Introduction

As per Globocan 2018 data colorectal cancer (CRC) is the third most common cancer (10.2%) and the second most common cause of cancer-related death among all cancer cases.1 Metastatic colorectal cancer (mCRC) has dismal outcomes, with the 5-year survival rate of less than 10%. The median survival time of patients with untreated mCRC is approximately 5 months.2 The goal of treatment in majority of cases remain palliative unless there is limited metastatic disease which is resectable, as surgery is the only curative treatment option.3 However, the landscape of treatment of mCRC has significantly evolved over the past two decades with the availability of newer chemotherapeutic, targeted agents.4 A better understanding of the administration of combination chemotherapy (oxaliplatin and irinotecan) with use of biological agents (bevacizumab, cetuximab, and panitumumab), molecular biology of the disease, approval of newer agents (regorafenib, Her2neu inhibitor) immune checkpoint inhibitors, and improvement in supportive care delivery have largely revolutionized the outcomes of metastatic patients.5 A small subset of these patients may have durable responses and survival even without surgery. The data regarding this subset are lacking from the Indian as well as South East Asian subcontinent regarding long-term survivors. Here we report a case series from India, of long-term survivors of mCRC mainly treated with chemotherapy.

Methods

This is a single-center retrospective analysis of patients of mCRC registered at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, from the year 2005 to 2015. Main inclusion criteria were mCRC patients who were treated at the centre mainly with chemotherapy, who had either initial presentation as metastatic disease or those who progressed after initial surgery with or without adjuvant therapy, and those who survived for 5 or more years. Data were retrieved from the hospital-based record system. Demographic details including age, sex, Eastern cooperative oncology group (ECOG)performance status, primary and metastatic sites stage, and various treatment lines including biologics received by the patient were documented in a structured proforma. Treatment response and current status of the patient were obtained telephonically and from case records. Common terminology criteria for adverse events (CTCAE) 4.0 was used to document toxicities. Median and range were used to describe quantitative variables. Kaplan–Meier curve was used for survival analyses. Cox proportional hazards model was used to assess the association of clinical variables with survival. P values of <0.05 were considered statistically significant. Statistical analysis was done using STATA software (ver13 StataCorp, College Station, Texas, United States). Data were censored on September 30, 2020.

Results

Outcomes

At the time of analysis, 10 patients are currently surviving. Six patients are maintaining radiological complete response. Three patients were lost to follow-up. Median overall survival (OS) of this cohort is 81.6 months (95% confidence interval [CI], 69.73–117.9) (Fig. 1) and median progression-free survival (PFS) to first line therapy was 17.23 months (95% CI 13–46.8).

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Fig. 1: Overall survival of metastatic colorectal cancers (long term survivors).

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Discussion

Long-term survivors of mCRC in literature has been defined conventionally as survival more than 5 years. mCRC has a median survival of 6 to 10 months with time-tested single agents like 5 FU.6 Advent of doublet chemotherapeutic regimen including oxaliplatin and irinotecan has further contributed to the armamentarium against this disease.78 The new era of biologicals and targeted therapy has ushered in changes in the outcomes and there is still uncertainty on how and to what extent these agents have an impact on survival. In the metastatic setting, “cure” per se has been a rare occurrence in colorectal cancers. However, in recent times long-term follow ups of various large multicenter trials have demonstrated a significant rise in patient population who have survived beyond the 5-year mark.910 Evolution in surgical techniques like hepatic resection of metastasis has also contributed to prolongation in survival as reported in various studies.11 Addressing the most common site of metastasis with improved infusional chemotherapy as well as newer surgical techniques has resulted in improvement of disease outcomes.1213 Concrete data to substantiate correlations of factors to long-term survival and actual magnitude of patient population who are achieving cure in real life is not much reported. Till date, only two large studies, MD Anderson Cancer Center9 and NCCTG,10 have addressed these patients and their characteristics. No data from India cohort are currently available which can provide us with the prevalence of prolonged survivors in our population.

In our study, 77% of patients presented to us as upfront metastatic disease. This analysis demonstrates that only a small proportion of our patients (10%) underwent metastatectomy and majority received chemotherapy only as part of therapy. Hence, our analysis highlights good and durable response achieved with chemotherapy alone. Presently six patients are maintaining complete response. This is somewhat comparable to the large retrospective study of mCRC by Ferrarrato et al from MD Anderson Cancer Centre,9 where they reported six patients in CR on chemotherapy alone. Majority of our patients presented with left-sided colon cancer which now we know has a better prognosis.14 The most common used biologic in our study was cetuximab. However, as the current evidence of use of cetuximab according to sidedness of the colon cancer was not available at the time of institution of biologics in our patients, the response correlation according to primary tumor location needs to be assessed in a larger cohort.15

Toxicity is also a concern in long-term survivors and adverse effects like neuropathy can be disabling and have a bearing on quality of life.16 Seven percent of our patients had residual grade III peripheral neuropathy.17 Quality of life also takes precedence in analysis of long-term survivors and very few studies are available in literature to highlight this aspect. Our study did not include quality of life analysis.

It is hard to overlook the concepts of precision medicine and tailoring of therapy in subsequent lines. The approved agents like bevacizumab, cetuximab, and panitumumab have shown promise in prolongation of survival.18 Our study almost 50% patients received at least one biologic agent. Genetic determinants of prolonged survival can be further analyzed in retrospective manner from bedside to the bench by tissue preservation and subjecting sample to specific of molecular and genetic testing.

The limitations of our study is its retrospective nature, less number of patients (n = 31), limited number of patients exposed to all available options, and unavailability of MSI (microsattelite instability) and RAS (RA\at sarcoma virus gene) status in majority of the patients.

Survival data on newer regimens are sparse owing to heterogeneous nature or retrospective nature of studies. Addition of biologics may have a contribution to patients achieving and maintaining complete and partial responses beyond 5 years and needs to be examined in detail.

Conclusion

The term “cure” might not be a remote possibility in mCRC. A close scrutiny needs to be maintained on all the large multicenter trials and their long-term follow-ups to ascertain and validate these data. Although the patient number is small, durable responses achieved with chemotherapy and biological agents alone in a metastatic setting is encouraging and possible. Analysis from large institutional database should be carried out.