This study demonstrated that fewer than half of stage II (37.5%) and just over half of stage III (54.2%) rectal cancer patients diagnosed from 1992 through 1999 initiated combined chemoradiation therapy. This is consistent with earlier studies of stage II and III rectal cancer patients according to 1992–1996 SEER-Medicare data that reported chemoradiation initiation rates of 37% and 42%.12,13
For stage II patients, we found significantly increasing rates of adjuvant chemotherapy from 1992 to 1999 (from 34.0% to 53.0%) and consistently higher rates among stage III compared with stage II patients. Adjuvant radiation therapy use also significantly increased for stage II patients from 44.2% to 59.1% over this study period. Although no statistically significant trend could be detected, adjuvant chemotherapy use by stage III patients increased from 60.7% in 1992 to 75.2% in 1999, and adjuvant radiation therapy increased from 64.4% to 67.9% over that period. This is consistent with a report that used the SEER registry from 2000, wherein about ⅓ of patients with nonmetastatic advanced rectal cancer did not receive adjuvant radiation therapy.28
The most dramatic change over the course of our study was the increase in use of neoadjuvant therapy for both stage II and III patients. Although still infrequently received, by 1999, neoadjuvant chemotherapy rates had more than tripled to approximately 20%, and neoradiation therapy more than doubled for stage II patients and increased 4-fold for stage III patients, both to more than 20%. During this period, oncologists recognized that neoadjuvant treatment was more easily tolerated than adjuvant treatment,29,30
and there were indications that neoadjuvant therapy offered improved disease control.31,32
Recent studies have confirmed that neoadjuvant therapy offers more favorable local control and an increased likelihood of a sphincter-sparing surgical procedure.30,33,34
Although neoadjuvant therapy has beneficial aspects, it does not constitute a complete course of adjuvant therapy.
Our data suggest that completion of therapy had a significant impact on survival for stage II and III patients. These findings confirm the results of clinical trials that have demonstrated that the addition of chemotherapy to external-beam pelvic radiation provides optimal post-treatment survival.8
The adjusted relative risk of cancer-related death for patients initiating but not completing chemoradiation was comparable to that of patients with no adjuvant therapy, emphasizing the importance of completing adjuvant treatment once it has begun.
Stage III patients in our study who received a complete course of chemotherapy but an incomplete course of radiation therapy had a lower risk of cancer-related death than those with no therapy, but this finding did not achieve statistical significance, perhaps because of the small number in this group (n = 89). Future work with a larger population should explore whether treatment with surgery and only complete chemotherapy is necessary for improved survival of stage III rectal cancer patients. However, this does not take into account the importance of preventing local recurrence, where the role of radiation therapy is, perhaps, most important.33,35
Whereas some have argued that meticulous surgical technique may be adequate to provide excellent local rectal cancer control,36,37
the Dutch rectal cancer trial demonstrated that even with optimal surgical technique, radiation therapy significantly decreased local recurrence rates.35
Our data do not allow us to examine surgical technique or local recurrence, the outcome most affected by inadequate radiation treatment. Therefore, our findings cannot be interpreted as rationale for changing adjuvant radiation therapy recommendations for these patients.
Our data indicated that only 54.2% of stage III patients and 37.5% of stage II patients initiated both chemotherapy and radiation therapy as indicated by NIH guidelines. Complying with recommended therapy for rectal cancer is challenging because the course for chemotherapy and radiation is lengthy, and there is significant toxicity. The majority of patients who initiated radiation therapy completed the recommended course, but fewer patients who started chemotherapy completed treatment. Of those who initiated chemoradiation, 47.6% of stage II patients and 67.5% of stage III patients completed both treatments. Given the relatively low rates of treatment initiation and significant attrition from therapy completion, a strikingly low proportion of all rectal cancer patients completed chemoradiation, 22.6% of all stage II and 43.6% of all stage III patients in 1999.
Do these findings reflect physician skepticism about the necessity of these treatments, particularly for elderly patients for whom the survival benefit may be outweighed by treatment toxicity? Although it is difficult to answer this question with the current data set, the higher completion rates for patients with stage III compared with stage II disease suggest that patients and physicians may be using their judgment on the level of disease advancement to decide how vigorously to pursue treatment completion. An alternative explanation is that stage III patients have less treatment-related toxicity than stage II patients, but research suggests similar toxicities for both groups.14,30
This study has several limitations. First, this is a retrospective study based on administrative data. We did not have access to detailed clinical records that could provide additional variables influencing treatment, such as severity of comorbidity. Although we used logistic regression modeling techniques to adjust for all confounding variables identifiable in these data, including age, sex, stage of disease, comorbidity, and year of treatment, there may be unmeasured confounders.
Second, we do not have data on treatment rates for populations younger than 65 years of age. Future work could explore treatment in these younger populations, as well as treatment among patients with different characteristics (eg, sex, marital status, residence location) to determine whether there are subpopulations that are more and less likely to receive adjuvant chemoradiation therapy for rectal cancer.
Third, our findings of a more favorable mortality rate associated with completion of therapy may be related to other unexplored factors. Recent studies suggest that mortality is related to tumor characteristics, such as size, number of nodes, location of the primary tumor, surgical method, and complete pathologic response to neoadjuvant therapy.38–44
Although we controlled for tumor extent (T classification) and number of nodes, we were unable to control for other tumor and treatment factors. Needed is future analysis of the association of these variables with cancer-specific mortality. The lower mortality rate associated with completion of therapy may also be related to patient selection rather than to therapeutic benefit, although we used cancer-specific survival to minimize potential confounding from noncancer-related medical conditions.
Our results demonstrate clear, cancer-specific, survival benefit for a general population of elderly stage II and III rectal cancer patients who complete a full course of recommended therapy yet who have low rates of chemoradiation completion. Although the past decade has brought refinements in surgical technique and a move toward neoadjuvant therapy, this study underscores the importance of a complete course of adjuvant chemoradiotherapy for patients with stage II and III rectal cancer. This study’s findings provide large-scale, real-world confirmation of the clinical trial data that has shaped our practice patterns in rectal cancer therapy and should serve as encouragement for primary care physicians, medical oncologists, radiation oncologists, and oncology nurses to make all possible efforts to support rectal cancer patients through a full course of adjuvant therapy.