The standard treatment of locally advanced but resectable cancer in the middle or lower rectum is preoperative radio-chemotherapy and in the upper part initial surgery. Radio-chemotherapy induces response in most patients and 10-20% have complete clinical response. The clinical benefit from radio-chemotherapy is primarily through a reduction in local relapse and the treatment is associated with acute toxicity and long term functional dysfunction. Subsequently, patient selection is important in order to select patients with high risk of local relapse. In Denmark only mid and low rectal T3 tumors threatening the mesorectal fascia and T4 tumors are offered radio-chemotherapy. The effect of the treatment in high rectal tumors is questionable and these patients are offered initial surgery.
The risk of local relapse is low, under 10% in recent studies, but the risk of distant relapse is high with about 30% metastatic disease within five years. Initiatives aimed at reducing the incidence of metastases are therefore needed. Randomized trials have only shown benefit from adding chemotherapy to radiation treatment with respect to reducing local and not distant relapse. Intense systemic combination chemotherapy reduces the risk of distant relapse and increases survival in the postoperative setting. The biological rationale is eradication of micrometastases and hence it may be anticipated that earlier, i.e. neoadjuvant, combination therapy may improve systemic control.
Neoadjuvant chemotherapy in patients with rectal cancer has mostly been evaluated in combination with radiotherapy. Chemotherapy before radiation treatment induces response and downsizing. None of 68 locally advanced rectal cancers patients with poor prognosis had radiological progression after combination chemotherapy, and a total of 88% had clinical response measured before start of radiochemotherapy treatment. However, neoadjuvant chemotherapy as the sole modality has only been evaluated in small materials.
In 26 Japanese patients with T3-4, N0-2 rectal cancer, two cycles of Irinotecan and 5FU reduced the tumor stage in 15. Five had relapse of which three were local within the pelvis. Five-year relapse free survival was 74% and OS 84%.
In 46 Spanish patients with T3 rectal cancer, four cycles of capecitabine, oxaliplatin and bevacizumab was given before surgery. The primary endpoint, overall response rate, evaluable in 36 patients was 78% (95% CI: 63%-89%) and no patients progressed. All had an R0 resection and complete pathological response was seen in 20% (95% CI: 9-33). No long term results have been published, but the 1-year disease free survival (DFS) was 75% (95% CI: 60%-85%), and the rate of 2-year local relapse was 2% (95% CI: 0%-11%).
Thirty out of 32 American patients completed six cycles of FOLFOX and bevacizumab without radiotherapy. All patients had tumor reduction and eight complete responses were observed. With 4.5 years of follow-up, no local relapses were seen, but four patients had distant metastasis.
These three single-arm phase II trials point towards neoadjuvant chemotherapy without radiotherapy as a promising approach with frequencies of complete response comparable to radio-chemotherapy and an acceptable rate of local relapse and survival.
The routine application of neoadjuvant radio-chemotherapy for upper rectal cancers (10-15 cm from the anal verge) is controversial. Thus, it is generally accepted that neoadjuvant treatment is only given in high rectal tumors with involvement of the lateral pelvic wall or neighboring organs. There is a general view that upper rectal cancers may be treated as colon cancer. The local recurrence rate in patients with upper rectal cancer and colon cancer are similar. In colon cancer the introduction of neoadjuvant chemotherapy has resulted in downstaging, lower rate of apical node involvement, lower rate of resection margin involvement and tumor regression compared with controls, and patients may be spared of adjuvant chemotherapy. Both studies have now proceeded to phase III and the first with a planned expansion of the patient population to include locally advanced high rectal cancer.
In addition, concerns have been raised of increased local recurrence rate in patients undergoing partial mesorectal excision (PME) for rectal cancer 10-15 cm from the anal verge. Thus, a Danish study showed a local recurrence of 13.5% after PME compared with 2.9% after total mesorectal excision (TME) and 5.7% after abdomino-perineal excision (APE). The concerns about the high rate of recurrence are related not only to the surgical technique, but also to the lack of neoadjuvant therapy.
Data and biological material
Clinical baseline data, treatment data (chemotherapy, radiotherapy and surgery) and follow up data on relapse and survival are collected. Furthermore, quality of life questionnaires are filled in by the patient.
A biobank is established collecting plasma and serum samples.
Collaborating researchers and departments
Department of Surgery, Roskilde & Koege Hospital
- Professor Ismail Gögenur,
The Research Unit, Lillebaelt Hospital
The Scientific Committee, Danish Colorectal Cancer Group