1 Centre Léon Bérard, Lyon; 2 UMRS 5823 CNRS Gressac Lyon; 3 Clinique Eugène André, Lyon; 4 Hospices Civils de Lyon; 5 Centre hospitalier Montélimar; 6 SOR FNCLCC, Paris, France
Received 16 June 2003; revised 16 September 2003; accepted 30 September 2003
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ABSTRACT |
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The primary management of adult soft tissue sarcomas (STS) is characterized by heterogeneity across centers. Several studies suggest that it is improved when coordinated by specialized sarcoma centers.
Patients and methods:
This study, comparing STS patients of the RhôneAlpes region treated within and outside the cancer network, retrospectively assesses the conformity of medical practice with evidence-based medicine (EBM) reported under the clinical practice guidelines (CPGs) of the French Federation of Cancer Centers. Institutional records of 100 new STS patients seen between 1999 and 2001 in the regional comprehensive cancer center and Lyon University hospital were analyzed retrospectively (50/300 new files randomly selected in each institution). Medical decisions were checked for conformity with CPGs.
Results:
Median age was 58 years (range 1888) and median tumor size was 9 cm (range 126). The most common primary sites were extremities, viscera or trunk. The most frequent histology was leiomyosarcoma (21%) or liposarcoma (12%). Only 7% of cases were reviewed by formal multidisciplinary committee before biopsy (with 42% pre-surgery biopsies only). The first surgical resection was R0, R1 and R2 in 26, 29 and 45% of cases, respectively. Conformity to CPGs was rated 52, 81, 94 and 95% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. At multivariate analysis, pre-surgery multidisciplinary discussion, management in reference center and management within cancer network independently predicted conformity to CPGs.
Conclusions:
Conformity with EBM was similar to previous reports. Elaboration of treatment strategy within a formal multidisciplinary staff and treatment within a cancer network are both important prognostic factors for optimal clinical care.
Key words: audit, cancer, guidelines, management of soft tissue sarcoma, medical practice, outcome
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Introduction |
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In France, the management of STS had not been specifically analyzed or published. A retrospective study of patients with localized STS was therefore initiated. We will describe the patterns of diagnosis, treatment and outcome, as well as parameters correlated with optimal medical practice over a recent 3-year period in the RhôneAlpes region. The purpose of this study was to describe the primary management of STS, and assess the impact of recently published national clinical practice guidelines (CPG) [12] and of multidisciplinary committee on management organization.
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Patients and methods |
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Criteria for optimal procedure (outline from the Standards, options et recommandations pour la prise en charge des sarcomes[12])
Criteria for optimal initial examination and diagnosis. (i) Clinical size and depth of the mass must be recorded; (ii) computed tomography (CT) is required for abdominal localization, or magnetic resonance imaging (MRI) of the mass for limb localization; (iii) chest radiograph or CT scan is required to identify metastases; and (d) pre-operative biopsy (incisional or needle), preferably by the surgeon in charge of future surgical management. Exception is made for small tumors <3 cm, where excisional biopsy is accepted.
Criteria for optimal surgical management. Whenever possible, primary surgery should perform wide excision with 12 cm margins. For high-grade lesions, large (>3 cm) tumors or deep-seated tumors, surgery alone is acceptable only in case of amputation or compartimental resection with negative histological margins (R0). Wide excision alone, with no adjuvant treatment, is acceptable only for superficial, small (<3 cm) and low-grade lesions. Histologically positive margins (R1) or incomplete excision (R2) have to be considered inadequate, and should be followed by further appropriate treatment (further surgery or adjuvant therapy if formal review by a multidisciplinary sarcoma committee considers surgery non-feasible).
Criteria for optimal histopathology report. The report should describe: (i) histological diagnosis; (ii) status of the resection margins; (iii) grade of the tumor; and (iv) pathological staging.
Criteria for optimal radiation therapy management. Association of wide excision and adjuvant radiation therapy should be considered the standard treatment. The absence of adjuvant radiotherapy is acceptable for superficial, small (<3 cm) and low-grade tumors, and for limb sarcomas when amputation is performed. For non-operable sarcomas, primary radiation therapy could be an option. Optimal technical criteria are: (i) 50 Gy delivered dose [with an additional boost of 10 Gy in case of microscopic residual tumor (R1)]; (ii) target volume to irradiate encompassing tumor bed, scars, including draining orifices, with adapted security margins; and (iii) delay from surgery to radiation therapy not exceeding 8 weeks.
Criteria for optimal chemotherapy management. For non-readily, non-operable sarcomas, primary chemotherapy can be an option, as can radiation therapy. For readily operable sarcomas, neo-adjuvant chemotherapy should be performed only as part of a clinical research protocol. In the adjuvant setting, systemic chemotherapy should be performed only within the context of a prospective clinical trial. Adjuvant chemotherapy could be performed for patients with histologically positive margins after wide surgery.
Criteria for optimal post-therapeutic surveillance. There is no consensus concerning the surveillance of STS. Recommendations of the SOR are follow-up with clinical examination every 12 weeks during the first 3 years, then every 4 months until the fifth year post-management. Clinical examination and chest radiograph or CT scan are the prevailing tools to identify metastases. Ultrasound examination can be performed for deep trunk localizations.
Methods for patient selection
Following approval of the oncology subcommittees of the two major institutions for STS management in the region (Centre Leon Bérard and Hospices Civils de Lyon), surgeons, oncologists and pathologists were approached for consent to produce hospital records of patients under their care for the purpose of this audit data collection.
Patients included in the audit were selected by (i) automatic retrieval/extraction from the computerized database of the Centre Léon Bérard, or (ii) manual extraction from the database of the oncology unit in charge of STS at Hospices Civils de Lyon.
Criteria for patient selection. Patients diagnosed and/or treated for a primary STS within the RhôneAlpes region between 1999 and 2001 were eligible for the audit. Tumors of the bone, the central nervous system and Kaposi sarcomas were excluded, as were patients with distant metastases at initial diagnosis. Only localized or locally advanced STS were selected.
Data sources
Data on the primary care of STS were collected by two authors (I.R.-C. and J.-Y.B.) and analyzed by one (I.R.-C.). I.R.-C. is a medical oncologist working independently of the practitioners caring for patients in the different hospitals. Extracted data were double-checked by blind examination of a 10% random sample by the second author (J.-Y.B.).
Selection of patient records
As previously reported, at least 50 patient records were necessary to detect a statistically significant increase in the compliance rate [13]. No matching procedure was elaborated to select patients in both hospitals. Because of the high accrual rate in the two institutions, a computerized procedure (random numbers) was used to select a sample of 50 patients from the 350 and 300 newly treated STS seen in these two institutions during the relevant time-frame. Randomly selected patients not eligible for the study were excluded, and the random procedure was reapplied to replace them. A record was considered to be assessable when biopsy or surgical procedure had been reported.
Setting
The RhôneAlpes region (with an area of 43 500 km2 and 5.5 million inhabitants) has 100 public hospitals, three university hospitals, one comprehensive cancer center and 87 private hospitals, with a total of nearly 26 000 beds. The cancer network evaluated here (ONCORA) includes 15 private and 26 public hospitals within the region, with a total of
5500 beds. Approximately 22 000 new malignant tumors are treated annually in the area, 40% of which are within the organized cancer network. Because of the rarity of STS (1200 estimated new cases annually in France), only two hospitals manage enough STS patients to meet selection criteria: one university hospital (not included by the cancer network) and one comprehensive cancer center (participating in the cancer network). Both agreed to participate in this evaluation.
Main outcome measurement
First, characteristics of STS management were described. The main outcome was the number of overall treatment sequences judged to conform with national CPGs. An overall treatment sequence comprised decisions for every type of procedure (i.e. diagnosis, surgery, radiotherapy, chemotherapy, initial examination, follow-up). Each procedure was individually assessed for conformity with CPG recommendations described above. Finally, overall treatment sequences were considered to have conformed when all assessable component procedures were respected. Only medical decisions covered by the CPGs were taken into consideration for assessing compliance.
We decided to use overall treatment sequences (i.e. sequences of medical decisions all along the patient management pathway), because decisions for each procedure are interdependent. For example, if surgeons have submitted only records of patients with large, high-grade tumors to the multidisciplinary staff for chemotherapy indication and discussion, only the initial overall treatment sequence, including surgery, radiotherapy and chemotherapy with initial examination and follow-up, is taken into account. Hence, only one overall treatment sequence can be assessed for each patient.
The second level of evaluation was the number of medical decisions judged to be based on multidisciplinary medical decision. Multidisciplinary sarcoma committees started functioning in 1992 at the comprehensive cancer center and 1999 at the university hospital. At least one radiologist, one pathologist, one surgeon, one medical oncologist and one radiation oncologist were present at each weekly committee meeting.
Statistical analysis
Conformity was scored 1 if the recommendations had been followed, and 0 if not. Categorical data were analyzed using Pearsons 2-test or Fishers exact test, as appropriate. Continuous data were analyzed with Students t-test. The statistical significance level was set at P = 0.05 in a two-sided test. The correlation between any clinical or biological parameter and the incidence of death or relapse was analyzed using the KaplanMeier test [14]. Univariate analyses were performed to assess whether patient characteristics were correlated with conformity or non-conformity to CPGs. A logistic regression analysis including parameters studied in the univariate analysis was performed using SPSS® Logistic software: a step-down regression procedure of conformity rates was used with a P-value <0.05 for entry. Risk factors (e.g. type of surgery) were dichotomized. The end point (i.e. conformity with CPGs) was also dichotomized (0 if absent, 1 if present). Factors evaluated for conformity were multidisciplinary committee before initial surgical procedure (yes versus no), management in the cancer network (yes versus no), hospital in charge of treatment (university hospital or comprehensive cancer center versus others), specialty of the surgeon (orthopedics, general, sarcoma, abdominal), age, gender, topography of the tumor (viscera versus other), tumor size <10 cm (yes versus no), deep versus superficial tumor, histological grade of the tumor (I versus II and III), radiation therapy (yes versus no) and use of chemotherapy (yes versus no). Factors evaluated for survival were type of surgery (wide versus marginal), type of resection (R0, R1 or R2), specialty of the surgeon (sarcoma versus other), hospital in charge of treatment, multidisciplinary committee before first surgical procedure, radiation therapy, radiation therapy complying with CPGs, age, gender, topography of the tumor, tumor size <10 cm, deep or superficial tumor, and histological grade of tumor.
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Results |
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The mean age of patients was 58 years (range 1888), with 17 patients >70 years old. Tumor site, localization, AJCC/UICC (American Joint Committee on Cancer/Union Internationale Contre le Cancer) staging, histological type and grade are described in Table 1. Clinical tumor size was recorded in 52% of the patients only, with a median of 80 mm (range 10260).
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Patterns of treatment. First surgical procedure: A formal multidisciplinary committee decision preceded eventual surgical procedure in only 39% of cases. Primary surgical excision was performed in 95 patients: 37 (39%) were operated on in a private institution, 14 (15%) in a general hospital, 27 (28%) in the university hospital and 17 (18%) in the comprehensive cancer center. Only 42 (44%) of patients undergoing first surgical procedure (with or without preliminary biopsy) had wide excision; 53 (56%) had only marginal or incomplete excision. Twenty-five patients (26%) were considered to have R0 surgical resection (i.e. micro- and macroscopically complete), 27 patients (29%) had R1 (i.e. microscopically incomplete and macroscopically complete) and 43 (45%) had R2 (i.e. microscopically and macroscopically incomplete). Interestingly, the risk of R2 resection was higher in patients operated on without previous formal multidisciplinary committee decision. Only 16% (seven of 43) of patients in the R2 subgroup had multidisciplinary decision prior to surgery, versus 48% (13 of 27) in R1 and 60% (15 of 25) in R0 (P = 0.001). The rate of R2 resection was also correlated with the place of initial surgery: 61% (31 of 51) in private or general hospitals versus 27% (12 of 44) in university or cancer hospitals (P = 0.021), and with the specialty of the surgeon: 11% (two of 18) for specialized sarcoma surgeons, versus 45% (14 of 31) for orthopedists, 55% (11 of 20) for general surgeons and 64% (16 of 25) for abdominal surgeons (P = 0.029). Finally, initial surgical procedure was judged to conform with CPGs in 52% of all cases.
Second surgical procedure: Twenty-nine (31%) of all patients benefited from multidisciplinary committee evaluation before possible second surgical resection. In the R2 resection subgroup (43 patients), only 19 patients (49%) were evaluated for re-excision, of whom 16 (37%) underwent second surgery. In the R1 subgroup (27 patients), only seven patients (26%) were evaluated for re-excision, of whom four (15%) underwent second surgery.
A second surgical excision was finally performed in 21 patients. Six (29%) were operated on in a private institution, eight (38%) in the university hospital and seven (33%) in the comprehensive cancer center. Nineteen patients (90%) undergoing second surgery had wide excision and two (10%) had marginal or incomplete excision. Thirteen patients (62%) were considered as having R0 surgical resection, six patients (29%) had R1 resection and two (9%) had R2 resection.
Of the remaining 57 (60%) patients (70 minus 13) who did not have wide surgical margins, i.e. R1 or R2 resection with or without re-operation, 28 (48%) received postoperative radiotherapy (plus chemotherapy in 14), and 30 (52%) did not, although 11 had adjuvant chemotherapy.
Histological analysis: Histological subtypes are described in Table 1. Twenty sarcomas did not have grade specified. Grade was reported for 89 patients: 17 grade I, 13 grade II and 59 grade III. Histological margins were specified for 95 cases.
Adjuvant therapy: A multidisciplinary sarcoma committee reviewed the files of 73 patients after surgery to determine further adjuvant treatment procedures or surveillance. Sixty-two patients received adjuvant radiotherapy or chemotherapy: 18 (29%) had radiotherapy alone, 20 (32%) had chemotherapy alone, and 24 (39%) received both chemotherapy and radiotherapy. The median time from last surgery to first adjuvant treatment was 1.37 months (range 02.4). Of the 44 patients who received chemotherapy, only 10 were included in a prospective clinical trial. Twenty-one patients received chemotherapy in neo-adjuvant phase only, 11 in adjuvant phase only, and 12 in both neo-adjuvant and adjuvant phases. Radiation therapy was delivered with a median time of 1.11 months (range 117.8) after primary surgery; the dose delivered to the tumor bed was 50 Gy for 20 patients and 60 Gy for the 22 remaining patients. Rates of conformity with CPGs of radiation therapy and chemotherapy were 81% and 94%, respectively.
Follow-up. Seventy patients were alive at the end of August 2002. Of the 100 initial patients, eight were not valuables for post-treatment surveillance, but we have information on relapse or death. Fourteen patients died or relapsed rapidly (<1 year after diagnosis of tumor) and were not assessable for surveillance. A total of 78 patients were therefore evaluable for the management of surveillance after initial clinical management: 74 received surveillance in agreement with CPGs, while four did not.
Local relapse and metastasis
In the whole study population, 54 patients experienced local (n = 14), metastatic (n = 18), or local and metastatic (n = 22) relapse. Median time between diagnosis and relapse was 26 months (range 1437). Median time between diagnosis and local recurrence was 48 months (range 2472). As expected, at univariate analysis, local relapse correlated to quality of resection (20% of local relapse for R0, 26% for R1 and 51% for R2; P = 0.01); macroscopic extent of surgery (19% of local relapse for wide surgery versus 49% for marginal surgery (P = 0.002; Figure 2); subspecialty of the surgeon; type of hospital; review of patient file by multidisciplinary committee or not before surgery; management in the cancer network or not; and conformity of radiotherapy to CPGs. See Table 2 for details of the univariate analysis.
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Conformity to CPGs
In summary, the rates of conformity to CPGs at initial biopsy, first surgery, second surgery, radiotherapy, chemotherapy and follow-up were 65, 52, 49, 81, 94 and 95%, respectively. The global conformity rate of the complete treatment sequence (from initial examination to follow-up) was 32%.
Using logistic regression analysis, independent factors predictive of global conformity to CPGs in this study were: multidisciplinary committee decision before surgery [odds ratio (OR) 30.7; 95% confidence interval (CI) 6144], management in cancer center or university hospital with a sarcoma committee (OR 11.5; 95% CI 257) and management in the cancer network organization (OR 13.9; 95% CI 1.1170). Results are detailed in Table 3.
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Discussion |
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The most important bias in our study was the mode of patient selection. Indeed, patients seen by multidisciplinary committees might well be the most severe cases in the region, and consequently difficult to handle according to reported CPGs. However, and importantly, comparing the incidence rate in the region [19] to the recruitment of these structures shows that very few patients were systematically treated outside referral centers throughout the management of their disease. In the period studied (15 months), the number of evaluated patients was relatively high considering the estimated incidence in the region. In addition, results of the study in terms of patients and management were exactly the same as those described in the literature [3, 68, 18], thus confirming that identical management is provided in all western countries, whatever the social system or the health policy, or the mentality of people or opinion leaders.
Concerning the initial management of STS, this study compared investigations performed before surgery to the guidelines. Within the subset of patients with a clinically suspicious mass, only 57% benefited from pre-treatment evaluation. It was also found that a diagnostic biopsy was performed in only 42% of the patients of the study. Pre-clinical evaluation and biopsy are essential steps to guarantee good surgical results [9, 12]; the lack of pre-treatment examinations may explain why only 44% of the patients had adequate initial primary wide excision. Only 42% of patients with marginal excision received either radiation therapy (77%) or chemotherapy alone (33%). Comparing patients with marginal excision with patients with wide excision shows a significantly higher rate of local relapse in the first population. Gustafson et al. [3] and Clasby et al. [6] previously reported similar information with identical percentages of marginal excision and local relapse.
Given that close margins are often inevitable, it is of greater concern that 45% of the patients in this study had R2 surgical resection, and that only 19 (49%) patients of this particular subgroup were discussed for re-excision. R2 resection in this study was correlated with the site of surgery, the specialty of the surgeon and the presence or absence of formal multidisciplinary committee. It is noteworthy that 29 of the 42 patients (70%) undergoing wide excision were operated on in the referral center, thus confirming information described by other authors who reported that adequacy of surgery paralleled the constitution of multidisciplinary STS committees [20]. Local control was acceptable and the number of amputations was similar to that of recent series [21]. A significant improvement was noted compared with previous results from this hospital, but control data were too outdated to make formal comparison possible [22].
The present work stresses the importance of specialized sarcoma groups, which encourages us to recommend the development of multidisciplinary STS committees for defining routine sarcoma management. Yet, running a multimodality group is costly and resource demanding, and it is probably not possible to offer management by multidisciplinary staff in all hospitals. Gathering resources and human expertise in a cancer network seems a potentially valuable solution. The results presented here open the possibility to improve STS management, as recommended by Rydholm [2]. In the 1990s, two out of three patients managed for STS did not have access to specific centers. In 2000, 10 years after the recommendations that diagnosis and treatment should be given in specialized centers were published, four out of five patients were managed in this setting [23]. Furthermore, as described previously, the multidisciplinary setting seems to increase conformity with guidelines [20].
Assessing histological reporting showed that while tumor size, diagnosis and status of margin resection were stated more frequently, tumor grade (an important factor for prognosis in some sarcoma subtypes) was less frequently assessed. This factor, with multidisciplinary committee staff, appears in this study as the only prognostic factor after surgery for metastatic relapse. All previous studies on prognostic factors and overall survival except one have also described tumor grade as a potent prognostic factor [2426]. This has heavy implications for clinicians attempting to plan optimal care. In our study, histological evaluation presents satisfying results and a nearly optimal examination compares with other procedures.
Concerning follow-up, 95% of patients follow-up in this study conformed to CPGs. This very high rate of conformity could be explained by the fact that 73% of patient cases were reviewed and discussed in a multidisciplinary committee before the end of the complete therapeutic sequence, and that the modalities of follow-up may have been determined by the committee. Conversely, the global conformity rate of the complete therapeutic sequence was low: only 32% in this study. In previous studies of the RhôneAlpes region, the conformity of breast and colon cancer management with locally developed and implemented guidelines was >50% [27, 28]. The type of disease and the fact that CPGs were implemented and broadcasted only at the national level might account for the lower rate of conformity of biopsy and surgery. Deficiency in following the guidelines could be due to other reasons as well: (i) the physicians who write the rules are more likely to follow them; (ii) lack of dissemination of the information to the involved surgeons is almost certainly a problem (and one that is very difficult to fix); and (iii) the ability to achieve the goals of the CPGs as outlined may vary depending on the specialty involved. Factors predictive of good conformity with CPGs were the presence of multidisciplinary committees, the management of the patients in a referral center and, more particularly, within the cancer network organization.
In conclusion, the management of STS in this region of France appears to be suboptimal, in particular at the beginning of treatment (diagnosis and first surgical procedure). Our observations are consistent with other studies, originating from various countries. Developing national guidelines without local implementation and local broadcasting seems to be an inefficient way of improving disease management. However, constituting multidisciplinary committees has been found to increase conformity to CPGs, and might help change medical practice and treatment outcome [29, 30]. This last, encouraging, possibility warrants further evaluation and confirmation in a prospective study, which will be elaborated in a collaboration with the entire French Sarcoma Group.
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Acknowledgements |
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FOOTNOTES |
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