DDS, PhD J L Roodenburg

MD, DDS a , M.J G W Jaspers
email: g.w.c.jaspers@kchir.umcg.nl

MD, DDS, PhD M J Witjes

MD, PhD b , H H J Groen

MD, PhD L A Rödiger

MD, DDS, PhD Witjes

MD, PhD Groen

Strategies for patients with newly diagnosed oral squamous cell carcinoma and a positive chest CT. A cohort study on the effects on treatment planning and incidence

Keywords: Chest CT, Oncology, Treatment delay, Treatment planning, Cost analysis

Strategies for patients with newly diagnosed oral squamous cell carcinoma and a positive chest CT. A cohort study on the effects on treatment planning and incidence

Introduction

During the process of initial tumor staging of patients suffering from head & neck squamous cell carcinoma (HNSCC), the extent of the imaging required needs to be considered.

According to the National guidelines of the Dutch Cooperative Head and Neck Oncology Group, patients with three or more, bilateral, low jugular or N3-neck lymph node metastasis in the neck have the highest risk for distant metastasis. [START_REF] Alvi | Development of distant metastasis after treatment of advancedstage head and neck cancer[END_REF][START_REF] De | Screening for distant metastases in patients with head and neck cancer[END_REF][START_REF] Loh | A rational approach to pulmonary screening in newly diagnosed head and neck cancer[END_REF] In these patients a computed tomogram (CT) of the chest is indicated. For all other patients, a conventional X-ray of the chest is dictated by this guideline to screen for intrapulmonary tumor growth. In current practice a CT however is the golden standard for this purpose. [START_REF] Ong | The role of thorax imaging in staging head and neck squamous cell carcinoma[END_REF][START_REF] Loh | A rational approach to pulmonary screening in newly diagnosed head and neck cancer[END_REF][START_REF] Tesche | The value of chest CT-scanning for staging of progressed or recurrent head and neck squamous cell carcinomas (HNSCC)[END_REF][START_REF] Warner | Evaluation of chest radiography versus chest computed tomography in screening for pulmonary malignancy in advanced head and neck cancer[END_REF][START_REF] Arunachalam | Role of computerized tomography (CT) scan of the chest in patients with newly diagnosed head and neck cancers[END_REF] There is a strong rationale for pulmonary diagnostic imaging in patients with SCC of the oral cavity. Besides the importance of excluding pulmonary metastasis, lung carcinoma and SCC of the oral cavity share much of the same etiology. It is therefore known that the patient with a SCC of the oral cavity can have a simultaneous lung carcinoma. [START_REF] Schildt | Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case-control study[END_REF][START_REF] Blot | Smoking and drinking in relation to oral and pharyngeal cancer[END_REF] Incidence reports on these second primary tumors and intrapulmonary metastasis vary from 3% to 19%. This broad variance on risk of intrapulmonary metastasis or synchronous tumor depends on size and location of the squamous cell carcinoma of the head & neck. A tumor more distal in the upper aero digestive tract (larynx e.g.) will show a higher incidence of pulmonary metastasis than one located more proximal such as in the oral cavity. [START_REF] Blot | Smoking and drinking in relation to oral and pharyngeal cancer[END_REF][START_REF] Houghton | Role of chest CT scanning in the management of patients presenting with head and neck cancer[END_REF] Also patients with locally advanced or recurrent tumor show more distant metastasis. [START_REF] Keski-Santti | CT of the chest and abdomen in patients with newly diagnosed head and neck squamous cell carcinoma[END_REF][START_REF] Houghton | Chest computerized tomography scanning in patients presenting with head and neck cancer[END_REF][START_REF] Keith | The role of thoracic computed tomography in staging newly-diagnosed oral squamous cell carcinoma[END_REF][START_REF] Mercader | CT surveillance of the thorax in patients with squamous cell carcinoma of the head and neck: a preliminary experience[END_REF][START_REF] Deleyiannis | Risk of lung cancer among patients with head and neck cancer[END_REF][START_REF] Jackel | Efficacy of radiologic screening for distant metastases and second primaries in newly diagnosed patients with head and neck cancer[END_REF] It is this riskassessment the guideline is based upon. The current Dutch guideline does not consider a diagnostic search for a synchronous second tumor in all HNSCC patients due to the low incidence. [START_REF] Brouwer | Screening for distant metastases in patients with head and neck cancer: what is the current clinical practice?[END_REF][START_REF] Ferlito | Screening tests to evaluate distant metastases in head and neck cancer[END_REF] However, the presence of a second primary pulmonary tumor will have a profound effect on treatment choices and planning. This is a valid reason for screening more extensively patients with newly diagnosed SCC of the oral cavity. The added value of a chest CT is either detecting a lung carcinoma in a curable stage or scaling down the treatment of the index tumor in case of an incurable lung carcinoma or distant metastasis. [START_REF] Houghton | Chest computerized tomography scanning in patients presenting with head and neck cancer[END_REF][START_REF] Reiner | The impact of routine CT of the chest on the diagnosis and management of newly diagnosed squamous cell carcinoma of the head and neck[END_REF] Known disadvantages of scanning patients with a low risk of distant metastasis are the radiation dose, unnecessary costs and delay in treatment start of the index tumors in case of false positive findings. [START_REF] Tan | Role of screening chest computed tomography in patients with advanced head and neck cancer[END_REF] The current study was initiated to investigate the value of a CT scan of the chest in newly diagnosed SCC of the oral cavity irrespective the tumor stage. Data were collected from a cohort of patients that was routinely subjected to a CT scan of the head and neck as well as the chest. The objectives of the study were to establish how often this diagnostic approach yields positive findings on a chest CT and how it influences the treatment of the patient in terms of extra diagnostic procedures and treatment delay. Next to this the cost effectiveness of diagnostic imaging for pulmonary tumors in this selected group was calculated.

Patients and methods

Incidence of secondary pulmonary tumors and clinical work up

From a cohort of 196 consecutive patients we selected the hospital files of 142 patients diagnosed with a biopsy proven squamous cell carcinoma in the oral mucosal lining, which were treated with a curative intent at the Department of Oral and Maxillofacial Surgery of the University Medical Center Groningen between January 2004 and July 2006. Information was collected on smoking behavior, disease stage, used imaging technique, additional imaging and start of treatment. Before treatment all patients underwent a diagnostic CT scan of the chest. CT's were performed with a Siemens Sensation 16 multislice and/or a Siemens Sensation 64 multislice scanner (Siemens, Erlangen, Germany)) with a slice thickness of 1.5 or 2.5 mm respectively. During CT, 60 ml of contrast medium (Visipaque 320, iodixanol, GE Healthcare, Canada) was administered intravenously at a rate of 2.5 ml per second. A qualified radiologist assessed all CT scans. When reviewing the CT scan, distinction was made in (1) no abnormalities (2) non suspicious abnormalities such as micro-calcifications or lymph nodes smaller than 1 centimeter (3) abnormalities suspicious for distant metastasis in lung parenchyma and/or lung (lymph nodes larger than 1 centimeter, pleural involvement, chest wall lesions) (4) abnormalities suspicious for a primary carcinoma of the lung (solitary pulmonary nodule with irregular surface) (5) abnormalities without clear radiological diagnosis that need additional diagnostics or follow up (infectious causes such as tuberculosis or pneumonia or an inflammatory condition such as sarcoidosis).

In case of suspicious findings (item 3, 4 and 5) a chest physician was consulted and subsequently procedures such as whole body FDG-PET, bronchoscopy and Trans-Esophageal Ultra Sound-Fine Needle Aspiration were performed to come to a definitive pulmonary diagnosis. In case of a small lesion (<1 cm) with a low incidence of suspicion a follow-up CT of the chest was performed within a maximum of 6 months. All cases were finalized in a multi-disciplinary panel. During the entire process of work up the following time points were defined:

(1) date of first presentation with known pathology of the index tumor

Cost effectiveness

The extra costs to detect a second primary tumor and distant metastasis in the work up, were calculated by summing up costs of all additional diagnostic procedures (chest CT, FDG-PET and bronchoscopies), as well as costs of consultations and follow-up CT scans of the chest. These costs were divided by the number of patients that benefited from the CT scan to calculate the costs per additional malignancy detected. All diagnostic procedures were valued according to the Dutch tariffs or standard prices as issued by the Dutch Health Care Insurance Board. [START_REF] Oostenbrink | Manual for cost studies; methods and standard costs for economic evaluations in Health Care[END_REF]

Results

Incidence of secondary pulmonary tumors

A total of 142 hospital files were eligible for reviewing because of completeness of required data, and possibility of a curative intent. Demographic and tumor characteristics are described in table 1. In all patients a chest CT was performed routinely. Twenty of 142 had abnormalities on the CT scan of the chest suspicious for malignancy (table 2). After additional diagnostic procedures (whole body FDG-PET, consultation with a chest physician, bronchoscopy) a biopsy proven second primary tumor of the lung was found in 4 patients and distant metastasis from the SCC of the oral cavity in 2 patients (total of 6 patients). The other 14 patients were also assessed with extensive further investigations to finalize a diagnosis on the chest abnormalities, including follow up CT of the chest. No pulmonary malignancies could be found during follow-up CT after 6 months. Tumor characteristics of the index tumors of all 6 true positive patients are described in table 3. This shows an incidence of 4% pulmonary malignancies in SCC of the oral cavity.

The treatment-plan for two patients with lung metastasis from the SCC of the oral cavity was altered from a curative intent to palliative radiotherapy. Two patients that had a primary lung carcinoma underwent a treatment with curative intent for both tumors, and are still free of disease 3 years after treatment. One patient had palliative radiotherapy and one patient was treated completely for his carcinoma of the head and neck and subsequently a thoracotomy, which showed irresectability for his lung carcinoma. In a total of six out of 142 patients the original treatment plan changed.

Clinical work up

The mean work up time (time between the first consult to start of treatment) for all patients was 35 ± 16.5 calendar days. Patients with an unsuspicious (negative) CT scan (n=132) had a work up time of 34 ± 16.6 calendar days. For those with a true positive CT scan (n=6) the work up time did not differ from those with a false positive CT scan (n=14)(41 ± 8.9 days versus 38 ± 18.3 days). The results are summarized in Table 4. These work up times were not statistically different.

Cost effectiveness

We collected all information on the costs of the diagnostic procedures from the Dutch Healthcare research board [START_REF] Oostenbrink | Manual for cost studies; methods and standard costs for economic evaluations in Health Care[END_REF]. Besides the routine CT scan of the chest in all patients, 9 patients underwent a FDG-PET scan and 7 patients underwent a bronchoscopy for confirmation of the imaging diagnosis. All false positive patients underwent a follow up CT scan of the chest after six months. The total costs of 142 CT scans of the chest (€219 per CT), 9 FDG-PET scans (€1.172 per PET scan), 20 consultations with the pulmonary oncologist (€106 per consult), 7 bronchoscopies (€351 per bronchoscopy) and 14 follow-up CT scans of the chest were calculated, and divided by the 6 patients that all benefited from the CT scan. This resulted in the calculated amount of €8.214 per patient benefiting from the CT scan.

Discussion

Incidence of secondary pulmonary tumors

We found malignant lesions on CT scan of the chest in six patients out of 20 CT scans that were suspicious on the CT scan of the chest. Additional diagnostic procedures did not significantly lengthen the time interval between first consult and start of treatment. The costs of the diagnostic imaging for pulmonary malignancies in the group were €8.214 per observed pulmonary malignancy.

The low prevalence of 4% does seem to be within the range of the reported 3 -19% of pulmonary malignancies. [START_REF] Keski-Santti | CT of the chest and abdomen in patients with newly diagnosed head and neck squamous cell carcinoma[END_REF][START_REF] Keith | The role of thoracic computed tomography in staging newly-diagnosed oral squamous cell carcinoma[END_REF][START_REF] Mercader | CT surveillance of the thorax in patients with squamous cell carcinoma of the head and neck: a preliminary experience[END_REF][START_REF] Deleyiannis | Risk of lung cancer among patients with head and neck cancer[END_REF] The inclusion of all newly diagnosed SCC patients in the current study without making a selection on risk factors for a lung carcinoma may partially explain the low prevalence. Exclusion of all non-smoking patients would only slightly increase the incidence of pulmonary malignancies to 5.6%. However, the group of non-smokers should not be excluded since pulmonary metastasis of HNSCC can occur irrespective of smoking. In studies with a higher prevalence of pulmonary involvement the data analysis was performed on a selected group. In these studies patients with small head & neck tumors were excluded. [START_REF] Keski-Santti | CT of the chest and abdomen in patients with newly diagnosed head and neck squamous cell carcinoma[END_REF][START_REF] Keith | The role of thoracic computed tomography in staging newly-diagnosed oral squamous cell carcinoma[END_REF][START_REF] Mercader | CT surveillance of the thorax in patients with squamous cell carcinoma of the head and neck: a preliminary experience[END_REF][START_REF] Deleyiannis | Risk of lung cancer among patients with head and neck cancer[END_REF] Other contributing factors to a higher prevalence are the inclusion of recurrent tumors and the selection of tumors more distally located such as in the hypopharynx and larynx. [START_REF] Blot | Smoking and drinking in relation to oral and pharyngeal cancer[END_REF][START_REF] Houghton | Role of chest CT scanning in the management of patients presenting with head and neck cancer[END_REF] When analyzing the 6 patients with a proven pulmonary malignancy of this study it appeared that none of these patients met the criteria of the guidelines of the Dutch Cooperative Head and Neck Oncology Group for a CT scan of the chest. [START_REF] De | Screening for distant metastases in patients with head and neck cancer[END_REF][START_REF] Loh | A rational approach to pulmonary screening in newly diagnosed head and neck cancer[END_REF] This can be explained by the fact that the current guideline is based on the likeliness of the occurrence of a distant metastasis and not on the occurrence of a simultaneous second primary lung carcinoma. Both patients that had distant metastasis had stage IV disease without extended cervical lymph node metastasis. The other 4 patients had stage II and III disease and had a simultaneous second primary tumor of the lung without having complaints. All these patients underwent preoperative screening by the anesthesiologist in preparation of possible resection, which included a plain X-ray of the chest. In all six patients with a positive CT of the chest there were no abnormalities on this X-ray of the chest. Without this diagnostic CT scan of the chest these patients would have underwent an extensive treatment for their index tumor irrespective of their pulmonary involvement. In all 6 patients the CT scan of the chest changed the treatment strategy. In 14 patients additional diagnostics were performed. This burden of imaging tests to exclude those patients with a false positive CT of the chest is a disadvantage of our approach.

Recent lung cancer screening studies found a prevalence between 0.36% -2.7% at baseline screening, in a population with comparable risk on lung malignancies as our patient cohort. [START_REF] Chong | Lung cancer screening with low-dose helical CT in Korea: experiences at the Samsung Medical Center[END_REF][START_REF] Nawa | Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies[END_REF][START_REF] Carter | Comparison of pathologic findings of baseline and annual repeat cancers diagnosed on CT screening[END_REF] The prevalence of 4% malignant finding of which 2.7% were primary lung carcinoma in the current study is high compared to these reports. It could be debated that patients with a SCC of the oral cavity may have a somewhat higher susceptibility for developing a second pulmonary tumor in this population of heavy smokers. When screening for second tumors one apparently finds a selection of patients who are more prone to develop malignancies due to smoking.

Clinical work up

Despite the extra diagnostic work up, there was no significant increase in work up time between patients with a true positive and false positive CT scan of the chest. Nor was there an increase in work up time between patients with a true positive or a negative CT scan of the chest. It should be mentioned that because of the retrospective character of the study there was no awareness that this study would be undertaken at the time of the work up. We therefore consider these data to be a reliable reflection of daily clinical practice. The majority of the patients that were screened did not benefit from the CT scan, but since the introduction of fast multislice CT scanners, the extra scan following the head and neck scan gives little extra discomfort. We therefore consider a chest CT as part of the routine diagnostic work up for patients with a SCC of the oral cavity not as a significant burden for the patient.

Cost effectiveness

The costs of screening programs for breast and cervical cancer in The Netherlands are comparable to the cost per lung carcinoma and/or distant metastasis detected in this study.

For breast and cervical cancer these costs are €8.134 and €10.270 for each observed malignancy respectively [START_REF] Ekwueme | Cost analysis of the National Breast and Cervical Cancer Early Detection Program: selected states, 2003 to 2004[END_REF]. In this study costs were calculated to be €8.214 per observed lung malignancy. Given the radical interventions with profound impact on quality of life when treating patients with SCC of the oral cavity, we consider a chest CT as part of the routine diagnostic work up for patients with a SCC of the oral cavity. The 20 chest abnormalities in 142 patients leading to the detection of 6 chest malignancies and a change in management in these patients outweighed the diagnostic burden for the patient. In our daily practice we use the diagram as shown is figure 1, as a guide in our treatment planning.

In conclusion we would like to advocate that CT imaging of the chest should be routinely performed in the diagnostic work up of all patients with a newly discovered SCC of the oral cavity, irrespective of the tumor stage. The burden for the patient is low and additional diagnostics do not delay the start of treatment. From the cost analysis and the impact of the extra diagnostics on the total work up time we found no arguments against integration of this diagnostic tool. A true positive finding changes the treatment plan profoundly and may even improve the chance for survival.

Conflicts of interest: None declared. distant disease in oral SCC of 92% and 93%, respectively [START_REF] Henschke | Survival of patients with clinical stage I lung cancer diagnosed by computed tomography screening for lung cancer[END_REF][START_REF] Ekwueme | Cost analysis of the National Breast and Cervical Cancer Early Detection Program: selected states, 2003 to 2004[END_REF]. Therefore, findings on a chest CT that do not show uptake on a FDG-PET can be considered negative. In case of a positive FDG-PET it is important that the chest physician determines if it is considered a metastasis or second primary tumor. In case of metastasis palliation is most likely the choice of treatment. When a second primary tumor is present in the lung, a decision should be made whether it is considered potentially curable. If the lung tumor is considered not curable but the oral cavity tumor is, than the average length of survival becomes important. Often the prognosis of a lung tumor extents the average progression of the oral cavity SCC, especially when the lung tumor is an accidental finding on a CT. It can be considered as a adequate form of palliation to treat the oral cavity carcinoma with curative intent, depending on its morbidity and prognosis. When both the lung and oral cavity SCC are considered curable, the sequence of treatment should be established. Often the oral cavity SCC is treated first since the functional outcome of this tumor worseness sometimes at moderate growth of the tumor, whereas the morbidity of the treatment of the lung tumor most likely does not increase that much when it increases in size.

( 2 )

 2 date of conclusion of the CT scan (3) date of FDG-PET scan (4) date of consultation by the expert on pulmonary malignancies (5) date of initial start of the treatment of the index tumor The work up time was measured from (1) primary presentation with pathologic evidence to (5) start of the primary treatment.

Figure 1 .

 1 Figure 1. A schematic drawing of a diagnostic and treatment algorithm of patients with oral

Table 1 :

 1 Patient and tumor characteristics

		Non Smoking	Smoking	Quitted Smoking
	Smoking habits	42	68	32
	Pack years	0	31.45	30.76
	Mean patient	68	65	72
	age
	Male / Female	12/30	49/19	28/4
	Tumor Stage¹
	I	18	15	9
	II	9	16	9
	III	2	10	7
	IV	13	27	7
	Tumor Location
	Tongue	15	12	17
	Gingiva	12	18	6
	Floor of mouth	4	23	9
	Other	11	15	0
	Primary Lung	0	2	2
	carcinoma
	Metastasis	0	1	1
	¹ According to TNM classification from the UICC 2002

Table 2 :

 2 Number of patients with pulmonary tumors detected on preoperative CT of the chest.¹ Of these 2 patients had distant metastasis of their SCC of the oral cavity and 4 patients had a second primary tumor of the lung. All patients with suspicious CT had either pathological confirmation of the pulmonary tumor or during follow up no signs of malignancy.

		Number of	%
		patients
	Total included	142	100
	True positive for	6	4¹
	malignancy
	False positive for	14	10
	malignancy
	Negative	122	86

Table 3 :

 3 Tumor characteristics of patients with a pulmonary malignancy .

		Localization	Staging	Finding on CT	Treatment goal
		primary tumor		Chest
	Patient 1	Tongue	cT2N0	Primary lung	Curative
	Patient 2	Maxilla	cT4N1	Primary lung	Curative
	Patient 3	Tongue	cT1N1	Primary lung	Curative ¹
	Patient 4	Floor of mouth	cT2N1	Primary lung	Palliative
	Patient 5	Mandible	cT4N0	Metastasis	Palliative
	Patient 6	Floor of Mouth	cT4N1	Metastasis	Palliative
	¹ This patient was treated first for his carcinoma of the tongue. During this procedure, his
	pulmonary tumor became irresectable. Therefore he continued with chemotherapy for his
	pulmonary tumour.

Table 4 :

 4 Comparison between findings on CT Chest and days between first presentation and primary treatment.

	Finding on CT	Number of	Average	Average	Standard
	Chest	patients	calendar days	working days	Deviation
			until primary	until primary
			treatment	treatment
	Negative	122	34.2	24.2	16.6
	False positive	14	37.9¹	27.9	18.3
	True positive	6	40.8²	28.8	8.9
	¹ No significant difference in duration until treatment between negative and false positive (p =
	0.43). ² No significant difference in duration until treatment between negative and true positive
	(p = 0.33).


M Van Hezewijk
email: m.van_hezewijk@lumc.nl

E T M Hille

A N Scholten

C A M Marijnen

A M Stiggelbout

C J H Van De Velde

Professionals' opinion on follow-up in breast cancer patients; perceived purpose and influence of patients' risk factors

Keywords: breast, cancer, follow-up, professionals, questionnaire, survey

Aim: To provide insight into professionals' opinions on breast cancer follow-up to facilitate implementation of new follow-up strategies. The study focuses on current practice, purpose and perceived effects, and preferred frequency and duration of followup.

Design: A 29-item questionnaire on professionals' demographics, current practice, opinion on the current guideline, preferences in frequency and duration of tailored followup, and the purpose and perceived effects of follow-up was sent to 633 Dutch professionals.

Results: The current national guideline is followed by 81% of respondents. All different specialists are involved in follow-up. Sixty-nine percent of respondents' report nurse practitioners to be involved in follow-up. When asked for tailored follow-up, professionals indicate more factors for increased follow-up (age<40 years, pT3-4 tumour, pN2-3, treatment related morbidity, and psychosocial support), than for reduced schedules (age >70 years and DCIS histology). Alternative forms of follow-up are not endorsed by >90% of respondents. Detection of a new primary tumour of the breast is considered the most important purpose of follow-up (98%), 57% still indicates detecting metastases as a goal.

Conclusions: Professionals tend towards longer and more intensive follow-up than the current guideline for a large group of patients. Limitations and developments in follow-up need to be considered to facilitate alternative follow-up strategies.

Introduction

Although the effectiveness of routine clinical follow-up of breast cancer patients has been debated over the last decades, a routine follow-up schedule is still standard care for most patients. Due to better therapeutic strategies and increasing age of the population, numbers of breast cancer survivors increase over the years. Therefore we need to reconsider the need for routine visits, as they will become a burden for both professionals and patients.

Aims of follow-up are early detection of local recurrence or second malignancy, social support and monitoring treatment effects [START_REF]Follow-up in oncology. Identify objectives, substantiate actions[END_REF][START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF] . Although annual mammograms have shown to improve patient outcome [START_REF] Lash | Reduced Mortality Rate Associated With Annual Mammograms After Breast Cancer Therapy[END_REF] , no improvement is found for increased frequency or intensity of follow-up [START_REF] Jacobs | Routine Follow-Up Examinations in Breast Cancer Patients Have Minimal Impact on Life Expectancy: a Simulation Study[END_REF][START_REF] Palli | Intensive Vs Clinical Follow-Up After Treatment of Primary Breast Cancer: 10-Year Update of a Randomized Trial. National Research Council Project on Breast Cancer Follow-Up[END_REF][START_REF] Rojas | Follow-Up Strategies for Women Treated for Early Breast Cancer[END_REF][START_REF] Del | Intensive Diagnostic Follow-Up After Treatment of Primary Breast Cancer. A Randomized Trial. National Research Council Project on Breast Cancer Follow-Up[END_REF][START_REF] Schapira | Breast Cancer Surveillance--a Cost-Effective Strategy[END_REF] . The second aim of follow-up, psychosocial support, has also been questioned. Outpatient visits have been demonstrated to induce anxiety because of the risk of detecting tumour relapse [START_REF] Allen | The Meaning of the Breast Cancer Follow-Up Experience for the Women Who Attend[END_REF][START_REF] Pennery | A Preliminary Study of Patients' Perceptions of Routine Follow-Up After Treatment for Breast Cancer[END_REF] . For assessment of treatment morbidity less frequent outpatient visits or questionnaires may suffice. In two systematic reviews of evidence supporting alternative follow-up schedules, Montgomery et al. and Collins et al. concluded that neither the optimum frequency nor duration has been established. [START_REF] Montgomery | Alternative Methods of Follow Up in Breast Cancer: a Systematic Review of the Literature[END_REF][START_REF] Collins | Follow-Up Care of Patients Treated for Breast Cancer: a Structured Review[END_REF] .

The Dutch national guideline [START_REF]Dutch National Guidelines on Breast Cancer Treatment and Follow-up[END_REF] advises patient history taking and physical examination every 3 months the first year after treatment, every 6 months the second year, and annually thereafter, irrespective of the risk profile or treatment of the patient. An annual mammogram is advised. Duration of follow-up is not specified, although it is advised to consider termination of outpatient visits after 5 years of follow-up in patients over 75 years of age. After the first 5 years, age (<60 vs. >60 years), treatment (breast conserving therapy vs. mastectomy) and the presence of BRCA1/2 gene mutation determine whether annual physical examination is indicated and whether a mammogram is performed annually or biennially.

Research has shown that patients accept alternative follow-up strategies such as decreased frequency, nurse-led follow-up and telephone follow-up, without increased anxiety or decreased patient satisfaction [START_REF] Montgomery | Alternative Methods of Follow Up in Breast Cancer: a Systematic Review of the Literature[END_REF][START_REF] Gulliford | Popularity of Less Frequent Follow Up for Breast Cancer in Randomised Study: Initial Findings From the Hotline Study[END_REF][START_REF] Montgomery | Follow-Up by Telephone After Treatment for Breast Cancer[END_REF] . Few studies report on health care professionals' opinion on follow-up and the role of specialised nurses. Previous reports show that professionals prefer routine follow-up by their own professional group [START_REF] Grunfeld | Evaluating Primary Care Follow-Up of Breast Cancer: Methods and Preliminary Results of Three Studies[END_REF] . Donnelly et al. reported that professionals do not always adhere to national guidelines, with 80% continuing follow-up beyond the prescribed duration of follow-up in asymptomatic patients [START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF] .

The aim of the present study among Dutch health care professionals was to evaluate their opinion on common clinical practice and the perceived purpose of breast cancer follow-up. Furthermore we surveyed the influence of individual risk factors on preferred follow-up to facilitate the implementation of tailored follow-up.

Methods and materials

Questionnaire

A structured web based questionnaire was developed, based on Donnelly's questionnaire on specialists' attitudes 2 and Stiggelbout's Questionnaire on patients' attitudes towards follow-up [START_REF] Stiggelbout | Follow-Up of Colorectal Cancer Patients: Quality of Life and Attitudes Towards Follow-Up[END_REF] . The questionnaire was tested on an internal test panel, consisting of surgeons, radiation oncologists, nurse practitioners, an epidemiologist and experts in medical decision making. The questionnaire consisted of 29 questions on 4 themes: 1. professionals' demographics, 2. opinion on the current guideline, 3. opinion on frequency and duration of tailored follow-up, and 4. opinion on the purpose of followup; we stated 10 possible reasons for follow-up and asked the respondent to indicate to what extent they agreed (5 point scale). From Stiggelbout's questionnaire [START_REF] Stiggelbout | Follow-Up of Colorectal Cancer Patients: Quality of Life and Attitudes Towards Follow-Up[END_REF] , we derived 6 additional questions on perceived effect of follow-up (4 point scale).

The anonymous questionnaire was sent as a hyperlink by the Dutch Comprehensive Cancer Centres to all members of the 'breast cancer' and 'oncology nurses' teams of the different regions between March and June 2009. The 633 members consisted of 194 (31%) surgeons, 96 (15%) radiation oncologists, 162 (26%) medical oncologists and 181 (28%) nurse practitioners / breast care nurses, grouped hereafter as 'nurse practitioners' (NP). A single reminder was sent several weeks after the first mailing.

Statistical analysis

Frequencies and percentages were used to display responses to individual questions. Differences between groups were analysed using the Pearson chi-square and students t-test. The statistical package SPSS version 16.0 (SPSS Inc, Chicago, IL) was used to conduct statistical analyses.

Results

Professionals' demographics

One hundred ninety-nine professionals (31%) started the questionnaire (51 surgeons, 44 radiation oncologists, 33 medical oncologists and 71 NPs) of whom 130 (65%) finished the questionnaire. Of the NP's that started the questionnaire, only 45% finished. For other professionals this percentage was higher: 77% of surgeons, 88% of medical oncologists and 68% of radiation oncologists. For information on region and type of hospital of the respondents see table 1.

Current practice

The current national guideline was known by 99%, and was followed by 81% of the professionals. Seventy-three percent was satisfied in general with the frequency of follow-up set by the national guideline. Concerning the number of years of follow-up, 55% was satisfied. The content of the prescribed follow-up (history, physical examination, mammography) was sufficient according to 82% of the professionals, 9% found it insufficient and 7% too extensive.

Patients' opinion on their follow-up schedule was routinely considered in only 12% of respondents' practices. Twenty-one percent of the respondents gave their patients a written follow-up plan, in only 10% of respondents' practices all patients received such a plan.

Frequency and duration of tailored follow-up

When asked about their own preferences regarding follow-up in the years after treatment compared to the current Dutch guideline, professionals agree in general with the recommended frequency and duration. Reasons for at least 40% of professionals to see patients more frequently were the following patient risk factors: age<40 years, pT3-4 tumour, pN2-3, treatment related morbidity, and psychosocial support. Of these factors, age<40 and pN3 status were also arguments for respondents to follow patients longer than the 5 years that the national guideline recommends (fig. 1).

Professionals reported few arguments for less frequent follow-up. More than 25% of respondents indicated the following factors: age >70, N0, DCIS and grade 1 tumour.

Only age >70 years and DCIS histology were considered arguments for shorter follow-up than the guideline in more than 25% (fig 1)

Significant differences between the disciplines in preferred frequency of follow-up were found. Medical oncologists often prefer more frequent follow-up than the guideline, as opposed to radiation oncologists and surgeons who tend to less frequent follow-up (table 2). Medical oncologist name twice as many factors for which more frequent follow-up is needed compared to other professionals (8 vs. 4, p= 0.002)

The only risk factor for which the opinion on preferred duration of follow-up differed significantly between the disciplines was hormone positive status. Medical oncologists indicated that these patients should be followed longer more often (31%) than surgeons (3%) radiation oncologists (10%) or NPs (6%) (p=0.005).

The number of factors that professionals indicated to influence frequency and duration of follow-up corresponded well with the general satisfaction on the current guideline.

Professionals who indicated that follow-up according to the current guideline was too infrequent indicated significantly more arguments for more frequent follow-up than those who indicated that the current guideline recommends too frequent outpatients visits: 17 vs. 4 factors (p<0.001).

Specialists involved in follow-up

In current practice, virtually all surgeons (94%) are involved in follow-up, followed by two-thirds of other professionals. Coordination of follow-up is not done by a single professional in 69% of respondents' practices. When a single coordinator is appointed, this is most often the surgeon (66%), followed by the NP (27%).

When asked who should be involved, even in case of reduced follow-up, the general opinion is that surgeons should 'always' be involved in 44%, followed by the NP according to 39% of the respondents. Only 13% of all respondents indicate that radiation oncologist and medical oncologist should 'always' stay involved. In contrast, 32% of professionals in these two groups think they should 'always' be involved themselves. All professionals agree that the general practitioner (GP) should play a small role in followup in the Netherlands; only 8% indicates GP's should 'always' be involved and 24% even thinks they should 'never' be involved in breast cancer follow-up.

Content of follow-up

When asked how follow-up should be performed after the first year, the majority agreed with the national guideline. Essential elements of follow-up according to professionals were to see patients in the hospital to perform a medical history (84%), physical examination (88%) and mammography (92%). Alternative forms of follow-up such as history by telephone, laboratory tests and MRI were not endorsed by 90%, 94% and 96% of respondents respectively. On laboratory tests and medical history taking as part of follow-up opinions differ significantly between disciplines (fig 2).

Purpose and perceived effect of follow-up

Detection of a new primary tumour of the ipsi-or contra lateral breast was indicated by 98% of professionals as a purpose of follow-up. Other purposes were indicated as follows: detecting local recurrence (95%), detecting (late) sequelae of treatment (89%), detecting psychological problems (83%), assessment of quality of life and social integration of patient after treatment (73%), informing about cosmetic operations (73%), advising on family risk and prevention (72%), organising mammography's (68%) , detecting metastases (57%) and assessing patients' status for research (54%) (fig 3).

Concerning the perceived effect, breast self examination and physical examination was thought to aid detection of a new tumour by 22% and 33% of respondents respectively, as opposed to 91% for mammography (fig 3). Seventy-five percent of professionals indicated that early detection of a recurrence or new tumour would increase the chance of cure. Early detection of metastases was indicated to increase this chance by 9% of professionals.

Forty-eight percent of respondents, who agreed that detecting metastases is a purpose of follow-up, think detection will 'not at all' increase the chance on cure.

Only 24% think frequent follow-up visits will significantly improve patients' quality of life (5% 'very much' and 19% 'rather').

Although no significant differences between the different disciplines were reported for the purposes of follow-up, the perceived effect of follow-up significantly differs between the disciplines on two items. Medical oncologist indicate significantly more often than other specialists that physical examination will 'very much' help in detecting a new tumour (24 %, p=0.05) and significantly more radiation oncologists indicate that detecting metastases does 'not at all' increase the chance of cure (93%, p<0.001).

Discussion

In this large survey among Dutch health care professionals on follow-up of breast cancer patients we managed to get a good overview of the opinion on follow-up in the different professional groups involved. In addition to professionals' views on duration and purpose of follow-up, as reported previously by Donnelly [START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF] , also their preferred frequency and supposed effect of follow-up were assessed. This is the first study to have included the NPs as a professional group. Their role has been studied separately before [START_REF] Koinberg | Nurse-Led Follow-Up on Demand or by a Physician After Breast Cancer Surgery: a Randomised Study[END_REF][START_REF] Koinberg | Breast Cancer Patients' Satisfaction With a Spontaneous System of Check-Up Visits to a Specialist Nurse[END_REF] , but no reports on professionals' opinion regarding their role in everyday practice have been published.

Professionals' demographics

Although the response rate was not optimal, it is comparable to prior reported web based surveys to professionals [START_REF] Grossmann | Results of a National Survey Among Dutch Surgeons Treating Patients With Colorectal Carcinoma. Current Opinion About Follow-Up, Treatment of Metastasis, and Reasons to Revise Follow-Up Practice[END_REF] . Possibly the response to web based surveys is lower than mailed surveys [START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF][START_REF] Tomiak | Follow-Up Practices for Patients With Early Stage Breast Cancer: a Survey of Canadian Oncologists[END_REF] , because of the anonymity. Our respondents well reflect the professionals involved in breast cancer follow-up in the Netherlands, from all regions, all specialties, and different types of hospitals.

Current practice

In contrast to Donnelly's findings 2 we found good (reported) adherence, with 99% knowing the national guideline, and 81% stating to follow it. The Dutch adherence is higher than in the UK, which might be explained by the fact that the Dutch guideline prescribes follow-up for at least 5 years after treatment, whereas the NICE guidelines propose discharge after only 3 years.

Previous studies show that patient involvement increases perceived quality of life [START_REF] Andersen | Involvement in Decision-Making and Breast Cancer Survivor Quality of Life[END_REF] . We found the patients' role still to be limited, however, as only one in eight professionals indicates that their patients are routinely involved in making the follow-up plan. A written follow-up plan for patients as recommended in the National Health Council 1 and Miller et al. [START_REF] Miller | Implementing a Survivorship Care Plan for Patients With Breast Cancer[END_REF] to strengthen care connections and coordination of services, is also rare in everyday practice. With the role of patients in follow-up moving towards 'survivor' as opposed to 'patient', we think involving patients in the considerations and decisions regarding their own follow-up is essential and informing patients should be a priority in follow-up care. In our view NPs could play an important role in this communication.

Frequency and duration of tailored follow-up

In contrast to the tendency to see patients more frequently and longer than guidelines prescribe, almost all respondents indicate that they perceive that frequent follow-up visits do not significantly improve quality of life. Evidence on this subject is conflicting as earlier reports state that anxiety is increased before follow-up visits [START_REF] Grogan | The Value of Follow-Up of Patients With Early Breast Cancer Treated With Conservative Surgery and Radiation Therapy[END_REF][START_REF] Koinberg | Satisfaction With Routine Follow-Up Visits to the Physician--the Needs of Patients With Breast Cancer[END_REF] , but others found positive attitude towards follow-up visits [START_REF] Kiebert | Psychological Effects of Routine Follow Up on Cancer Patients After Surgery[END_REF] and reduced rates of cancer worries in patients with guideline follow-up as opposed to reduced follow-up visits [START_REF] Lash | Reduced Rates of Cancer-Related Worries and Mortality Associated With Guideline Surveillance After Breast Cancer Therapy[END_REF] . Gulliford et al.

already reported that less follow-up was acceptable to patients, except for those under the age of 50 [START_REF] Gulliford | Popularity of Less Frequent Follow Up for Breast Cancer in Randomised Study: Initial Findings From the Hotline Study[END_REF] .

Our study suggests that professionals, especially medical oncologists, indicate more factors to follow patients more frequently or longer, than factors for less frequent followup or earlier discharge than guidelines prescribe. This is in line with previous reports suggesting that professionals tend to see patients too often and have difficulty discharging them [START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF][START_REF] Holli | Effectiveness of Routine and Spontaneous Follow-Up Visits for Breast Cancer[END_REF] . This might be based on personal clinical experience of detecting a local recurrence which changed outcome for a patient.

More intensive follow-up has never been reported to improve survival and most recurrences are still found in between follow-up visits [START_REF] Montgomery | Follow-Up in Breast Cancer: Does Routine Clinical Examination Improve Outcome? A Systematic Review of the Literature[END_REF][START_REF] Montgomery | Locoregional Relapse After Breast Cancer: Most Relapses Occur Late and Are Not Clinically Detected[END_REF][START_REF] Oltra | Cost-Benefit Analysis of a Follow-Up Program in Patients With Breast Cancer: a Randomized Prospective Study[END_REF] . Ongoing hormonal treatment was a reason for a longer follow-up preference, which may be explained by long term risks of hormone use, such as decreased bone density and the fact that late local recurrences are seen in ER positive tumours [START_REF]Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: an Overview of the Randomised Trials[END_REF] .

Specialists involved in follow-up

From our results we conclude that the NPs have become part of standard care in current practice, as they are involved in follow-up in two thirds of respondents' practices.

Surgeons are in almost all cases involved in the follow-up, medical and radiation oncologists less, but still to a large extent. The coordination of follow-up is, in contrast to national recommendations, most often done by multiple specialists. This might lead to suboptimal scheduling and possibly too many follow-up appointments with different disciplines. If a single coordinator is appointed, this is most often the surgeon, followed by the NP, which again underlines the increasing role of the latter in follow-up care.

All specialists agreed that the GP plays only a minor role in follow-up, despite the evidence that in the British and Canadian system quality of life and outcome are similar when follow-up is done by GP after the first year, with annual mammogram [START_REF] Grunfeld | Follow Up in Breast Cancer. Quality of Life Unaffected by General Practice Follow Up[END_REF][START_REF] Grunfeld | Comparison of Breast Cancer Patient Satisfaction With Follow-Up in Primary Care Versus Specialist Care: Results From a Randomized Controlled Trial[END_REF][START_REF] Grunfeld | Randomized Trial of Long-Term Follow-Up for Early-Stage Breast Cancer: a Comparison of Family Physician Versus Specialist Care[END_REF] . In our view, it is most important that patients receive clear instructions who to contact during follow-up, preferably a dedicated NP.

Content of follow-up

Most professionals in our study agree with the content of the follow-up prescribed by the guideline (physical examination/history taking/mammography). The majority indicate no extra tests are needed, in line with previous reports that show no decrease in morbidity or mortality from extra testing [START_REF] Rojas | Follow-Up Strategies for Women Treated for Early Breast Cancer[END_REF][START_REF] Collins | Follow-Up Care of Patients Treated for Breast Cancer: a Structured Review[END_REF] . Like other authors [START_REF] Keating | Surveillance Testing Among Survivors of Early-Stage Breast Cancer[END_REF][START_REF] Simon | Clinical Surveillance for Early Stage Breast Cancer: an Analysis of Claims Data[END_REF] , we found that medical oncologists tend to do more laboratory tests, although this is not effective for detecting recurrent disease. Increased tests may be related to checking blood results during ongoing hormone therapy; we did not specify this question on patient or tumour characteristics. Alternative forms of follow-up such as medical history by telephone, although effective and acceptable to patients [START_REF] Montgomery | Follow-Up by Telephone After Treatment for Breast Cancer[END_REF] , are not preferred by our respondents, possibly as a result of preference for the familiar.

Purpose and perceived effects of follow-up

When asked for the purpose of follow-up, as expected virtually everyone agrees that detecting new tumour of the breast or local recurrence is important. Also a considerable part of respondents indicated detection and treatment of (late) sequelae to be important, in accordance with Donnelly who reported treatment related toxicity to be the most important consideration for follow-up [START_REF] Donnelly | Questioning Specialists' Attitudes to Breast Cancer Follow-Up in Primary Care[END_REF][START_REF] Kimman | Follow-Up After Treatment for Breast Cancer: One Strategy Fits All? An Investigation of Patient Preferences Using a Discrete Choice Experiment[END_REF][START_REF] Beaver | Comparing Hospital and Telephone Follow-Up After Treatment for Breast Cancer: Randomised Equivalence Trial[END_REF] . Unexpectedly, detecting psychological problems is the fourth agreed-on purpose in our study. There is little evidence that routine clinic visits are useful in detecting side effects of treatment or psychological problems [START_REF] De Bock | Patient's Needs and Preferences in Routine Follow-Up After Treatment for Breast Cancer[END_REF][START_REF] Beaver | Follow-Up in Breast Cancer Clinics: Reassuring for Patients Rather Than Detecting Recurrence[END_REF] . Furthermore, if no other examinations are required, the question should be raised whether the hospital is the best place for this support. Also the organisation of mammograms, a purpose of follow-up visits according to two thirds of respondents, could perhaps be organised outside the outpatient clinic, particularly if a national survey programme exists. Surprisingly, 6 out of 10 professionals still indicate that detecting metastases is a goal of follow-up, although only one in ten thinks it improves cure, in spite of evidence that detecting distant disease early through intensive follow-up does not improve survival and even decreases quality of life [START_REF] Palli | Intensive Vs Clinical Follow-Up After Treatment of Primary Breast Cancer: 10-Year Update of a Randomized Trial. National Research Council Project on Breast Cancer Follow-Up[END_REF][START_REF] Del | Intensive Diagnostic Follow-Up After Treatment of Primary Breast Cancer. A Randomized Trial. National Research Council Project on Breast Cancer Follow-Up[END_REF][START_REF] Del | The Efficacy of Intensive Follow-Up Testing in Breast Cancer Cases[END_REF] . Better education on this subject is needed for professionals to realise the limitations of follow-up and, perhaps more importantly, to be able to communicate this to patients.

Limitations

A limitation of our study is the suboptimal response rate and the length of the questionnaire. As a result of the latter, 30% of the respondents failed to answer the complete list of questions. There is a chance of response bias, as professionals who take the time to fill out our questionnaire might think that follow-up is more important than those who did not. Another limitation is that we only asked for the influence of the different risk factors separately, where in reality a combination of factors will lead to treatment decisions. Finally, we did not directly assess professionals' knowledge of the literature nor the reasons behind the preference for frequency of follow-up.

Nevertheless, we are convinced this study gives insight in professionals' daily practice and considerations.

Conclusions

Although the national guideline is well known, many different specialists are involved in follow-up and the coordination is often unclear. When asked about tailored follow-up, professionals, especially medical oncologists, tended to follow-up that is longer and more intensive than the current guideline for a large group of patients, despite the lack of evidence that it improves outcome. Professionals need to be aware of the limitations of and developments in follow-up, so they can communicate these to their patients.

Accordingly they could offer alternative ways of follow-up, reduce the number of visits, discharge patients timely and provide a clear written follow-up plan to patients. The nurse practitioners and breast care nurses, who have established their role over the last years, can possibly play an even more prominent role in coordinating and conducting follow-up visits and providing written information to patients. a 'more' refers to the percentage of respondents who indicated a preference for more frequent followup visits than the current Dutch guideline prescribes. The guideline prescribes follow-up every 3 months the first year after treatment, every 6 months the second year, and annually thereafter [13] b 'less' refers to the percentage of respondents that indicated a preference for less frequent follow-up visits than the current Dutch guideline. c The remainder of the respondents, not explicitly shown in the table, indicated to prefer the frequency according to the Dutch guideline.

Table 1 .

 1 Respondents' demographics

	Total (n=130)	N	% of total
	Discipline
	Surgeon	39	30
	Medical oncologist	29	22
	Radiation oncologist	30	23
	Nurse Practitioners	32	25
	Hospital
	University hospital	32	25
	District training hospital	71	55
	District non-training hospital	27	21
	# New patients per hospital/year
	0-100	25	19
	100-200	44	34
	200-500	46	35
	>500	5	4
	Unknown	10	8
	# Follow-up contacts per week per
	specialist
	0-5	23	18
	5-10	42	14
	10-20	46	35
	>20	19

Table 2 .

 2 Patient and tumour characteristics for which preferred frequency of follow-up differs significantly between disciplines

	Risk factor	Preferred	Surgeons	Radiation	Medical	Nurse	P (pearson
		frequency of follow-up c	(%)	(%) Oncologists	(%) Oncologists	(%) Practitioners	chi-quare)
	< 40 yr	More a Less b	40 0	43 7	76 0	42 0	0.02
	50-60 yr	More	0	3	14	0	0.03
		Less	5	13	7	3
	60-69 yr	More	0	0	10	0	0.01
		Less	18	20	7	3
	T1	More	0	0	10	0	0.04
		Less	18	30	10	12
	Mastectomy	More	3	0	10	0	0.01
		Less	18	33	7	9
	Grade 1	More	0	0	14	0	0.001
		Less	38	40	7	18
	ER/PR+	More	0	0	17	0	0.001
		Less	8	20	3	3
	Hormonal	More	5	10	35	9	0.04
	treatment (ongoing)	Less	5	10	3	3

Acknowledgements

The authors are grateful for the support by the Dutch Comprehensive Cancer Centres in distributing the questionnaires and to all members of the 'breast cancer' and 'oncology nurses' teams of the different regions who responded to our survey.

Conflict of interest

The authors have declared no conflicts of interest.

Role of funding source

The financial support of the Dutch Cancer Society is gratefully acknowledged (project number UL 2008-4192). The sponsor had no involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript or in the decision to submit the manuscript for publication. B.