Annals of Surgery Journal Club
Interactive resource for surgery residents and surgeons to discuss and critically evaluate articles published in Annals of Surgery selected by a monthly guest expert who will review an article each month, offer questions and respond to reader's comments.
Wednesday, April 6, 2016
Dr Lee Gravatt Wilke is a Professor of Surgery at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. She is the Director of the University of Wisconsin Breast Center and Interim Division Chair of the UW Section of General Surgery. Dr Wilke is the Chair of the Research Committee for the American Society of Breast Surgeons and Board Member for the Alliance for Clinical Trials in Oncology. Her primary interests include novel breast cancer clinical trials and translational breast cancer research.
Relationship Between Margin Width and Recurrence of Ductal Carcinoma In Situ: Analysis of 2996 Women Treated with Breast Conserving Surgery for 30 years. Van Zee KJ, et al.
Ductal Carcinoma In Situ or DCIS is a non invasive breast malignancy in which histologically malignant cells are detected within the mammary duct versus outside the basement membrane. The diagnosis of DCIS occurs primarily through screening mammography and most commonly presents as microcalcifications. In the past 30 years the incidence of DCIS has grown from insignificant to greater than 20% of the breast "cancer" cases, now accounting for more than 60,000 cases annually.  DCIS has recently been a focus of national media attention (Time Magazine October 2015) due to the frustration felt by providers and patients in understanding which DCIS events will actually lead to invasive disease and for whom the disease will remain indolent. There is an active interest in the breast cancer community to identify biologic markers within DCIS which can better advise patients on their surveillance options to reduce overtreatment and identify those who should consider surgical and adjuvant therapies.
Dr Van Zee and colleagues from Memorial Sloan Kettering have provided an important adjunct to the literature on DCIS. Through a retrospective review of a prospective database maintained at their institution, 2996 patients with DCIS between the years 1978 and 2010 were identified and a multi-variate model created to evaluate the influence of margin width (distance of DCIS from the edge of the resected tissue) and radiation therapy on breast cancer recurrence. Included in the model were factors that are also considered influential on recurrence; patient age, family history, clinical presentation, endocrine therapy, cancer grade and year of surgery. Consistent with prior literature the authors report an overall recurrence rate of 12% (363/2996) of which approximately ½ were invasive disease and ½ DCIS. The patient demographics described in this cohort included women of median age 57, the majority (65%) were post menopausal, 59.6% had low or intermediate grade DCIS and 43% had a 2nd surgery or re-excision. An important feature of this cohort is the fact that 46% did not undergo radiation following surgical excision. Although the study was not randomized there was a sizeable group who did not receive post surgical radiation. Fifteen percent of patients with positive margins experienced a recurrence while those with greater than 10mm margins had a 10.8% recurrence rate. For those patients who did not receive radiation, wider margins was statistically significantly associated with a lower recurrence while those women who underwent radiation did not have an association between margin width and recurrence. In the multivariate model only margin width, not age or tumor grade, was associated with lower recurrence rates with sequentially lower hazard rates for recurrence with wider margins. For those patients who did not receive radiation therapy, the link between margin width and recurrence was strong while for those patients undergoing radiation there was no association.
Any retrospective study has limitations due to biases created from physician influence, patient preferences, time changes in treatment options offered and competing medical co-morbidities. Important however to note in this study is the fact that "in the worst" case for patients with positive margins and no radiation therapy there was only a 23.3% (crude) recurrence risk while women with radiation therapy and margins greater than 10mm had a 8.6% risk of recurrence. Our ideal world would certainly be to identify those 8-20% of women who are at risk for recurrence and provide them with additional adjuvant therapy while offering the vast majority of patients either surgical removal alone and/or surveillance. Drs Van Zee and Morrow have provided the breast community with important statistics to convey to our patients during the shared decision making discussion regarding the options for treatment of DCIS; highlighting the importance of margin width in those interested in avoiding radiation treatment. Notable in all studies of DCIS is the fact that regional treatment of surgery and/or radiation does not influence survival. Published in a similar time period was a 120,080 patient study of DCIS from SEER which showed that patients who undergo lumpectomy vs lumpectomy plus radiation vs mastectomy have similar disease free survival in the 98% range.
The "horizon" for the DCIS therapy includes several important clinical studies which will help elucidate the importance of genomic characterization as well as the role of "active surveillance" for patients with low risk DCIS. In the meantime we can use the data provided by Dr Van Zee to inform patients on the pros and cons of a second surgery vs radiation therapy.
- The SSO and ASTRO recently published quidelines regarding recommendations for margin width for patients with invasive cancer; recommending "no tumor on ink" as a standard for patients with early stage disease who are undergoing breast conservation and whole breast radiation therapy. Is this consistent with the paper provided by Drs Van Zee and collegaues? Can radiation obviate the need for obtaining "wider margins?"
- What are the consequences and or risks associated with the use of a re-excision to obtain wider margins vs radiation therapy?
- Should the breast cancer community consider a randomized trial assessing the use of <2mm vs >2mm margins for DCIS; for invasive breast cancer?
- What clinical trial recently completed accrual evaluating the use of "neoadjuvant" endocrine therapy for women with estrogen positive DCIS?
1. Siegel R, Ma J , Zou Z et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64 (1):9–29
2. Worni M, Akuskevich I, Greenup R et al. Trends in Treatment patterns and Outcomes in DCIS. JNCI 2015; Sep30; 107.
3. Moran MS, Schnitt SJ, Giuliano AE, et al., 2014 Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole breast irradiation in stage I and II invasive breast cancer. Ann Surg Oncol 21:704–716
Wednesday, March 2, 2016
Moderator: Lillian S. Kao, MD, MS
S. Kao, MD, MS, CMQ is Professor, Vice-Chair for Research and Faculty
Development, and Vice-Chair for Quality of Care in the Department of Surgery at
the McGovern Medical School at The University of Texas Health Science Center at
Houston. She is the co-founder and co-director of the Center for Surgical
Trials and Evidence-based Practice (C-STEP). She is also faculty for the
Masters Program in Clinical Research at McGovern Medical School, for which she
co-directs courses in Clinical Trials and Advanced Clinical Study Design. Her
research interests include surgical infections, surgical quality improvement,
and implementation of evidence-based practices.
Haugen et al performed a two-hospital, five-specialty, stepped wedge cluster randomized controlled trial in the Netherlands to evaluate the effect of the World Health Organization (WHO) checklist on surgical outcomes. After adaptation, the checklist consisted of 20 items at 3 critical steps of the procedure: the "sign in" before induction of anesthesia, the "time out" before start of surgery, and the "sign out" before the head surgeon left the operating room. All patients undergoing elective or emergency surgery requiring all 3 steps of the checklist were included. The primary outcomes were both major and minor complications and in-hospital mortality up to 30 days after surgery. The secondary outcome was patients' length of stay. Based on an intention-to-treat analysis, the trial demonstrated a significant reduction in complication rates from 19.9% to 12.4% (p<0.001). Based on a per-protocol analysis, the complication rates were reduced to 11.5% (p<0.001) when all 3 steps of the checklist were completed, resulting in a number needed to treat of 12. The checklist also resulted in a non-statistically significant reduction in mortality from 1.6% to 1.0% (p=0.151) and a significant reduction in mean length of stay from 7.8 to 7.0 days (p=0.022).
Several other multi-center studies of checklists have been performed, the majority of which were pre- and post-intervention studies which can be prone to biases caused by regression to the mean and secular trends. The authors in this study chose to use a stepped wedge design whereby each "cluster", which in this trial was one of five surgical specialties (cardiothoracic, neurosurgery, orthopedic, general, and urologic), received the intervention starting on a different month that was assigned in a random order. A significant advantage of this design was that each cluster served as its own control as well as a control for the other clusters. Furthermore, adjusting for time in the multivariable analysis allowed for minimization of confounding based on month of checklist initiation. A second advantage to the stepped wedge design was that all participants received the intervention, which was preferable since the intervention is perceived to have a high chance of benefit and a low risk of harm. On the other hand, in a randomized trial, only a proportion of participants (i.e., half if there is 1:1 allocation) receive the potential benefits of the intervention. Third, contamination is minimized with a cluster randomized trial where the unit of randomization is not an individual but rather a group of individuals. Contamination refers to adoption of the intervention by those in the control arm and results in underestimation of the treatment effect. Lastly, there may be logistical, practical, and financial reasons to use the stepped wedge design. For example, not all clusters may be ready to implement the intervention at the same time. Disadvantages of the stepped wedge design include the large amount of data and the complexity of the statistical analysis required.
There were a few limitations to this study. First, because participants in a given specialty or cluster are more similar to each other than to those in other specialties, the analysis should have adjusted for intra-cluster correlation which would have increased the calculated sample size. Second, more information about implementation measures would have been helpful. For example, in this trial, complete compliance was not observed in 27% of procedures randomized to receive the checklist. Details regarding whether procedures that did not receive the complete intervention were systematically different than those that did would have been helpful in informing future implementation efforts. Third, blinding was not performed in that the healthcare providers were aware of the intervention. Although a Hawthorne effect could have been present whereby participants improve based on observation alone, the authors argued in a letter to the editor that this was unlikely due to the duration of the study over several months and the lack of 100% compliance with the checklist. Furthermore, the authors argued that the participants were blinded as to the primary and secondary outcomes of the study.
The importance of this study is that it used the most rigorous, feasible study design to demonstrate improved patient outcomes after checklist implementation at two hospitals. A cluster randomized trial without the stepped wedge design would have been difficult given the small number of hospitals and specialties and would have restricted the benefits of the checklist to only half of the participants. However, questions remain regarding the mechanism(s) by which checklists improve patient outcomes and the optimal strategies for effective implementation.
- Multiple studies have been performed evaluating the effect of the surgical safety checklist on patient outcomes across a wide variety of settings. These studies have had conflicting results. In the absence of known harms associated with the checklist, do you think that more studies need to be done that focus on patient outcomes? What studies, if any, are needed to better inform effective dissemination and implementation of surgical safety checklists?
- What do you think was the mechanism by which checklists improved patient outcomes in this and other checklist studies? Increased compliance with evidence-based process measures? This trial did not measure the effect of checklists on compliance with process measures. Improved safety culture? Previous studies have reported a correlation between checklist effectiveness and change in safety attitudes; however, Haugen et al did not identify any improvement in safety culture.
- In this trial, the authors adapted the checklist to their context prior to implementation. Do you think that such adaptation contributed to the effectiveness of the checklist? What implementation factors do you think influence effectiveness the most? For institutions that do not currently employ the checklist, what can be done to maximize its successful implementation?
Haugen AS, Softeland E, Almeland SK et al. Reply to "Letter to the Editor Concerning the Article-Effect of the World Health Organization Checklist on Patient Outcomes: A Stepped Wedge Cluster Randomized Controlled Trial". Ann Surg 2016; 263: 324-5.
Monday, February 15, 2016
Dr. Martin A. Croce is a Professor of Surgery at the University of Tennessee Health Science Center in Memphis, Tennessee. He is the Chief of Trauma and Surgical Critical Care, and the Medical Director of the Elvis Presley Memorial Trauma Center at Regional One Health. He has a particular interest in shock and resuscitation, surgical infections (especially ventilator associated pneumonia), and patients managed with an open abdomen, including acute and long term management.
The authors conducted a randomized controlled trial comparing two methods for temporary abdominal closure – the commercially available ABThera (Kinetic Concepts Inc.) and the “homemade” negative pressure dressing as described by Barker. The patient population included trauma patients and those suffering from abdominal sepsis. The primary endpoint was the difference in plasma concentrations of the proinflammatory cytokine IL-6 at 24 and 48 hours. Peritoneal drainage was also measured. There were 45 patients randomized – 23 to ABThera and 22 to the Barker device. Patients were fairly well matched according to age, reason for temporary closure, and other measures. There were no differences in cytokine levels or other secondary outcomes such as peritoneal fluid cytokines, SOFA scores, PaO2/FiO2, or rates of delayed fascial closure between the two groups. Interestingly, there was a difference in 90 day mortality – 21.7% ABThera vs. 50% Barker, HR 0.32 (0.11-0.93; p=0.04). Whether this is due to the type of device used or some unknown factors is unknown.
1. Were the patients evenly matched? Suggest other patient factors that could account for differences between groups.
2. Are the statistics appropriate for the analysis?
3. Was there enough patient information given, such as organs injured or etiology of abdominal sepsis?
4. What were the indications for open abdomen? Would that impact the delayed fascial closure rates?
5. Even though there were no substantial measured differences between groups, why was there a difference in 90 day mortality?
Tuesday, December 1, 2015
Moderator:Erik G. Van Eaton, MD
Schreiber MA, McCully BH, Holcomb JB, et al. Transfusion of Cryopreserved Packed Red Blood Cells is Safe and Effective After Trauma. Ann Surg. 2015;262:426-433.
This double-blinded study randomized 256 stable trauma patients across five US Level I trauma centers who needed red blood cell transfusion to receive one of three red cell transfusion products: liquid packed red blood cells (LPRBCs) that were young (≤ 14 storage days), or that were old (> 14 storage days), or cryopreserved packed red blood cells (CPRBCs). The primary outcome variable was differences in thenar eminence tissue oxygenation measured by near-infrared spectroscopy (StO2%). Secondary outcome variables included biochemical markers of impaired red blood cell function; measures of hemolysis and coagulation; systemic concentrations of inflammatory mediators; and clinical outcomes such as acute renal failure, infection, pulmonary embolism, mortality, etc.
About the Author
Dr. Erik G. Van Eaton is an Associate Professor of Surgery at the University of Washington School of Medicine in Seattle, Washington. There, he serves as a trauma and critical care surgeon in the Division of Trauma, Critical Care, and Burns. He completed his General Surgery Residency at the University of Washington, and his Surgical Critical Care Fellowship at Harborview Medical Center in Seattle, Washington. He is also an Adjunct Associate Professor in the Department of Biomedical Informatics and Medical Education. The recipient of a National Institutes of Health Ruth L. Kirschstein National Research Service Award for research in biomedical health informatics, Dr. Van Eaton developed a process for delivering trauma and critical care algorithms and protocols to clinical users at the bedside; a system for integrating morbidity and mortality event monitoring into the electronic medical record; and a computerized rounding and sign-out software system that changed the ways in which clinicians communicate about and manage their patients.
The authors found no differences among the three groups in demographics or injury severity. There was no difference in the change in thenar eminence tissue oxygenation among the three groups. There was a significant increase in free hemoglobin in the old LPRBC group but not among the other groups. IL-2 levels were higher 12 hours after transfusion in the cryopreserved packed red blood cells group compared to the other groups. There were no differences among the groups in measures of coagulation or clinical outcomes. The authors concluded, “Transfusion of CPRBCs is as safe and effective as transfusion of young and old LPRBCs and provides a mechanism to deliver PRBCs in a wide variety of settings.”
- The authors chose thenar eminence near-infrared spectroscopy StO2% as the primary outcome for this study. For what physiologic outcome is this a surrogate end point? What other objective metrics could you use as surrogates for that outcome?
- Is this a traditional comparative study, an equivalence study, or a noninferiority study? How does the type of study affect the null hypothesis and power analysis?
- The study did not achieve the target enrollment set by its power analysis. Do you think that affects the statistical results? Do you think it affects the authors' conclusions?
- This study intended to show that CPRBCs could be safely administered to trauma patients. Do you think it succeeded? Do you think it provides a solution to the challenges described by the authors regarding the RBC supply for trauma? If not, what questions do you think still need to be answered?
- If CPRBCs become widely available and indicated for use in trauma patients, do you think the patients in this trial are likely to be representative of those who will receive this therapy? If not, do you think repeating this study in those patients will yield different results? Why or why not?
Thursday, November 5, 2015
Moderator:Paul G. Gauger, MD
Adam MA, Pura J, Gu L, et al. Extent of Surgery for Papillary Thyroid Cancer Is Not Associated With Survival: An Analysis of 61,775 Patients. Ann Surg. 2014;260:601-607.
With a thoughtful and thorough analysis of a more contemporary cohort of papillary thyroid cancer patients in the NCDB, this study provides important considerations around the still unsettled question of whether or not a more extensive thyroid resection is associated with a clear survival benefit. The study made an excellent effort to isolate the effect of total thyroidectomy on patient survival by adjusting for patient comorbidities and tumor characteristics and concluded that no survival benefit could be demonstrated for patients with tumors between 1.0-4.0 cm who were treated with total thyroidectomy (compared to lobectomy). This multifactorial adjustment was important because more of the patients in the NCDB who were treated with total thyroidectomy had concerning tumor characteristics such as nodal disease, extrathyroidal extension, multifocal disease, distant metastases, etc. The authors' primary conclusion was preserved after multiple subgroup and sensitivity analyses. The conclusion does not agree with an important previous analysis of the same database (which was less-contemporary and adjusted for fewer factors) and also supports some other recent studies which have suggested equivalent survival influence between total thyroidectomy and lobectomy for some patients. This article is particularly timely considering the recent update to the American Thyroid Association treatment guidelines.
About the Author
Paul G. Gauger, MD, is the William J. Fry Professor of Surgery and Professor of Learning Health Sciences at the University of Michigan where he is Chief of the Division of Endocrine Surgery. He also serves as Program Director for the General Surgery residency.
The conclusion of the study seems most appropriately applied to patients with low or intermediate risk papillary thyroid cancers. There is some concern that over-application of this conceptual equivalence could meet with worsened long-term outcomes in patients who are treated with lobectomy for higher-risk tumors. Just because no survival advantage could be proven in a population-level database analysis does not mean that these are equivalent surgical options for all or even most of the individual patients encountered in surgical practice. This clinical equipoise should largely be reserved for decision-making in patients who have no concerning clinical features and after thorough pre-operative assessment which should include ultrasound assessment of the tumor, the entire thyroid, and the cervical node basins.
One Important limitation to the study is that survival was the primary measure analyzed as the NCDB does not track tumor recurrence or cause-specific mortality well. Therefore, there may be other very real advantages to total thyroidectomy which are not able to be ascertained in this study.
One thing that is clear from this important work is that as surgeons, we should be precise and fair in our pre-operative discussions with our patients. The rationale for total thyroidectomy may be sound and anchored by a number of advantages in facilitation of post-operative radioiodine scanning/treatment and long term surveillance. However, to lead our patients to think that we are extending their lives through more complete initial thyroid resection may not be an accurate or meaningful message.
- Some additional factors influence recommendations about extent of thyroid resection [e.g. age, large tumor size, and ultrasound suggestions of multifocal disease or extra-thyroidal extension (particularly in the posterior aspect)]. Will the conclusion of this study likely change your practice over time, or will it instead change the details of the discussions you have with your patients during pre-operative planning?
- Considering overall treatment strategies which prioritize complete elimination of detectable tumor burden, how would a more flexible surgical strategy around extent of thyroid resection likely be met by the endocrinology community as a whole?
- Although fundamentally and obviously important, overall survival may not the sole best metric for evaluating treatment strategies for this particular cancer. In a cancer such as PTC where long survival is the expectation for most patients, are there other advantages to total thyroidectomy besides survival that should take precedence in guiding this initial decision about extent of surgery?
- How will this study affect your decision about the necessity of completion thyroidectomy in a patient whose diagnosis of PTC is not made until after permanent histology of a lobectomy specimen? What if the patient has a low-risk PTC?