Case Study: Downstaging liver metastases in colorectal cancer

The patient was admitted for an emergency appendectomy but at laparotomy, she was found to have a right-sided colonic tumour. An extended right hemicolectomy was then performed. Histological examination of the resection specimen confirmed caecal adenocarcinoma that was locally advanced, with spread to regional lymph nodes (pathological stage T4N1).

A subsequent staging CT scan of the chest, abdomen and pelvis showed synchronous liver metastases, with five lesions in the right lobe measuring up to 1.5cm in diameter and an ill-defined lesion in the left lobe. There was also a 6mm nodule in the left upper lobe of the lung of uncertain significance.

Following surgery, the patient was offered combination chemotherapy using oxaliplatin and 5-fluorouracil (modified de Gramont schedule): oxaliplatin 85mg/m² IV and 5-fluorouracil 400mg/m² bolus IV followed by 2,400mg/m² infusion over 48 hours, every two weeks. She tolerated chemotherapy well.

After six cycles of chemotherapy, the patient had a repeat CT scan of the chest, abdomen and pelvis, and an MRI of the liver. Both scans showed significant reduction in the liver metastases. Those in the right lobe now measured up to 6mm in diameter and the left lobe lesion had undergone a complete radiological resolution. The lung nodule had reduced from 6mm to 4mm, increasing suspicion of its metastatic nature.

Discussion by the multidisciplinary team indicated that the liver lesions were amenable to resection and a right hemi-hepatectomy was performed. During this operation, no lesions were identified in the liver and histology showed only nodular congestive changes in keeping with chemotherapy-induced liver damage, with no evidence of malignancy. The patient will shortly undergo resection of the lung lesion.

Discussion
Combination chemotherapy improves survival for patients with colorectal cancer in the adjuvant and palliative settings.^1,2 A quarter of patients diagnosed with colorectal cancer have liver metastases at presentation (synchronous metastases) and the liver is the most common site for recurrence at a later date (metachronous metastases).

Untreated, patients with metastatic disease have a median survival of about six months.³ Chemotherapy with sequential exposure to the three most active drugs (5-fluorouracil or its oral analogue capecitabine, with oxaliplatin and irinotecan) can prolong median survival to approximately 20 months, but with few long-term survivors. Further modest increments can be achieved with the addition of newer monoclonal antibody therapies, such as bevacizumab, an anti-angiogenic antibody, but these are not routinely available on the NHS because of cost.

Liver resection in selected cases can improve patient survival rates (the five-year survival rate in surgical series is 25-40 per cent), but is applicable to less than 15 per cent of cases.⁴ Traditionally, patients considered for resection were those with four or fewer metastases, or metastasis confined to one lobe of the liver with no extra-hepatic spread. With improved surgical techniques and better systemic therapy, this is shifting to include patients with more advanced disease. A proportion of patients with unresectable disease can be rendered resectable by neoadjuvant chemotherapy. In this group, survival appears to be equivalent to those undergoing primary liver resection.^5,6

In this case, chemotherapy was used to downstage the known metastases and facilitate their resection. Despite the apparent complete pathological response, current consensus is that chemotherapy alone is not curative and that without surgery, future disease progression is inevitable.

Given the synchronous presentation of the metastatic disease, it is possible that further, as yet undetectable, microscopic metastases might be present. Thus, neo-adjuvant chemotherapy provides early treatment of potential micrometastatic disease to reduce the risk of later recurrence.

An alternative strategy is to resect the primary colon cancer and later resect the liver and lung metastases in staged procedures, with adjuvant chemotherapy to treat micrometastatic disease following completion of all surgery. Although there is no consensus to guide the timing of chemotherapy in this situation, there is a perceived risk that delaying chemotherapy may allow micrometastases to progress to an incurable stage. The role of adjuvant chemotherapy in relation to liver resection for patients who present with metachronous metastases remains uncertain and is the subject of continuing clinical trials. Improvements in systemic chemotherapy for colorectal cancer mean that it is now possible to downstage patients with unresectable liver metastasis to facilitate resection and provide the prospect of long-term survival from a previously incurable disease.

References
1. De Gramont A, Figer M, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47.
2. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-51.
3. Bengtsson G, Carlsson G, Hafstrom L et al. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981;141:586-9.
4. Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 1999;49:231-55.
5. Adam R, Huguet E, Azoulay D et al. Hepatic resection after down-staging of unresectable hepatic colorectal metastases. Surg Oncol Clin N Am 2003;12:211-20.
6. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005;23:2038-48

Originally published in the June 2009 edition of MIMS Oncology & Palliative Care.