Key points

Background

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers globally in both men and women. Based on the most recent global cancer statistics, an estimated 1.2 million new CRC cases were diagnosed in 2008, with 608,700 patients dying of the disease. The highest incidence rates are found in the developed world, where risk factors such as obesity, poor dietary choices, and physical inactivity are most prevalent. In Canada, an estimated 23,300 new CRC cases and 9,200 deaths are estimated to have occurred in 2012. CRC has consequently been the focus for many new screening and treatment initiatives to improve patient care.

Optimizing CRC care is imperative for improving overall survival (OS) and disease-free survival (DFS) rates. As with many solid tumors, the cornerstone of curative CRC treatment is surgical resection. Surgical techniques for resection vary depending on the tumor location and characteristics; however, it is recommended that all colorectal tumors are removed en bloc. Because colorectal tumors often extend into neighboring structures, en bloc removal maximizes the curative potential of surgery, as well as aiding in the staging process.

In addition to optimal surgery, governing cancer institutions’ guidelines also state that patients with high-risk stage II and all patients with stage III CRC are candidates for adjuvant chemotherapy (AC) treatment. This article explores the types of chemotherapy available for patients with CRC, the critical issue of timing of AC, and the barriers to treatment.

Background

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers globally in both men and women. Based on the most recent global cancer statistics, an estimated 1.2 million new CRC cases were diagnosed in 2008, with 608,700 patients dying of the disease. The highest incidence rates are found in the developed world, where risk factors such as obesity, poor dietary choices, and physical inactivity are most prevalent. In Canada, an estimated 23,300 new CRC cases and 9,200 deaths are estimated to have occurred in 2012. CRC has consequently been the focus for many new screening and treatment initiatives to improve patient care.

Optimizing CRC care is imperative for improving overall survival (OS) and disease-free survival (DFS) rates. As with many solid tumors, the cornerstone of curative CRC treatment is surgical resection. Surgical techniques for resection vary depending on the tumor location and characteristics; however, it is recommended that all colorectal tumors are removed en bloc. Because colorectal tumors often extend into neighboring structures, en bloc removal maximizes the curative potential of surgery, as well as aiding in the staging process.

In addition to optimal surgery, governing cancer institutions’ guidelines also state that patients with high-risk stage II and all patients with stage III CRC are candidates for adjuvant chemotherapy (AC) treatment. This article explores the types of chemotherapy available for patients with CRC, the critical issue of timing of AC, and the barriers to treatment.

AC for colorectal cancer

Although surgery is the mainstay of CRC treatment, AC is also an important aspect of increasing DFS and OS. The role of AC is to eradicate micrometastatic tumor deposits, which can increase the chance of cancer recurrence. Recommendations regarding the role and type of AC for patients with CRC have evolved greatly in the past 20 years because of the growing number of clinical trials searching for more effective treatment.

One of the first chemotherapy regimens that showed a definitive DFS benefit in patients with CRC was 5-fluorouracil with levamisole. A randomized controlled trial showed that patients with stage III colon cancer who received levamisole with 5-fluorouracil had a significant reduction (41%) in the relative risk of cancer recurrence compared with patients who did not receive any chemotherapy. A later study showed similar results for patients with stage II and stage III colon cancer, but failed to show any positive effect for patients with rectal cancer. This chemotherapy regimen remained the standard of care in the 1990s, until 5-fluorouracil and folinic acid (leucovorin) were found to be more beneficial. The subsequent QUASAR (Quick and Simple and Reliable) trial determined that patients with stage II CRC also received benefits, although small, from adjuvant treatment with 5-fluorouracil and folinic acid. As a result, this established the basis for offering AC to high-risk patients with stage II CRC.

In 2004, the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin [FOLFOX] in the Adjuvant Treatment of Colon Cancer) study further enhanced the treatment regimen, showing that the addition of oxaliplatin to 5-fluorouracil plus leucovorin improved DFS. Although the FOLFOX regimen in the MOSAIC study has proven efficacy, administration of this chemotherapy is not ideal: each cycle is composed of a 2-hour infusion of leucovorin and oxaliplatin, followed by a bolus of 5-fluorouracil, and then a 22-hour infusion of 5-fluorouracil on 2 consecutive days every 2 weeks, for a total of 12 cycles. Furthermore, the X-ACT trial found oral capecitabine (Xeloda) to be an equally effective chemotherapeutic option to 5-fluorouracil and leucovorin, although still less effective than FOLFOX. Hence, common AC for high-risk patients with stage II and all stage III CRC is either FOLFOX or capecitabine, unless drug reactions or comorbidities dictate otherwise.

Chemotherapy regimens vary slightly in patients with rectal cancers compared with patients with colon cancers. Patients with rectal cancer also receive neoadjuvant chemotherapy combined with radiation therapy, because this has been found to increase local control of the tumor (thereby increasing the rate of curative surgery) and increase the number of sphincter preservations in patients with low-lying tumors. However, chemotherapy is commonly continued after surgery, and treatment types are like those available for patients with colon cancer.

In recent years, targeted molecular therapies have also gained prominence as cancer treatment options in combination with chemotherapy. One such drug, bevacizumab (Avastin), is a monoclonal antibody against vascular endothelial growth factor (VEGF), and thus is an antiangiogenic agent that helps suppress tumor growth. This targeted therapy yields the greatest benefit when used in combination with chemotherapy in patients with metastatic CRC. Another antiangiogenic agent, aflibercept (Zaltrap), has been approved for use in metastatic CRC, but many oral VEGF inhibitor therapies have yet to show any improvement in progression-free survival. Anti–epidermal growth factor receptor therapy has also been explored, with cetuximab and panitumumab showing promise for patients with metastatic CRC who have the wild-type KRAS gene. However, to date these targeted therapies have not shown benefit in the adjuvant setting. Current clinical trials are underway to investigate optimal sequencing strategies in combination with chemotherapy as novel molecular targeted therapies emerge as the forerunners in the future of cancer treatments.

Timing of AC: is it important?

Based on the aforementioned studies, current governing health institutions recommend that all high-risk stage II and all stage III patients with CRC receive AC, ideally within 8 weeks of surgical resection. In Canada, government health agencies responsible for improving provincial cancer care, such as Cancer Care Ontario (CCO), mandate treatment timelines. In addition to the overall 8-week treatment timeline, CCO advises that Ontario cancer centers should aim for the following wait times: time from surgeon’s referral to medical oncology consult should be no longer than 14 days, and medical oncology consult to the start of AC treatment should be no longer than 28 days. However, these timelines are arbitrary, set on the basis that most clinical trials randomize patients to a treatment arm and begin AC within 6 to 8 weeks after surgical resection.

Animal and mathematical modeling, in addition to human molecular-based studies, have provided strong clues that the timing of AC is important. Research in animals has shown that the surgical removal of tumors may stimulate an increase in the number of residual tumor cells by prompting the conversion of arrested (G0) cells into a cycling phase. There is similar evidence that the surgical resection of tumors may activate dormant distant metastasis and the stimulation of angiogenesis via the release of circulating factors. Research also suggests that major surgery can trigger altered host defense mechanisms, in which cytotoxic T cells and natural killer cell activity are suppressed, facilitating the proliferation of micrometastatic sites. These data suggest that the time between surgery and the start of AC is critical in preventing the development of metastatic cancer. Mathematical modeling based on empirical data has indicated the same concept: that the probability of eradicating micrometastatic cancer after surgical resection is inversely proportional to the tumor burden that remains to be destroyed, and consequently is inversely proportional to the time from surgery to AC. Based on this model, the window of opportunity to eradicate these metastatic sites is 100 days, after which the curative potential of AC has been surpassed.

The issue of optimal timing between surgery and AC has also been studied for other tumor sites. Studies have shown that patients with breast cancer who start AC beyond 4 months (12 weeks) after surgery show a marked decrease in the effectiveness of their therapy. The International Breast Cancer Study Group also investigated the matter of optimal timing of AC; their research suggested that ER-negative, premenopausal patients experienced a significant increase in DFS when AC commenced within 20 days of surgery compared with patients who commenced AC within 21 to 86 days of surgery. A more encompassing meta-analysis of patients with breast cancer also found that a 4-week delay in time to AC was significantly associated with a decrease in OS and DFS. These studies, although focused on another tumor type, also provide strong evidence that the timing of AC is essential in achieving optimal DFS.

The association between the timing of AC and CRC outcomes has also been increasingly studied. Several retrospective reviews and prospective trials have corroborated the theory that a delay in the commencement of AC is associated with worse outcomes in patients with CRC; specifically, most studies showed that a delay of greater than 8 to 12 weeks greatly reduces the efficacy of adjuvant treatment. However, optimal treatment times were not well studied until recently. In a recent meta-analysis, Biagi and colleagues investigated the correlation between time to AC and survival outcomes in patients with CRC; an analysis of 10 studies (7 published articles, 3 abstracts) involving 15,410 patients yielded an association between longer wait times to AC and worse survival outcomes. Their findings also suggest that relative OS decreases by 14% for every 4-week delay to the initiation of treatment. Based on these results, AC treatment should optimally begin within 4 to 6 weeks of surgical resection.

Timely AC treatment is imperative in improving patient outcomes. As such, some hospitals have begun to investigate their institutional wait times for AC following surgical resection. A recent retrospective review conducted as St Michael’s Hospital (SMH), an inner-city academic Toronto hospital, sought to investigate hospital wait times and elucidate barriers to timely AC treatment. Only 37.1% of patients at SMH were treated within the timeline of 4 to 6 weeks recommended by Biagi and colleagues, and the wait time between surgery and first AC treatment averaged 50.4 days (7.2 weeks). A larger retrospective study, which included patients from both SMH and Mount Sinai Hospital in Toronto, found similar results: the mean time from surgery to first AC treatment was 8.2 weeks. Based on these results, steps need to be taken to reduce the time between surgical resection and AC in order to improve outcomes for patients with CRC.

Challenges and barriers to AC

There are several barriers that may delay the start of adjuvant treatment. There are both clinical and systemic challenges to initiating therapy. Among clinical barriers to treatment, age and socioeconomic factors seem to present the biggest challenges to timely treatment. As with any treatment decision, patient preference may also play a role in the time to initiation of AC.

However, perhaps one of the biggest challenges to timely AC treatment is the presence of postoperative complications, which prolong patient recovery times. Several studies have shown that surgical complications, such as problems with wound healing, are significantly associated with delays to the initiation of AC. Furthermore, surgical complications have also been linked to worse OS and DFS. As a result, efforts have been made to encourage surgical research designed to minimize these complications and optimize patient care during recovery. For example, a recent study found that the use of a Pfannenstiel incision, commonly used in gynecologic surgery, is associated with a minimized risk of postsurgical would complications in minimally invasive CRC surgery.

Efforts should also be made to properly counsel patients regarding modifiable factors that could affect their surgical outcomes. For example, proper nutrition before surgery and early initiation of enteral feeding after surgery have both been shown to minimize hospital stay and shorten recovery times after surgical resection. Smoking and alcohol cessation have also been attributed to better surgical outcomes. It is also important that diabetic patients are well controlled, because poor postoperative glycemic control has been associated with an increase in surgical site infections. Thus, it is critical that postoperative recovery pathways are in place to minimize surgical healing times, and hence allow patients to begin AC as soon as possible.

Systemic barriers, primarily institutional wait times, also play a key role in delaying the start of AC. A retrospective review conducted at an inner-city Toronto hospital identified the time from surgery to medical oncology referral, time awaiting port-a-cath or central venous access device insertion for the AC treatment infusion, and time from medical oncology consult to first AC as significant systemic barriers to timely treatment. These wait times may also depend on other factors, such as the time to procure a pathology report, which could be optimized by critically evaluating the clinical care pathway. For example, institutions with on-site pathology laboratories may receive pathology results more quickly than those who depend on outside laboratories. These significant wait times also clearly indicated the importance of timely referrals among health care professionals, and also highlight the need for a cohesive, multidisciplinary, team-based approach to oncology care. The introduction of multidisciplinary cancer conferences (MCCs) has improved the communication between cancer-treating physicians, engaging all health care professionals involved in the patient’s cancer care pathway. These MCCs are usually weekly meetings of surgeons, medical oncologists, radiation oncologists, pathologists, and radiologists who discuss cancer cases to ensure that optimal treatment is recommended based on current treatment guidelines.

Delays in initiation of treatment may also be related to physician or patient indecision and reluctance. Maintaining dose-intense regimens is efficacious, and dose modifications may detract from the full benefits of chemotherapy. As such, physicians may delay the start of treatment until they are confident that patients are well enough to begin a treatment at full dose intensity, to increase the chances of receiving the full benefits of AC.

Physicians may also be reluctant to administer chemotherapy to elderly patients, because patients more than 70 years old are often underrepresented in clinical trials (most CRC trials have an age exclusion of greater than 71–75 years), and thus the results may be difficult to extrapolate to the older patient population. This underrepresentation is surprising, because the median age of patients with CRC is 63 to 65 years; this disease is a disease of the elderly. However, age should not be seen as a barrier to treatment; physiologic age, rather than biological age, is a better predictor of treatment tolerance. The functional status of elderly patients more than 70 years of age should be assessed in collaboration with geriatric oncologists when discussing chemotherapy treatment, preferably by the use of a comprehensive geriatric assessment. For this reason, it is up to the physician’s discretion as to how best to administer the chemotherapy for their patients’ greatest benefit.

Some studies have begun to explore the issue of chemotherapy regimens for elderly patients. A prospective study of 844 patients with CRC found that patients older than 70 years in good performance status tolerated 5-fluorouracil-containing therapies just as well as younger patients, with similar beneficial outcomes. A recent phase III trial, AVEX, also evaluated the safety and efficacy of capecitabine with bevacizumab for patients with metastatic CRC more than 70 years of age, and showed that this chemotherapy regimen was well tolerated and safe with improvements in survival. Finally, a patient’s indecision to begin a chemotherapy regimen may also factor into the delay to AC.