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First Published Online November 7, 2008
The Oncologist, Vol. 13, No. 11, 1137-1148, November 2008; doi:10.1634/theoncologist.2008-0162
© 2008 AlphaMed Press
Presurgical Systemic Treatment of Nonmetastatic Breast Cancer: Facts and Open Questions
Alfredo Berrutia,
Maria Pia Brizzia,
Daniele Generalib,
Mara Ardinec,
Luigi Dogliottia,
Paolo Bruzzid,
Alberto Bottinib
aOncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Azienda Ospedaliera Universitaria San Luigi, Orbassano, Italy;
bUnità di Patologia Mammaria – Breast Cancer Unit, Azienda Instituti Ospitalieri di Cremona, Cremona, Italy;
cOncologia Medica, Ospedale di Carmagnola, Carmagnola, Italy;
dDipartimento di Epidemiologia Clinica, Istituto Nazionale per la Ricerca contro il Cancro, Genova, Italy
Key Words. Primary systemic treatment • Pathological complete response • Breast cancer • Surrogacy
Correspondence: Alfredo Berruti, M.D., Oncologia Medica, Azienda Ospedaliera Universitaria San Luigi di Orbassano, Regione Gonzole 10, 10043 Orbassano, Italy. Telephone: 39-011-9026512; Fax: 39-011-9026992; e-mail: alfredo.berruti{at}gmail.com
Received July 29, 2008;
accepted for publication September 30, 2008;
first published online in THE ONCOLOGIST Express on November 7, 2008.
Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.
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Learning Objectives
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After completing this course, the reader should be able to:- Identify the great advantages of primary systemic therapy from a research perspective and also the problems preventing the recommendation to adopt this treatment modality instead of adjuvant therapy in clinical practice.
- Define pathological complete response and discuss its clinical significance.
- Define the concept of a surrogate parameter of treatment efficacy and discriminate it from a prognostic parameter.
- Summarize the main characteristics and findings of randomized trials of primary systemic therapy in comparison with randomized trials of adjuvant therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
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ABSTRACT
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There are several advantages of administering primary systemic therapy (PST) instead of adjuvant therapy in the management of early breast cancer patients: (a) PST allows for a quantifiable evaluation of the sensitivity or resistance of any treated case and (b) the response assessment offers the opportunity to "cross over" to a different regimen for an individual patient, leading to more flexible, "tailored" therapies. Indeed, these advantages are tenable if one assumes that the primary tumor response serves as a surrogate marker of the efficacy of PST in terms of survival. Unfortunately, this has not yet been validated. The data that are actually available show that both clinical complete response (cCR) and pathological (p)CR have prognostic significance. pCR after chemotherapy has a greater prognostic impact than cCR; however, it is frequently observed in a subset of tumors—such as those that are estrogen receptor negative, are human epidermal growth factor receptor positive, and have elevated proliferative activity—but occurs rarely in their human epidermal growth factor receptor-2/neu counterparts. cCR is more sensitive than pCR, but its assessment presents many hindrances. cCR after chemotherapy can predict early on which tumors are destined to undergo pCR, suggesting a role for this endpoint guiding further treatment decisions early on. The pCR rate in small randomized PST studies comparing chemotherapy with chemotherapy plus trastuzumab was able to predict the difference in survival observed in large, randomized adjuvant trials with a similar study design. Conversely pCR cannot predict the outcome benefit of patients undergoing different hormonal therapies.
In conclusion, pCR may be a reliable surrogate endpoint for PST efficacy in a subset of patients undergoing chemotherapy.
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INTRODUCTION
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Primary systemic therapy (PST), chemotherapy, or endocrine therapy followed by surgery is an increasingly popular sequence in the multidisciplinary approach of operable breast cancer (BC). Randomized studies indicate that the survival benefit from particular systemic treatments is similar, regardless of whether the treatments are administered preoperatively or postoperatively [1–4]. As a consequence, if a patient is judged to be a candidate to receive systemic therapy on the basis of presurgical staging procedures, it is rational to question whether the treatment should be administered before surgery or afterward.
The are several advantages of administering PST. However, it is important to distinguish between direct clinical benefits, which involve the individual patient receiving the PST, and benefits from a research perspective.
From a clinical standpoint, one must consider that adjuvant therapy is a "blind treatment," because we lack individual patient endpoints able to indicate whether the treatment is actually active in that specific patient. The results are expressed in terms of a reduction in the absolute or relative risk for relapse or death comparing a population of treated patients with a population of controls [5]. With adjuvant therapy, treatment choices are based on patient and tumor characteristics (e.g., receptor status) that are statistical predictors of the efficacy of the alternative treatment options [6]. In contrast, PST allows a quantifiable evaluation of the sensitivity or resistance of any treated case. The potential for clinical response to predict a reduction in micrometastatic tumor volume as well as clinical benefit might allow for the individualization of systemic treatments and the rapid assessment of new drugs in early BC. In addition, the response assessment also offers the opportunity to "cross over" to a different regimen for an individual patient on the basis of the initial results, because, if no response is observed, the inactive treatment could be discontinued and replaced with another, possibly more effective, one. All these clinical benefits are to be considered plausible, but they have not yet been confirmed by sound clinical studies.
In prospective research, PST permits the exploration of the effect of treatment on tumor biology in order to detect new biologic or molecular discriminants of either response or resistance and provide new surrogate parameters of efficacy [7]. Trials of adjuvant chemotherapy are usually time-consuming, and the final results are obtained many years after the end of the accrual. With primary chemotherapy, however, results are available quickly (a few months after the enrolment of the last patient), and valuable information can be gathered from proof-of-concept studies involving a relatively small number of patients [8].
Indeed, many of the advantages of PST over adjuvant therapy are tenable, either from a research perspective or in clinical routine, if one assumes that the primary tumor response might serve as a surrogate marker of the efficacy of chemotherapy in terms of survival, that is, of its effect on micrometastases.
This paper provides an overview of the advantages and limits of the use of disease response after PST in clinical studies.
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EFFICACY OF PST IN TUMOR DOWNSTAGING
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PST is very active in downstaging primary BC. Table 1 reports on the results of large series and randomized clinical trials [9–27]. As a whole, single agents or regimens commonly employed in the management of BC are able to obtain significant tumor shrinkage (>50% according to World Health Organization response criteria) in >70% of patients: complete clinical response (cCR) (i.e., the total disappearance of clinically assessable tumor) is less frequent (20%–30%), and pathological complete response (pCR) (no tumor in the residual histology) occurs rarely (<10%). Noteworthy is the fact that tumor progression is rather uncommon (1%–2%), so that operable patients before PST rarely become inoperable at the end of treatment. As expected, polychemotherapy is more active than single agents and taxane- plus anthracycline-containing schemes are more active than anthracycline-containing regimens alone. Disease response also depends on the number of cycles administered: six to eight cycles of the same regimen are more active than three to four cycles, but it is unknown whether this trend can be maintained by further increasing the number of cycles. The sequential use of anthracyclines plus taxanes leads to a greater response rate than with concomitant administration.
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CLINICAL RESPONSE VERSUS PATHOLOGICAL RESPONSE
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PST offers the opportunity to assess disease response either clinically or pathologically. In all trials, clinical response to treatment is obtained by palpation. This technique is simple but has several limitations: (a) it requires an experienced clinician, (b) measurement of the tumor size is unreliable when the tumor is irregular or diffuse because margins cannot delineated precisely, and (c) residual fibrosis can be misinterpreted as an incomplete response whereas necrosis can actually cause enlargement at the time when the active tumor is shrinking. Moreover, in the case of patient inclusion in a clinical trial, the results cannot be assessed by external reviewers. Multicenter clinical trials may add heterogeneity to the interpretation of the results.
In four prospective PST trials conducted at the Breast Unit of Cremona, enrolling 478 consecutive patients, 130 (27.2%) attained a cCR and 239 (50.0%) had a clinical partial response (cPR). Nineteen patients attained a pCR. Among them, 14 were classified as cCR, four were classified as cPR, and one had stable disease. On the basis of these results, clinical examination is inadequate in predicting pCR. The limited role of clinical response in predicting pCR was confirmed in a recently published study [28].
pCR is considered by most authors as the best intermediate endpoint to assess the efficacy of antineoplastic treatments administered preoperatively. However, there is no standard method for grading pathological response of breast tumors to PST. Several classifications have been proposed, as summarized in Table 2 [11, 29–37]. Most of them consider various grades of response on the basis of residual tumor on postchemotherapy histology. pCR is the total disappearance of malignant disease in either breast and the axillary lymph nodes in some classifications, whereas other classification systems define pCR as the absence of invasive carcinoma, thus considering together the absence of neoplastic cells and residual in situ carcinoma. Some classifications refer to response of the primary breast tumor only, whereas others also include axillary lymph node evaluation. These differences in pCR assessment account for differences in the pCR rate observed in clinical trials and may complicate interpretation of the trial results. For instance, four cycles of a primary anthracycline regimen led to pCR in about 10% of patients enrolled the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial [3] but in only 4% of patients included in a single-institution experience of the National Cancer Institute of Milan [38]. The total absence of cancer cells was the pCR definition used in the Milan series, whereas residual in situ carcinoma was included in the NSABP B18 study. A recent experience of the MD Anderson Cancer Center (MDACC) found that pCR in axillary lymph nodes is a parameter that is significantly associated with an excellent prognosis, even in cases of residual primary tumor [39]. The recent update of the American Society of Clinical Oncology guidelines on primary chemotherapy recommends the total disappearance of malignant cells, both in the breast and axillary lymph nodes, as a standard criterion [40].
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PREDICTORS OF PCR AFTER PRIMARY CHEMOTHERAPY
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Several recent papers addressed the issue of which patients have the greatest chance of attaining a pCR [30, 41–43]. Estrogen receptor (ER) status is the most frequently observed predictive factor. At least six studies using various chemotherapeutic regimens [41–45] reported a greater pCR rate in ER– tumors than in ER+ ones.
Other factors associated with the greatest chance of attaining a pCR were tumor grade, proliferative activity, human epidermal growth factor receptor (HER)-2/neu positivity, vascular/lymphatic invasion, and primary histology. Accordingly, patients with poorly differentiated, highly proliferating, HER-2/neu–positive ductal primary tumors without vascular and lymphatic invasion have a greater chance of pCR after primary chemotherapy than their counterparts. Because most of these predictive factors are reciprocally correlated, it is unclear which of them show an independent association.
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PROGNOSTIC ROLE OF TUMOR RESPONSE AFTER PRIMARY CHEMOTHERAPY
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The NSABP B18 study [3] found a significant 5-year distant disease-free survival (DFS) advantage for patients having a cCR (79.3%) than for patients with a cPR (72.5%) or no clinical response (cNR) (65%) (p = .005), but there was no significant overall survival (OS) advantage (cCR, 81.5% versus cPR, 78.4% versus cNR, 76.9%; p = .19). In contrast, women in the NSABP B18 trial who had a pCR had significantly longer DFS and OS than those who had a cCR but invasive cells on residual histology (p = .001). Similar results have been obtained in the majority of trials (randomized and not randomized) published up to now [4]. In these trials, pCR, regardless of the definition adopted, led to a significantly greater disease-free interval and survival benefit compared with the persistence of residual malignancy. Whether the presence of residual ductal carcinoma in situ led to a different survival perspective than no residual malignancy remains to be elucidated. This issue was addressed in a recent study [44]. The results showed no difference in DFS and OS comparing patients achieving true pCR following PST with patients showing in situ carcinoma on postchemotherapy residual histology. As a result of the small proportion of patients achieving pCR and in situ carcinoma, the results could not be considered as definitive.
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CLINICAL RESPONSE AND PATHOLOGIC RESPONSE AS ENDPOINTS OF PROSPECTIVE STUDIES
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pCR after treatment has been used as an early measure of treatment efficacy in many phase III trials. Here, we examine the results of four randomized clinical trials addressing the efficacy of adding docetaxel to standard anthracycline-containing schemes. The NSABP B28 [45] trial randomized 2,411 stage I–III patients to one of three treatment groups: four cycles of primary doxorubicin plus cyclophosphamide (AC) before surgery, four cycles of primary AC followed by four cycles of docetaxel before surgery, and four cycles of AC followed by surgery and then four cycles of docetaxel. The results of that trial show a clear advantage of adding docetaxel to AC in terms of both clinical and pathological response. The NSABP B28 trial, however, cannot establish whether the superiority of the sequential scheme is attributable to the addition of docetaxel or to the greater number of cycles administered. The answer to this question was provided by the Aberdeen trial [46], in which only 162 patients received four cycles of cyclophosphamide, vincristine, doxorubicin, and prednisone (CVAP). At the end of this first step, nonresponders received four cycles of docetaxel, whereas responders were randomized to either continue the CVAP regimen for a further four cycles or cross over to four docetaxel cycles. The pathological and clinical response rates of the patients who responded to the first four CVAP cycles and who subsequently received docetaxel were significantly higher than those of patients randomized to continue CVAP. Although this trial was considerably less powerful than the NSABP study, it nevertheless provided the first evidence that sequential administration of a doxorubicin-containing regimen and docetaxel is more active than the full dose of the doxorubicin-containing scheme.
The question of whether a dose-dense regimen may be superior to a sequential regimen was addressed by the GeparDuo study [23]. In that study, 913 patients were randomized to receive a dose-dense doxorubicin plus docetaxel (ADoc) regimen or sequential AC followed by docetaxel (AC–Doc). The results of the GeparDuo trial were confirmed by the Arbeitsgemeinshaft Gastroenterologische Onkologie trial, in which 631 patients were randomized to receive epirubicin and docetaxel administered sequentially versus the two drugs administered concomitantly [10]. Sequential AC–Doc led to higher cCR and pCR rates than with concomitant dose-dense ADoc. In summary, all these trials, under the assumption that pCR is a surrogate parameter for efficacy, have provided, in just a few years, answers to two important issues: (a) the addition of docetaxel to anthracyclines or anthracycline-containing regimens leads to greater efficacy than with anthracyclines alone and (b) sequential anthracycline–docetaxel is more efficacious than concomitant administration of the two drugs. The same results in the adjuvant setting would have required many years and thousands of patients. The superior efficacy of taxanes given sequentially with anthracyclines over anthracycline-based regimens has been demonstrated in the adjuvant setting in five randomized phase III trials—the Cancer and Leukemia Group B (CALGB) 9344 trial [47], the PACS 01 trial [48], the Grupo Español de Investigaciôn de Cáncer de Mama 9906 trial [49], and the MDACC 94–002 trial [50])—enrolling >7,000 node-positive patients. Conversely, no data are available on a direct comparison between sequential and concurrent adjuvant schedules. Only one ongoing study, the Breast Cancer International Research Group 005 trial [51], compares docetaxel, doxorubicin, and cyclophosphamide (the TAC regimen) with AC followed by docetaxel, and in fact, only data on toxicities are known.
It has been demonstrated that very small randomized PST studies are able to predict the results of large randomized adjuvant trials. In a phase II trial, 42 patients with HER+ primary BC were randomized to receive four cycles of fluorouracil, epirubicin, and cyclophosphamide followed by four cycles of paclitaxel with or without trastuzumab. The results showed a dramatically higher pCR rate in favor of the trastuzumab arm (66.7% versus 25.0%) [52]. The dramatic improvement in the pCR rate by adding trastuzumab to chemotherapy was confirmed in further trials (Table 3) [52–55]. The efficacy of adding trastuzumab to cytotoxic chemotherapy in terms of survival prolongation was demonstrated in the adjuvant setting by the combined analysis of two multicenter U.S. studies (the NSABP B31 trial and the North Central Cancer Treatment Group N9831 trial) [56]. These trials randomized 3,351 HER+ patients to receive AC followed by paclitaxel or the same regimen plus trastuzumab administered concomitantly with paclitaxel and continued for 12 months after the completion of chemotherapy.
Possible Integration of Clinical and Pathological Response
The GeparTrio trial [57, 58] addressed the question of whether clinical response to primary chemotherapy is an early predictor of pCR. In that study, 913 patients after receiving two chemotherapy cycles of the TAC regimen were stratified according to disease response; patients attaining a disease response continued to receive the TAC scheme for a total of six cycles, whereas patients with disease stabilization were randomized to either continue the TAC regimen or receive a potentially noncrossresistant combination such as vinorelbine and capecitabine. This study demonstrated that early responders to this regimen achieved a high pCR rate, whereas patients who did not respond after two TAC cycles had a lower chance of attaining a disease response whether they continued the TAC scheme or received a vinorelbine–capecitabine regimen. This study suggests an optimal integration of two different techniques of response evaluation. The identification of nonresponders early in the course of therapy is a new indication that clinical palpation may allow for a change in therapy, with potentially better results on overall patient outcome.
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ENDOCRINE THERAPY TRIALS
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Four randomized trials of primary endocrine therapy addressed the issue of the superior antineoplastic activity of aromatase inhibitors (AIs) over tamoxifen. Two trials compared anastrozole with tamoxifen [59–61], one trial compared letrozole with tamoxifen [62, 63], and one trial compared exemestane with tamoxifen [64].
The results of these trials are presented in Table 4. The efficacy of upfront anastrozole and letrozole against tamoxifen was tested in two large, randomized adjuvant trials (the Arimidex®, Tamoxifen, Alone or in Combination [ATAC] and Breast International Group [BIG] trials) [61, 63], so that the differences in disease response to primary endocrine therapy could be indirectly compared with the differences in terms of efficacy of the adjuvant trials.
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Table 4. Clinical and pathological responses of primary tamoxifen or aromatase inhibitors in randomized clinical trials, with disease-free survival comparisons in corresponding randomized adjuvant trials
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Noteworthy is the fact that discrepant results among primary endocrine therapy trials have been obtained regarding clinical response. Letrozole and exemestane were found to be more active than tamoxifen, while anastrozole was not (the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen and the Pre-Operative "Arimidex" Compared to Tamoxifen trial trials). Both the BIG and ATAC trials showed a clear superiority of either letrozole or anastrozole over tamoxifen in terms of DFS, so that disease response paralleled the results in terms of DFS in the adjuvant setting for letrozole but not for anastrozole. On the basis of these results, the role of clinical response as an early predictor of DFS after primary endocrine therapy is controversial.
Furthermore, pCR results were reported in the letrozole and exemestane studies. In both studies, the pCR rate after AIs was very low (<2%) and superimposable on that observed after tamoxifen. These data suggest that pCR is not a reliable endpoint to test the efficacy of endocrine therapy. The reasons are not clear. The exposure to AIs and tamoxifen in these trials was only of a few months duration, and it is expected that endocrine therapy requires much more time to be fully effective. On the other hand, the efficacy of endocrine therapy in humans could be mainly a result of an antiproliferative effect instead of an apoptotic mechanism, as recently suggested [65].
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RESPONSE TO PST AS A SURROGATE ENDPOINT OF TREATMENT EFFICACY
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A surrogate parameter is an outcome variable, that is, a clinical, instrumental, or laboratory test, that can be used as a primary endpoint in a clinical trial. It enables the prediction of treatment effects on the "true" primary endpoint [66].
According to the Prentice criteria [67], prerequisites for surrogacy are correlation with the primary endpoint and sensitivity to the treatment effect, but a crucial requirement is that the treatment effect on the primary outcome should disappear when the surrogate is adjusted for.
As previously shown, disease response to PST meets the first two of Prentice's [67] prerequisites: (a) it is induced by the treatment and (b) responding patients live longer than nonresponders [4]. As depicted in Table 5, many data are in favor of the notion that pCR could meet the criteria of surrogacy, but others do not support surrogacy. There are no studies showing that the difference in survival disappears once there has been adjustment for the response.
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Table 5. Available data in favor of or against the notion that treatment response is a surrogate efficacy endpoint
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The validation of response to primary chemotherapy as a surrogate endpoint of treatment efficacy requires a randomized trial, or, even better, trials with meta-analyses comparing two different regimens that are large in size (>2,000 patients) and in which a large difference in response is obtained (>10%), and, even better yet, trials that show a significant difference in terms of survival.
Data in Favor of Disease Response as a Surrogate Endpoint
Several data are in favor of the notion that disease response to PST may be a surrogate endpoint for efficacy (Table 5). For instance, the relationship between pCR and negative prognostic factors (ER–, high grade, high proliferative activity, HER-2+) does not match with the assumption that pCR can select a patient population already destined to have a good prognosis. In addition, the recent finding of an independent prognostic role for pCR with respect to ER status [68] provides further data that this endpoint is not influenced by tumor biology. In the Aberdeen trial, docetaxel sequential to the CVAP regimen, in addition to producing a higher pCR rate, led to significantly longer survival [46]. pCR in a selected population of patients with a HER+ primary malignancy perfectly paralleled the results of the survival endpoint of large randomized trials. Two published studies demonstrated that response to chemotherapy in cancer patients with metastatic disease met all the criteria of surrogacy. The first paper reported on a population of advanced colon cancer patients who underwent two different schedules of 5-fluorouracil infusion [69]; the second one is a meta-analysis of a number of trials comparing two different schedules of chemotherapy administration, conventional versus intensified, in advanced BC patients [70]. Both papers reported that responding patients had superimposable survival irrespective of the treatment received, and this is a clear demonstration of surrogacy.
Data Against Disease Response as a Surrogate Endpoint
There are also data that do not support the surrogacy of disease response to PST. The survival differences observed in the Aberdeen trial should be interpreted with caution because that study was clearly underpowered. A recent update of the large NSABP B27 study failed to demonstrate a significant difference in terms of DFS or OS for patients treated with sequential anthracycline and docetaxel despite mature follow-up data and an adequate number of events [14, 71].
HER-2 positivity notoriously correlates with the absence of ER expression and elevated proliferative activity, and both features are associated with a high prediction of pCR. pCR, therefore, may be a surrogate endpoint in this patient subset but not necessarily in other subsets.
The Herceptin® Adjuvant trial [72] confirmed the advantage in terms of OS of adding trastuzumab to chemotherapy. In that study, however, trastuzumab was administered for 12 months sequentially with adjuvant chemotherapy. On the basis of these data, it is impossible to discriminate whether the potentiating effect of adding trastuzumab to chemotherapy may be attributable to a higher pCR rate or to a maintenance effect, that is, the switching off of a metabolic pathway.
The patient populations enrolled in the two studies showing that disease response to chemotherapy met the criteria for surrogacy studies (i.e., advanced colon cancer and BC) are quite different from patients needing PST, so we cannot extrapolate the results of these trials to PST trials.
Finally, in patients undergoing primary endocrine therapy, pCR is not a reliable endpoint and there are no data showing a correlation between clinical response and survival.
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NEW METHODS OF ASSESSING DISEASE RESPONSE TO PST
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Imaging Techniques
Imaging techniques may potentially give more objective findings than clinical examination. In addition, if patients are enrolled in clinical trials, disease response assessed by imaging techniques has the advantage that it can also be assessed by an external reviewer. Our experience failed to show any advantage of using echography and mammography over clinical examination in assessing response to treatment [73].
Contrast magnetic resonance imaging (MRI) is an emerging technology that is very promising in this respect. This technique is very sensitive, being able to detect tumors as small as a few millimeters in size [74, 75]. The rationale behind the use of MRI also lies in its ability to detect vascularity [76].
In our experience, MRI was able to represent the extent of cancer more accurately than clinical palpation, even though this technique failed to accurately predict the nature of residual disease [74]. No data are actually available on the relationship between response assessed using MRI and disease outcome. This issue is being evaluated in an intergroup multicenter randomized clinical trial (American College of Radiology Imaging Network [ACRIN] 6657/CALGB Intergroup trial 49808) comparing an anthracycline-based regimen with anthracyclines followed by taxanes in locally advanced BC. Promising preliminary results have been obtained using positron emission tomography (PET) in assessing response to PST [77]. It would be interesting in the future to combine the information obtained using PET with those obtained using MRI.
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CONCLUSIONS
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Disease response (and pCR in particular) is potentially a valid surrogate parameter for the efficacy of PST in human BC; however, it has not yet been validated. Clinical response assessment presents many hindrances and cannot be considered as the gold standard. However, it predicts patients early on who are more frequently destined to undergo a pCR. The use of clinical response to guide further treatment decisions in the PST setting is a very interesting issue leading to more flexible "tailored" therapies that has been introduced by a new generation of clinical trials. Disease response assessed using MRI is promising but needs validation in large clinical trials.
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AUTHOR CONTRIBUTIONS
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Conception/Design: Alfredo Berruti, Maria Pia Brizzi, Daniele Generali, Paolo Bruzzi
Financial support: Alfredo Berruti, Luigi Dogliotti, Alberto Bottini
Administrative support: Daniele Generali, Luigi Dogliotti, Alberto Bottini
Provision of study materials: Maria Pia Brizzi, Mara Ardine, Alberto Bottini
Collection/assembly of data: Maria Pia Brizzi, Daniele Generali, Mara Ardine, Alberto Bottini
Data analysis: Alfredo Berruti, Maria Pia Brizzi, Paolo Bruzzi
Manuscript writing: Alfredo Berruti, Paolo Bruzzi
Final approval of manuscript: Alfredo Berruti, Maria Pia Brizzi, Daniele Generali, Mara Ardine, Luigi Dogliotti, Paolo Bruzzi, Alberto Bottini
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Learning Objectives
Abstract
