Timing Versus Duration of Adjuvant Therapy for Pancreatic Cancer: All the Lessons We Need in Life Are Taught to Us As Children

As children most of us heard Aesop’s fable, “The Tortoise and the Hare,” in which a slow, cautious tortoise wins a race against a much faster but far less cautious rabbit. The tortoise plods on with a singleminded purpose of completing the race, whereas the rabbit allows other distractions to cause him to lose the race. In the article by Valle et al that accompanies this editorial, we are once again taught this important lesson. These investigators failed to show an advantage for early institution of postoperative adjuvant therapy in patients with localized pancreatic cancer. Rushing to start therapy has always been a guiding principle of oncologic practice and is based on the belief that we should not give micrometastases a chance to grow. However, it is possible to lose sight of our ultimate goal, which is to deliver adequate adjuvant therapy to prevent the cancer from returning, even if it is in only a small cohort of patients. Although the data in the study by Valle et al are provocative, it is important to consider that this was a retrospective analysis and therefore is vulnerable to bias. For instance, incomplete administration of chemotherapy may be a surrogate for another factor, such as intercurrent illness or even bone marrow infiltration by the cancer, limiting the use of drugs that cause hematologic toxicity. We do not know if completion of chemotherapy over an extended period provides the same benefit as completion of chemotherapy over the planned 6-month time course. The study by Valle et al suggests that early institution of adjuvant chemotherapy, when the patient might not have fully recovered from recent surgery, does not provide the advantage that may have been predicted. In breast cancer, it has been shown that early initiation of chemotherapy within 21 days of surgery did not result in improved 5-year disease-free survival (DFS) or overall survival (OS) compared with initiation of chemotherapy 21 days or longer after surgery. However, the breast cancer literature also shows that initiation of chemotherapy later than 12 weeks after surgery compromised the effectiveness of the adjuvant therapy with worsening OS, which supports the idea that although one should not rush into therapy, it is important to avoid excessive delays as well. In colon cancer, the meta-analysis by Biagi et al concluded that every 4-week delay in initiation of adjuvant chemotherapy resulted in poorer OS and DFS. A similar detriment was not seen in pancreatic cancer in the current analysis. There is no question that pancreatic surgery is a more morbid surgery than colon resection, with a higher complication rate and longer recovery time. Hence, earlier initiation of chemotherapy before the patient has fully recovered may result in more complications or delays of therapy, which may compromise the effectiveness of therapy. More importantly, Valle et al show that rather than the timing of the start of chemotherapy, it is the ability to receive all planned cycles of chemotherapy that is important (OS, 28.0 v 14.6 months; P .001; relapse-free survival, 16.56 v 8.90 months; P .001). In fact, for patients unable to complete all six cycles, those who started adjuvant therapy later did better with regard to relapsefree survival. It is unclear why that may be, given that the authors supply insufficient data to make that assessment. One may conjecture that those patients who started later were in better shape and were able to receive more therapy on schedule than those who started earlier. It seems that in pancreatic cancer, slow and steady does win the race, rather than a rush to start with an inability to finish. The importance of completing all planned therapy has been seen in other diseases as well. An analysis of the SEER database by Neugut et al, evaluating the duration of adjuvant chemotherapy for stage III colon cancer and survival in the elderly (age 65 years or older) revealed that for those who lived 8 months or longer after diagnosis, more than 30% of elderly patients discontinued chemotherapy early, and that those who received 1 to 4 months of chemotherapy had poorer survival (hazard ratio, 0.59) and poorer cancer-specific survival (hazard ratio, 0.53) than those who received 5 to 7 months of chemotherapy, supporting the importance of completing the planned treatment program. The data presented by Valle et al will help allay patient fears of losing ground, so to speak, by not starting treatment right away, before they have sufficiently recovered from surgery. In this long distance race, it is not who sprints fastest from the starting line, but who can keep up the pace and complete the race that will determine the winner. What the current analysis of European Study for Pancreatic Cancer (ESPAC) trial 3 does not answer is whether initiation of chemotherapy after 12 weeks is beneficial, given that patients had to be eligible to start therapy within 12 weeks of surgery; thus, the current analysis is a comparison between patients who started therapy within 8 weeks versus those who started therapy between 8 and 12 weeks after surgery. With the data presented, we know that adjuvant therapy can be initiated as late as 12 weeks without detriment, but we have no data JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 6 FEBRUARY 2