Which preoperative approach is superior: long-course or short-course?
Despite a wide consensus regarding preoperative RT followed by TME for locally advanced presentations (eg, T3-T4, N+), the preferred RT remains undetermined (SC RT vs LCRTCT). A recent survey of surgeons from 123 centers in the US, Europe, and Asia with at least 5 years of experience in rectal cancer management noted variations and inconsistencies in the indications for preoperative RT. Of those interviewed, 92% preferred LCRTCT preoperatively. SC therapy was preferred by 10% of US surgeons and 16% of non-US surgeons, although these preferences were insignificant.
As Minsky has highlighted, the choice of preoperative approach is influenced by historical practices. North American and European groups reported improved results with postoperative RTCT through the 1980s, leading to its shift to the preoperative setting: this preoperative approach was adopted by Central and Southern European countries.
In contrast, since their initial experiences in the 1980s and 1990s, groups such as the Scandinavian, Dutch, and British (who considered systemic CT for colon and rectal cancer as investigational), have been concerned about the risk of additional toxicity from simultaneous RT and CT and have questioned the value of concomitant use of RT and CT. These groups have considered the radiobiological features of various RT schedules and their impact on the biological equivalent dose, and they have preferred to increase the dose per fraction rather than use chemosensibilization to obtain a more effective schedule.[10,34]
The direct comparison of outcomes from phase III trials has failed to indicate the preferred approach: few randomized studies have evaluated this issue by direct comparison. In a Polish trial of 312 patients who received SC RT (and surgery within 7 days) or LCRTCT (with a 5-FU–based chemotherapy regimen) followed by surgery 4 to 6 weeks later, no significant difference in survival and local control was found between groups at a median follow-up of 4 years. However, the LC group had a significantly lower rate of CRM involvement than the SC arm (4% vs 13%). An Australian study randomized 326 patients to similar SC and LC schedules, with postoperative adjuvant chemotherapy in both arms. At a median follow-up of 5.9 years, 5-year survival and 3-year local recurrence did not differ.
Both trials reported significantly higher rates of grade III/IV acute toxicity in the LCRTCT arm.
In a recent review, Buiko lamented the lack of sufficient evidence on local control and survival to suggest the superiority of one schedule or the other. Clinical considerations were not addressed extensively in the Polish and Australian studies. Generally, LCRTCT results in a higher proportion of sphincter-saving procedures and manages threatened or involved CRMs and MRFs better; it can also render an initially unresectable lesion resectable and can effect higher downstaging and pCR rates. Most series have reported improved long-term outcomes and excellent local control rates for patients who achieve a pCR after preoperative RTCT, independent of initial T and N stage.
Although increases in pCR rates with RTCT have not improved survival in randomized studies, a recent pooled analysis of randomized trials of preoperative RTCT reported that pCR identifies a subgroup with better survival indicators with regard to local control, distant metastases, and overall survival.[31,38] Few studies have addressed the question of whether surgery can be avoided in the best responders after RTCT.[39,40] In contrast, SC RT (with early surgery) has a low likelihood of inducing a pathological or clinical response because it requires adequate time after radiation-induced biological damage; however, this approach is less demanding, is associated with less acute toxicity (increasing the adherence to protocols), and is shorter in duration than LCRTCT. The chief advantages of SC RT and LCRTCT are listed in Table 1.
The payment system should also be considered, since this has influenced the choice of SC RT or LCRTCT in some European countries. For instance, Germany and Switzerland (where LCRTCT is usually preferred, as in the “German Study”) have a fee-for-service reimbursement system that records each service (eg, simulation, planning, treatment session); thus, longer treatments do not pose an economic problem, because they are reimbursed more than shorter treatments. In the Netherlands and the UK (where SC therapy is preferred, as in the “Dutch trial”), reimbursements are made through a budget or case payment. The department receives a set amount of money for each patient or treatment; thus, in some cases, fewer fractions per treatment or less complex therapies are preferred to longer treatments.
Two of the most important oncological guidelines are those issued by the National Comprehensive Cancer Network (NCCN) and the National Cancer Institute (NCI) (in its Physician Data Query [PDQ] database). These guidelines are not directly comparable, because the former classifies by T, N, and M parameters, whereas the latter uses stages (0 to IV); the recommendations given by the NCCN for some TNM-based classes of presentations do not always correspond to one single stage-based classification.
However, both guidelines agree on the treatment approach for locally advanced resectable lesions included in stages II and III; presentations from T3N0 to Tany N+ are grouped together by the NCCN—a system that includes T4N0 (for Stage II per the PDQ schema) and T4N+ (defined as “Tany, N1-2” in the NCCN schema, and corresponding to stage III in the PDQ schema) in the same group of indications. The organization of these guidelines also reflects the fact that even initially unresectable lesions can undergo significant downstaging after integrated treatment (as occurs more often with LCRTCT, although SC therapy is usually preferred for T3 lesions).
Both guidelines recommend a preoperative RTCT 5-FU–based regimen (or oral capecitabine(Drug information on capecitabine) [Xeloda]); transabdominal TME; postoperative RTCT for patients who do not receive preoperative therapy (eg, due to clinical understaging or comorbidities); and eventual adjuvant chemotherapy.
The institutions that issued these guidelines are both American; that they recommend that preoperative RT be delivered as LCRTCT is not surprising, given that this schedule is widely used in the US. It is also widely used in Central/Southern European countries, whereas Northern Europe and the UK often use an “SC RT alone” schedule.
The indications in European guidelines vary widely. In 2008, the “EURECA (European Rectal Cancer) project” was conducted in Europe to determine the degree of consensus on several topics, with the aim of improving clinical practice and research. Endorsed by the European Society of Medical Oncology (ESMO), the European Society of Surgical Oncology (ESSO), and the European Society of Therapeutic Radiation Oncology (ESTRO), the consensus document was published in 2009. For treatment of intermediate stages (clinically [c] resectable or pathological [p] T3–4 or N1–2 M0), there was moderate consensus that SC therapy reduces local relapse. LCRTCT was also considered one of the primary options; however, LCRTCT was the preferred modality for more advanced unresectable lesions.
Other guidelines for LARC are summarized in Table 2.[44-50]
Thus, we conclude that due to its potential ability to increase downstaging and pCR and its efficacy in CRMs, LCRTCT is the preferred option for more advanced lesions or cases in which MRI of the MRF shows a risk of involvement. LCRTCT has tremendous potential for lower-lying lesions, increasing the likelihood of organ sparing; it also identifies the best responders and nonresponders to treatment—patients for whom decisions to modulate surgery or intensify postoperative treatments might be made differently, on the basis of the magnitude of their response to LCRTCT (which significantly correlates with prognosis).