Debashis Biswas and Thankamma Ajithkumar
Case history
A 57-year-old woman presented with 2 days of abdominal pain and vomiting. On examination she had a distended abdomen with absent bowel sounds. There was no significant past medical history. Abdominal X-ray was suggestive of small bowel obstruction. Her CT scan is shown in Fig. 12.1 (no intravenous contrast was given due to previous history of allergy).
Fig. 12.1
Questions
1. What does the CT scan show?
2. Outline your initial approach.
Answers
1. What does the CT scan show?
The CT scan shows a caecal mass and appearances consistent with transmural spread and possibly serosal involvement. There are six enlarged mesocolic lymph nodes (not shown). There is no evidence of liver, peritoneal, or any other metastases.
2. Outline your initial approach.
Up to 16% of patients with colorectal cancer present with bowel obstruction. Emergency surgery in these patients is associated with significant morbidity (e.g. stoma formation) and mortality, particularly in the elderly. For example, mortality in patients aged ≥65 years having emergency surgery is 17% compared with 7.7% for those having an elective operation. The optimal management of obstructed colon cancer depends not only up on the patient’s age but also on the general condition of patient, tumour location, and integrity of the bowel wall. Initial treatment options include:
♦ Segmental resection with primary anastomosis with or without proximal diversion. This is the preferred option provided there is no diffuse peritonitis or perforation and the patient is medically stable. This approach is more suitable for right-sided cancers, as in the case illustrated.
♦ (Sub)total colectomy with primary anastomosis. This is an option in left-sided obstructing tumours where there is associated with loss of bowel wall integrity or the colon proximal to the obstruction cannot be evaluated and synchronous lesions cannot be ruled out (these occur in up to 15% of patients).
♦ Resection of tumour without an anastomosis and with an end colostomy (Hartmann resection). This is an approach in left-sided tumours and allows for elective evaluation of the proximal colon with a potential for bowel preservation.
♦ Proximal colostomy only. This is carried out in medically unstable patients, as it allows for improvement in their general condition and consideration of subsequent neoadjuvant treatment.
♦ Stenting. This is an interim measure in distal colonic obstruction to restore luminal patency while awaiting full staging and allowing time for surgical optimization. Stents are less frequently used in proximal colonic obstruction as most lesions can be managed with one-stage operation and anastomosis without the need for a formal bowel preparation. However, a recent Cochrane Review suggested that in acute malignant colonic obstruction stenting has no advantage compared with emergency surgery in terms of either morbidity or mortality.
Since this patient has a right-sided tumour with small bowel obstruction, she can be managed with an emergency one-stage operation without significant anticipated risk of post-operative morbidity.
She underwent a right hemicolectomy. The pathology confirmed a grade 3 K-ras wild-type adenocarcinoma of the caecum with extramural vascular invasion and clear excision margins. Seven out of 12 lymph nodes showed metastases, including the apical group.
Questions
3. What is the stage of her disease?
4. Would you advise adjuvant treatment?
5. How do you follow her up?
Answers
3. What is the stage of her disease?
pT3N2Mx R0 according to the AJCC TNM system (7th edition) and stage C2 according to the Dukes staging system (as the apical node was involved).
4. Would you advise adjuvant treatment?
In node-positive (stage III) colon cancer 5-FU-based adjuvant chemotherapy for 6 months improves 5-year OS by 10–15% (Marsoni 2001). Studies show that oral capecitabine is an effective alternative to 5-FU plus leucovorin (Twelves et al. 2005).
The addition of oxaliplatin to 5-FU improves survival further, especially in stage III patients aged less than 65 years. The MOSAIC study showed that the addition of oxaliplatin improved 5-year disease-free survival (DFS) by 7% (André et al. 2009). In addition, the 6-year OS in stage III patients was improved by 4%. The NSABP C-07 study confirmed this clinical benefit. The XELOXA study, which compared capecitabine plus oxaliplatin with 5-FU plus leucovocin in stage III colon cancer, showed that capecitabine plus oxaliplatin improves 3-year DFS by 4.4% (Haller et al. 2011). However, a subset analysis of the MOSAIC study suggests that patients older than 65 years do not benefit from the addition of oxaliplatin. Similarly, the ACCENT group database analysis suggests that patients aged over 70 years do not benefit from 5-FU-based chemotherapy (McCleary et al. 2013). Thus, the choice between 5-FU or capacitabine, and whether to combine this with oxaliplatin, depends on the patient’s age and fitness, their predicted tolerance of each regime, and individual patient choice.
The combination of cetuximab with chemotherapy improves survival in patients with metastatic colorectal cancer whose tumours express wild-type K-ras. However, in stage III resected colon cancer, adjuvant treatment with cetuximab plus chemotherapy does not improve DFS (NCCTG N0147 trial), and therefore is not recommended.
The two useful web-based tools to calculate relative risk of disease-recurrence and mortality are Adjuvant! Online (<http://www.adjuvantonline.com>) and Mayo Clinic Adjuvant Tools (<http://www.mayoclinic.com/calcs/>). Using Adjuvant! Online the estimated 5-year survival of this patient is 40%, which will be improved by 22.6% with adjuvant oxaliplatin plus 5-FU/leucovorin. Therefore she was recommended to have adjuvant combination chemotherapy with capecitabine and oxaliplatin for 6 months.
5. How do you follow her up?
Disease relapse in colon cancer most commonly occurs within 3 years of surgery and there is evidence that early identification and treatment of recurrence improves survival. Regular follow-up is advised with clinical review and estimation of CEA every 3–6 months for 3 years and then 6–12-monthly until 5 years. A CT scan of the chest, abdomen, and pelvis should be performed annually for the first 3 years and colonoscopy is recommended 1 year after surgery and then every 3–5 years.
She received a combination of capecitabine and oxaliplatin for 6 months. Post-treatment staging CT and MRI scans are shown in Fig. 12.2.
Fig. 12.2
Questions
6. What do the scans show?
7. Discuss your management.
Answers
6. What do the scans show?
The CT scan shows two hypodense areas in the right lobe of the liver suggestive of metastases (A). The MRI scan shows at least two liver lesions involving segments 7 and 8 that are hypodense on T1-weighted images consistent with metastases (B). On T2-weighted images the lesions are iso- to mildly heterogeneously hyperintense. The lesion in the segment 7 mildly compresses the right hepatic vein, but otherwise the hepatic veins and portal veins appear unremarkable.
7. Discuss your management.
The liver is the dominant site of metastasis in colorectal cancer, but more than two-thirds of patients with liver metastases will also have extrahepatic disease. Therefore palliative systemic chemotherapy is the treatment of choice in this situation.
In patients who present with liver as the only site of metastasis, surgical resection, when technically feasible, results in a 5-year OS of 30–35% (compared with 10% when treated with palliative chemotherapy). However, the optimal selection of patients for hepatic resection is controversial and is still evolving. Liver metastases are generally categorized as being immediately resectable, absolutely unresectable, and potentially resectable after downstaging.
Patients with immediately resectable disease have metastatic tumour with adequately resectable margins (i.e. no involvement of any major hepatic vasculature or bile ducts), no portal lymphadenopathy, absent or treatable extrahepatic disease, and adequate liver function which is likely to be preserved after resection. However, the definition of ‘immediately resectable’ is subjective and based to a degree on the expertise of the liver surgeon.
Patients are considered to have absolutely unresectable disease if they have non-resectable extrahepatic disease, liver failure, are unfit for surgery, or have involvement of more than 70% of the liver or six segments involved.
Approximately 12–33% of patients with isolated liver metastasis are potentially resectable after downstaging. For these patients initial systemic treatment is recommended to improve resectability.
Her case was discussed in the colorectal MDT. Although there was no extrahepatic disease on imaging, one liver metastasis was deemed to be adherent to a bile duct, and therefore her liver metastases were classified as potentially resectable after downstaging.
Question
8. Which chemotherapy regimen would you recommend?
Answer
8. Which chemotherapy regimen would you recommend?
The optimal regimen for downstaging is not known. Since there is a strong correlation between the response rate and the resection rate, a regimen with a high objective response rate is often chosen. The EORTC 40983 study showed that oxaliplatin-based chemotherapy given before and after surgery improves 3-year PFS by 9.2% compared with surgery alone for patients with liver metastasis (Nordlinger et al. 2008). However, there is no significant difference in OS between both treatments.
The addition of cetuximab to chemotherapy improves the response rate and PFS in patients with K-ras wild-type metastatic disease in the liver alone. The CRYSTAL trial has shown that the addition of cetuximab to irinotecan modestly improved the resection rate from 3.7 to 7% (Van Cutsem et al. 2009). In the OPUS trial, in patients with wild-type K-ras the addition of cetuximab increased the resectability of liver metastasis from 4 to 10% (Bokemeyer et al. 2008).
Treatment and follow-up
This woman has progressive disease immediately after oxaliplatin and capecitabine and is therefore switched to a different regimen, irinotecan plus capecitabine. Since her tumour is K-ras wild type, cetuximab is added to improve the chances of resection.
Further reading
André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. Journal of Clinical Oncology 2009; 27: 3109–3116.
Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. Journal of the American Medical Association 2012; 307: 1383–1393.
Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. Journal of Clinical Oncology 2008; 26: a4000.
Cunningham D, Atkin W, Lenz H-J, et al. Colorectal cancer. The Lancet 2010; 375: 1030–1047.
Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. Journal of Clinical Oncology 2011; 29: 1465–1471.
Mahmoud N, Bullard Dunn K. Metastasectomy for stage IV colorectal cancer. Diseases of the Colon and Rectum 2010; 53: 1080–1092.
Marsoni S. Efficacy of adjuvant fluorouracil and leucovorin in stage B2 and C colon cancer. InternationalMulticenter Pooled Analysis of Colon Cancer Trials Investigators. Seminars in Oncology 2001; 28(1 Suppl 1): 14–19
McCleary NJ, Meyerhardt JA, Green E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. Journal of Clinical Oncology 2013; 31: 2600–2606.
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. The Lancet 2008; 371: 1007–1016.
Patel SS, Floyd A, Doorly MG, et al. Current controversies in the management of colon cancer. Current Problems in Surgery 2012; 49: 398–460.
Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. New England Journal of Medicine 2005; 352: 2696–2704.
Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. New England Journal of Medicine 2009; 360: 1408–1417.