the Cancer Outcomes Research Program, Cancer Care Nova Scotia and Dalhousie University, Halifax, Nova Scotia
    Ottawa Regional Cancer Centre and University of Ottawa
    Ottawa Hospital and University of Ottawa, Ottawa
    Ontario Clinical Oncology Group
    Juravinski Regional Cancer Centre and McMaster University
    Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton
    Toronto-Sunnybrook Regional Cancer Centre and University of Toronto, Toronto
    Northwestern Ontario Regional Cancer Centre, Thunder Bay
    Kingston Regional Cancer Centre, Kingston, Ontario
    University of British Columbia, Vancouver, British Columbia, Canada

    ABSTRACT

    PURPOSE: Most women with breast cancer are diagnosed at an early stage and more than 80% will be long-term survivors. Routine follow-up marks the transition from intensive treatment to survivorship. It is usual practice for routine follow-up to take place in specialist clinics. This study tested the hypothesis that follow-up by the patient's family physician is a safe and acceptable alternative to specialist follow-up.

    PATIENTS AND METHODS: A multicenter, randomized, controlled trial was conducted involving 968 patients with early-stage breast cancer who had completed adjuvant treatment, were disease free, and were between 9 and 15 months after diagnosis. Patients may have continued receiving adjuvant hormonal therapy. Patients were randomly allocated to follow-up in the cancer center according to usual practice (CC group) or follow-up from their own family physician (FP group). The primary outcome was the rate of recurrence-related serious clinical events (SCEs). The secondary outcome was health-related quality of life (HRQL).

    RESULTS: In the FP group, there were 54 recurrences (11.2%) and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) and 30 deaths (6.2%). In the FP group, 17 patients (3.5%) compared with 18 patients (3.7%) in the CC group experienced an SCE (0.19% difference; 95% CI, –2.26% to 2.65%). No statistically significant differences (P < .05) were detected between groups on any of the HRQL questionnaires.

    CONCLUSION: Breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that HRQL will be negatively affected.

    INTRODUCTION

    The majority of women with breast cancer are now diagnosed at an early stage and more than 80% will be long-term survivors.1,2 A combination of high incidence and survival makes breast cancer the most prevalent cancer in women.3,4 It is estimated that there are more than 2 million breast cancer survivors in the United States5 and 151,000 in Canada,6 and that this number is increasing steadily.4

    For women with breast cancer, post-treatment routine follow-up marks the transition from intensive treatment to survivorship.7 It is generally accepted that the principal elements of routine follow-up are periodic visits for history and physical examination and annual surveillance mammograms.8-11 For patients and physicians, detection of recurrent and new primary breast cancers underpin the follow-up program.12-14 Providing psychosocial support to maintain health-related quality of life (HRQL) is an important goal of follow-up.9,12,13,15-18

    Many authors have speculated that follow-up visits engender anxiety about possible recurrence.19-23 Conversely, many others have suggested that although there may be a transient increase in anxiety,15 patients are ultimately reassured by this practice.24 There is little empirical evidence to support either view,19,23 and both views are likely to be correct because there is a substantial variation between patients in both needs and preferences.19,25 Less frequent or less intensive follow-up programs are well accepted26,27 and do not affect HRQL.27 Patients with anxiety are likely to prefer routine investigations28 and are more likely to be observed long term in cancer clinics or by oncologists.29,30 Studies on breast cancer patients’ views show that the aspects of follow-up they value most are regular and thorough clinical examination, continuity of clinician, and access to specialist care when needed.25,31-33

    It is usual practice in most Western countries for breast cancer follow-up to be provided by specialists in cancer clinics or community practice.25,28,34-36 Three guideline statements8-10 recommend continuity of care with a physician who has the skills to provide follow-up. Family physicians are typically the providers of general and preventive health care services. Although traditionally they have not played a formal role in breast cancer follow-up, studies suggest they play an important informal role: many studies have shown that most recurrences are detected when patients develop symptoms between regularly scheduled follow-up appointments,14,20,37,38 often presenting first to their family physician.39-42 Several studies have shown that family physicians prefer a more active role in follow-up.22,43,44

    We hypothesized that routine follow-up by the patient’s family physician, who is the practitioner best suited to provide continuity of care, is a safe and acceptable alternative to specialist follow-up of breast cancer patients. In a preliminary pilot study conducted in the United Kingdom, we found that the transfer of routine follow-up care to the family physician did not result in an increase in the time to diagnosis of recurrence.40 Anxiety and other domains of HRQL were unaffected, patient satisfaction was greater,45 and patient and health service costs were less.46 However, that study had a small sample, only 18 months of follow-up, and used an intermediary outcome. We report here the results of a large, multicenter, randomized, controlled trial designed to test this hypothesis further.

    PATIENTS AND METHODS

    Study Design

    We conducted a multicenter, randomized, controlled trial of routine follow-up care after patients completed adjuvant therapy for early-stage breast cancer. Six of the nine regional cancer centers in Ontario, Canada, participated in the study. The institutional review board of each participating institution approved the study protocol and all patients gave written informed consent. Patients were enrolled between January 1997 and June 2001, and were observed until June 2003.

    Study Population

    Women with early-stage breast cancer who had completed adjuvant chemotherapy, radiotherapy, or both at least 3 months previously; who were disease free; and who were between 9 and 15 months after diagnosis were targeted. Patients may have continued receiving adjuvant hormonal therapy. Patients were excluded if they had persistent complications of primary treatment; were unable to comply with the study protocol including completing questionnaires; were previously enrolled in a study that required continued specialist follow-up; or were actively observed at a cancer center for another primary cancer.

    Study Procedures

    Patients were enrolled onto the study through tertiary-care cancer centers in Ontario where they had received their adjuvant treatment and were now receiving routine follow-up care. After patients provided informed consent, they were randomly allocated to treatment groups by a telephone call to the trial coordinating center of the Ontario Clinical Oncology Group. Randomization was conducted using a computer-generated center-specific schedule. Patients were allocated in a 1:1 ratio to receive follow-up either in the cancer center according to usual practice (CC group) or from their own family physician (FP group). Family physicians were provided with a one-page guideline on follow-up that recommended the following: physical examination and medical history every 3 to 6 months for 3 years, every 6 months for 2 years, and then yearly indefinitely; mammograms yearly; diagnostic tests to investigate signs or symptoms suggestive of recurrent or new primary cancer, but such tests were not to be performed routinely (Fig 1) . For women taking tamoxifen, the guideline recommended that a history of vaginal bleeding be taken at each visit and a pelvic examination be performed annually. Family physicians were instructed to refer patients back to the cancer center if a recurrence or new primary breast cancer developed. For patients in the FP group, if a surgeon had been involved in the patient’s follow-up care, that follow-up was also transferred to the FP.

    Outcomes

    The primary outcome was a recurrence-related serious clinical event (SCE) defined as any one of spinal cord compression, pathologic fracture, hypercalcemia, uncontrolled local recurrence, brachial plexopathy, or poor functional status (Karnofsky performance score [KPS]  70)47 at the time of diagnosis of recurrence. The secondary outcome was HRQL as assessed using the Medical Outcomes Study Short Form 36-Item General Health Survey (SF-36)48 and the Hospital Anxiety and Depression Scale (HADS)49 while patients were recurrence free. The SF-36 is scored to yield two summary scales: the Physical Component Summary (PCS) scale measuring physical health and the Mental Component Summary (MCS) scale measuring mental health. In all cases, SF-36 scales yield a score from 0 to 100, with a higher score indicating better quality of life.48 The HADS contains two subscales measuring anxiety and depression, with scores ranging from 0 to 21.49 Higher scores indicate greater levels of anxiety or depression.

    Patients were observed until their 5-year anniversary after random assignment or until June 30, 2003, whichever came first. Patients completed regular assessments until diagnosis of recurrence or study end. For patients who developed recurrence, SCEs were documented at the time of recurrence. All SCEs were adjudicated by a committee, the members of which were unaware of treatment allocation.

    For the primary analysis, the proportion of women with SCEs during follow-up (maximum of 5 years) was tabulated, and the two follow-up strategies were compared and summarized using a risk difference and its associated 95% CI using the Wilson score method. The calculated sample size of 1,045 women was based on the assumption that the SCE proportion would be 4% in both arms, with an upper level of tolerance of 5.5% in the FP arm (ie, a noninferiority margin of 1.5%). A similar analysis was conducted for the secondary outcomes of recurrence and death. Date of diagnosis was defined as the earliest date of a breast cancer–related procedure. All analyses were performed according to the intention-to-treat principle.

    The HRQL standardized scores assessed at baseline and during the subsequent seven follow-ups at 6, 12, 18, 24, 36, 48, and 60 months were summarized as means and change scores from baseline within each group. All available data were included without imputation. Polynomial growth curve models as a function of the actual time from randomization to assessment were fit to the data. The model included a fixed treatment effect, a spatial power correlation structure for the repeated measurements, and an unstructured correlational model for the random patient-specific profiles. The degree of the polynomial (up to a maximum of 5) was selected using the Bayesian Information Criterion.50 All group comparisons at various follow-up times were made within the context of the fitted model. The MIXED procedure in SAS version 9.1 (SAS Institute, Cary, NC) was used. Using this approach, missing data were assumed to be missing at random. Differences between groups were reported as means and their associated 95% CIs.

    Role of the Funding Source

    The sponsors of the research had no role in any aspect of the development, conduct, analysis, or reporting of the study.

    RESULTS

    Study Population

    Between January 1997 and June 2001, 968 women were enrolled onto the trial: 483 patients were allocated to the FP group and 485 were allocated to the CC group. Median follow-up was 3.5 years from randomization (4.5 years from diagnosis), which was identical in both groups: 31.9% of patients were observed for 5 years, 22.1% were observed for 4 years, 22.3% were observed for 3 years, and 23.7% were observed for 2 years or less. The two groups were reasonably well balanced for baseline characteristics (Table 1). The average age was 61 years; 68.7% were node negative; 73.3% had a lumpectomy; 77.3% had radiation; 26.1% had chemotherapy; and 53.2% were receiving adjuvant hormonal therapy.

    Study Outcomes

    In the FP group, there were 54 recurrences (11.2%) or new contralateral breast cancers and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) or new contralateral breast cancers and 30 deaths (6.2%; Table 2). The rate of SCEs was low (35 for 3,240 patient-years of follow-up). In the FP group, 17 patients (3.5%) experienced an SCE compared with 18 patients (3.7%) in the CC group (0.19% difference; 95% CI, –2.26% to 2.65%). The lower bound of the 95% CI was beyond the noninferiority tolerance of 1.5%. We included KPS  70 as one of the SCEs because patients usually have high functional status when recurrence is first diagnosed. Low functional status could suggest the potential for poor management of recurrence related symptoms. As a sensitivity analysis, we examined the effect on the results of excluding the KPS  70 criterion from the main outcome measure. Eleven patients in the FP group and eight patients in the CC group had KPS  70 and no other SCE. By removing these events, only six patients (1.24%) in the FP arm and 10 patients (2.06%) in the CC arm experienced SCEs (0.82% difference; 95% CI, –0.90% to 2.64%).

    HRQL

    Table 3 lists the SF-36 completion status by assessment for each group. A similar pattern was observed for the HADS (data not shown). Figure 2A presents the mean SF-36 MCS and PCS scores over time, and Figure 2B displays the mean HADS anxiety and depression scores during the 60 months of the trial. The SF-36 MCS scores were consistently higher than the normal score of 50, whereas the PCS mean scores were consistently lower. A first-degree polynomial fit all four response profiles well on the basis of the Bayesian Information Criterion. Using the growth curve model, no statistically significant differences (P < .05) were detected between groups over time for any of these scores. Overall, SF-36 PCS declined over time (0.4 units per year; P < .001), SF-36 MCS increased slightly (0.2 units per year; P = .08), HADS anxiety declined (0.08 per year; P = .01), and HADS depression increased slightly (0.04 per year; P = .12).

    DISCUSSION

    Breast cancer survivors often undergo well follow-up by specialists. We have conducted a trial that compared specialist follow-up with FP follow-up. This study showed both that SCEs are extremely rare (35 during 3,240 patient-years) and that they occur with equal frequency, regardless of the follow-up arrangements. Prompt diagnosis of recurrence is a principal concern of both patients and physicians during follow-up. Although it is recognized that early diagnosis of recurrence does not alter prognosis,1,27,51,52 it remains a goal because of the importance given to the timely initiation of treatment for the amelioration of symptoms and sequelae of recurrence. This was the rationale for selecting, as the primary outcome of this study, the rate of serious clinical events associated with recurrence. These events were selected because they are potentially preventable if identified early, and may not be recognized by a physician who is not specifically trained and experienced in oncology.

    The study was originally designed to establish noninferiority of family physician follow-up. A noninferiority design was used to demonstrate that the proportion of patients with SCEs was no worse in the FP group than in the CC group. We could conclude noninferiority only if the lower bound of the 95% CI for the SCE risk difference (CC group minus FP group) was  –1.5%, our prespecified maximum tolerance (ie, noninferiority margin). That is, allowing for random error, the SCE% in the FP group would need to decrease below 5.5% when the SCE in the CC group is 4%. In this study we were not able to demonstrate that the FP group was not worse than the CC group with regard to SCEs. In hindsight, we believe that the choice of the noninferiority margin (ie, maximum tolerance) of 1.5% was overly restrictive. However, the observed lower bound of the 95% CI (–2.26%) was only slightly larger. We believe this is well within clinically acceptable limits, particularly because these events occurred so rarely. Moreover, in our sensitivity analysis in which the KPS  70 events were not included, the lower bound of the 95% CI (–0.90%) was within the noninferiority margin.

    The quality of life of the two study groups was compared using standardized validated questionnaires. No difference was detected between groups for any of these measures. For the SF-36 scales, a difference of 5 points generally is considered clinically meaningful.48 Given the large number of quality of life assessments done, we are confident that any observed difference between scales is not clinically important. In addition to the core elements of follow-up care, breast cancer patients have special psychosocial and supportive care concerns such as fatigue, weight management, sexual functioning, cognitive functioning, and management of menopausal symptoms.1,7,9 A limitation of this study is that it did not specifically measure outcomes related to these domains. However, research suggests that this is a neglected area even in the specialist setting.7,18,32,33

    One of our objectives was to determine the acceptability of family physician follow-up to breast cancer patients. In this study, 55% of the patients (968 of 1,760) approached agreed to participate. This is similar to the 58% acceptance rate in another trial involving breast cancer survivors,53 but lower than the 67% who agreed to participate in our previous trial involving transfer of follow-up care to the family physician.40 It is impossible to know whether the reasons for nonacceptance relate to trial participation in general,54 or to the specific intervention being tested in this study. However, it does lead to the conclusion that family physician follow-up is acceptable to the majority of patients, and that some patients will be unwilling to have follow-up care transferred to their family physician.

    This study has a number of strengths. Consistent with the need to evaluate health care services,55 we conducted a pragmatic trial56 that was intended to reflect usual practice: the patient’s own family physician (not one with special oncology training) provided follow-up care; family physicians were provided with a one-page guideline on follow-up based on published evidence-based guidelines8,9; and family physicians used the usual procedures when referring patients with recurrence back to the cancer center—no special procedures were put in place. For 83% of patients (1,760 of 2,130), family physicians agreed to provide follow-up care. A committee that was blinded to treatment allocation adjudicated all events. In addition, to ensure that we had captured all clinical events, particularly because the intervention involved transfer of care to a community-based physician, we conducted a comprehensive review of the clinical status of all patients at the end of the study. No new recurrences or SCEs were identified through this process, thus confirming the completeness of our data collection procedures.

    The majority of distant recurrences will occur within the first 5 years postdiagnosis.57,58 Patients in this study were observed for a median of 4.5 years postdiagnosis, a period within which most recurrences are expected to have occurred. However, it is recognized that some breast cancer recurrences can occur even 10 or more years after diagnosis.18,57 Are late recurrences likely to have a different pattern of detection, and is that pattern likely to be different under family physician care compared with specialist care Although the design of this trial does not provide an answer to this question, based on the experience in this trial we anticipate that late SCEs will be extremely rare. The results of this study are generalizable to the majority of breast cancer survivors in that almost 70% of participants had node-negative breast cancer, a result consistent with the general population of women diagnosed with breast cancer.59

    The results of this study will provide important health care benefits and challenges. Many breast cancer survivors routinely see their family physician for the prevention and treatment of other diseases. As such, family physician follow-up for breast cancer is likely to be more convenient for patients and potentially less costly. If family physicians take on the primary responsibility for follow-up care, knowledge of new treatments (for example, the benefits of additional hormonal therapy with an aromatase inhibitor after tamoxifen60) will need to be made available to family physicians. Methods for disseminating new knowledge are both essential and challenging for all domains of medicine.61 Family physicians have shown their ability to incorporate new practices of care, and approaches such as regularly updated practice guidelines have been identified by family physicians themselves as important tools.8,9,62

    In conclusion, the results of this study show that breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that quality of life will be negatively affected. When patients have completed adjuvant treatment, these findings, together with evidence about other aspects of breast cancer follow-up,27,52,63,64 should be discussed so that patients can make an informed choice about additional follow-up arrangements.28,64

    Authors' Disclosures of Potential Conflicts of Interest and Author Contributions

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Eva Grunfeld, Mark N. Levine, Doug Coyle, Doug Mirsky, Shailendara Verma, Susan Dent, Carol Sawka, Kathleen I. Pritchard, David Ginsburg, Marjorie Wood

    Administrative support: Barbara Szechtman

    Provision of study materials or patients: Eva Grunfeld, Mark N. Levine, Doug Mirsky, Shailendara Verma, Susan Dent, Carol Sawka, Kathleen I. Pritchard, David Ginsburg

    Collection and assembly of data: Eva Grunfeld, Mark N. Levine, Jim A. Julian, Barbara Szechtman, Susan Dent, Carol Sawka, Kathleen I. Pritchard, David Ginsburg

    Data analysis and interpretation: Eva Grunfeld, Mark N. Levine, Jim A. Julian, Doug Coyle, Barbara Szechtman, Kathleen I. Pritchard, Tim Whelan

    Manuscript writing: Eva Grunfeld, Mark N. Levine, Jim A. Julian, Tim Whelan

    Final approval of manuscript: Eva Grunfeld, Mark N. Levine, Jim A. Julian, Doug Coyle, Barbara Szechtman, Doug Mirsky, Shailendara Verma, Susan Dent, Carol Sawka, Kathleen I. Pritchard, David Ginsburg, Marjorie Wood, Tim Whelan

    Acknowledgment

    We thank the women who participated in this study; the family physicians, oncologists, and cancer centers involved in this study; and the central office staff of the Ontario Clinical Oncology Group who oversaw the conduct of the trial.

    NOTES

    Supported by Grant No. 010413 from the Canadian Breast Cancer Research Alliance. While conducting this study, Dr Grunfeld was a Career Scientist with the Ontario Ministry of Health and Long-term Care. The conclusions are those of the authors and no endorsement by the Ministry is intended or should be inferred.

    Presented as a poster at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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