Cancer survivorship research: the challenge of recruiting adult long term cancer survivors from a cooperative clinical trials group

With the growing number of adult cancer survivors, there is increasing need for information that links potential late and long term effects with specific treatment regimens. Few adult cancer patients are treated on clinical trials; however, patients previously enrolled in these trials are an important source of information about treatment-related late effects. Focusing on colorectal cancer survivors, we used the database from five phase III randomized clinical trials from the National Surgical Adjuvant Breast & Bowel Project (NSABP) to recruit and enroll long term survivors in a study of late health outcomes and quality of life. We describe the challenges to recruitment of patients more than 5 –20 years after treatment. Sixty-five NSABP treatment sites were invited to enroll patients in the study. Sixty participated with the potential to recruit 2,408 patients. We received registration forms on only 976 patients (41%) of whom 744 (76%) expressed interest in participating and 708 completed interviews (95% of those expressing interest; 29% of total potential sample). There were multiple barriers to recruitment (difficulty locating patients, lack of institutional commitment, lack of patient interest). Patients treated on clinical trials are an important potential source for examining the late effects of cancer treatments. Retrospective recruitment has substantial limitations. In the future, mechanisms should be established for prospective long-term follow-up to identify and understand the frequency and type of late effects associated with cancer treatments. As cancer patients are living longer, it will be important to learn from participants in clinical trials whether or not specific treatment regimens are associated with any serious late effects

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 × 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135–1.856, P=0.0028; HR 1.506, 95% CI 1.150–1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially

Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

Oral capecitabine (Xeloda<sup>®</sup>) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK

An individual patient data meta-analysis of adjuvant therapy with uracil–tegafur (UFT) in patients with curatively resected rectal cancer

Uracil–Tegafur (UFT), an oral fluorinated pyrimidine chemotherapeutic agent, has been used for adjuvant chemotherapy in curatively resected colorectal cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with rectal cancer. The objective of this study was to perform a reappraisal of randomised clinical trials conducted in this field. We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of UFT for curatively resected rectal cancer in terms of overall survival (OS), disease-free survival (DFS), and local relapse-free survival (LRFS). We analysed individual patient data of five adjuvant therapy randomised clinical trials for rectal cancer, which met the predetermined inclusion criteria. These five trials had a combined total of 2091 patients, UFT as adjuvant chemotherapy compared to surgery-alone, 5-year follow-up, intention-to-treat-based analytic strategy, and similar endpoints (OS and DFS). In a pooled analysis, UFT had significant advantage over surgery-alone in terms of both OS (hazard ratio, 0.82; 95% confidence interval (CI), 0.70–0.97; P=0.02) and DFS (hazard ratio, 0.73; 95%CI, 0.63–0.84; P<0.0001). This individual patient-based meta-analysis demonstrated that oral UFT significantly improves both OS and DFS in patients with curatively resected rectal cancer

Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients

Background: although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up. Methods: patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3-4/anyN, or anyT/ N1-2; ECOG Performance Status 0-2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 \ub1 2 days after RT completion, adopting the total mesorectal excision technique. Results: 24 men and 23 women were enrolled; median age was 55 years (r.: 39-77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18-84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence. Conclusion: bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT

Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer

Adjuvant treatment of patients with colorectal cancer is hampered by a lack of reliable prognostic factors in addition to the clinicopathological staging system. A poorly defined but considerable fraction of Astler–Coller stage B patients will experience tumour recurrence, and some of the stage C patients will probably survive for a prolonged time after surgery without adjuvant treatment. Assessing parameters related to tumour angiogenesis has provided valuable prognostic information in different tumour types. The formation of new microvessels is part of the malignant phenotype in the majority of tumours. Alterations in tumour-suppressor genes, such as the p53 gene, or oncogenes, such as the ras gene, have been found to be responsible for changing the local balance of pro- and antiangiogenic factors in favour of the former. In this prospective study, intratumoral microvessel density (IMD) was assessed by immunostaining tissue sections for CD31 and counting individual microvessels in selected and highly vascular regions in specimens of 145 colorectal cancer patients. p53 protein overexpression was semiquantitatively determined after immunohistochemistry. In both uni- and multivariate analysis, high IMD was significantly associated with shorter survival in the patients undergoing surgery with curative intent (Astler–Coller stages A–C). p53 added prognostic power to IMD, both in Astler–Coller stage B and stage C patients. An association between IMD and mode of metastasis was also noted. High IMD was strongly associated with the incidence of haematogenous metastasis during follow-up, but not with the presence of lymphogenic metastasis observed at surgery. This study confirms the results of previous retrospective analyses of IMD and survival in colorectal cancer and warrants a clinical validation by randomizing stage B tumour patients with high IMD and p53 overexpression between adjuvant treatment or not. © 1999 Cancer Research Campaig

Updates in Gastrointestinal Oncology – insights from the 2008 44th annual meeting of the American Society of Clinical Oncology

We have reviewed the pivotal presentations rcelated to colorectal cancer (CRC) and other gastrointestinal malignancies from 2008 annual meeting of the American Society of Clinical Oncology (ASCO). We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. The report on KRAS status in patients with metastatic CRC receiving epidermal growth factor receptor (EGFR) targeted antibody treatment has led to a change in National Comprehensive Cancer Network guideline that recommends only patients with wild-type KRAS tumor should receive this treatment. The results of double biologics (bevacizumab and anti-EGFR antibody) plus chemotherapy as first-line treatment in patients with metastatic CRC has shown a worse outcome than bevacizumab-based regimen. Microsatellite Instability has again been confirmed to be an important predictor in patients with stage II colon cancer receiving adjuvant treatment

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40–50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity