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Colorectal Cancer: Perspective on recent advances

Rajath Govind 1,Pooja Sethi 2, Smita Kayal1

1Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.

2Department of Radiation Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India

Dr. Smita Kayal

Department of Medical Oncology, Regional Cancer Centre, JIPMER, Dhanvantari Nagar, Puducherry-605006, India,

Tel: 0413-2297308, +917598118439

Email: kayalsmita@gmail.com

ORCID ID: 0000-0001-7275-7377

Globally, colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality. One of the emerging and worrisome trends is the rising incidence rate among young adults. Advances in understanding disease biology, tools for early detection, optimization of primary treatment, novel approaches as targeted drugs, biologicals and immunotherapy have led to a steady though modest decline in mortality rates over past few decades. In this update, we highlight some of the latest research in CRCpresented and/or published in 2020, in the midst of the challenges posed by the COVID-19 pandemic, that show a promising future for the patients as well physicians managing this common cancer.

Screening for colorectal cancer

In February 2020, the U.S. Multisociety Task Force (USMSTF) on CRC reviewed their older 2012 recommendations and provided an updated schedule for follow-up colonoscopy following a patient's initial high-quality exam. MSTF experts provided a timeline for patients to be rechecked for CRC based on their initial colonoscopy and also gave recommendations for physicians to apply the safest and most effective techniques to completely remove polyps.[1]

In October 2020, the U.S. Preventive Services Task Force posted a draft recommendation statement on screening for CRC, for the first-time recommending screening to start at the age of 45 (Grade B recommendation)[2], based on several recent reports consistently demonstrating a rising incidence and shift in the CRC burden to individuals younger than 50. Review of this revised guideline for screening is still in progress and expected to be released this year. A meta-analysis published in August 2020 by Zhnag et al., showed that colonoscopy was associated with a 52% relative risk (RR) reduction in incidence of CRC (RR: 0.48, 95% CI: 0.46–0.49) and 62% RR reduction in mortality of CRC (RR: 0.38, 95% CI: 0.36–0.40)[3].

Community based or organized screening is non-existent in India. Even though the incidence is rising especially in the younger population, given the relatively low incidence rates (age adjusted incidence, AAR of 6.6-7.3 per 100,000) compared to the western countries, benefits of a screening program will be very marginal and not clinically meaningful.

Early-Stage CRC

We know that the most powerful prognostic tool for CRC following potentially curative surgery are pathological factors in the resected specimen and stage. Several other clinical, histologic, molecular factors, including gene expression profiling signatures (Oncotype DX Colon Cancer Assay), have been shown to influence prognosis. However, there is significant variability in the test methodology, conflicting results from studies, and lack of validation and conclusive data,and hence most of these markers are not incorporated into clinical stratification systems in practice. In the last American society of clinical oncology (ASCO) and European society for medical oncology(ESMO), two novel approaches have been proposed to predict CRC recurrence risk and once validated can become useful tools for prognostication in clinics.

New clinical calculator may predict recurrence risk after curative surgery for colon cancer[4]

From Memorial Sloan Kettering Cancer Center (MSK), Weiser et al., have developed a "third-generation" clinical calculator which integrates molecular and clinicopathologic characteristics to provide an accurate prediction of disease recurrence following curative surgery of stage I to III colon cancer. The calculator was developed using prospective data from 1,095 patients who underwent colectomy between 2007 and 2014;among whom, 120 experienced disease recurrence, with a 5-year freedom from recurrence rate of 85%. The final clinical calculator incorporated six variables: microsatellite genomic phenotype; American joint committee on cancer (AJCC)T category; number of tumor-involved lymph nodes; presence of high-risk pathologic features such as venous, lymphatic, or perineural invasion; presence of tumor-infiltrating lymphocytes; and use of adjuvant chemotherapy. Among 299 patients in the external validation cohort, 46 experienced disease recurrence, with a 5-year freedom from recurrence rate of 80%; concordance index was 0.738 (95% CI = 0.703–0.811). The investigators concluded, “this third-generation calculator successfully incorporates microsatellite genomic phenotype and the presence of tumor-infiltrating lymphocytes, resulting in improved predictive accuracy. This exemplifies evolution of a clinical calculator to maintain relevance by incorporating emerging variables as they become validated and accepted.”

Performance of Immunoscore in Asian patients with early-stage colon cancer[5]

Immunoscore® is an in vitro diagnostic test predicting the risk of relapse in early-stage CRC by measuring the host immune response at the tumor site in terms of densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin by immunohistochemistry (IHC) and digital pathology. This risk-assessment tool provides independent and superior prognostic value than the usual risk parameters as was shown in the SITC (Society for Immunotherapy in Cancer) led validation study published in the Lancet 2018. In the present study, the authors have investigated Immunoscore® clinical performance in the Asian population from the international SITC-led validation study. Out of the 2681 eligible stage I-III patients of the international Immunoscore® study, 423 were collected from four expert centres in Asia including Japan (n=330), China (n=35), and India (n=58). Immunoscore® Low and High were observed in 37% and 63% of the Asian cohort, respectively. Immunoscore® was positively and significantly correlated with TTR. At five years, 87% (95% CI = 82.7%–91.4%) of Immunoscore high patients were event-free compared to 77% (95% CI 70.5%–84.1%) of Immunoscore low (HR = 0.52, 95% CI = 0.32–0.86, P = .0085).It was concluded that Immunoscore® is a strong prognostic indicator of the risk of recurrence in stage I-III CRCafter standard of care treatment in real-life clinical practice in Asia.

This IHC based scoring system seems promising, can be incorporated into clinical practice and can help in designing future trials of adjuvant therapy, however, in the Indian setting, the challenge being lack of availability of digital pathology platform in majority of centres.

Adjuvant therapy for Colon Cancer

Historically, and until very recently, the standard adjuvant chemotherapy for CRC after colectomy have been six months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) in stage III CRC and fluoropyrimidine monotherapy in high risk stage II disease. Results from the IDEA collaboration studies have redefined the duration of adjuvant chemotherapy in CRC, updated results in high-risk stage II and stage III CRC are discussed below.

Duration of adjuvant doublet for high-risk stage II CRC: Three vs. six months – IDEA results[6]

In an analysis of data from the IDEA collaboration, Iveson, et al., found that three months (vs.six months) of adjuvant CAPOX may be a potential treatment option for patients with high-risk stage II CRC.

The analysis included data from four of six trials in the IDEA collaboration that included patients with high-risk stage II CRC. Per physician or patient choice, patients received adjuvant therapy with either FOLFOX or CAPOX. They were randomly assigned to threevs.six months of treatment between 2007 and 2017. The primary endpoint was disease-free survival (DFS), with non-inferiority of 3-month treatment defined as a hazard ratio (HR) of < 1.2 vs. 6-month treatment. 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. Median follow-up at time of analysis in December 2018 was 60.2 months. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; p [for non-inferiority] 0.39). This crossed the non-inferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). Data showed worse outcomes among patients with stage T4 or with two or more risk factors. Overall, patients receiving six months of treatment had a significantly higher rate of adverse events (AEs), particularly diarrhea, peripheral neuropathy (grade ≥ 2 in 36% vs. 13%), hand-foot syndrome, and mucositis.

The investigators concluded, “Although non-inferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.”

Patients with stage II colon cancer represent a heterogeneous group. Results from the MOSAIC trial had shown that addition of oxaliplatin to fluoropyrimidine did not improve overall survival (OS) for patients with high-risk stage II CRC though disease free survival (DFS) was improved. Four of the six studies in the IDEA collaboration included patients with high-risk stage II disease as these studies were conceived before the OS results of MOSAIC were known. More recent data suggests that in stage II disease, only patients with proficient mismatch repair benefit from fluoropyrimidine monotherapy in the adjuvant setting. A limitation to the study was absence of micro satellite instability (MSI) data. Thus, the results of the IDEA collaboration on duration of adjuvant chemotherapy in high-risk stage II CRC only apply to patients receiving an oxaliplatin and fluoropyrimidine doublet (patients with either T4 and/or more than two risk factors could be considered for combination treatment). If patients with high-risk stage II receive single-agent fluoropyrimidine treatment such as capecitabine, we have to recommend the current standard duration of six months.

Duration of adjuvant doublet for high-risk stage III CRC: Three vssix months – IDEA results[7]

As reported in the Lancet Oncology by André et al., the prospective pooled analysis of six phase III trials in the IDEA collaboration has shown that non-inferiority in OS for three versussix months of adjuvant chemotherapy was not established in patients with stage III colon cancer, but the absolute difference in 5-year OSwas only 0.4% which has to be placed in clinical context.

The analysis included patients with stage III colon cancer, recruited between 2007 and 2015 in 12 countries in one of the sixtrials of IDEA collaboration who started any treatment (modified intention-to-treat population).Patients in all trials were randomly assigned to three or six months of adjuvant FOLFOX every two weeks or CAPOX every three weeks, as chosen by the treating physician. The primary endpoint was DFS, with OS being the prespecified secondary endpoint. The non-inferiority margin for OS was set as a HR of 1.11. Pre-planned subgroup analyses included analysis by regimen and by risk group. Non-inferiority was demonstrated if the one-sided false discovery rate adjusted (FDRadj) P value was < 0.025. The analysis included 12,835 patients, with 39.5% receiving CAPOX, 60.5% receiving FOLFOX, and 6,425 receiving 3-month and 6,410 receiving 6-month regimens. Median follow-up was 72.3 months. Among all patients, the 5-year OS was 82.4% (95% CI = 81.4%–83.3%) with three months of therapy versus 82.8% (95% CI = 81.8%–83.8%) with six months of therapy (HR = 1.02, 95% CI = 0.95–1.11; non-inferiority FDRadj P = 0.058). The absolute difference in 5-year OS was 0.4%.

Among patients receiving CAPOX, the 5-year OS was 82.1% in the 3-month group vs 81.2% in the 6-month group (HR = 0.96, 95% CI = 0.85–1.08;FDRadj P = .033), absolute difference in 5-year OS was 0.9%.Among patients receiving FOLFOX, the 5-year OS was 82.6% in the 3-month group versus 83.8% in the 6-month group (HR = 1.07, 95% CI = 0.97–1.18; FDRadj P =.34), absolute difference in 5-year OS was 1.2%.Among patients with low-risk disease (T1, T2, or T3 and N1), the 5-year OS was 89.6% vs 88.9% (HR = 0.95, 95% CI = 0.84–1.08; FDRadj P = .033). Among patients with high-risk disease (T4, N2, or both), the 5-year OS was 72.0% vs. 74.1% (HR = 1.08, 95% CI = 0.98–1.19; FDRadj P = 0.39). In total, for all patients included, the 5-year OS was 89.3% in the low-risk group and 73.1% in the high-risk group.HR for updated 5-year DFS for the 3-month vs. 6-month groups among all patients was 1.08 (95% CI = 1.02–1.15; FDRadj P = 0.25). Among patients receiving CAPOX, HR was 0.98 (95% CI = 0.88–1.08; FDRadj P = 0.027). Among those receiving FOLFOX, HR was 1.16 (95% CI = 1.07–1.26; FDRadj P = 0.80). For low-risk versus high-risk patients, the 5-year DFS was 78.5% vs 57.7%.Data on AEs were not recorded beyond the initial primary analysis. Analysis at that time showed that grade ≥ 2 neurotoxicity during active therapy and in the first month after stopping study treatment occurred in 16% in the 3-month group vs. 44.5% of those in the 6-month group.

The investigators concluded: “Non-inferiority of threeversussix months of adjuvant chemotherapy in stage III colon cancer was not confirmed in terms of OS, but the absolute 0.4% difference in 5-year OS should be placed in clinical context. Overall survival results support the use of six months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, especially neurotoxicity, and cost associated with a shorter treatment duration.”

For practice, the overall results support the use of three months of adjuvant CAPOX as the standard for most patients with stage III colon cancer. The final decision on treatment duration and regimen used for each individual should depend on a careful discussion between the clinician and patient, taking into account the risk of recurrence, co-morbidity, patient’s wishes, likely absolute difference in survival, and risk of long-term toxicity.

Metastatic Colorectal Cancer

Over the past two decades, with the advent of monoclonal antibodies, targeted agents, and more recently immunotherapy with checkpoint inhibitors, the median survival for metastatic CRC (mCRC) have moved from 12 months to 30 - 36 months. Some recent advances in the treatment of mCRC in 2020 are summarized here.

Keynote – 177: Pembrolizumab in MSI high mCRC in first line[8]

The phase III KEYNOTE-177 study demonstrated that front-line therapy with the immune checkpoint inhibitor pembrolizumab doubled the PFS versus standard of care chemotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC.

The study included 307 patients with MSI-H or dMMR mCRC. Patients were randomly assigned to receive either first-line pembrolizumab for up to two years or the investigator’s choice of six different standard chemotherapy regimens with or without monoclonal antibodies, selected prior to randomization. At 12 and 24 months follow up, PFS was 55.3% and 48.3%, respectively, with pembrolizumab versus 37.3% and 18.6% with chemotherapy. The overall response rate (ORR) was also better with pembrolizumab as well, 43.8% compared with 33.1% for chemotherapy. Response with pembrolizumab was also durable, with 83% patients having a response longer than two years, compared with 35% receiving chemotherapy.Severe treatment-related AEs ≥ grade-3, were also less common with pembrolizumab than chemotherapy (22% vs. 66%). However, profile of toxicities was very different between both groups, with immune-mediated AEs observed with pembrolizumab (colitis and hepatitis) and the most frequent toxicities observed with chemotherapy being diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia, and neurotoxicity. Patients were allowed to cross over at progression to the pembrolizumab group. The study will continue to evaluate OS.

Overall, patients with MSI-H represent 5% of all patients with mCRC, generally are associated with decreased survival rates, and these patients also tend to be less responsive to conventional chemotherapy. The data presented have the potential to change the standard of care for this subset of patients, cost effectiveness needs to be evaluated in the Indian context.

DESTINY_CRC01[9] Trastuzumab deruxtecan(T-DXd; DS-8201) in human epidermal growth factor receptor (HER-2) expressing mCRC. In the open-label, multicenter, phase 2 trial, investigators enrolled patients with HER2-expressing, Rat sarcoma(RAS)/B-rapidly activating fibrosarcoma(BRAF) wild-type, unresectable, and/or metastatic CRC, who had previously received two or more lines of treatment. Prior anti-HER2 therapies was permitted, patients with interstitial lung disease (ILD) were ineligible for enrolment.Trastuzumab deruxtecan was administered at 6.4 mg/kg intravenously every three weeks until either disease progression or unacceptable toxicity. Cohort A comprised of 53 patients with HER2-positive disease as defined by IHC 3+ or IHC 2+. Cohort B included seven patients with HER2-positive and FISH negative tumors. Cohort C enrolled 18 patients with HER2-positive by IHC 1+. Nearly 90% of patients’ primary tumors were located in their left intestine, including the rectum. Most patients (98.7%) had RAS and BRAF wild-type disease. In cohort A, all patients also received cetuximab or panitumumab, and one-third of patients received prior anti-HER2 agents. Results showed a confirmed ORR of 45.3% (n = 24/53) in cohort A; CR 1 and PR for 23 patients. No confirmed responses were reported in cohorts B or C.Analysis of responses by predefined subgroups revealed that only HER2 status IHC 3+ versus IHC 2+/ISH+ discriminates better responses with trastuzumab deruxtecan, with an ORR of 57.5% versus 7.7%.Median PFS was 6.9 months in cohort A (95% CI, 4.1-NE) and the median OS was not yet reached in any cohort (overall 95% CI, 0.74—NE).AEs were observed in 96.2% (grade ≥ 3 in 60%) of patients in cohort A and 93.6% (grade ≥ 3 in 61.5%) in the overall patient population.

Based on the data from DESTINY-CRC01, trastuzumab deruxtecan, demonstrated promising and durable activity in patients with HER2-positive mCRC refractory to standard therapies.

Phase II (SWOG S1406) trial: addition of vemurafenib to irinotecan/cetuximab in BRAF mutated mCRC[10]

The addition of vemurafenib to irinotecan and cetuximab led to a significant improvement in PFS versus irinotecan and cetuximab alone in patients with BRAF V600E–mutated mCRC, according to the results of the SWOG S1406 study.

Eligible patients had metastatic, or locally advanced, or unresectable, BRAF V600E mutated adenocarcinoma of the colon or rectum; Neuroblastoma-RAS (NRAS) or Kirsten-RAS (KRAS) wild type. Patients were allowed one to two prior lines of chemotherapy for metastatic disease prior to enrolment, but previous treatment with epidermal growth factor receptor (EGFR), BRAF, or Mitogen-activated protein kinase (MEK) inhibitors was not permitted. In the open-label phase two study, patients were randomized 1:1 to receive either the triplet or doublet regimen. Both cohorts were administered 180 mg/m2 of irinotecan and 500 mg/m2 of cetuximab intravenously every two weeks and oral vemurafenib (960 mg daily) in the triplet arm. Primary end point was PFS; key secondary outcomes included toxicity, OS, ORR. Median PFS was 4.2 months with the triplet versus twomonths with the doublet (HR, 0.50; 95% CI, 0.32-0.76; p = .001). The triplet regimen also elicited higher response rate compared with the doublet regimen, at 17% and 4%, respectively (p= .05). The disease control rates in the experimental and control arms were 65% and 21%, respectively. No significant difference in OS was observed between the two arms (HR, 0.77; 95% CI, 0.50-1.18; p = 0.23). Regarding safety, grade 3/4 AEs were more frequent in the triplet arm compared with the doublet; toxicities included neutropenia (30% vs. 7%), anemia (13% vs. 0%), and nausea (19% vs. 2%), respectively. Other exploratory analysis was done with respect to PIK3CA mutations, MSI status and circulating tumor DNA.

Preclinical data have suggested that irinotecan may augment the activity of BRAF and EGFR inhibitors. Early findings led to a phase 1b study of vemurafenib, cetuximab, and irinotecan, in which the triplet demonstrated a response rate of 35%, as well as a promising PFS benefit. SWOG 1406 trial reinstated the benefit of this active triplet combination in improving PFS. This represents a rationally designed combination based on understanding of the mechanisms of adaptive resistance in CRC.

BEACON trial: [11] FDA announced in April 2020 that the combination of encorafenib and cetuximab (doublet) was approved for the treatment of adult patients with mCRC with a BRAF V600E mutation detected by an FDA-approved test after prior therapy.This approval is based on updated results from the BEACON trial. Preliminary result from the BEACON study have shown for the first time that a combination of three targeted agents (triplet) —encorafenib(BRAF inhibitor), cetuximab(EGFR inhibitor) and binimetinib(MEK inhibitor)—leads to improved outcomes for patients with mCRC positive for the BRAF V600E mutation who have failed first-line treatment. In updated results based on 444 patients randomised in the phase III study, the triplet had identical median OS as for doublet (9.3 months in both the groups compared to 5.9 months in the chemotherapy control group). PFS was comparable, at 4.5 months with the triplet and 4.3 months with the doublet, compared to just 1.5 months in the control arm. Triplet therapy had higher rates of gastrointestinal (GI) toxicity and anemia, which was not seen with the doublet thus also providing toxicity advantage for doublet.

BRAF mutations occur in approximately 5-10% of mCRC. It’s been well-established that patients with BRAF-V600E mutations, typically have worse outcomes compared to those without the mutation. These results provide a promising chemotherapy free therapeutic options for this subset of high-risk disease.

Japanese phase III trial (JCOG1007; iPACS): addition of primary tumor resection to chemotherapy for asymptomatic primary CRC and synchronous unresectable metastases[12]

Kanemitsu and colleagues devised the randomized phase III iPACS trial, conducted at 38 treatment centers in Japan, to prospectively compare the two strategies.Chemotherapy options in iPACS included either mFOLFOX6 or CAPOX plus bevacizumab. Patients assigned to surgery underwent open or laparoscopic surgery with D1 to D3 lymph node dissection, followed by chemotherapy. The first interim analysis conducted on 160 patients, after more than half of the planned 280 patients had been enrolled, brought the iPACS trial to a swift end. Median OS, the primary endpoint, was 25.9 months with primary tumor resection followed by chemotherapy versus 26.7 months with chemotherapy alone (HR 1.10, 95% CI [0.76, 1.59]; p = 0.69). The Data Safety Monitoring Committee recommended terminating the trial early due to futility. Other outcomes proved no better. Median PFS reached 10.4 months in the resection group and 12.1 months in the upfront chemotherapy group (HR 1.08, 95% CI [0.77, 1.50]). Grade 3/4 nonhematologic AEs associated with chemotherapy occurred more often with upfront primary tumor resection versus upfront chemotherapy (49% vs. 36%).

Although real-world data suggest that resection of primary tumor may confer a survival advantage, the iPACS findings help address the long-standing question of whether the best approach to treating asymptomatic patients with synchronous unresectable mCRC involves primary tumor resection followed by chemotherapy or immediate chemotherapy and has confirmed the futility of surgery in this subset.

Follow up

Following radical surgery and appropriate adjuvant therapy for early stage CRC, the 5 year recurrence rate may range from 15% to 35% in patients with stage II or stage III respectively. Regular follow up in these patients may identify oligometastatic disease which can be treated with a potentially curative intent. Two important aspects of follow up with clinical relevance were reported last year and are discussed below.

Circulating tumor DNA (ctDNA) in stage I to III CRC-in predicting postoperative recurrence[13]

Investigators from the University of Denmark studied 218 patients with stages I-III colon cancer and measured postoperative ctDNA to assess whether it could be used to successfully stratify patients into high- and low-risk groups. Investigators were able to conclude that patients who had ctDNA detected immediately following surgery were at a higher risk of recurrence. Moreover, ctDNA was detected a median of eight months prior to radiological detection of recurrence. Longitudinal monitoring was found to increase the predictive power of ctDNA, which outperformed carcinoembryonic antigen in predicting relapse-free survival (RFS) in the study. The recurrence rate reached 89% for patients with detectable ctDNA at any time, as compared with a rate of 3% for patients with consistently undetectable ctDNA. This means the risk for recurrence was 51 times greater for patients with ctDNA detectable on any test (P < .0001), during a median follow-up of nearly 30 months.Assessment of postoperative ctDNA status prior to adjuvant chemotherapy, revealed that 9.17% of patients were MRD positive; 75% of these patients relapsed. Conversely, 13.6% of patients with minimal residual disease (MRD) negativity relapsed. Based on this, investigators concluded that a positive postoperative ctDNA test was associated with a recurrence (HR, 11.0; 95% CI, 5.9-21, p <.0001). Among patients who received adjuvant chemotherapy, a positive ctDNA test after completion of treatment was associated with a recurrence rate of 83.3% compared with 12.5% in those who had a negative ctDNA test post treatment (HR 12; 95% CI, 4.9-27; P <.0001).

The current treatment strategy for patients with early-stage colon cancer consists of up-front resection in all patients and administration of adjuvant chemotherapy in a select group deemed to be at risk of recurrence. Goal of adjuvant chemotherapy is to eradicate micro metastatic disease, to achieve cure. Decision of adjuvant chemotherapy has been guided by clinicopathologic risk factors considered to be a surrogate marker of MRD for decades.However, accumulating data indicate that patient selection for adjuvant chemotherapy based on clinicopathologic risk factors is flawed and leads to both overtreatment and under-treatment in a large number of patients. For example, onlyone of five patients with stage III CRC have been found to derive a benefit from adjuvant chemotherapy. These data underscore the value of finding a reliable biomarker for MRD assessment. In this context, ctDNA has shown incredible promise and trials are underway incorporating ctDNA in treatment decisions.

PRODIGE 13 - after Surgery for Colorectal Cancer, Intensive Monitoring of Little Benefit[14]

PRODIGE 13 was a prospective multicentre trial evaluating by double randomisation the impact of a) intensive radiological monitoring (CT-scan/6m) versus a standard one (abdominal ultrasound/3m and thoracic radiography/6m) and b) carcinoembryonic antigen assessment versus no, in the follow-up of resected stage II or III CRC with no evidence of residual disease post-surgery. Primary endpoint was 5-year OS. A total of 1995 patients were included (80%< 75 years, 16% rectal, 44% left colon cancer). Among Colon cancers 52 % were Stage II (25% received adjuvant chemotherapy). With a median follow-up of 6.5 years, cancer recurrence was detected in 22% of the cases and second CRC in 1.7%. Surgical treatment of recurrence with curative intent was 41% in the minimum follow-up group (No CEA & standard imaging), 66.3% in the CEA & standard imaging group, 50.7% in the no CEA & CT, and 59.5% in the maximum follow-up group (CEA & CT) (p=0.0035). None of the follow-up modalities resulted in a difference in OS.

Intensive follow-up of patients after curative surgery for CRC is recommended by various scientific societies mainly based on expert opinions, and results of the few clinical trials performed are controversial. Moreover, no survival benefit has been demonstrated. Based on the results of PRODIGE 13, the addition of CEA and/or CT during follow-up does not provide any benefit in 5-year OS, but allows more curative intent secondary surgeries for patients with a more intensive follow-up.

Rectal cancers

Preoperative chemo-radiation therapy with capecitabine, followed by total mesorectal excision (TME) and adjuvant capecitabine-based chemotherapy is standard of care in localized rectal cancer stage II/III (cT3/4 or any lymph node involvement). The five–year survival rate for locally advanced rectal cancer is less than 70%. High rate of systemic failure is main concern. To reduce distant failure, following randomized control trials assessed the benefit of addition of second drug to standard of care.

PETACC6 trial[15] described addition of oxaliplatin to preoperative capecitabine-based chemoradiation and adjuvant capecitabine in locally advanced rectal cancer. Addition of oxaliplatin failed to demonstrate any benefit in DFS, OS, or pathologic end points. Moreover, tripled rate of grade 3/4 toxicities was observed in neoadjuvant CRT part, making the regimen highly intolerable.

Ji Zhu et al. evaluated the impact of addition of dose-escalated irinotecan on the basis of UGT1A1 status in neoadjuvant chemoradiation with capecitabine in locally advanced rectal cancer[16]. The pathological complete response rates (ypCR) were 15% and 30% in the standard and experimental groups respectively, (risk ratio=1.96, 95% CI=1.30–2.97, p=0.001). Grade 3-4 toxicities (leukopenia, neutropenia, diarrhea) were more in experimental group compared to standard group (38% vs. 6%).

The strategy of total neoadjuvant therapy (TNT) i.e., delivering radiotherapy and chemotherapy all upfront was tested in prospective randomized control trials toallow earlier treatment of micro metastatic disease and to increase compliance by delivering chemotherapy prior to surgery. Results of RAPIDO, OPRA and PRODIGE trials are encouraging as presented during ASCO 2020 virtual scientific event and are reported below.

Rectal cancer and preoperative induction therapy followed by dedicated operation (RAPIDO)[17]

Randomized Controlled Trial conducted by Renu R Bhadoer and colleagues, offer a new standard of care for locally advanced rectal cancer in a shorter overall treatment time. Experimental arm patients received short-course radiotherapy followed by CAPOX or FOLFOX4 followed by TME, whereas standard arm patients received long course radiotherapy with concomitant oral capecitabine followed by TME and, adjuvant chemotherapy CAPOX or FOLFOX4. At 3 years, the cumulative probability of disease-related treatment failure (DrTF) was 23.7% in the experimental group versus 30.4% in the standard of care group (HR 0.75, 95% CI 0.60-0.95, p = .019). TNT offered not only benefit in reducing distant metastasis but also benefit of delivering same biologic dose of radiation in a shorter time thus making whole treatment completion in shorter overall treatment time i.e., 31 weeks compared to 44 weeks in standard arm.

Organ preservation of rectal adenocarcinoma (OPRA) trial is testing safety and efficacy of watch and wait strategy (WW) after total neoadjuvant therapy (TNT) in MRI stage II & III rectal adenocarcinomas [18]. Preliminary analysis showed WW strategy for patients who achieve a clinical complete response to TNT results in organ preservation for a high proportion of patients without compromising survival. Up-front CRT followed by consolidation chemotherapy resulted in a numerically higher WW rate compared to induction chemotherapy followed by CRT. 3-year Organ preservation rates were 43% in induction vs. 58% in consolidated CRT arm. 3-year DFS rates were 78% in induction vs. 77% in consolidated CRT arm.

PRODIGE 23: RCT investigated safety and efficacy of neoadjuvant mFOLFIRINOX before preoperative chemoradiation, with TME-surgery and adjuvant chemotherapy in resectable locally advanced rectal cancer[19]. Compliance and surgical morbidity were not different in two groups. Complete pathological response rates (ypCR) were more in experimental arm (27.5%. vs.11.7%). 3-year DFS was significantly better in experimental arm (75.7% vs. 68.5%, HR 0.69, 95% CI (0.49-0.97), p - 0.034).

Other interesting and promising updates in the management of CRC included futility of addition of celecoxib to standard adjuvant chemotherapy in stage III CRC, efficacy of Trifluridine/tipiracil and bevacizumab as first-line treatment for mCRC patients not candidate for intensive oxaliplatin- or irinotecan-based chemotherapy, no benefit of addition of HIPEC to cytoreductive surgery in mCRC with peritoneal disease, and can be read from references mentioned in the recommended reading.

Table 1 Summary of Recent Updates in Colon Cancer
What is known until 2020? What is new? Insight
Screening of CRC to start at age of 50 years USPSTF for the first-time recommended screening to start at age 45 (Grade B recommendation) [2]
May help in identifying early-stage cancers in the young adults where incidence is steadily rising.
Given the relatively low incidence rate compared to west, benefits of screening program will be very marginal and not clinically meaningful in the Indian context
Early-stage CRC
Most powerful prognostic tool for CRC following surgery are pathological factors in resected specimen and stage; several other clinical, histologic, molecular factors, including gene expression profiling signatures have been studied and shown to influence prognosis


Immunoscore was validated as an independent prognostic tool in an international patient cohort in 2018
New clinical calculator predicts recurrence risk after curative colectomy for colon cancer (Weiser et al.),by successfully incorporating microsatellite genomic phenotype and presence of tumor-infiltrating lymphocytes[4] Performing genomic phenotype will be a limitation for clinical application in our settings
These novel scoring systems can help in designing future trials of adjuvant therapy in CRC
In Asian patients, Immunoscore can predict the risk of relapse in early-stage CRC by measuring the host immune response at the tumor site and in the invasive margin (Galon et al.) [5] This immunohistochemistry-based scoring system seems promising, can be incorporated into clinical practice, however, in the Indian setting, the challenge being lack of availability of digital pathology platform in majority of centres.
Adjuvant therapy for Colon Cancer
In stage II disease, only patients with proficient mismatch repair benefit from fluoropyrimidine monotherapy of 6 months in the adjuvant setting. IDEA results on duration of adjuvant doublet for high stage II CRC:[6] 3 vs. 6 months - although non-inferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable Results of the IDEA collaboration in high-risk stage II CRC only apply to patients receiving an oxaliplatin and fluoropyrimidine doublet (patients with either T4 disease and/or more than two risk factors can be considered for combination treatment for 3 months).
In patients with stage III colon cancer receiving adjuvant therapy with CAPOX, 3 months of therapy is as effective as 6 months, particularly in the lower-risk subgroup (T1-3, N1) Updated results (IDEA collaborators) on Duration of adjuvant doublet for high-risk stage III CRC:[7] 3 vs. 6 months – Non-inferiority of 3 vs. 6 months of adjuvant chemotherapy for stage III CRC was not confirmed in terms of OS, but the absolute 0.4% difference in 5-year OS should be placed in clinical context In practice, overall results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. The final decision for each individual patient should depend on a careful discussion, taking into account the risk of recurrence, co-morbidity, the patient’s wishes, likely absolute difference in survival, and risk of long-term toxicity.
Metastatic CRC
First line therapy for mCRC traditionally consists of cytotoxic chemotherapy with either FOLFOX or CAPOX along with anti VEGF or anti EGFR monoclonal antibodies KEYNOTE-177:[8] phase III study - front-line therapy with the immune checkpoint inhibitor pembrolizumab doubled the PFS versus standard of care chemotherapy [median, 16.5 vs. 8.2 months; HR 0.60; 95% CI, 0.45 to 0.80] in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC Overall, patients with MSI-H represent 5% of mCRC, have poor prognosis, also tend to be less responsive to conventional chemotherapy. First line Pembrolizumab have the potential to change the standard of care for this subset of patients, however, financial constraints will limit clinical use for majority of patients in the Indian setting
HER2/neu positivity in CRC range from 2.7% to 47.7%; role in prognosis remains uncertain, its role as a therapeutic target is rising. With ER2-directed therapies, ORR 30%–38%, median PFS 5.2 months has been observed.
HER2 is also emerging as a negative predictor of response to EGFR-targeted treatments.
DESTINY - CRC01:[9] Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing mCRC, who had previously received 2 or more lines of treatment. Results show an ORR of 57% and median PFS of 6.9 months in patients with HER2 3+ by IHC Trastuzumab deruxtecan, given at 6.4 mg/kg every 3 weeks, demonstrated promising and durable activity in patients with HER2-positive mCRC refractory to standard therapies; again cost will limit wider clinical utility
Phase 1b study of vemurafenib, cetuximab, and irinotecan, demonstrated a response rate of 35%, as well as a promising PFS benefit. Phase II trial (SWOG S1406):[10]addition of vemurafenib to irinotecan/cetuximab in mCRC (BRAF V600E mutated CRC; NRAS or KRAS wild type) ; ORR 17% and median PFS 4.2 months was observed with the triplet Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E–mutated CRC
Preliminary result from the BEACON study have shown for the first time that a combination of three targeted agents (triplet) —encorafenib (BRAF inhibitor), cetuximab (EGFR inhibitor) and binimetinib (MEK inhibitor)—leads to improved outcomes for patients with mCRC positive for BRAF V600E mutation who have failed first-line treatment BEACON trial:[11] updated results - combination of encorafenib and cetuximab (doublet) was approved for the treatment of adult patients with mCRC with a BRAF V600E mutation; triplet had identical median OS as for doublet (9.3 months in both groups) and comparable PFS (4.5 and 4.3 months respectively) BRAF mutations occur in approximately 5-10% of mCRC; results provide a promising chemotherapy free therapeutic options for this subset of high risk disease.
Real-world data suggest that resection of the primary tumor may confer a survival advantage in patients with synchronous mCRC Japanese phase III trial (JCOG1007; iPACS):[12] addition of primary tumor resection to chemotherapy for asymptomatic primary CRC and synchronous unresectable metastases – trial terminated early due to futility of surgery; at interim analysis, median OS was 25.9 months vs 26.7 months with or without surgery Primary tumor resection should no longer be considered a standard of care for CRC with asymptomatic primary tumors and synchronous unresectable metastases.
Follow up
Goal of adjuvant chemotherapy is to eradicate micrometastatic disease, to achieve cure; decision for which has been guided by clinicopathologic risk factors considered to be a surrogate marker of MRD for several decades Circulating tumor DNA in stage I to III CRC - patients who had ctDNA detected immediately following surgery were at a higher risk of recurrence [HR, 11.0; 95% CI, 5.9-21, P <.0001][13] ctDNA has shown incredible promise in assessing MRD post curative surgery, and trials are underway incorporating ctDNA in treatment decisions of adjuvant chemotherapy
Intensive follow-up of patients after curative surgery for CRC is recommended by various scientific societies. These recommendations are mainly based on expert opinions and results of the few clinical trials performed are controversial. PRODIGE 13:[14] after surgery for CRC, intensive monitoring is of little benefit - the addition of CEA and/or CT does not provide any benefit in 5-year OS, but allows more curative intent secondary surgeries for patients with a more intensive follow-up Standard follow-up (abdominal ultrasound/ 3m and thoracic radiography/ 6m) can be equally efficacious alternative to a more intensive FU with 6m CT scan, especially in resource limited settings
References
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  • 2. Printz C. US Preventive Services Task Force issues new draft recommendation statement regarding lung cancer screening. Cancer. 2020 Oct 1;126(19):4269-.
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Recommended reading:

  • Van Cutsem E, Danielewicz I, Saunders MP, Pfeiffer P, Argiles G, Borg C et al. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival. Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021) 14-14.
  • Meyerhardt JA, Shi Q, Fuchs CS, Niedzwiecki D,Zemla TJ, Kumthekar P, et al. Celecoxib in addition to standard adjuvant therapy with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) in stage III colon cancer: Results from CALGB/SWOG 80702. Journal of Clinical Oncology 2020 38:15_suppl, 4003-4003.
  • Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, et al; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):256-266.

Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni