell membranes of post-chemotherapy biopsies (p = 0.03). PKCh presence in cell membranes, indicating activation, was in correlation with poor survival (p = 0.007). Conclusion: PKCh staining in cell and nuclear membranes is an indicator for poor survival and a predictor for the effectiveness of neoadjuvant treatment. Other avenues of treatment should be considered for these patients. PKCh presents a target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.     

Patterns of Use and Tolerance of Anti–Epidermal Growth Factor Receptor Antibodies in Older Adults With Metastatic Colorectal Cancer

BackgroundLimited data are available regarding the tolerance of anti–epidermal growth factor receptor (EGFR) antibodies among elderly patients with metastatic colorectal cancer (mCRC). We retrospectively reviewed our experience of treating elderly patients with mCRC with these agents between 2004 and 2011.MethodsPatients with mCRC ≥ 65 years treated with anti-EGFR agents were included in this analysis. We recorded demographic and disease characteristics, treatment regimen and duration, KRAS status, and overall survival (OS). Toxicity evaluation included common hematologic and nonhematologic toxicities seen with these agents.ResultsOne hundred seventeen patients were included, with a median age at treatment initiation of 73 years (range, 65-86 years), 59% of male sex, 82% with colon primary tumors, and 51% with metastatic disease at presentation. Median time on anti-EGFR treatment was 2.4 months. Older age at treatment initiation was associated with use of anti-EGFR antibody as monotherapy versus combination therapy (P = .0009). Worse performance status (PS) at treatment initiation was associated with a shorter overall survival (OS) (P = .013) and shorter treatment duration (P = .01). The incidence of hematologic/nonhematologic grade ≥ 3 was 36% and 15%, respectively. No association was found between age and presence of grade ≥ 3 toxicity. Longer treatment duration and better PS at treatment initiation were the only factors associated with higher incidence of grade 3 toxicity.ConclusionOur data demonstrate that anti-EGFR antibodies can be used in older patients with mCRC, with toxicity profiles similar to those reported in large phase III studies of younger patients. Advanced age was associated with receipt of anti-EGFR agents as monotherapy but did not impact treatment outcomes in this population.     

Skin Rash During Cetuximab Treatment in Advanced Colorectal Cancer: is Age a Clinical Predictor?

Purpose

The aim of this study is to evaluate the intensity and the duration of skin rash in young and elderly patients treated with cetuximab for advanced colorectal cancer, in order to define a possible relationship between age and skin toxicity.

Methods

We retrospectively analyzed all consecutive patients with advanced colorectal cancer who developed skin rash during cetuximab treatment at the Clinical Oncology Unit from June 2006 to May 2011. We divided the general case study into two subgroups: young and elderly patients (≥65 years old), and we compared clinical, pathological, and therapeutical characteristics of both subgroups.

Results

Among the 31 patients affected by advanced colorectal cancer (64.5 % with colon cancer and 35.5 % with rectal cancer) treated with cetuximab, 19 patients (61.3 %) developed skin toxicities: seven patients (36.8 %) had grade 1 skin rash, nine patients (47.4 %) had grade 2, three patients (15.8 %) had grade 3, and no grade 4 was found. Ten (52.6 %) out of 19 patients were elderly (>65 years). Concerning skin rash, grading was substantially comparable between the two subgroups, but median duration of skin rash was higher in the first subgroup for all grades. The univariate analysis showed no statistical significant difference in overall survival between young and elderly patients (p?=?0.171), such as age that does not seem to statistically influence the appearance (p?=?0.386), duration (p?=?0.455), and grade of skin rash (p?=?0.765).

Conclusions

Age is an insufficient predictor of skin toxicity during cetuximab treatment in advanced colorectal cancer and does not seem to statistically influence the appearance, duration, and grade of skin rash.     

Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group

Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.     

Analyses of Multiple Factors for Determination of “Selected Patients” Who Should Receive Rechallenge Treatment in Metastatic Colorectal Cancer: a Retrospective Study from Turkey

Background: Repeating a prior chemotherapy (rechallenge therapy) is an option for selected patients withmetastatic colorectal cancer, but there is very little evidence in the literature for this approach. Thus, we reviewedour registry to evaluate prognostic factors and survival of patients who received irinotecan and oxaliplatinbasedregimens as rechallenge third and fourth-line therapy. Materials and Methods: Patients who receivedirinotecan-based or oxaliplatin-base regimen as first-line had been rechallenged with third-line or fourth-linetherapy. These patients were selected from the database of Turkish mCRC registry archives between October2006 and June 2013 and evaluated retrospectively for factors effecting progression free survival (PFS) and overallsurvival (OS) by the Kaplan-Meire and Cox-regression methods. Results: Thirty-nine patients were enrolled. Themedian duration of follow-up was 36 months (14-68 months). Thirty-one patients (76%) died during follow-up.In terms of rechallenge treatments, 29 patients had received third-line and 10 patients had received fourth-line.Response rate (RR) was found to be 12.9%, with stable disease in 19 (48.7%) patients. The median PFS was 6months (95%CI=4.64-7.35 months) and the median OS was 11 months (95%CI=8.31-13.68 months). The factorseffecting survival (PFS and OS) were only being PFS after first-line chemotherapy ≥12 months (p=0.007, 95%CI=1.75-35.22 and p=0.004, 95%CI=1.44-7.11), both in univariate and multivariate analyses. Conclusions: Thisstudy indicates that rechallenge treatment could be a good option as a third or later line therapy in patients whohad ≥12 months PFS onreceiving first line therapy.     

Previous Bevacizumab and Efficacy of Later Anti–Epidermal Growth Factor Receptor Antibodies in Metastatic Colorectal Cancer: Results From a Large International Registry

Background

The FIRE-3 [5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment colorectal cancer (CRC)] study reported that first-line FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab resulted in similar progression-free survival (PFS) but improved overall survival (OS). A potential explanation is that the initial biologic agent administered in metastatic CRC (mCRC) affects later line efficacy of the other treatments. We sought to test this hypothesis.

Considering Efficacy and Cost,Where Does Ramucirumab Fit in the Management of Metastatic Colorectal Cancer?

Health care institutions, physicians, and patients can—and should—be more involved in evaluating the role of new therapies such as ramucirumab in metastatic colorectal cancer based on their value. This is especially true in the case of a treatment that adds no additional benefit in terms of efficacy or toxicity compared with the current standard of care and has a higher cost.Ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR2) recently gained approval by the U.S. Food and Drug Administration (FDA) for use in gastric and lung cancer [1–3]. Based on safety and efficacy, it was subsequently approved in April 2015 by the FDA for use in metastatic colorectal cancer.The RAISE trial, a randomized phase III trial, confirmed the benefit from ramucirumab in colorectal cancer after progression on bevacizumab, oxaliplatin, and a fluoropyrimidine [4]. A total of 1,072 patients with metastatic colorectal cancer who had progressed on FOLFOX plus bevacizumab were randomized to receive either FOLFIRI plus ramucirumab or FOLFIRI plus placebo. The trial demonstrated a median overall survival (OS) benefit of 1.6 months (hazard ratio [HR]: 0.84) with the use of ramucirumab.The control arm of the study (FOLFIRI) is not the current standard of care in the U.S. The ML18147 trial previously demonstrated a median OS benefit of 1.4 months (HR: 0.81) when bevacizumab was continued beyond progression in combination with second-line 5-fluorouracil-based chemotherapy [5]. The VELOUR study previously demonstrated a median OS benefit of 1.4 months (HR: 0.82) when ziv-aflibercept was added to second-line FOLFIRI [6]. In addition to the antiangiogenic therapeutic options, patients whose tumors are RAS wild type are also eligible for EGFR-targeted therapy in combination with standard chemotherapy in this setting [7–12].Oncologists now have three options for antiangiogenic agents that can be added to the chemotherapy backbone in patients with colorectal cancer refractory to FOLFOX plus bevacizumab. Although all three agents have not been compared in a head-to-head trial, they appear to have similar efficacy and toxicity profiles in randomized trials. If cost is incorporated into the decision-making process, there are major differences. We have made calculations of the monthly drug cost using a mean U.S. body weight of 82 kg [13]. We used the Medicare average sale price to calculate the monthly costs of each drug [14]. Open in a separate windowWe propose that there are two types of low-value cancer treatments. Type 1 is a new therapy that has a statistically significant but clinically modest benefit at a high cost. In this scenario, the precise value can be formally determined by a cost-effectiveness analysis. If the incremental cost-effectiveness ratio is above a certain threshold, the treatment can be described as a low-value treatment. Type 2 is a treatment that adds no additional benefit in terms of efficacy or toxicity compared with the current standard of care options and has a higher cost. In this situation, a formal cost-effectiveness analysis is not required. A perfect example is ziv-aflibercept in the second-line setting of metastatic colorectal cancer. In 2012, ziv-aflibercept was approved by the FDA, and the drug price was significantly higher than bevacizumab. At that time, there was a public protest by physicians at Memorial Sloan Kettering Cancer Center [15], and the price was subsequently decreased by the manufacturer. Ramucirumab in metastatic colorectal cancer falls into the second category of a low-value treatment.Health care cost is a huge social and economic challenge in the U.S. Drug costs represent a sizable portion of health care costs. Unfortunately, at this time, there is no formal process to regulate the cost of new therapeutic agents and to ensure that the cost justifies the added benefit of new therapies. The FDA evaluates clinical trial data regarding safety and efficacy of a drug prior to granting approval. The FDA has no mandate to consider the cost of a drug prior to approval. Furthermore, Medicare is prevented from negotiating the cost of a drug with pharmaceutical companies as a result of the Medicare Modernization Act of 2003. Both policy makers and physicians in the U.S. usually are not willing to deny a particular treatment in the case of a type 1 low-value treatment. Policy makers are reluctant to address this issue to avoid criticism relating to rationing of care. Physicians consider their prime objective to be bringing the best possible care to their patients regardless of cost. In the case of a type 2 low-value treatment, however, both policy makers and physicians should be willing to deny such a therapy, given the presence of comparable and cheaper alternatives. At our institution, ramucirumab is currently on the formulary for use in advanced gastric cancer. The gastrointestinal oncology group has decided not to use ramucirumab for colorectal cancer at the current price. In our opinion, health care institutions, physicians, and patients can—and should—be more involved in evaluating the role of new therapies based on their value, especially in the case of a type 2 low-value treatment.     

High-Intensity Focused Ultrasound in the Treatment of Hepatic Metastases from Colorectal Cancer of 18 Patients

OBJECTIVE To evaluate the safety and effectiveness of treatment of hepatic metastases from colorectal cancer using high-intensity focused ultrasound (HIFU). METHODS Thirty-one lesions in 18 patients with hepatic metastases from colorectal cancer after colectomy were treated with HIFU therapy. The vital signs, function of the vital organs, complications and pathological outcome were studied using imaging examinations such as CT or MRI. RESULTS The vital signs of all patients remained stable and their liver and kidney functions normal. Two of the 18 patients were not followed-up. After a mean follow-up of 16.1 months (6-38 months), 13 survived. The survival rates at the 12th and 18th months were 83.3% and 66.7%, respectively. The median survival rate was 16 months. Among the 25 lesions followed-up, 17 shrank over 50%, 5 grew new metastases and superficial degree II skin injury occurred in 8. CONCLUSION HIFU is a safe, effective and non-invasive option for the treatment of hepatic metastases from colorectal cancer.     

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand–Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Background

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.