MA Nagement of METastatic Disease In Campania (MAMETIC): Epidemiologic Data and Palliative Radiotherapy in an Italian Region. Study Protocol

Background. In the Italian Campania Region, 30.517 new cases of solid cancer have been diagnosed, in 2019. Of those, patients with metastatic disease are up to 20%. This class of patients is extremely diversied and copious, and the offer of radiotherapy may vary in different geographical areas within the same region. The aim of this observational multicenter retrospective and prospective trial is to evaluate the occurrence of metastatic disease in several areas of a great Italian region, the management of the disease through RT approaches, and its impact on cancer-related pain and overall HRQoL. Methods. This is a multicenter, retrospective and prospective observational investigation. The retrospective part of the study concerns all patients enrolled with a diagnosis of metastatic disease and treated in RT centers within the Campania Region between January 2019 to July 2020. The prospective phase is going to involve all the metastatic patients with an indication of palliative RT. Considering regional epidemiological data, we expect an enrollment of 12.500-21.000 patients in 5 years. Conclusion. The MAMETIC Trial is an epidemiological study designed for investigating the different prevalence of tumors in the metastatic phase within a regional area, and for evaluating the local response to the patient's request. It can be a unique opportunity, not only to highlight possible geographic differences but also to regularly collect and share data to standardize the therapeutic offer within the regional area. ClinicalTrials.gov ID NCT04595032.


Background
The overall survival is the main outcome for evaluating healthcare system e ciency in cancer treatment.
It is highly in uenced by the diagnosis phase and cancer treatment e cacy. Secondary prevention, availability, and rapid access to treatments have a crucial in uence.
Although it was demonstrated that the number of cancer deaths in 2005 and 2016 is roughly the same, the number of cancer deaths recorded with metastasis as a contributing cause of death tripled from 1953 (18.5%) to 2016 (55.5%) 1 . Furthermore, metastases are responsible for about 90% of cancer deaths The proportion of all cancer deaths recorded with metastases ranged from 100% (testicular, sinus cancer) to 9.3% for central nervous system cancers. For prostate cancer, the cancer death rate recorded with metastasis as a contributing cause was only 50.5%. Breast cancer incidence has increased over the past decade, while breast cancer deaths are declining. The death rate from metastatic disease, however, is remarkably stable 2 . In the Italian context, data from the Italian Association of Medical Oncology (AIOM) showed that for all solid tumors, 66.7% of cancer deaths were recorded with metastasis as a concomitant cause, although the proportions varied substantially between tumor groups 3 .
In metastatic disease, palliative care has the essential purpose to improve the health-related quality of life (HRQoL). The earliest diagnosis is provided, the greater will be the aims achieved and the e cacy of the treatments. The local presence of diagnostic and therapeutic possibilities can be decisive in the patient's perspective on life. Nevertheless, in some geographical contexts, there may be de ciencies in the provision of particular palliative care interventions, such as radiation therapy (RT) approaches. These de ciencies can be expressed in terms of reduced supply of procedures, delays in delivery, and poor quality of the offer. Moreover, within a geographical region, inequality in access to diagnostic-therapeutic pathways can be detected.
Territorial cancer registers give a fundamental contribution for evaluating the incidence of cancer, the stage at diagnosis, and the correlation with particular environmental situations. In the Italian Campania Region, the recording cancer network has provided a General Cancer Registry of the population within each Local Health and a Regional Children's Cancer Registry. Despite this, there is a lack of important data such as the prevalence of metastatic cancer, referring to the different territorial areas within the region.

Study Rationale
From the data mainly obtained from the SEER (Surveillance, Epidemiology, and End Results) archive, it is estimated that patients with metastatic disease represent up to 20% of the total number of solid tumors On these premises, the MAnagement of METastatic disease In Campania (MAMETIC) study aims to evaluate metastatic cancer patients living in the Italian Campania region who refer to RT centers for palliative radiation treatments. Moreover, the management of the disease through RT approaches and its impact on cancer-related pain and overall patients' HRQoL will be investigated.
All the data will be transmitted to the coordinating center and the initiative will be integrated with the regional oncology network (the General Cancer Registry). We estimate that this study will be useful not only to the RT community but it will also provide a regional assessment on the management of malignant disease, enhancing in turn the functioning of the network.

Overall design
The MAMETIC Trial is a multicenter, retrospective and prospective observational investigation (Fig. 1).
a. The retrospective part of the study concerns all patients enrolled with a diagnosis of metastatic disease, treated in RT centers of the Campania Region. RT was performed through several approaches including three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic body radiation therapy (SBRT). Treatments were performed from January 2019 to July 2020.
Because in 2019, about 12.500 patients have been treated in the centers and it is estimated that 20-30% of the above-mentioned patients had metastasis, approximately 2.560 patients are expected to be enrolled.
b. The prospective part of the study is going to involve all the metastatic patients with indication of palliative RT, treated with 3DCRT, IMRT, VMAT, SBRT techniques from December 2020 to December 2025. Considering regional epidemiological data, we expect an enrollment of patients between 500 -4.200 patients per year, 12.500-21.000 in 5 years.

Study setting
RT centers joining the study can enter patient data in appropriate eCRFs. An eCRF will be provided for the retrospective part of the study. About the prospective part, RT centers can choose 3 levels of membership: Level A: epidemiological data entry on clinical features (metastatic cancers) and RT offered.
Level B: level A plus pain features and analgesic therapy data.
Level C: adds to the two previous levels data on HRQoL.
We have chosen to offer a different membership option to collect the greatest number of epidemiological information (primary objective). From the centers that will be able to enter the most complete data (Level B and level C), it will be possible to obtain data to achieve the secondary objectives.

Outcome measures
The primary objective of the study is focused on the data collection concerning metastatic cancers in the Campania region. This objective regards both the retrospective and prospective phases of the study.
For this purpose, will be recorded: Patients with bone metastases. They are about 70% of cancer patients in advanced stage of disease 5. They often have complicated lesions, with tumor tissue invading the muscle or nerve structures close to the bone. These lesions usually cause constant or intermittent pain, with a neuropathic component. In addition to baseline pain, the patient may have episodes of BTcP (Breakthrough cancer Pain) that compromise the HRQoL. As a result, they may have severe movement restrictions and an increased risk of pathological bone fracture 6-9 .
Patients with metastases affecting the thoracic district with primary or secondary locally advanced disease. Symptoms such as dyspnea, chest pain, cough, hemoptysis, and dysphagia can be controlled with radiation treatments in 2/3 of these patients. Palliative mediastinal RT can improve obstructive dysphagia in locally advanced esophageal cancer 10  Patients with brain or spinal cord metastases. This category includes patients with symptomatic or asymptomatic brain metastases, patients with symptomatic or asymptomatic bone marrow compression, and those with cauda equina syndrome. In patients with paraplegia caused by spinal cord compression, 10% of motility can be recover if treatment is early. The presence of brain metastases can cause severe symptoms such as epilepsy, focal neurological symptoms, or intracranial hypertension symptoms such as nausea, vomiting, or headache 12 .
Patients with symptomatic lymph node lesions who may have neck lymph node packages or pelvic district.
Eligibility criteria are summarized in Table 1  Type of pain (neuropathic, nociceptive, mixed) and intensity measured through the Numeric Rating Scale (NRS) score. This latter is an 11-point scale (from 0 to 10), with higher scores indicating greater pain intensity.
Breakthrough cancer pain (BTcP) [de ned as 'a transitory are of pain that occurs on a background of relatively well-controlled baseline pain' 13 ] in terms of number of episodes/day; pain intensity 14 .
Pain are (a transient worsening of the bone pain after RT) in terms of intensity (NRS).
Data about pain therapy: drugs (adjuvant drugs, opioids, non-opioid analgesics) and doses.
Adverse events of the pain therapy.
For the pain evaluation, patients will report pain data (NRS, episodes of BTcP) and therapy in a Pain Diary. Follow-ups will be performed on the 15 th (telephone revaluation) and 30 th day (outpatient revaluation) after the end of RT treatment.
C. Level C. In addition to what is speci ed for levels A and B, the following tools for assessing the patients' HRQoL will be adopted before starting and at the end of the RT treatment: The  22 for assessing cognitive function in patients with brain metastases.

Data collecting and Statistical considerations
The data collection and registration procedures will be carried out through speci c CRFs organized on an electronic platform managed by the coordinating center which will be responsible for the privacy of sensitive data. The data will be transmitted to the coordinating center when each form is completed by the operator of the individual center. Every 3 months a report of the total amount of patients entered in the platform will be sent by the coordinating center to every center participating in the study.
A descriptive analysis will summarize the total number and strati cation of patients with metastatic disease by place of residence and tumor location. Metastatic tumors at diagnosis will be differentiated from metastatic disease developed later. Every center is going to ll a form for each patient with mandatory socio-demographic and anamnestic information (Level A) and information on pain and HRQoL (Levels B and C). This process lets the study produce a compliance survey by a single center and Each interested center will submit the protocol to its ethics committee to be approved before accrual. After approval, the center will receive a dedicated electronic case report form (CRF). Eligible patients who provided consent and meet the inclusion criteria are anonymously registered on the CRF by assigning a numerical code.
The Trial will be conducted in accordance with the approved protocol and the Helsinki Declaration (1996),

Discussion
Palliative RT is an e cient component of supportive and palliative care in the oncology eld and palliation of advanced and metastatic cancers symptoms are one of the most common indications for RT.
Although it was estimated that patients with metastatic disease represent up to 20% of the total number of solid tumors diagnosed, the use of palliative RT treatments potentially involves only up to 40% of patients in a radiation oncology center 22 .
The oncological incidence data, detected by population risk and collected from the Cancer registries, show different standardized rates in various regional territorial areas. Moreover, at the regional level, data on territorial distribution and evolution of tumors towards the advanced stages are absent. In addition to oncological mortality data, this knowledge could occur signi cantly to understand the causes of the several territorial possibilities in the organization of diagnostic-therapeutic-care pathways in terms of socio-economic structure of reference population, degree of diagnostic anticipation and different stage at diagnosis, availability of territorial diagnosis and treatment structures, level of care standards. Furthermore, there is a lack of precise knowledge on coverage and methods of RT services regional delivery in the advanced stages of neoplastic pathology in Campania.

Conclusion
A regional epidemiological study that provides information on the occurrence of late-stage tumors, their territorial management, and their impact on the HRQoL of patients, can represent an important opportunity to observe territorial alternatives and improve the therapeutic offer. At the same time, since this is a multicenter study involving several RT centers, it can represent a useful moment of standardization and sharing of RT protocols adopted in the treatments of advanced tumors and their complications in a great Italian region. MDN, AP, contributed to the development of the study protocol. AC, and EC (lead trial statistician) developed the study design and statistical analysis plan. All authors provided feedback on drafts of this paper and read and approved the nal manuscript. Figure 1 Study design owchart. Legend: RT, radiation therapy