Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer: a population-based study

Abstract

Purpose

Adjuvant ‘classical’ oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective audit of treatment guideline adherence and quality of CMF in hospitals in the CCCN area.

Methods

The CMF treatment data of 251 consecutive axillary lymph node-positive breast cancer patients <50 years old, diagnosed between 1993 and 1996, were analyzed.

Results

Ninety-four patients (42%) completed adjuvant CMF without dose adjustment or delay. Overall median relative dose intensity (RDI) was 92.6 (IQR 85.5–97.7). Sixty patients (24%) had an RDI <85, and 7% had an RDI <65. Myelotoxicity was the main reason for reductions and delays. Of 176 irradiated patients, 96% received radiotherapy simultaneously with CMF. Median CMF dose intensity nor median duration differed between patients who underwent mastectomy, mastectomy and radiotherapy, or breast-conserving therapy. Radiotherapy did not influence the median RDI (94 without versus 92 with radiotherapy). G-CSF, administered at least once to 76 patients, did not result in a higher median RDI. Median RDI was slightly higher when >3 patients/year (P=0.014) were treated by one specialist or >10 patients classified for adjuvant chemotherapy yearly in a hospital (P=0.037).

Conclusion

The adherence to CMF treatment guidelines was generally good. Simultaneous radiotherapy did not affect the median RDI of CMF. G-CSF had no impact on the median RDI but patient volume did influence the RDI.

Introduction

Breast cancer is the most common malignancy in women in Western Europe and North America and the most frequently diagnosed cancer in the Netherlands. In 1998 almost 10,000 new invasive female breast cancers were diagnosed translating into an age-standardized incidence (European Standard Population) of 1.15/1,000 women per year, one of the highest rates in Europe (Visser et al. 2002). About one-fourth of all breast cancers were diagnosed in women younger than 50 years of age of whom in 1996 more than 40% still had axillary lymph node metastases.

Extensive meta-analyses, involving numerous poly-chemotherapy trials, have shown that systemic adjuvant chemotherapy reduces the occurrence of distant metastases and prolongs disease-free and overall survival of breast cancer patients (Early Breast Cancer Trialists’ Collaborative Group 1992; Early Breast Cancer Trialists’ Collaborative Group 1998). For premenopausal women adjuvant chemotherapy resulted in a decreased odds of dying of 25–30% during the first 10 years following surgery. Although only one decade ago, guidelines generally restricted adjuvant chemotherapy to premenopausal women with tumor-positive axillary lymph nodes, the results of more recent trials have indicated that age, negative tumor estrogen receptor status, intermediate or high malignancy grade and tumor size should influence the decision to administer adjuvant chemotherapy in both pre- and postmenopausal women.

In the Netherlands the treatment of breast cancer can be regarded as an example of protocolized medicine. The first (regional) guidelines for diagnosis and treatment were written in the 1970s. For premenopausal node-positive patients the 6 cycle 1,8 CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen, as described by Bonadonna and colleagues (Bonadonna et al. 1976), was the standard adjuvant treatment during the 1980s and for most of the 1990s. Only recently has anthracycline-based combination chemotherapy gained support especially for high-risk node-positive patients. There is some evidence in the literature that reducing the dose of CMF or altering the schedule of CMF in the adjuvant setting may compromise its efficacy. In 1981, Bonadonna had already published a dose-response effect in a retrospective analysis of two of their adjuvant CMF-chemotherapy trials, in which patients who received less than 65% of the ideal CMF dose had survival similar to a control population which did not receive CMF (Bonadonna and Valagussa 1981). Several subsequent retrospective and prospective studies of the effect of dose intensity on recurrence and survival have shown contradictory results; however, some prospective studies at least support the hypothesis of a threshold effect for adjuvant chemotherapy (Ottevanger et al. 1999; Bonadonna et al. 1995; Colleoni et al. 1998; Ferreira et al. 2002; Poikonen et al. 1999; Wood et al. 1994; Piccart et al. 2001; Budman et al. 1998). Nonetheless, appropriate and optimal dose intensity of CMF chemotherapy is a good indicator for protocol adherence and can be used as a marker for the quality of care. Furthermore, protocol deviations in actual administration of CMF may have consequences for the effectiveness of treatment in terms of clinical benefit. Being common, breast cancer is diagnosed and treated in nearly every hospital in the Netherlands. Referral for treatment, outside the framework of clinical trials, is uncommon. Most patients receive adjuvant chemotherapy in the same hospital were they undergo surgery. The breast cancer tumor working group of the Comprehensive Cancer Center North Netherlands (CCCN) proposed a review of the diagnostic procedures and cytotoxic treatment of node-positive breast cancer patients diagnosed from January 1993 to January 1996 to evaluate the implementation of and compliance with the regional treatment guidelines. The results of this study are presented here.

Patients and methods

Since the late 1970s tumor working parties, consisting of delegated medical specialists with various medical backgrounds, representing all hospitals within the working area of the CCCN, have formulated, implemented, and revised evidence-based guidelines for diagnosis and treatment of all common and a multitude of rare cancers. The guidelines reflect a consensus on diagnosis and treatment within the CCCN area. The delegated specialists were expected to deliver feedback to their colleagues through the oncology committees within the regional hospitals during every stage of the guideline development. Finalized guidelines were disseminated in booklets to all medical specialists involved in the treatment of cancer patients in the region. During the study period the guideline for diagnosis and treatment of invasive breast cancer was revised once (Otter et al. 1992; Otter et al. 1994). The CCCN consultancy teams, generally comprising a surgical oncologist and a medical oncologist with an academic position and a radiotherapist, regularly visit all regional community hospitals in the CCCN area to discuss and advise on diagnosis and treatment of cancer patients in scheduled patient presentation/discussion sessions. During these on-site conferences, the consultants in the team, being physicians and opinion leaders, use and actively propagate the use of the CCCN guidelines.

Selection of patients

For this review patients diagnosed between 1 January 1993 and 1 January 1996 with histologically proven axillary lymph node-positive primary breast cancer, without evidence of distant metastases at diagnosis, and younger than 50 years of age were considered for inclusion. Patients were selected from the database of the CCCN regional cancer registry. This registry covers the northern part of the Netherlands, a mainly rural area with a population of about 2.2 million people. During the study period about 1,300 patients were diagnosed with invasive breast cancer on a yearly basis within the CCCN cancer registry area, being about 13.5% of all breast cancers diagnosed in the Netherlands, of whom on average 24% were younger than 50 years.

In total, 397 patients met the eligibility criteria of this study and 372 patients were finally included. The study was conducted in 17 out of the 20 hospitals within the region covered by the CCCN cancer registry. One hospital closed down in 1994–1995 making review of the medical charts impossible and two hospitals decided not to participate in the review. The 25 patients not included in this review were all diagnosed and treated in the non-participating hospitals. Among the participating hospitals were one university hospital and three affiliated teaching hospitals.

Data on diagnosis, staging, and treatment were retrieved directly from the patient’s medical files inside the hospitals and stored in an encrypted fashion in a database at the CCCN regional cancer registry. Within the database no information is available which would allow contacting the patient directly.

Regional guidelines for the diagnosis and treatment of primary breast cancer

Preoperative assessment included liver and renal function tests and in case of disturbed liver functions tests, ultrasound imaging of the liver. A chest X-ray was supplemented with a bone scan in case of locally advanced cancer or axillary lymph node involvement. Breast conserving surgery was indicated for small tumors (<4 cm), without extension to skin or chest wall and in the absence of an extensive in situ component and multifocality. The expected cosmetic outcome and patient preference should guide the surgeon’s decision for breast-conserving surgery or a modified radical mastectomy. Radiotherapy (RT) to the whole breast (50 Gy in 2 Gy fractions in 5–6 weeks) with a boost of 15–20 Gy to the tumor area should follow breast conserving surgery, preferably within 6 weeks but no later than 3 months following surgery. Regional RT to the parasternal, axillary, infra-, and supraclavicular lymph node stations was indicated in case of more than three positive axillary nodes, extranodal tumor growth, and/or a positive apical axillary node. Adjuvant chemotherapy, consisting of six cycles of CMF (cyclophosphamide, methotrexate and 5-fluorouracil), was advised for patients <50 years old with one or more tumor positive axillary nodes, with the treatment starting within 28 days following surgery. CMF was administered every 28 days until the completion of the sixth cycle, each cycle of CMF consisting of two courses of 40 mg/m² methotrexate and 600 mg/m² 5-fluorouracil given intravenously on day 1 and day 8, and 100 mg/m² cyclophosphamide orally during days 1 to 14. Most patients received oral cyclophosphamide as 50-mg tablets, therefore the actual cyclophosphamide dose may differ from the prescribed dose (as cyclophosphamide will be given in multitudes of 50). In case of a white blood cell (WBC) count between 2.0 and 3.0×10⁹/l and/or platelet (PLT) count between 75–100×10⁹/l, the CMF dose should be adjusted to 50%. If the WBC count was lower than 2.0×10⁹/l and/or the PLT count lower than 75×10⁹/l, CMF had to be delayed until sufficient bone-marrow recovery. Although use of growth factors was not propagated in the guidelines, from 1991 to 1994 effect and feasibility of granulocyte colony stimulating factor (G-CSF) with standard adjuvant CMF were studied in the CCCN region (de Graaf et al. 1996). Generally G-CSF was given in a dose of 300 μg subcutaneously once a day for 5 days if the WBC count was <3.0×10⁹/l on day 1 or <2.0×10⁹/l on day 8. Once started, G-CSF was given prophylactically for 10 days (days 15–24). G-CSF was not given simultaneously with chemotherapy.

The relative dose intensity (RDI) of CMF chemotherapy was calculated using the method of Bonadonna (Bonadonna and Valagussa 1981) as modified by Ottevanger (Ottevanger et al. 1999). For all patients, the administered dose of each drug was summarized over the administered number of courses (maximum 12 courses) and divided by the projected total dose of each drug over this number of courses. Next, this ratio was multiplied by the number of administered cycles and divided by six (the projected number of cycles). Dose intensity (DI) of CMF followed from the arithmetical mean of the resulting figures for the three drugs. Multiplying the DI with the ratio of the projected number of days for completion of the administered number of courses over the actual period of treatment results in the RDI of CMF. The actual period of treatment was calculated as the number of days from day 1 of the first administered cycle to day 8 of the last administered cycle plus 20 days or day 1 of the last administered cycle plus 27 days, in case a patient stopped during a cycle. A delay was defined as a postponement of any cycle or part of a cycle for 4 days or more, and a dose reduction was defined as a reduction in the dose of any single drug of 10 percent or more. In case a postponed cycle was not completed later, only a dose reduction was scored.

Statistical analysis

Descriptive statistics including median, interquartile range (IQR, the range from 25th to 75th percentile) and range were used to study patient and chemotherapy characteristics [time-intervals, dose intensity (DI) and RDI]. The distribution of continuous variables (such as the interval between surgery and chemotherapy, duration, and RDI of CMF) among subgroups of patients were compared with the t-test or analysis of variance if the distribution of these variables approached a normal distribution. If test-assumptions were violated, non-parametric (Kruskal-Wallis, median test) tests were used. The Chi-square test was used to analyze categorical variables. Overall survival time was calculated from the date of surgery to the date of death or last contact. Disease-free survival was calculated to the date of any documented relapse, death without relapse not due to another cancer, or last contact, whichever occurred first. Patients alive without relapse at the date of last contact and patients who died of a cause other than breast cancer, not attributable to breast cancer, were censored at these dates. Any unknown cause of death was attributed to breast cancer for disease-specific survival, given the young age of the patient group and the low risk of dying of competing causes of death. Time to event curves were estimated by the Kaplan-Meier method and evaluated by the log-rank test in univariate analysis. The Cox proportional hazards model was used for multivariate analysis of factors affecting the risk of relapse or death.

Results

Patient volume

The medical charts of 372 consecutive breast cancer patients were reviewed for this study. Six of the participating hospitals diagnosed less than four breast cancer patients <50 years old with positive axillary lymph nodes on average yearly, and only three hospitals diagnosed >10 of these patients yearly. Twenty-five patients were diagnosed and treated in the University hospital, and another 44 patients were referred to the University hospital for treatment, of whom 42 participated in a high-dose chemotherapy trial. During the 3-year study period, 53 specialists in internal medicine treated at least one of the included patients with adjuvant chemotherapy. Five specialists treated on average 4–6 patients yearly, and six specialists treated >6 patients yearly.

Chemotherapy

Three hundred and thirty-two patients (89%) received adjuvant chemotherapy, of whom 258 (78%) received CMF chemotherapy. Of the 40 patients who did not receive adjuvant chemotherapy, four received neoadjuvant chemotherapy, 31 patients adjuvant hormonal therapy only, three patients adjuvant RT only, and only two patients no adjuvant therapy. The reasons for withholding chemotherapy are listed in Table 1. Twenty-one patients, who did not receive chemotherapy, were all treated by the same medical oncologist.

Table 1.

Reasons for withholding chemotherapy in 36 patients

	Number
Preference of treating physician	23
Poor physical condition or severe co-morbidity	3
No CMF after consultation with CCCN specialists	2
Not referred to internist	2
Patient refused chemotherapy	2
Mental retardation	1
Ovariectomy	1
Severe thrombocytosis	1
Unknown	1
Total	36

Six of the 258 patients treated with CMF received cyclophosphamide intravenously in a three weekly scheme. Seventy-two patients received anthracycline based adjuvant chemotherapy, mostly FEC (5-fluorouracil, epirubicin, cyclophosphamide). Anthracycline based chemotherapy was administered almost exclusively to patients with >3 positive axillary lymph nodes (Table 2). Fifty-three (74%) of the patients treated with anthracycline-based chemotherapy were treated in the University hospital.

Table 2.

Type of chemotherapy according to nodal status

Chemotherapy regimen	All patients		Number of positive lymph nodes
			<4	4–9	≥10
	Number	%	%	%	%
Adjuvant CMF	258	69	88	50	36
Adjuvant FEC	71	7	1	41	43
Other regimena	7	2	1	3	5
No chemotherapy	36	10	10	7	16
Total	372	100	100	100	100

^aCMF neo-adjuvant (1), FEC neo-adjuvant (2), FAC neoadjuvant (1), FAC adjuvant (1), FEC/CMF (2)

Adequacy of staging, the association between type of surgery, and the interval between surgery and CMF, timing of RT, duration of CMF therapy, RDI of CMF administered, and reasons for dose reduction or delay were only studied for the group of 252 patients treated with ‘classical’ CMF with oral administration of cyclophosphamide.

Surgery and adjuvant RT

The median time between first pathological confirmation and definitive surgery was 12 days (IQR 6–16 days), 6% of the patients waited longer than 4 weeks. Of the 252 patients treated with adjuvant CMF, 79 (31%) underwent breast-conserving surgery and all but two of these patients received RT. The median interval between breast conserving surgery and the start of RT was 33 days (IQR 19–42 days). Sixty patients (77%) started within 6 weeks and all patients started within 10 weeks following surgery. Of the patients who had a mastectomy, 100 (58%) received RT to the thoracic wall and/or parasternal and/or supraclavicular and/or axillary lymph node regions. All these patients started RT within 12 weeks following surgery.

CMF chemotherapy

The median interval between surgery and the start of CMF was 22 days (IQR 16–32 days); 72% of the patients started within the advised 28 days after surgery. Patients generally received RT simultaneously with the CMF cycles (Fig. 1). All but seven patients finished RT prior to the start of the fourth CMF cycle. Nineteen (25%) patients treated with breast conserving surgery and 18 (18%) patients treated with a mastectomy, receiving locoregional RT, started RT before CMF. Eight patients completed RT before starting CMF. The median interval between the date of surgery and start of CMF did not differ (P=0.126) for patients treated with mastectomy without RT (20 days; IQR 16–25), mastectomy followed by RT (24.5 days; IQR 17–30.5) or breast-conserving treatment (25 days; IQR 17–35.5).

Fig. 1.

Timing of radiotherapy during adjuvant CMF chemotherapy among 176 patients

Quality of CMF chemotherapy

The quality of CMF could be evaluated for 251 patients receiving ‘classical’ partially oral CMF chemotherapy, and one patient was excluded because of insufficient treatment data. The actual starting dose of cyclophosphamide, methotrexate, and 5-fluorouracil was <85% of the reference dose according to the guideline in 36 (14%), 14 (6%), and six patients (3%), respectively. Overall, the planned DI at the start of the first cycle of CMF was <85% of the reference dose for nine (4%) patients.

Twenty-nine patients (12%) did not complete all 12 courses (6 cycles), of whom four completed CMF treatment with intravenous cyclophosphamide. Table 3 lists the reasons for discontinuation of CMF as recorded in the medical charts. Out of a total of 2,884 administered courses, 245 (9%) courses were reduced in 66 patients. Of the 222 patients, who completed all 12 courses, only 94 (42%) did so without dose adjustments or delay (Fig. 2). Sixty (27%) patients had at least one course reduced. When explicated in the medical chart, bone marrow toxicity or continuation of an earlier reduction was the most common reason for reduction (Table 4; twelve reduced courses were administered with delay). The median DI of cyclophosphamide was 94% (IQR 85–100%), 98% (IQR 91–102%) for methotrexate, and 98% (IQR 92–100%) for 5-fluorouracil. The overall median DI of CMF was 96% (IQR 89–100%). In total 208 patients (83%) received ≥85% of the ideal dose; 204 of the 222 patients (92%) who completed all CMF courses received ≥85% of the ideal dose.

Table 3.

Reasons for and timing of discontinuation of CMF in 251 patients

	Stopped during CMF cycle						Total
	1	2	3	4	5	6
Leucocytopenia/ thrombocytopenia	-	1	2	-	4	6	13
Patient refusal	1	2	1	-	1	-	5
Continuation with intravenous cyclophosphamide	-	-	2	-	2	-	4
Grade III mucositis	-	-	1	-	-	-	1
Infection venous access port	-	-	-	-	1	-	1
RT-induced pneumonitis	-	-	-	1	-	-	1
Sudden death	1	-	-	-	-	-	1
Grade III liver function toxicity	1	-	-	-	-	-	1
Diarrhea	-	-	-	-	-	1	1
Unknown	-	-	-	-	1	-	1
Total	3	3	6	2	8	7	29

Fig. 2.

Cumulative frequency of delay and dose reduction of adjuvant CMF chemotherapy among 251 patients

Table 4.

Reasons for treatment delay and/or dose reduction during 2,884 courses of CMF among 251 patients

Reason for reduction or delay	No reduction or delay		Delay		Reduction/continuation earlier reduction		Delay and reduction		Total
	n	%	n	n	n	%	n	%	n	%
No reason/reason unknown	1844	76	25	11	68c	30	1	14	1938	67
WBC 3.1–3.5 and/or PLT100–125	314	13	5	2	24	11	-	-	343	12
WBC 2.0–3.0 and/or PLT 75–100	257	11	113	51	92	41	3	43	465	16
WBC <2.0 and/or PLT <75	14	1	42	19	21	9	2	29	79	3
Leucocytopeniaand/or thrombocytopenia, values not specified	-	-	12	5	15	7	-	-	27	1
Fever	-	-	6	3	1	<1	-	-	7	<1
Holidays	-	-	7	3	-	-	-	-	7	<1
Mental depression	-	-	2	1	-	-	1	14	3	<1
Oesophagitis/stomatitis	-	-	1	<1	1	<1	-	-	2	<1
Wound abscess	-	-	4	2	-	-	-	-	4	<1
Thrombosis/embolism	-	-	1	<1	1	<1	-	-	2	<1
Other	-	-	4a	2	3b	<1	-	-	7	<1
Total	2429	100	222	100	226	100	7	100	2884	100

^aOther reasons for delay: colonoscopy, dyspnea, and administration of G-CSF

^bOther reasons for reduction: cerebellar ataxia, adjustment of overdosage, and severe liver function disorder

^c53/68 courses were continuations of earlier reductions

The median interval between the start and the last day of CMF treatment was 168 days (IQR 167–174 days), 102 (46%) patients actually completed all 12 courses within 168 days, the projected duration of CMF chemotherapy according to the guideline. Sixty-one patients (28%) had a delay of 7 days or less, 32 patients (14%) a delay of 8–14 days, and 27 patients (12%) had >14 days delay. According to our definition, 107 (49%) of the 222 patients completing all 12 CMF courses had at least one course delayed once. Again, myelotoxicity was the main reason for delay (177/229 delayed courses in 125 patients). Twenty-six courses in 24 patients were postponed for reasons other than leuco- or thrombocytopenia, the reason for delay was unknown for 26 courses in 21 patients.

Forty-six patients had a grade 3 leucocytopenia (WBC <2.0×10⁹/l) at least once or a grade 2 or 3 trombocytopenia (PLT <75×10⁹/l), an indication for delay according to the guideline. Thirty-eight courses were actually postponed, and 15 courses were given without reduction or delay. A WBC count of 2.0–3.0×10⁹/l or a PLT count of 75–100×10⁹/l, an indication for dose reduction, was found at the start of 503 courses (175 patients). This resulted in a dose reduction of 68 (14%) courses, and 275 courses (55%) were neither delayed nor reduced. G-CSF was administered to 76 patients (30%), 33/46 (72%) patients who experienced a grade 3 neutropenia at least once and 40/128 patients who had WBC counts of 2.0–3.0×10⁹/l during treatment. Use of G-CSF varied between hospitals (specialists), especially when a WBC count of 2.0–3.0×10⁹/l was regarded as indication for use. Stratified for indication, i.e., a WBC count of 2.0–3.0×10⁹/l or <2.0×10⁹/l, the use of G-CSF did not result in higher median RDI (P=0.161). The median RDI of CMF for the 251 patients was 92.6 (IQR 85.5–97.7), and sixty patients (24%) had a RDI of <85, 157 patients (63%) a RDI of 85–100, and 34 patients (14%) a RDI of >100 (Fig. 3).

Fig. 3.

Relative dose intensity of adjuvant CMF chemotherapy among 251 patients

RT did not influence the quality of CMF. Grade 3/4 neutropenia appeared to be increased in patients treated with mastectomy and RT but not in patients who had breast-conserving therapy compared to patients treated with mastectomy without RT [26%, 15%, and 11%, respectively, (P=0.049)]. However, neither the median DI (P=0.698) nor the median duration of chemotherapy (P=0.590) differed between the three patient groups. The median RDI was 94.2 (IQR 86.2–98.0) for patients treated with mastectomy, 92.1 (IQR 88.1–96.9) for patients who had a mastectomy and RT, and 92.5 (IQR 84.0–97.8) for patients receiving breast-conserving treatment (not significant); 80%, 72%, and 78% of the patients reached a RDI ≥85%, respectively, (not significant). Specialist and hospital volume did influence the RDI of CMF. Although the absolute differences were small, significant variation in the median RDI was observed between hospitals (Fig. 4, median test P=0.005). The median RDI was slightly higher if more than three patients a year were treated, which was slightly higher compared to hospitals treating ≤ three patients a year (median RDI 95.4 versus 91.8; P=0.009). The median RDI was also higher if more than ten patients were eligible for adjuvant chemotherapy yearly per hospital (P=0.027). Again the absolute differences were small (median RDI 94.6 versus 91.8).

Fig. 4.

Relative dose intensity (median, IQR, range, outliers+/extremes*) of adjuvant CMF for patients who completed six courses according to hospital

Survival

The median follow-up for all 251 patients treated with classical CMF was 4.8 years (range 0.1–7.4 years). Eight patients were lost to follow-up, 56 patients developed distant metastases, and four patients had a local recurrence (of whom two also had distant metastases). Five contra-lateral breast cancers were diagnosed (two after diagnosis of distant metastasis). Five other patients had a second primary malignancy at another site; these patients were censored at the date of diagnosis of the second cancer. Eight patients died without documented relapse or metastasis.

The overall 5-year survival was 83% [95% Confidence Interval (CI) 78–88%], and the 5-year relapse free survival was 75% (95% CI 68–81%). The median RDI of CMF was unrelated to relapse-free survival, and the 5-year relapse-free survival rates were 78% (95% CI 67–90%) for patients with a median RDI <85 and 73% (95% CI 66–80%) for patients with a median RDI ≥85 (log rank test: P=0.76). In a Cox proportional hazard model a higher number of metastatic lymph nodes and younger age at diagnosis increased the risk of disease recurrence. The risk of recurrence was 2.4 (1.3–4.3) for 4–9 and 5.0 (4.4–10.0) for ten or more positive lymph nodes compared to 1–3 positive nodes. Patients younger than 30 years old had a 3.6 (1.2–10.4) times increased risk of recurrence compared to patients aged 40–49 years. Only the number of metastatic lymph nodes predicted the risk of dying from breast cancer. Compared to patients with 1–3 positive nodes patients with 4–9 and 10 or more positive nodes had a 2.7 (1.3–5.3) and a 5.4 (2.5–11.7) times increased risk of dying, respectively.

Discussion

Fairly little is known about the quality of cancer care in daily clinical practice in West European countries. In this retrospective study the quality of adjuvant chemotherapy as given by the average medical internist was analyzed. The study demonstrates the organization of consultation by specialists from a regional Cancer Centre, the logistics involved, and the results of these efforts.

Although breast cancer is a common tumor, the number of breast cancer patients eligible for adjuvant cytotoxic treatment according to the prevailing guideline in the early 1990s, i.e., patients with positive lymph nodes <50 years old, was actually low. Only three out of the 17 participating hospitals diagnosed more than 10 patients on a yearly basis who classified for adjuvant chemotherapy. Even so, a large number of internists was involved in the actual treatment of these patients and only 20% of these specialists treated more than three patients yearly.

Just over 89% of the patients eligible for adjuvant chemotherapy according to the guideline, actually received some form of adjuvant chemotherapy. Most patients who did not receive chemotherapy did so because their specialist was skeptical about the effect of adjuvant chemotherapy. Nevertheless, the proportion of patients receiving adjuvant chemotherapy was high and compares favorably with literature data (Ottevanger et al. 1999; Ma et al. 1997; Voogd et al. 1994). CMF therapy accounted for the major part (78%) of the adjuvant regimens used during the study period, in agreement with the prevailing regional and national guideline (Otter et al. 1992; Otter et al; 1994; Glick et al. 1992; Goldhirsch et al. 1995). The proportion of patients treated with CMF was comparable with other pattern of care studies pertaining to the early 1990s (Ottevanger et al. 1999; Link et al. 2001). Most patients who received adjuvant anthracycline-containing chemotherapy were treated within the framework of a clinical trial examining the effect of high-dose chemotherapy with autologous stem cell reinfusion in premenopausal patients with >3 positive lymph nodes. Many hospitals in our region participated in this trial and referred eligible patients to the University Hospital for protocol treatment.

The timing of postoperative RT and adjuvant chemotherapy following breast cancer surgery has been subject of controversy over the last decades (Recht et al. 1991; Hartsell et al. 1995; Pronzato et al. 1993; Dubey et al. 1999; Recht et al. 1996; Wallgren et al. 1996). Some studies have suggested an increased risk of local failure associated with delayed administration of RT. On the other hand, delaying the start of chemotherapy may be associated with an increased risk for regional or distant recurrence. Recht (Recht et al. 1991) found a borderline significant difference in local recurrence rate (5% vs 14%) and in distant recurrence rate (32% vs 20%) for patients first treated with RT versus chemotherapy. The most important rationale for simultaneous chemo- and radiotherapy are prevention of delay and shortening of the treatment period. However, concomitant RT and adjuvant chemotherapy have been associated with increased toxicity, and consequently impairment of RDI, and poorer cosmetic outcome in case of breast conserving surgery (Levine et al. 1984; Habibollahi 1989). In our study the simultaneous administration of RT and CMF chemotherapy resulted in a relatively short median interval between surgery and the start of adjuvant chemotherapy (25 days). In contrast, Ottevanger (Ottevanger et al. 1999) found an interval between surgery and adjuvant chemotherapy of 75 days for patients treated with RT as the majority of the patients completed RT before the start of chemotherapy. Further, simultaneous RT did not appear to affect the RDI of CMF in our population. Patients treated with RT had a median RDI of >92% and almost 75% reached a RDI ≥ 85%. These figures were comparable with the non-irradiated patient group. Dubey (Dubey et al. 1999) treated 112 patients with concurrent CMF and RT (reduced dose) of whom 93% attained a RDI ≥ 85%, although 14% of the patients experienced grade 4 neutropenia. In our experience concurrent CMF and RT is feasible without compromising adequate delivery of CMF. We cannot comment on the cosmetic outcome of breast conserving surgery following simultaneous CMF and RT.

Compliance with the guideline for administration of adjuvant chemotherapy was generally good. The RDI was high for most patients, although 17% had a DI <85% and 6% a DI <65%. Twenty-two patients (9%) stopped before the start of the 6th cycle, comparable with figures reported by others (de Graaf et al. 1996; Early Breast Cancer Trialists’ Collaborative Group 1992; Early Breast Cancer Trialist’s Collaborative Group 1998; Otter et al. 1992). Of the 222 patients who completed all 12 courses, almost 88% did so with a delay of <2 weeks. Delays and reductions were mostly due to myelotoxicity. Although the CMF regimen is generally considered to have an acceptable toxicity profile, reductions and delays during treatment are common. Link (Link et al. 2001) found reduction or delay at least once in 70% of the patients receiving either six cycle ‘classic’ or intravenous CMF regimens. In our series 58% of the patients experienced dose reduction or delay. Nonetheless the RDI was acceptable for most patients as >76% of the patients reached a RDI ≥85% and <7% of the patients had an RDI <65%.

The quality index of CMF chemotherapy was not associated with recurrence-free or overall survival. However, the power of our study to detect any difference was small given the total number of patients, the low number of events, and the limited variation in the RDI of CMF in the study population. The 5-year survival was reasonable and comparable with the 5-year survival rate of 79% reported by Bonadonna (Bonadonna and Valagusa 1981) for premenopausal patients receiving a level I CMF dose (RDI CMF ≥85). However, this comparison is probably biased due to a more favorable nodal status in our CMF group.

In conclusion, in this population-based study, the quality of adjuvant CMF treatment for node-positive breast cancer patients, measured using the interval between surgery and chemotherapy, the duration and dose of CMF chemotherapy, and the resulting RDI as indicators, was good. Attained DI and RDI were high for the majority of patients. These results may be attributable to good adherence to the guidelines by the practicing specialist, to increased awareness about the potential benefits of adjuvant chemotherapy or to peer pressure advocating adequate dose intensity in adjuvant chemotherapy. However as a retrospective study it contains the flaws inherent to this type of reporting. Further, it is not comparative in nature and the methodology of this study may hamper the drawing of valid scientific, and thus definite, conclusions. Although doubts have been raised about the effectiveness of guideline development as a tool to change physicians’ behavior and to improve quality and equality of care (Ford et al. 1987), the medical community generally complied well with the guideline in this pattern of care study, even though a large number of medical oncologists were involved in treatment of the patients. Guideline development in the CCCN region roughly resembles the model described by Wise and Billi (Wise and Billi 1995), stimulating the strengthening of network ties through collaborative work on guideline development and implementation. According to the conclusions of Grimshaw and Russel (Grimshaw and Russel 1993), following their review of evaluations of clinical guidelines, as the prevailing guideline was regionally developed and actively propagated during the study period it should have had a fair probability of proving effective.