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Open in new tab Download slide Open in new tab Download slide OBJECTIVES Spread through air spaces (STAS) is a unique pattern of invasion in primary lung cancers. However, little is known about STAS in pulmonary metastases (PMs). This study was to investigate the incidence of STAS among PMs and the association between STAS and clinicopathological characteristics of PMs. METHODS A total of 127 patients who underwent metastasectomy at our institution from June 2009 to December 2019 were retrospectively analysed. Survival analysis was performed in 40 patients with PM from colorectal cancer (CRC). RESULTS STAS was identified in 33.1% of patients (42 of 127) with PMs. STAS was found in PMs of various primary cancers, including CRC, breast cancer, renal cell carcinoma, cholangiocarcinoma and osteogenic and soft tissue sarcoma, but the incidence varies. PMs originating from epithelial tissue showed higher incidence of STAS than those from mesenchymal tissue (45% vs 11%, P  < 0.001). Elder age (P  = 0.006) and primary sites (P  < 0.001) were significantly correlated with STAS. In patients with PMs from CRC, the presence of STAS was an independent predictor of shorter recurrence-free survival (hazard ratio = 10.25, P  = 0.002) and poor overall survival (hazard ratio = 4.75, P  = 0.047) by multivariable analysis. CONCLUSIONS STAS might be a lung-specific tumour invasion pattern and STAS is commonly observed in PMs of different origins. The incidence of STAS was significantly higher in PMs originating from epithelial tissues than those from mesenchymal tissues. Presence of STAS was an independent predictor of poor prognosis in patients with PM from CRC. [ABSTRACT FROM AUTHOR]

The article discusses the practice of pulmonary metastasectomy (PM) in thoracic surgery. It references the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study, which was stopped due to poor recruitment but later showed a 5-year survival rate of 36.4% for the PM group compared to 29.6% for the control group. The authors of the article present their own study, which included lung metastases from various primary tumors and showed a 5-year overall survival rate of 62.0% and a 30-day morbidity rate of 14.5%. They argue that PM should not be dismissed as an obsolete medical practice and emphasize the importance of multidisciplinary teams in determining the appropriateness of the procedure. The authors conclude that further studies are needed to clarify the role of PM in treating pulmonary metastases. [Extracted from the article]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Surgical resection is widely employed as a potential curative treatment option for patients with limited lung metastases originating from a wide range of primary tumours. However, there are no clear national or international practice guidelines and, thereby, the risk for potential practice variation exists. This study aims to define the current practice for the surgical treatment of pulmonary metastases in the Netherlands by using data from the Dutch Lung Cancer Audit for Surgery (DLCA-S). METHODS Data from the DLCA-S were used to analyse patients undergoing a parenchymal lung resection for the treatment of pulmonary metastases between 2012 and 2017. Volume of metastasectomies per hospital was calculated as a proportion of the volume of primary lung cancer resection. Studied outcomes were overall complications and postoperative mortality and complicated course. For the latter, both the national average and between-hospital variation were calculated. RESULTS A total of 2090 patients, distributed over 45 Dutch hospitals, were included for analysis. The most common primary cancer was colorectal carcinoma (N  = 1087, 52.0%) followed by the urogenital carcinoma (N  = 296, 14.2%). The most common type of parenchymal resection was a wedge resection (N  = 1477, 70.7%) followed by a lobectomy (N  = 424, 20.3%). Resection was performed minimally invasively in 1548 patients (74.1%) with a conversion rate of 3.8%. Resection of a solitary metastasis was performed in 1663 patients (79.6%). In 40 patients (1.9%), 4 or more metastases were resected. A postoperative complicated course was noted in 3.6%, and the 30-day mortality rate was 0.7%. The variety between hospitals in the volume of metastasectomies in proportion to the volume of primary lung cancer resections was 3.4–41.5%. CONCLUSIONS This analysis of the DLCA-S registry provides a unique insight into current practice on pulmonary metastasectomies in the Netherlands over a 6-year period. The rate of postoperative adverse outcome was limited, and the morbidity and mortality were lower compared to primary lung cancer resections in the DLCA-S database. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Safety margins in pulmonary metastasectomy are not yet well defined. We hypothesize that histological subtype, size of the lesion and local growth characteristics must be taken into consideration during metastasectomy. This study was conducted to examine and classify growth patterns at resection margins and define the relationships between aggressive local growth, metastasis size and local recurrence to direct metastasectomy. METHODS: Histologic sections of pulmonary metastases were prospectively collected and haematoxylin-eosin stains were systematically evaluated and classified by their pattern of lung tissue infiltration. Logistic regression was used to model the association between the subgroups of colorectal, renal cell and epithelial cancers and melanomas and sarcomas. RESULTS: From 183 patients, 412 lung specimens were removed, which contained 459 pulmonary metastases. We found that 58% of all lesions had microscopic signs of aggressive local dissemination. The metastases showed histology-specific patterns of local growth: sarcoma was associated with pleural infiltration; colorectal metastases with interstitial spread and aerogenous spread of floating cancer cell clusters; and melanoma with perivascular growth and with lymph vessel involvement. Aggressive patterns of growth had an increasing probability of around 3% for each additional millimetre of metastasis diameter. Local intrapulmonary recurrence was significantly more common in association with interstitial growth and pleural penetration as well as safety margins <7 mm. CONCLUSIONS: Approximately 40% of all lung metastases have a smooth surface and might be resected with small margins. Growth characteristics within the lung differ with the histologic subtype and safety margins should generally increase with the size of the metastasis. [ABSTRACT FROM AUTHOR]

In the article, the editor discusses how surgery for pulmonary metastases is a pillar of modern thoracic surgery. Topics discussed include how surgical measures for the treatment of a general illness with low morbidity and mortality are now possible; the goal of surgery to remove metastases is to increase the patient's chance of survival or, depending on the type of tumor, cure the disease; and presents the views of World Health Organization on palliative care.

OBJECTIVES Surgical resection is widely accepted as a beneficial treatment of pulmonary metastases originating from osteogenic and soft tissue sarcomas despite adequate validation. The factors associated with the selection of patients who receive pulmonary metastasectomy (PM) are controversial and not well known. In this study, we aimed to identify the prognostic factors associated with survival after treatment with PM and to disclose the candidates who profit from PM being performed on patients with osteogenic and soft tissue sarcomas. METHODS We retrospectively reviewed the variables and survival outcomes in 52 consecutive patients who underwent PM to treat lung metastases originating from osteogenic and soft tissue malignancies from April 1996 to January 2011. Prognostic factors associated with overall survival after the first PM were evaluated using univariate and multivariate analyses. RESULTS Fifty-eight PM procedures were performed in 52 patients as the first PM including 6 bilateral diseases. Wedge resection was the most frequently performed PM procedure (84%), and video-assisted thoracic surgery was introduced in 34 (59%). The median follow-up of the patients was 33 months and the 5-year survival rate after the first PM was 50.9%. Forty-eight (92%) patients underwent complete resection during the first PM. Thirty-three patients (62%) experienced relapse after the first PM. Among those patients, 20 received redo surgeries for pulmonary relapse, and the 5-year survival rate in this group was 49.7%. According to univariate analyses, the use of complete resection, the number of metastatic nodules (one or two) and the length of the disease-free interval prior to the first PM were each found to be significant favourable factors. According to a multivariate analysis, the use of complete resection and the number of metastatic nodules were both found to be independent prognostic factors associated with overall survival. Although our cohort included 15 patients with poor prognostic factors (29%), 5 patients who underwent redo surgery survived >22 months. CONCLUSIONS The survival of those patients with one or two pulmonary nodules and those who underwent complete resection was favourable following the treatment of osteogenic and soft tissue sarcomas with PM. Redo surgery may also provide some survival benefit in patients with poor prognostic factors. [ABSTRACT FROM AUTHOR]

OBJECTIVES Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy. METHODS Pharmacokinetics: forthy-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations. Efficacy: twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days. RESULTS Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05). Efficacy: SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both). CONCLUSIONS SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Radiofrequency ablation (RFA) has been recently applied as an alternative option of pulmonary surgery in the treatment of pulmonary malignancies. In this study, we assessed the risk associated with percutaneous RFA, and discussed its safety and efficacy. Methods: The clinical data of 329 consecutive patients with primary (n =237) and metastatic (n =92) lung tumor treated with RFA from 1999 to 2006 in this hospital were considered for this study, and the character and clinical data of these patients were analyzed. Complications, local progression, and overall survival at 1, 2 and 5 years of these patients were evaluated. Results: Following the procedure 63 (19.1%) patients presented with pneumothorax, 14 (4.2%) with hemoptysis (one death), 10 (3.0%) hemothorax, 15 (4.5%) pneumonia, and three (0.9%) pericardial tamponade (one death); the 30-day mortality after the procedure was 0.6%. Needle-track implantation was observed in six (1.8%) patients. Median progression-free interval was 21.6 months. The overall survival at 1, 2 and 5 years was 68.2%, 35.3%, and 20.1%, respectively. A total of 78 (23.7%) patients developed local progression during the follow-up. Significant difference in the risk of local progression was found in tumors more than 4cm; however, no significant difference was found in tumors less than 3cm and 3–4cm in our group. Conclusion: RAF is a safe and well-tolerated procedure with satisfied efficacy in the treatment of malignant lung nodules. To avoid complications with potential fatal outcome, adequate training and careful patient selection by a multidisciplinary team might be helpful. [Copyright &y& Elsevier]

Abstract: Objective: Surgical resection of lung metastases is a widely accepted procedure but 5-year survival rates remain low and vary between 20% and 50%. Isolated lung perfusion (ILuP) is an experimental technique to deliver a high dose of chemotherapy to the lung, without systemic toxicity. Long-term survival of ILuP has not been reported yet and was determined in a phase I clinical trial. Methods: From May 2001 to December 2004, a phase I clinical trial was conducted to define the maximum tolerated dose (MTD) of ILuP with melphalan. Twenty-nine procedures were performed in 23 patients. The primary tumour was colorectal in 10 patients, renal in eight, sarcoma in four and salivary gland in one. Toxicity results were previously reported and the MTD of melphalan was determined at 45mg when given at 37°C. Follow-up was updated and long-term survival is reported. Results: Follow-up was complete, except for one patient who was lost to follow-up after 8 months. After a median follow-up of 62 months, 6 out of 23 patients were alive and free of recurrent disease. One patient died after a subsequent operation. Sixteen patients developed recurrent disease, of whom 11 died. Nine patients had intrathoracic recurrent disease only, one intra- and extrathoracic recurrences each and five extrathoracic only. In one patient, the location of recurrence was not known. Overall- and disease-free 5-year survival rates were 54.8±10.6% and 27.5±9.5%, respectively with an overall median survival time (MST) of 84 months (95% confidence interval (CI): 41–128) and disease-free MST of 19 months (95% CI: 4–34). Lung function and diffusion capacity initially dropped 1 month after perfusion, slightly improving afterwards. Radiographic follow-up with chest computed tomography showed no long-term toxicity from ILuP. Conclusion: ILuP can be applied without major long-term pulmonary toxicity. Five-year survival rate, overall and disease-free MST in this phase I clinical trial are promising. This is another incentive to perform further studies with ILuP. [Copyright &y& Elsevier]

Abstract: Objective: The use of VATS metastasectomy remains controversial because of doubt surrounding its ability to remove palpable but CT occult lesions. We aim to evaluate our policy of elective VATS and compare it with our results with open metastasectomy. Methods: Pulmonary metastasectomy was performed for metastatic colorectal adenocarcinoma in 52 patients: 27 open and 25 VATS over 8 years. The age and sex distribution was similar: median age was 66 for open and 69 years for VATS, p =0.48, 70% male in open and 64% male in VATS, p =0.31. Liver metastases were present in 37% in the open and 32% in the VATS group, p =0.46. The choice of surgical approach was dependent on the distance of the lesion from the surface of the lung. We examined the survival using the Kaplan–Meier method and we tested for differences in the incidence of missed lesions, pulmonary disease progression and repeat metastasectomy. Results: There was no in-hospital mortality. There was no difference in the incidence of missed lesions (1 in VATS, none in open, p =0.48), pulmonary disease progression (11 in open, 9 in VATS, p =0.47) or recurrence in the same lobe (4 in open, 3 in VATS, p =0.54). Median follow-up was 22 (1–70) months and there was no difference to the estimated actuarial survival. Mean survival for the open group was 47 months, SE 6 with 95% CI 36–59 months and mean survival for the VATS group 35.4 months, SE 3 with 95% CI 30–41.3 months. The estimated 1- and 2-year survival was 90% and 80% for open and 90% and 72% for VATS. Conclusions: The selective use of VATS therapeutic metastasectomy in conjunction with multi-detector CT is justified in metastatic colorectal adenocarcinoma. The insertion of the surgical digit is not mandatory. Trust the radiologist''s eye. [Copyright &y& Elsevier]

Abstract: Objective: Pulmonary metastasectomy is beneficial in select patients. The sensitivity of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for pulmonary metastasis is unknown. The aims of the study were to determine the accuracy of FDG-PET in detecting pulmonary metastasis and identify factors affecting sensitivity. Methods: All patients undergoing metastasectomy from September 2002 through December 2006 who had both chest computed tomography (CT) and FDG-PET scans or a fused CT/FDG-PET within 6 weeks prior to surgery were reviewed. Univariate and multivariate analysis were performed to determine predictors of positivity. Results: There were 83 patients (41 men, 42 women) who had 104 resections. Median age was 61 years (range, 32–87). In total 154 nodules were resected; 1 nodule in 47 patients and multiple in 36. Histopathology was adenocarcinoma in 94 nodules, sarcoma in 18, squamous cell carcinoma in 15, renal cell carcinoma in 7 and other in 20. At least one nodule was FDG-PET positive in 68 patients (81.9%). True positive FDG-PET was found in 104 nodules (67.5%) while 50 were false negative (32.5%). Multivariate analysis revealed tumor diameter and grade correlated with increased sensitivity of FDG-PET. Conclusion: FDG-PET is positive in only 67.5% of metastatic pulmonary nodules. Nodule size and grade affect the sensitivity of FDG-PET for metastatic pulmonary nodules. FDG-PET is not a sensitive test in the evaluation of patients considered for pulmonary metastasectomy. Moreover, a negative FDG-PET should not be used to rule out metastatic disease. [Copyright &y& Elsevier]

Abstract: Objective: Pulmonary resection in metastatic pediatric solid tumors is an accepted method of treatment. The purpose of this study was to determine the clinical course, outcome and prognostic factors after surgery. Methods: A retrospective analysis from 1985 to 2006 of 52 patients less than 17 years old at the time of tumor diagnosis and submitted to thoracotomy for pulmonary metastatic disease was performed. Three had nodules excised which proved to be benign at histology and were excluded from further analysis. There were 28 males and 21 females with median age of 13.2 years [2–36] at the time of metastasectomy. The primaries were osteosarcoma (25), Ewing’s sarcoma (6), Wilms’ tumors (4), hepatoblastoma (3) and miscellaneous (11). Pulmonary metastases were encountered either at the time of initial diagnosis (18%) or occurring within 1 month to 22 years. Disease free interval (DFI) was equal or less than 2 years in 31 (63%) patients and more than 2 years in 18 (37%). Results: Patients had one (24), two (16), three (2), four or more (7) metastasectomies resulting in a total of 95 thoracotomies. Wedges (75%) were performed more frequently than anatomic resections (25%). The number of resected metastatic nodules ranged from 1 to 45, median 3. There were no perioperative deaths. There were six complications: pneumothoraces requiring chest tube drainage in two cases. Resection was incomplete in four cases. The mean drainage time and hospital length of stay were 2.7 and 5 days, respectively. Using the date of pulmonary resection as the starting point, 5-year survival rate was 25%. By univariate analysis, we found that a significantly longer survival was observed for patients with a complete resection (p =0.004), with two or less metastases (p =0.0004), with unilateral metastases (p =0.001) or when the DFI was more than 2 years (p =0.003). By multivariate analysis, we showed that the number of pulmonary metastases was an independent predictor of survival. Conclusion: We conclude that resection of pulmonary metastases of pediatric solid tumors is a safe and effective treatment that offers improved survival benefit in carefully selected patients within a multidisciplinary approach for pediatric cancer. Prognosis related criteria that support patient selection for surgery are identified. [Copyright &y& Elsevier]

Summary: Surgical resection is a widely accepted treatment for pulmonary metastases on the condition that a complete resection can be obtained. However, many patients will develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Similar to the basic principles of isolated limb and liver perfusion, isolated lung perfusion is an attractive and promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biological response modifiers, like tumour necrosis factor, is also feasible. Other related methods of delivering high-dose locoregional chemotherapy include embolic trapping (chemo-embolisation) and pulmonary artery infusion without control of the venous effluent. Isolated lung perfusion has proven to be highly effective in experimental models of pulmonary metastases with a clear survival advantage. Lung levels of cytostatic drugs are significantly higher after isolated lung perfusion compared to intravenous therapy without systemic exposure. Phase I human studies have shown that isolated lung perfusion is technically feasible with low morbidity and without compromising the patient''s pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function and survival. [Copyright &y& Elsevier]

Objectives: To evaluate the effectiveness of radiological assessment (high-resolution CT (HRCT), helical CT (HCT) scan) of lung metastases and to verify if a complete manual exploration by thoracotomy is necessary. Materials and methods: From 1/96 to 1/00, 166 consecutive patients presenting with lung metastases were treated. Preoperative CT scan (HRCT in 78 patients, group A; HCT in 88 patients, group B) to assess the number, size and location of the lesions (slice thickness 5 mm; reconstruction interval 3–5 mm) was always performed. All patients underwent axillary thoracotomy (staged when lesions were bilateral); accurate palpation of the lung parenchyma was always performed to identify any undetected lesion. Non-metastatic lesions were excluded. Results: We performed 356 wedge resections in 161 patients (113 monolateral, 70.2%; 48 bilateral, 29.8%) and five lobectomies. In group A, primary neoplasm was epithelial in 44 patients, sarcoma in 26 and germ cell in eight, and in group B, epithelial in 61 patients, sarcoma in 20 and germ cell in seven. Three hundred and sixty-one histologically proven metastases were resected (188 in group A and 173 in group B). HRCT correctly identified 142/188 lesions (sensitivity 75%); HCT revealed 142/173 metastases (sensitivity 82.1%). Sensitivity for lesions less than 6 mm in maximum diameter was 48% (30/58 false negative) in group A and 61.5% (20/52 false negative) in group B. Conclusions: The sensitivity of HCT exceeds that of HRCT. However, complete manual exploration by thoracotomy remains the procedure of choice for patients undergoing pulmonary metastasectomy, because of limitation in preoperative radiological assessment of lung lesions smaller than 6 mm. [Copyright &y& Elsevier]

Objective: We reviewed our experience in the surgical management of 80 patients with colorectal pulmonary metastases and investigated factors affecting survival. Material and methods: From January 1980 to December 2000, 80 patients, 43 women and 37 men with median age 63 years (range 38–79 years) underwent 98 open surgical procedure (96 muscle-sparing thoracotomy, one clamshell and one median sternotomy) for pulmonary metastases from colorectal cancer (three pneumonectomy, 17 lobectomy, seven lobectomy plus wedge resection, six segmentectomy, three segmentectomy plus wedge resection and 62 wedge resection). Pulmonary metastases were identified at a median interval of 37.5 months (range 0–167) from primary colorectal resection. Second and third resections for recurrent metastases were done in seven and in four patients, respectively. Results: Operative mortality rate was 2%. Overall, 5-year survival was 41.1%. Five-year survival was 43.6% for patients submitted to single metastasectomy and 34% for those submitted to multiple ones. Five-year survival was 55% for patients with disease-free interval (DFI) of 36 months or more, 38% for those with DFI of 0–11 months and 22.6% for those with DFI of 12–35 months (P=0.04). Five-year survival was 58.2% for patients with normal preoperative carcino-embryonic antigen (CEA) levels and 0% for those with pathologic ones (P=0.0001). Patients submitted to second-stage operation for recurrent local disease had 5-year survival rate of 50 vs. 41.1% of those submitted to single resection (P=0.326). Conclusions: Pulmonary resection for metastases from colorectal cancer may help survival in selected patients. Single metastasis, DFI>36 months, normal preoperative CEA levels are important prognostic factors. When feasible, re-operation is a safe procedure with satisfactory long-term results. [Copyright &y& Elsevier]

Pulmonary metastases, Pulmonary metastasectomy, Oligometastatic disease, PulMiCC trial, National registry, Systemic therapy. [Extracted from the article]

Abstract: Objective: Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration. Methods: We randomized 20 rats into two groups. Group one underwent anterograde isolated left lung perfusion while group two underwent retrograde isolated left lung perfusion. A dose of 2mg/kg melphalan (MN) was administered to the lung at a flow of 0.5mL/min during 30min, followed by a 5-min washout with buffered hetastarch (BHE). The final melphalan lung concentration (FMLC) was determined in the hilum, at the apex, the mid-periphery and the base of the lung. Statistical analysis was done with an unpaired student''s t-test. Results: Retrograde left ILuP resulted in a higher FMLC in the hilum (P&#60;0.0001) and in the base of the lung (P=0.03), while anterograde ILuP induced a higher concentration at the apex of the lung (P=0.04). No difference was seen in the mid-peripheral area of the lung (P=0.92). Conclusions: In this experimental study, retrograde perfusion seems to increase final melphalan lung concentration in hilar and basal regions of the lung compared to anterograde perfusion. [Copyright &y& Elsevier]

The authors reflect on the pulmonary metastasectomy as an established practice for sarcoma treatment. They state that most of the sarcoma patients eventually die from this kind of cancer. They mention several misconceptions regarding the cancer such as the possibility of occasional cure to prolong life and survival rates. They suggest that mathematical modeling studies and clinical trials can help in the research to provide answers to the uncertainties.