Risk factors and a predictive nomogram for non-sentinel lymph node metastases in Chinese breast cancer patients with one or two sentinel lymph node macrometastases and mastectomy

Original Article


Risk factors and a predictive nomogram for non-sentinel lymph node metastases in Chinese breast cancer patients with one or two sentinel lymph node macrometastases and mastectomy


X.Y. Wang, MD*, J.T. Wang, PhD, T. Guo, MD, X.Y. Kong, MD PhD*, L. Chen, MD*, J. Zhai, MD*, Y.Q. Gao, MD§, Y. Fang, MD PhD*, J. Wang, MD PhD*


doi: http://dx.doi.org/10.3747/co.26.4295


ABSTRACT

Background

Two ongoing prospective randomized trials are evaluating whether omitting axillary lymph node dissection (alnd) in patients with breast cancer (bca) and sentinel lymph node (sln) macrometastases undergoing mastectomy is safe. Determining predictive risk factors for non-sln metastases and developing a model to predict the probability of those patients having non-sln metastases is also important.

Methods

This retrospective study enrolled 396 patients with bca and 1–2 slns with macrometastases who underwent alnd and mastectomy between January 2012 and December 2016. Factors influencing the non-sln metastases were determined, and a predictive nomogram was formulated. Performance of the nomogram was evaluated by its area under the curve (auc).

Results

We developed a predictive nomogram with an auc of 0.81 (cross-validation 95% confidence interval: 0.75 to 0.86) that included 4 factors (tumour size, histologic grade, and number of negative slns and axillary lymph nodes on imaging).

Conclusions

Our predictive nomogram assesses the risk of non-sln metastases in patients with bca and 1–2 sln macrometastases undergoing mastectomy.

KEYWORDS: Breast cancer, predictive nomograms, non-sentinel lymph nodes, macrometastases

INTRODUCTION

Breast cancer (bca) is one of the most commonly diagnosed malignancies and the primary cause of cancer-related morbidity and mortality in women all over the world. In patients with bca, one of the most critical prognostic factors is axillary lymph node (aln) status. Traditionally, aln dissection (alnd) in breast surgery has been used for staging and surgical treatment. However, since the late 1990s, sentinel lymph node biopsy (slnb) has replaced alnd in the treatment of patients with early-stage bca, and patients with positive sentinel lymph nodes (slns) undergo alnd. Compared with patients undergoing alnd, those with negative slns who undergo slnb have similar overall survival and disease-free survival, fewer postoperative complications, and better quality of life1,2.

During in-depth study of slns, some research has indicated that only approximately 40% of patients with positive slns have metastatic disease in non-slns. The other 60% of patients do not benefit from subsequent alnd35. Several clinical trials have reported that results are similar after alnd or slnb in patients with early-stage bca who have 1–2 positive slns and who undergo breast-conserving surgery and systemic therapy57. Guidelines for bca from the U.S. National Comprehensive Cancer Network recommend that patients who meet certain criteria (1 or 2 positive slns, breast-conserving surgery, and planned whole-breast radiotherapy) can avoid alnd. At the same time, several predictive models have been developed to estimate the risk of non-sln metastases based on clinicopathologic features8. The most popular nomograms, which are based on Western populations in developed countries, are the Memorial Sloan Kettering Cancer Center nomogram, the Stanford online calculator for metastasis, the Mayo Clinic model, and the MD Anderson Cancer Center score912. Numerous studies have reported that, despite performing well in one population, those models might not be reliable in another population914. Few studies have focused on safety for patients with bca and 1–2 positive sln macrometastases who undergo mastectomy.

In developing countries such as China, most bca patients undergo mastectomy15; even in the best cancer hospital in China, the proportion of patients undergoing breast-conserving treatment was less than 35% in 2017 (Fang Y. Chinese Academy of Medical Sciences Cancer Hospital, unpublished data). Studying the possibility of omitting alnd for patients with early-stage disease and 1–2 slns who undergo mastectomy is therefore of great importance. In the present study, we retrospectively analyzed potential predictive risk factors for non-sln metastases and developed a model to predict the probability of non-sln metastases in patients with 1–2 sln macrometastases who undergo mastectomy.

METHODS

Study Population

The study enrolled 396 consecutive patients with primary bca who were treated at the National Cancer Center (Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College) between January 2012 and December 2016. Patients were eligible for the study if they met all the following conditions: 1–2 slns with macrometastases (metastases > 2 mm), successful slnb and alnd, first-time bca diagnosis, no neoadjuvant systemic therapy, and mastectomy.

The study was approved by the Institutional Ethics Review Board of the National Cancer Center, National Clinical Research Center for Cancer, and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

SLNB Procedure

Sentinel nodes were located using a combined technique of radiocolloid and blue dye injection. First, 2 mCi of 99mTc–dextran was injected into the subareolar region 2–6 hours before surgery. Subsequently, 5–10 minutes before surgery, 1 mL methylene blue was injected into the subareolar plane. A handheld gamma probe was used to guide the incision and dissection sites in the axilla. Nodes with isotope counts greater than 10% of the count at the injection site were considered “hot” nodes. All hot, blue, hot and blue, and palpably suspicious lymph nodes were dissected and submitted for frozen sectioning. If slns were found to be positive for metastases, alnd was performed at the same time. Nodes obtained from slnb and alnd were submitted for routine histopathology. If a positive sln was diagnosed by postoperative pathology examination, affected patients underwent alnd within 3 weeks after the primary surgery.

Data Collection

Table I shows the data collected from patients. Histologic grade, estrogen receptor status, progesterone receptor status, her2 (human epidermal growth factor receptor 2) status, and Ki-67 index were classified as documented in the U.S. National Comprehensive Cancer Network guideline16.

TABLE I Patient and tumour characteristics

 

Statistical Analysis

The IBM SPSS Statistics software application (version 19.0: IBM, Armonk, NY, U.S.A.) was used to perform a backward stepwise binary logistic regression analysis to determine risk factors. We used the rms package in the R software application (version 3.3.3: The R Foundation, Vienna, Austria) with 5-fold cross-validation to formulate the predictive nomogram. The performance of the predictive nomogram was determined by the area under the receiver operating characteristic curve (auc). The auc represents the probability that the nomogram predicts greater risk for a randomly selected patient with the outcome (non-sln metastases) than for a randomly selected patient without the outcome17.

RESULTS

Clinical Characteristics

The 396 enrolled patients with sln-positive bca ranged in age from 25 to 80 years. In this cohort, 90 patients (22.7%) had non-sln metastases and 367 (92.7%) had invasive ductal carcinoma. The mean number of identified slns was 4.4, and the mean number of negative slns was 3.3. Table I presents other descriptive characteristics of the study cohort.

Predictive Model and Nomogram

Tumour size, histologic grade, and the numbers of negative slns and alns on imaging were selected to formulate the predictive model (Table II). The final model is presented as a nomogram that visually presents the individual risk. In the predictive nomogram, values for the individual patient are located along the variable axes, and a line is drawn upward to the Points axis to determine the number of points assigned for each variable. The sum of the points is located on the Total Points axis, and a line is then drawn downward to the Risk axis to determine the risk of non-sln metastases. Considering a sample patient with a T2 tumour of histologic grade 2, 1 negative sln, and abnormal alns on imaging, the Total Points score reaches approximately 223 (Figure 1), which translates to a risk ratio between 0.4 and 0.5 for non-sln metastases.

TABLE II Multivariable analysis of risk factors for non–sentinel lymph node metastases

 

 


 

FIGURE 1 The predictive nomogram.

Nomogram Performance

The auc of our model was 0.81 (cross-validation 95% confidence interval: 0.75 to 0.86; Figure 2). A useless prediction model, such as a coin flip, would result in an auc of 0.5, and a model that discriminates perfectly would result in an auc of 1. We therefore achieved a satisfying model. As shown in Table III, patients with a predictive risk of non-sln metastases less than 0.1 accounted for 49.0% of all patients.

 


 

FIGURE 2 Receiver operating characteristic curve for the predictive nomogram. The area under the curve is 0.81 (cross-validation 95% confidence interval: 0.75 to 0.86).

TABLE III Patient distribution by level of risk for non–sentinel lymph node (SLN) metastases and patients found to have non-SLN metastases

 

DISCUSSION

The importance of aln metastases in patients with bca has been recognized by doctors for a long time, and aln metastases are associated with poor prognosis. The effect of omitting alnd in patients with positive slns has been studied for more than 10 years. The 10-year follow-ups reported for the American College of Surgeons Oncology Group Z0011 trial7,18 and the International Breast Cancer Study Group 23-01 trial19 showed no statistically significant differences in the incidences of regional recurrence and distant metastases between the alnd and slnb-only groups. The European Organisation for Research and Treatment of Cancer amaros trial3 also reported similar rates of regional recurrence and overall survival in an alnd group and a slnb-only group. However, patients who underwent mastectomy accounted for only 9.2% of the patients (86 of 931) in the International Breast Cancer Study Group 23-01 trial, and the patients who underwent breast-conserving surgery received at least whole-breast irradiation. More patients in the amaros trial underwent mastectomy, but patients with a positive slnb in the slnb-only group received adjuvant axillary radiotherapy. Furthermore, in the International Breast Cancer Study Group 23-01 trial, overall survival was poorer for the patients who underwent mastectomy than for those who underwent breast-conserving surgery (82.1% vs. 90.4%, p = 0.038). We believe that the radiotherapy contributed to the low recurrence rate in patients undergoing slnb only and that distant metastases are influenced by metastases in the alns, as shown in the mouse model reported by Pereira et al.20 and Brown et al.21.

The ongoing prospect ive randomized Swedish senomac and U.K. posnoc trials are focusing on evaluating whether alnd can be safely omitted in patients with bca and sln macrometastases who are undergoing mastectomy22,23. Our retrospective study set out to discover the risk factors for non-sln metastases and to develop a predictive model adapted for patients with bca and 1–2 sln macrometastases undergoing mastectomy. Previous predictive models have usually included various sizes of sln metastases— that is, isolated tumour cells, micrometastases, and macrometastases—and a low proportion of patients undergoing mastectomy2426.

The present study included 1–2 sln metastases in patients with bca who underwent mastectomy. It showed that tumour size and histologic grade were risk factors for non-sln metastases and that larger tumour size and higher histologic grade were associated with a higher risk for non-sln metastases. Other investigators have also reported that those two factors influence non-sln metastasis2730.

We found that the number of negative slns was also associated with non-sln metastases. The risk of non-sln metastases was higher in patients with fewer negative slns. As the National Surgical Adjuvant Breast and Bowel Project B-32 study demonstrated, the false-negative rate was directly related to the number of resected slns31. Hence, all nodes that qualify as sentinel nodes should be removed, not just the bluest or hottest nodes. If more alns had been removed during the slnb when the surgeon sent palpably suspicious lymph nodes to pathology, the possibility of metastases in the remaining alns would be lower. Our study suggests that it is better to use a number of more than 2 for negative slns. Compared with patients having only a single aln metastasis, patients with more than 1 metastatic aln are more likely to be preoperatively detected with axillary ultrasonography26. In China, few patients undergo core or ultrasound-guided fine-needle aspiration biopsy when axillary ultrasonography finds abnormal lymph nodes that are impalpable. Most patients undergo slnb or, alternatively, alnd directly. Our results show that abnormal and normal lymph nodes on imaging were associated with 51.7% and 15.8% rates of non-sln metastasis respectively. Abnormal lymph nodes on imaging were significantly associated with an increased risk of non-sln involvement in patients with sln metastases. In a meta-analysis, van Wely et al.32 also found that patients with abnormal alns on imaging had a higher risk of having multiple metastatic lymph nodes. Patients with multiple metastatic lymph nodes might need postmastectomy radiotherapy to lower the recurrence rate33,34.

Patients less than 50 years of age accounted for 47.7% of our study cohort, which shows that the incident population of patients with bca in China is young. According to data published by the Chinese Cancer Center, Chinese patients less than 59 years of age accounted for 70.2% of new bca cases in 2015—an estimate based on previous population data35. Compared with the population of patients with bca in the United States, the population of such patients in China is nearly 10 years younger.

As has been reported previously, lymphovascular invasion is one of the main factors influencing sln metastases36, and so the proportion of patients with lymphovascular invasion in our study was higher than the proportion in the general bca population.

In the end, we established a predictive nomogram with a good auc in the 0.75–0.86 range, based on 4 risk factors. As Table III shows, almost half the patients in our cohort had a predictive risk for non-sln metastases of no more than 10%, and so those patients could avoid alnd. In the future, the two ongoing trials on this topic might reveal that omitting alnd for patients with early-stage bca and 1–2 macrometastases undergoing mastectomy is also safe. However, it is also important that doctors assess the individual risk of non-sln metastases. Our nomogram could be regarded as an ancillary tool in a multidisciplinary decision process for breast oncologists in clinical practice when a patient with early-stage bca and 1–2 sln macrometastases comes to consult about whether alnd is advisable.

Our study has several limitations in. First, the patient cohort came from a single cancer centre, which might result in selection bias. Second, our test cohort did not provide sufficient data for an external validation, and so we used the 5-fold cross-validation method to formulate and validate the nomogram in the test cohort, which might partly counter that deficiency. Furthermore, a prospective randomized clinical trial is better than a retrospective study, and so a prospective trial should be conducted in Chinese patients in the near future.

CONCLUSIONS

We developed a predictive nomogram with satisfactory predictive ability to assess the risk of non-sln metastases in patients with bca and 1–2 sln macrometastases undergoing mastectomy. The nomogram could be regarded as an ancillary tool in a multidisciplinary decision-making process for breast oncologists in clinical practice.

ACKNOWLEDGMENTS

We acknowledge all the doctors and nurses who took part in this study.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS

*Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R.C,
Department of Biostatistics, School of Public Health, Shandong University, Shandong, P.R.C,
Department of Breast Surgery, The First Hospital of Qiqihar, Qiqihar, P.R.C,
§Department of Oncology, Beijing Electric Power Hospital, Capital Medical University, Beijing, P.R.C.

REFERENCES

1 Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the nsabp B-32 randomised phase 3 trial. Lancet Oncol 2010;11:927–33.
cross-ref  pubmed  pmc  

2 Gill G on behalf of the snac Trial Group of the Royal Australasian College of Surgeons and nhmrc Clinical Trials Centre. Sentinel-lymph-node-based management or routine axillary clearance? One-year outcomes of Sentinel Node Biopsy Versus Axillary Clearance (snac): a randomized controlled surgical trial. Ann Surg Oncol 2009;16:266–75.
cross-ref  

3 Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (eortc 10981–22023 amaros): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;15:1303–10.
cross-ref  pubmed  pmc  

4 Gatzemeier W, Mann GB. Which sentinel lymph-node (sln) positive breast cancer patient needs an axillary lymph-node dissection (alnd)—acosog Z0011 results and beyond. Breast 2013;22:211–16.
cross-ref  pubmed  

5 Galimberti V, Cole BF, Zurrida S, et al. on behalf of the International Breast Cancer Study Group Trial 23-01 investigators. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (ibcsg 23–01): a phase 3 randomised controlled trial. Lancet Oncol 2013;14:297–305. [Erratum in: Lancet Oncol 2013;14:e254]
cross-ref  pubmed  pmc  

6 Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305:569–75.
cross-ref  pubmed  pmc  

7 Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the acosog Z0011 (Alliance) randomized clinical trial. JAMA 2017;318:918–26.
cross-ref  pubmed  pmc  

8 van den Hoven I, Kuijt G, Roumen R, Voogd A, Steyerberg EW, Vergouwe Y. A head to head comparison of nine tools predicting non-sentinel lymph node status in sentinel node positive breast cancer women. J Surg Oncol 2015;112:133–8.
cross-ref  pubmed  

9 Kocsis L, Svebis M, Boross G, et al. Use and limitations of a nomogram predicting the likelihood of non-sentinel node involvement after a positive sentinel node biopsy in breast cancer patients. Am Surg 2004;70:1019–24.
pubmed  

10 Alran S, De Rycke Y, Fourchotte V, et al. on behalf of the Institut Curie Breast Cancer Study Group. Validation and limitations of use of a breast cancer nomogram predicting the likelihood of non-sentinel node involvement after positive sentinel node biopsy. Ann Surg Oncol 2007;14:2195–201.
cross-ref  pubmed  

11 Klar M, Jochmann A, Foeldi M, et al. The mskcc nomogram for prediction the likelihood of non-sentinel node involvement in a German breast cancer population. Breast Cancer Res Treat 2008;112:523–31.
cross-ref  pubmed  

12 van den Hoven I, Kuijt GP, Voogd AC, van Beek MW, Roumen RM. Value of Memorial Sloan–Kettering Cancer Center nomogram in clinical decision making for sentinel lymph node-positive breast cancer. Br J Surg 2010;97:1653–8.
cross-ref  pubmed  

13 Zhu L, Jin L, Li S, et al. Which nomogram is best for predicting non-sentinel lymph node metastasis in breast cancer patients? A meta-analysis. Breast Cancer Res Treat 2013;137:783–95.
cross-ref  pubmed  

14 Mittendorf EA, Hunt KK, Boughey JC, et al. Incorporation of sentinel lymph node metastasis size into a nomogram predicting nonsentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. Ann Surg 2012;255:109–15.
cross-ref  

15 Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol 2014;15:e279–89.
cross-ref  pubmed  

16 Gradishar WJ, Anderson BO, Balassanian R, et al. nccn guidelines insights: breast cancer, version 1.2017. J Natl Comp Cancer Netw 2017;15:433–51.
cross-ref  

17 Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361–87.
cross-ref  pubmed  

18 Giuliano AE, Ballman K, McCall L, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the American College of Surgeons Oncology Group (Alliance) acosog Z0011 randomized trial. Ann Surg 2016;264:413–20.
cross-ref  pubmed  pmc  

19 Galimberti V, Cole BF, Viale G, et al. on behalf of the International Breast Cancer Study Group Trial 23-01. Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (ibcsg 23-01): 10-year follow-up of a randomised, controlled phase 3 trial. Lancet Oncol 2018;19:1385–93.
cross-ref  pubmed  

20 Pereira ER, Kedrin D, Seano G, et al. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 2018;359:1403–7.
cross-ref  pubmed  pmc  

21 Brown M, Assen FP, Leithner A, et al. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science 2018;359:1408–11.
cross-ref  pubmed  

22 de Boniface J, Frisell J, Andersson Y, et al. Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled senomac trial. BMC Cancer 2017;17:379.
cross-ref  

23 Goyal A, Dodwell D. posnoc: a randomised trial looking at axillary treatment in women with one or two sentinel nodes with macrometastases. Clin Oncol (R Coll Radiol) 2015;27:692–5.
cross-ref  

24 van den Hoven I, van Klaveren D, Voogd AC, Vergouwe Y, Tjan-Heijnen V, Roumen RM. A Dutch prediction tool to assess the risk of additional axillary non-sentinel lymph node involvement in sentinel node-positive breast cancer patients. Clin Breast Cancer 2016;16:123–30.
cross-ref  

25 Nadeem RM, Gudur LD, Saidan ZA. An independent assessment of the 7 nomograms for predicting the probability of additional axillary nodal metastases after positive sentinel lymph node biopsy in a cohort of British patients with breast cancer. Clin Breast Cancer 2014;14:272–9.
cross-ref  pubmed  

26 Meretoja TJ, Audisio RA, Heikkila PS, et al. International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases. Breast Cancer Res Treat 2013;138:817–27.
cross-ref  pubmed  

27 Asaga S, Kinoshita T, Hojo T, Jimbo K, Yoshida M. Predictive factors for non-sentinel lymph node metastasis in patients with clinically node-negative ipsilateral multiple breast cancer treated with total mastectomy. Clin Breast Cancer 2015;15:362–9.
cross-ref  pubmed  

28 Park HS, Chae BJ, Song BJ, et al. on behalf of the Korea Breast Cancer Society. Effect of axillary lymph node dissection after sentinel lymph node biopsy on overall survival in patients with T1 or T2 node-positive breast cancer: report from the Korean Breast Cancer Society. Ann Surg Oncol 2014;21:1231–6.
cross-ref  

29 Houvenaeghel G, Bannier M, Nos C, et al. Non sentinel node involvement prediction for sentinel node micrometastases in breast cancer: nomogram validation and comparison with other models. Breast 2012;21:204–9.
cross-ref  

30 Gur AS, Unal B, Ozbek U, et al. on behalf of the Turkish Federation of Breast Disease Associations Protocol MF08-01 investigators. Validation of breast cancer nomograms for predicting the non-sentinel lymph node metastases after a positive sentinel lymph node biopsy in a multi-center study. Eur J Surg Oncol 2010;36:30–5.
cross-ref  

31 Krag DN, Anderson SJ, Julian TB, et al. on behalf of the National Surgical Adjuvant Breast and Bowel Project. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the nsabp B-32 randomised phase iii trial. Lancet Oncol 2007;8:881–8.
cross-ref  pubmed  

32 van Wely BJ, de Wilt JH, Francissen C, Teerenstra S, Strobbe LJ. Meta-analysis of ultrasound-guided biopsy of suspicious axillary lymph nodes in the selection of patients with extensive axillary tumour burden in breast cancer. Br J Surg 2015;102:159–68.
cross-ref  

33 Lu C, Xu H, Chen X, Tong Z, Liu X, Jia Y. Irradiation after surgery for breast cancer patients with primary tumours and one to three positive axillary lymph nodes: yes or no? Curr Oncol 2013;20:e585–92.
cross-ref  pubmed  pmc  

34 Li Q, Wu S, Zhou J, et al. Risk factors for locoregional recurrence after postmastectomy radiotherapy in breast cancer patients with four or more positive axillary lymph nodes. Curr Oncol 2014;21:e685–90.
cross-ref  pubmed  pmc  

35 Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115–32.
cross-ref  pubmed  

36 Bevilacqua JL, Kattan MW, Fey JV, Cody HS 3rd, Borgen PI, Van Zee KJ. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J Clin Oncol 2007;25:3670–9.
cross-ref  pubmed  


Correspondence to: Yi Fang or Jing Wang, No. 17 Panjiayuannanli Chaoyang, Beijing 100021 P.R.C. E-mail: fangyi@cicams.ac.cn or wangjing@cicams.ac.cn

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Current Oncology, VOLUME 26, NUMBER 2, April 2019








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