Colorectal cancer is the third most common cancer diagnosed globally and is second most common cause of death [1]. Hepatic metastasis is the most common metastatic lesion seen in 50% - 60% of the patients, with synchronous hepatic metastasis in 15-20% of the patients [2-5]. Synchronous metastasis is more frequent (more than double) in elderly [6]. Patients with synchronous hepatic metastasis have poor prognosis compared to patients with metachronous hepatic metastases [5,7]. There has been an advance in surgical management of hepatic metastasis which has made perioperative mortality associated with surgical management acceptable [8]. This has resulted in the improvement of five years survival rate from <8%, using palliative chemotherapy (CT), to around 30%-60% following potentially ‘curative’ resection of isolated hepatic metastases with majority of them maintaining disease free status[3,4,8-11]. It drops to less than 20% in patients with positive resected margin [12]. Surgical resection is also associated with significant morbidity and mortality with 15% of patients undergoing resection succumbing to disease within 12 months of surgery [5]. In spite of all advancements, only around 20% of all patients with hepatic metastasis are suitable for surgical resection [4,6,10]. Colectomy followed by palliative chemotherapy is one of the option for such patients in absence of resection of hepatic metastasis as per NCCN guidelines [13]. Palliative chemotherapy is not always suitable particularly for elderly patients as incidence of adverse events needing hospitalisation, dose adjustments is very high [14-16]. Cur cumin is described to have a wide range of biological properties against colorectal cancer in vitro [17- 21]. Cur cumin has also been evaluated in humans against various cancers in a very high dose (up to 8 gm) without success as its bioavailability is very poor [22-26]. Nano suspension of cur cumin (NSC) has significantly improved bioavailability. NSC is available in India as an encapsulated in a soft gelatine capsule containing 50 mg of cur cumin in a capsule. It has been found useful in the cases of ulcerative colitis. Here, we present a case of colorectal cancer with hepatic metastasis, successfully treated with bio-enhanced cur cumin.

A 73 year old female had undergone left hemi colectomy on 26^th July, 2013 for symptomatic carcinoma of sigmoid colon with synchronous hepatic metastasis. Sigmoid colon lesion was around 7 Cm in length. Synchronous hepatic metastasis in left lobe of liver measured around 5.5 x 4.6 Cm. Histopathological evaluation revealed moderately differentiated adenocarcinoma of sigmoid colon infiltrating outermost layer of muscular is layer with focal invasion of fat, pathological stage IV. Biopsy of hepatic lesion taken during surgery also revealed adenocarcinoma. She did not receive any adjuvant/palliative chemotherapy following surgery. Instead she chose to have bio-enhanced NSC 50 mg twice a day. This was well tolerated without any side effects and she continues taking this till today. During follow-up evaluation, original synchronous hepatic metastatic lesion was found to have gradual decrease (over a period of five years) in size from 7.69 x 4.55 cm (Figure 1) to 2.41 x 1.98 cm (Figure 2) indicating partial response by resist as well as WHO criteria. There was neither any evidence of recurrence of lesion nor appearance of any new lesion. The lesion also has evidence of calcification which again indicates response to therapy which is durable.

Figure 1: Synchronous liver metastasis - initial image.

Figure 2:  Synchronous metastasis lesion - Dec, 2018.

Cur cumin is not known to have any effect in colorectal cancer in humans [27] in spite of its known efficacy in pre-clinical studies [18-20]. Shrinkage of a synchronous metastatic hepatic lesion, meeting resist criteria as well as WHO criteria of partial response, with appearance of calcification during course of therapy seen in the patient while consuming NSC is a unique feature. Shrinkage of lesion with appearance of calcification is indicative of efficacy of NSC. Calcification of hepatic metastasis during the course of treatment is known to be associated with response to therapy and caries good prognosis compared to those who do not develop calcification [28,29]. Calcification seen. Following therapy is believed to be due to dead cells (necrotic/apoptotic) cells in patients responding to treatment being replaced by inflammatory cells which in turn leads to calcification [29]. Calcification of metastatic hepatic lesion following therapy is described to be associated with lack of inflammation in surrounding tissue [28]. Cur cumin has action on multiple molecular target including COX₂ and PGE₂ [18-20]. Both are the markers of inflammation and NSC, by decreasing inflammatory activity, might have contributed to calcification. Anti- inflammatory activity of cur cumin is dose dependent and improved bioavailability of NSC might have contributed to this. Even after curative surgical resection, recurrence is common and seen in up to -80% of cases with almost all recurring within 30 months of resection [5,12,16] and needs multiple resection for disease control [30]. Recurrence rate is significantly higher when metastatic lesion is 5 cms or more in size [12]. Absence of development of new lesions anywhere for more than 5 years is another unique feature of the case. This might be indicative of sustained anti-proliferative activity with continued administration of cur cumin. Deepening of response over longer period and durable response like the one seen in this patient are known following immunotherapy but not following other therapies [31,32]. Cur cumin has immunomodulatory properties also which might have played role in achieving durable response [33]. The other possible explanation could be its action on multiple molecular targets. Though a case report, durable response with improved survival for more than 5 years seen in the case compares favorably with current standard of care. Colorectal cancer with hepatic metastasis has a median overall survival (OS) of around 6 to 12 months without treatment [3,8,11] and improves to 20–24 months with palliative chemotherapy [8,11]. However, 5-year survival rates are very low (<8%) with palliative chemotherapy [4]. The prognosis is poor in patients with synchronous disease compared to metachronus disease [5,7,30] and in those with hepatic metastasis >5 cm compared to those with hepatic metastasis < 5 cm [5,16,30]. Surgical excision improves a median survival to 3.6 years with a disease-free survival of 15, months and 5- year overall survival between 30 % and 60 % [3,10,11]. However, it drops to less than 20% in patients with positive resected margin [12]. Shrinkage of lesion with calcification and absence of development of any new lesion for more than five years seen in this case indicate successful disease control using NSC as a single agent. This is probably the first instance wherein cur cumin is found useful for disease control in a patient with colorectal cancer with hepatic metastasis. The successful outcome in this case can be attributed to improved bioavailability and effect of cur cumin on multiple molecular target including anti-inflammatory and anti-inflammatory property. This needs to be evaluated further in a larger study.

A case of colorectal cancer with synchronous hepatic metastasis received Nano suspension of cur cumin with improved bioavailability following hemi colectomy. The drug was well tolerated and patient achieved durable partial response lasting more than five years indicating potential of Nano suspension of cur cumin for management of metastatic colorectal cancer and needs further evaluation.

I am thankful to Mr. Anand Khamar for his secretarial assistant and help in preparing this manuscript.

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