SLN Biopsy in Melanoma Patients: Are we sufficiently informed to obtain an informed consent?

Transcription

1 SLN Biopsy in Melanoma Patients: Are we sufficiently informed to obtain an informed consent? Mac Machan, MD 1 and John A. Zitelli, MD 2 1 Jefferson Medical Center, Clairton, PA 2 Shadyside Medical Center, University of Pittsburgh Medical Center, Pittsburgh, PA. Informed consent has both legal and medical origins, but is understood to exist if the patient, with both substantial understanding and substantial absence of control by another, intentionally authorizes treatment. (1) In its simplest form, it is a process in which the physician provides sufficient information about the patient s condition and the recommended treatment benefits, risks, and alternatives to enable the patient to make an informed decision to accept or reject the recommendations.(2, 3) A physician s lack of familiarity with the available data, or bias regarding the disease or procedure for which they are considered an expert can pollute this process.(4, 5) It is our responsibility to know the facts, and it is the patient s right to make an informed decision without the influence of our personal biases.(2, 4) This article is intended to review the best available evidence with regard to sentinel lymph node biopsy (SLNB) in order to increase provider knowledge and decrease the influence of bias from surgical dogma. Is there a survival advantage provided by SLNB? One of the most important facts about SLNB is that it provides no melanoma-specific or overall survival advantage to patients.(6, 7) The final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1), the only randomized trial of SLNB ever conducted, reported 10-year melanoma-specific survival rates of 81.4% in the SLNB group and 78.3% in the observation group (p = 0.18, hazard ratio = 0.84 ( )). It should be mentioned that a subgroup analysis of patients with nodal metastases (i.e. SLN+ patients compared with observation patients who developed clinically palpable nodal disease) showed a 10-year melanoma-specific survival benefit for the SLNB group (62.1% vs 41.5% survival, p =0.006, hazard ratio = 0.56 ( )). However, this sub-analysis is a post-hoc comparison utilizing a novel, un-validated statistical method (accelerated-failure-time latent-subgroup analysis), and is neither powered, nor randomized to provide evidence-based conclusions. It can be used to generate theories, but not to determine patient care. The evidence based conclusion is that SLNB is not a therapy and does not provide a survival advantage over observation and regular lymph node exams. It is imperative that our patients understand these facts.

2 Is there a prognostic value? One of the most common misconceptions regarding SLNB is the prognostic value of the results. Eight years ago, the 3 rd interim analysis of MSLT-1 was published, and sentinel lymph node (SLN) status was touted as the most important prognostic indicator for melanoma,(6) and the MSLT-1 final report again emphasizes SLN status as the most powerful prognostic indicator (p < 0.001, hazard ratio = 3.09 ( )).(7) However, these statements apply to the entire group of mm thick melanomas included in the trial. They ignore the fact that we are able to provide prognostic information based on Breslow thickness (p value <0.001, hazard ratio = 1.59 ( ))(7) and other factors such as ulceration and mitotic rate, which are reported on nearly every standard pathology summary. There have been several studies providing more detailed prognostic information using both Breslow thickness and SLNB results. It is clear that a 1 mm thick melanoma with a positive SLN does not have the same prognosis as a 3.5 mm thick melanoma with a positive SLN. With this in understanding, the question we need to be asking is -- knowing a patient s prognosis based upon their Breslow thickness, what additional prognositic value is gained from the results of a SLNB? Breslow thickness is unique as a prognostic indicator. It is a precise and reproducible measurement, whereas other indicators are either qualitative (i.e. ulceration, tumor infiltrating lymphocytes) or vulnerable to observer variability (histologic grade, mitoses/high-power field).(8, 9) There is a proven direct relationship between Breslow thickness and survival. Additionally, at a time when cost containment and accessibility for patients are at the forefront of healthcare, Breslow thickness remains available to all at no additional cost, and no additional testing. There are two high quality, evidence-based studies evaluating the prognostic significance of SLN status for a given Breslow thickness that help clarify the value of SLNB for prognosis. A metaanalysis by Freeman et al compares overall 5-year survival with and without SLN stratification.(10) Although a survival difference between SLN+ and SLN- patients for tumors < 4 mm thick was seen, it was not statistically significant. Only tumors > 4 mm thick had a

3 statistically significant survival difference between SLN+ and SLN- patients, with a 5-year survival of 46% for SLN+, and 68% for SLN- patients. (Table 1) The second study was a Bayesian analysis by Rhodes which evaluated the available data using melanoma-related death (MRD) as an outcome measure.(11) He determined that the prognostic information provided by SLNB status may be variably useful for patients who have tumors of intermediate thickness (1-4 mm) and not very useful for patients who have thin and thick tumors. However, only 1 report was included in his analysis of tumors > 4 mm thick, and 2 reports for intermediate thickness tumors. (Table 1) He then concluded that if SLNB is being offered to obtain prognostic information, patients need to be informed how SLNB status will be used to predict melanomarelated mortality and guide treatment options. This question of prognostic refinement is especially pertinent for patients with thin melanoma (<1 mm). There has been recent support of SLNB for melanoma between 0.76 mm and 1.00 mm,(12, 13) and guidelines updated by the NCCN in April 2013 appended discuss and consider sentinel node biopsy for stage 1a disease > 0.75 mm.(14) 70% of newly diagnosed melanomas are < 1mm in depth, and the incidence of SLN positivity in patients with melanoma < 1 mm is only 4-6%.(12, 15) However, the best available evidence states that there is not enough prognostic information to recommend SLNB for these patients. The evidence is that patients with melanoma < 1mm thick have similar prognoses, regardless of sentinel node status, achieve no survival benefit, and have the same chance of a positive node as receiving a result that is falsely negative. Knowing this, there seems little to gain for these patients by performing a SLNB. With this in mind, the Dermatology Choosing Wisely List, approved by the American Academy of Dermatology Board of Directors in 2013 includes the statement: Do not perform sentinel lymph node biopsy, or other diagnostic tests for the evaluation of early, thin melanoma because they do not improve survival. (16) For intermediate thickness melanoma (1-4 mm) relatively little high quality data exists, and caution should be used when estimating prognosis in these patients. Freeman et al found that survival percentage by Breslow thickness falls between the SLN- and SLN+ subsets, with most studies showing worse survival in SLN+ patients although the difference was not statistically significant.(10) Therefore, we cannot counsel patients that SLNB will provide meaningful

4 prognostic information when the best available evidence shows no statistically significant difference in survival between SLN+ and SLN- patients. Although Freeman et al found a statistically significant difference for thick melanomas (> 4mm), the prognosis is poor regardless of sentinel node status, so only the patient can determine the value of the prognostic information gained, especially with the pitfalls and complications associated with the procedure. Pitfalls and Complications The pitfalls and complications inherent to the SLNB technique need to be recognized as well. False positivity, used to describe positive sentinel nodes, in which progression to palpable nodal disease would not have occurred even if the node had not been removed, has reported rates between 24-34%.(6, 17) This leads to an unnecessary upgrade in staging and imprecise prognostic information for these patients. Likewise, false negativity (i.e. those patients with a negative sentinel node who go on to develop metastatic nodal disease) occurs at a rate of 3-5%.(18, 19) False positive and false negative rates complicate our ability to predict prognosis, and these variables must be taken into account when evaluating prognostic values. In addition, SLNB is accompanied by a 4-5% complication rate (including seroma, infection, scarring, and chronic lymphedema) when performed by experienced surgeons. (18, 20) These risks need to be understood by patients considering SLNB. Can SLNB be used to guide therapy? SLNB has been used to stage patients for adjuvant therapy, as is done in breast cancer. Unfortunately, no adjuvant therapy, including interferon, immunotherapy, and chemotherapy, has shown to provide an overall survival advantage for stage III patients.(21, 22) The introduction of active drugs for metastatic disease (BRAF-inhibitors and check-point blockers) provides hope that effective adjuvant therapies for SLN-positive patients will be identified in the near future, however, until that time, SLNB as a staging procedure for recommending adjuvant therapy in stage III malignant melanoma is premature. SLNB may still have value in the setting of a clinical trial where refined prognostic data is needed to identify appropriate study participants.

5 Are we truly informing our patients when we consent them? As physicians and healers it is in our nature to never relent and do everything in our power for the benefit of our patients. Unfortunately in medicine there are diseases, such as melanoma, for which we do not have proven therapeutic options. As part of the Hippocratic Oath, we have sworn to do no harm and avoid the traps of overtreatment and therapeutic nihilism. We are treating individual patients, and should not expose patients to ineffective therapy simply to treat our own conscience and convince ourselves that we have done the best for the patient. We are duty-bound to present the available evidence to our patients in an unbiased, simple, and comprehensible manner. It is then our role to allow the patient to gauge the risks, benefits and value of the procedure, and make an autonomous decision regarding their care. This paper attempts to fill the practice gap between the dogma of SLNB in melanoma as the standard of care, (23) and the most current evidence. The best available data has been reviewed and should guide our patient discussions regarding SLNB. Patients deserve to know that SLNB, followed by complete lymph node dissection or observation, does not provide a melanomaspecific or overall survival advantage. SLNB in melanoma has limited value as a prognostic indicator over and above what is already known from Breslow thickness. And SLNB cannot guide evidence-based therapy because at this time no chemo-, immuno-, or radiotherapy has been shown to provide a survival benefit.

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8 Table 1 Estimating Melanoma Prognosis (Best Available Evidence) 5- year Overall Survival 5- year Melanoma- Specific Survival Breslow Thickness (mm) All Patients (%) A Median (Range) (%) B Range (%) C SLN+ SLN- p- value SLN+ < > (58-87) 94 (88-96) (22-55) 82 (76-90) 0.25 > (19-67) 68 ( ) A From Balch et al 12 B From Freeman et al 9 C From Rhodes 10 SLN-