Was Breast Conserving Surgery Underutilized for Early Stage Breast Cancer? Instrumental Variables Evidence for Stage II Patients from Iowa

The initial treatment decision for patients with early stage breast cancer (stages I, IIa, and IIb) is the surgical approach for local tumor control—mastectomy (MAS) or breast conserving surgery plus irradiation (BCSI). In its 1991 Consensus Statement on this decision, the National Institutes of Health (NIH) recommended BCSI for most women with early stage breast cancer (ESBC) based on randomized controlled trial (RCT) evidence showing equivalent survival benefits of BCSI and MAS and the cosmetic superiority of BCSI (National Institutes of Health Consensus Conference 1991). The NIH statement suggested that patients should be educated on the choices and they should make decisions consistent with their preferences. The BCSI rates increased in the United States afterward, but many ESBC patients still do not receive BCSI, and BCSI rates vary well beyond what would be expected based solely on differences in patient preferences (Benedict et al. 2001; Du et al. 2000; Guadagnoli et al. 1998; Keleman et al. 2001; Morrow et al. 2001; Riley et al. 1999). The slow and varied rate of BCSI diffusion in the United States puzzled researchers and policymakers (Morrow et al. 2001; Adams 2001, Keating et al. 2001). This phenomenon has been attributed to a lack of provider knowledge of the RCT evidence. Interventions to increase the BCSI rate have been suggested (Keleman et al. 2001; Benedict et al. 2001; Nold et al. 2000; Stafford et al. 1998). An alternative explanation for the slow and varied BCSI diffusion rate, though, necessitates further research prior to initiating efforts to increase BCSI rates. Providers may have been aware of the NIH Consensus Statement and its supporting RCT evidence and they may have had beliefs consistent with the NIH for patients clinically similar to those in the RCTs. However, providers may have differed with the NIH in whether the RCT evidence could be extrapolated to ESBC patients that were clinically different from the average patients in the RCTs. Providers may have believed that MAS offered survival benefits for many ESBC patients and BCSI rate variation may have resulted from regional differences in these beliefs. If providers sorted patients between MAS and BCSI appropriately, an increase in the BCSI rate would have worsened survival for patients whose surgery choices were affected (i.e., ESBC patients who would have otherwise received MAS). Therefore, before initiating efforts to increase BCSI rates, policymakers need estimates of the relative survival benefits of BCSI and MAS for the set of patients who would switch from MAS to BCSI as a result. In this study we assume that the set of patients whose surgery choice would be more likely affected by a BCSI rate increase would be those patients for whom the RCT evidence supporting the survival equivalence between BCSI and MAS is the least certain. The RCT evidence supports the survival equivalence of BCSI and MAS for the “average” ESBC patient in each RCT (Veronesi et al. 1990; Arriagada et al. 1996; Jacobson et al. 1995; Fisher et al. 1995; van Dongen et al. 2000). However, if the survival benefits of BCSI and MAS are heterogeneous across ESBC patients, it is not clear whether this evidence can be generalized to patients with clinical circumstances differing from the average patients in the RCTs. Patients with ESBC are classified with stage I disease if they have localized tumors less than 2 cm with no lymph node involvement; stage IIa if they have either a localized tumor less than 2 cm with positive lymph node metastasis on the same side, or a tumor between 2 and 5 cm with no lymph node involvement; and stage IIb if they have either a localized tumor between 2 and 5 cm with positive lymph node metastasis on the same side, or a tumor greater than 5 cm with no lymph node involvement. Two RCTs included only stage I patients and provided compelling evidence that MAS offers no survival benefit for these patients (Veronesi et al. 1990; Arriagada et al. 1996). The evidence for stage II patients is less certain. The remaining studies contained a mix of stage I and stage II patients and each estimated a single average treatment effect (Jacobson et al. 1995; Fisher et al. 1995; van Dongen et al. 2000). Because no studies contained only stage II patients, it is less certain whether these estimates can be generalized to stage II patients. In fact, in the study with the most stage II patients (mainly stage IIa) tumor size and nodal involvement were related to an increased risk of local recurrence for BCSI patients but not for MAS patients (van Dongen et al. 1992). As a result of this uncertainty, we focused this study on ESBC patients with stage II disease. We apply instrumental variable (IV) methods to obtain estimates of BCSI survival effects relative to MAS for stage II ESBC patients in Iowa from 1989–1994. Instrumental variable methods group using measured instrumental variables (instruments) that have the following two properties: (1) they are related to treatment choice and (2) they are assumed related to outcomes only through their effect on treatment choice (no direct effect on outcome and no indirect effect on outcome through unmeasured confounders). Instrumental variable estimates are obtained by exploiting the treatment variation across patient groups defined by the instruments. The inferences made from IV estimates are conditional on the assumption that instruments essentially ex post randomize unmeasured confounders across patient groups. Given this assumption, IV methods yield consistent estimates of treatment effects for marginal patients (Angrist, Imbens, and Rubin 1996; Imbens and Angrist 1994; McClellan, McNeil, and Newhouse 1994; Harris and Remler 1998; Brooks, McClellan, and Wong 2000; McClellan and Newhouse 2000) that are defined as the subset of patients whose treatment choices varied with the instrument. In addition, previous IV research assumed that IV estimates can be generalized to the set of patients affected by treatment rate changes as marginal patients are also theorized to come from the set of patients for whom the best treatment is least certain (McClellan, McNeil, and Newhouse 1994; Harris and Remler 1998; Brooks et al. 2000a). However, marginal patients associated with a single instrument may not be representative of all patients potentially affected by a treatment rate change. We assess the validity of this assumption by using different instrument specifications. The nature of IV estimation limits our ability to generalize the findings beyond the set of marginal patients defined by our instruments, but this empirical scenario provides an opportunity to demonstrate the applicability of IV methods to policy-based research questions.