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Cancer Treatment and Research
Series Editor: Steven T. Rosen
Karl Y. Bilimoria
Christina A. Minami
David M. Mahvi Editors
Comparative
Effectiveness
in Surgical
Oncology
Key Questions and How to Answer Them
Indexed in PubMed/Medline
Cancer Treatment and Research
Volume 164
Series editor
Steven T. Rosen, Duarte, CA, USA
More information about this series at http://www.springer.com/series/5808
Karl Y. Bilimoria Christina A. Minami
•
David M. Mahvi
Editors
Comparative Effectiveness
in Surgical Oncology
Key Questions and How to Answer
Them
123
Editors
Karl Y. Bilimoria David M. Mahvi
Department of Surgery Department of Surgery
Northwestern University Northwestern University
Chicago, IL Chicago, IL
USA USA
Christina A. Minami
Northwestern University
Chicago, IL
USA
ISSN 0927-3042
Cancer Treatment and Research
ISBN 978-3-319-12552-7 ISBN 978-3-319-12553-4 (eBook)
DOI 10.1007/978-3-319-12553-4
Most surgical oncology textbooks are distillations of the current literature that guide
us in treatment decisions and clinical practice. They are reliable, practical, and
comprehensive pictures of where our field stands. But how do we push forward?
Major unresolved questions persist in the oncologic world despite tremendous
strides in recent years. How do we address these and continue our advancement?
Comparative effectiveness research (CER) is a relatively new name for an old
concept. By the Institute of Medicine’s definition, it is the synthesis of evidence that
compares the benefits and harms of alternative methods to prevent, diagnose, treat,
and monitor a clinical condition or to improve the delivery of care. Though
randomized controlled trials function as our gold standard, we must often, for a
variety of reasons, look to alternative CER techniques for answers. These
approaches may include well-conducted retrospective cohort studies from cancer
registries and other data sources, decision and cost-effectiveness analyses, and other
novel methodologies.
This book lays out the current critical questions for a variety of solid-organ
malignancies, identifies the barriers to obtaining high-level evidence, and proposes
potential approaches to the fundamental questions of each disease.
We would like to recognize the creativity and expertise demonstrated by all of
the authors. While other textbooks require an intimate knowledge of a particular
malignancy, this book also required the authors to imagine solutions to the most
fundamental questions in their field. We believe that it is this type of progressive
thinking and research that will spur the evolution of surgical oncology.
Karl Y. Bilimoria
Christina A. Minami
David M. Mahvi
vii
Acknowledgments
The editors would like to acknowledge Ms. Remi Love for her dedication and
attention to detail in helping us compile this book.
ix
Contents
xi
xii Contents
xiii
xiv Contributors
Nabil Wasif Department of Surgery, Mayo Clinic Arizona, Phoenix, AZ, USA
Jason D. Wright Department of Obstetrics and Gynecology, Columbia University
College of Physicians and Surgeons, New York, US; Herbert Irving Comprehensive
Cancer Center, Columbia University College of Physicians and Surgeons, New
York, US
Approaches to Answering Critical CER
Questions
Christine V. Kinnier, Jeanette W. Chung and Karl Y. Bilimoria
Abstract
While randomized controlled trials (RCTs) are the gold standard for research,
many research questions cannot be ethically and practically answered using an
RCT. Comparative effectiveness research (CER) techniques are often better
suited than RCTs to address the effects of an intervention under routine care
conditions, an outcome otherwise known as effectiveness. CER research
techniques covered in this section include: effectiveness-oriented experimental
studies such as pragmatic trials and cluster randomized trials, treatment response
heterogeneity, observational and database studies including adjustment tech-
niques such as sensitivity analysis and propensity score analysis, systematic
reviews and meta-analysis, decision analysis, and cost effectiveness analysis.
Each section describes the technique and covers the strengths and weaknesses of
the approach.
Keywords
Comparative effectiveness research Surgical oncology Observational and
database studies Pragmatic trials
C.V. Kinnier
Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
J.W. Chung
Department of Surgery, Feinberg School of Medicine, Northwestern University,
Chicago, IL, USA
Contents
1 Introduction ............................................................................................................................ 2
2 Randomized Controlled Trials: Limitations and Alternatives .............................................. 3
3 Experimental Studies ............................................................................................................. 3
3.1 Pragmatic Trials ............................................................................................................ 4
3.2 Cluster Randomized Trials ........................................................................................... 4
3.3 Adaptive Trials ............................................................................................................. 5
4 Treatment-Response Heterogeneity ....................................................................................... 6
5 Observational and Database Studies ..................................................................................... 7
5.1 Commonly Used Datasets ............................................................................................ 7
5.2 Sensitivity Analysis ...................................................................................................... 8
5.3 Propensity Score Analysis ............................................................................................ 9
5.4 Subgroup Analysis........................................................................................................ 9
5.5 Instrumental Variable Analysis .................................................................................... 10
6 Systematic Reviews and Meta-Analysis ............................................................................... 11
6.1 Systematic Reviews ...................................................................................................... 11
6.2 Meta-Analysis ............................................................................................................... 12
7 Decision Analysis .................................................................................................................. 12
8 Cost Effectiveness Analysis .................................................................................................. 13
9 Conclusion ............................................................................................................................. 13
References .................................................................................................................................... 14
1 Introduction
Significant advances in evidence-based medicine have occurred over the past two
decades, but segments of medical care are still practiced without underlying sci-
entific evidence. Many practice patterns are so firmly established as the standard of
care that a randomized controlled trial (RCT) would be unethical. Where evidence
from RCTs exist, the study population is narrow and not easily applicable to most
patients. Finally, multiple treatments are firmly engrained in clinical practice and
have never been rigorously questioned.
Answering most of these knowledge gaps with an RCT, however, would be
unethical, impractical, or dissimilar to routine care. In the last case, this is because
an RCT is concerned with measuring efficacy: the effect of an intervention as
compared to placebo when all other variables are held constant. In other words, an
RCT creates a study environment in which outcome differences are most attribut-
able to the intervention. While RCTs accurately identify treatment effects under
ideal conditions, patients do not receive their routine care under those conditions.
When it comes to routine patient care, physicians are less interested in efficacy than
effectiveness: the effect of an intervention under routine care conditions. In order to
study effectiveness, health care investigators have developed a toolbox of alterna-
tive techniques, known collectively as comparative effectiveness research (CER).
Approaches to Answering Critical CER Questions 3
Both researchers and policy agencies have recognized the power of studying
effectiveness. The 2009 government stimulus package allocated $1.1 billion to CER
[1]. The following year, the Affordable Care Act proposed multiple health care
reforms to improve the value of the United States health care system. These reforms
included the foundation of the Patient-Centered Outcomes Research Institute
(PCORI), a publically funded, non-governmental institute charged with conducting
and funding CER projects [2]. As a result, funding for CER has grown substantially
in the past 5 years.
RCTs are the gold standard of medical research because they measure treatment
efficacy, but they remain dissimilar to routine care and are impractical under many
circumstances. First, RCTs are often prohibitively expensive and time consuming.
One study reported that Phase III, National Institutes of Health-funded RCTs cost an
average of $12 million per trial [3]. RCTs also take years to organize, run, and
publish. Consequently, results may be outdated by publication. Second, some events
or complications are so infrequent that enrolling a sufficiently large study population
would be impractical. Third, clinical experts working from high-volume hospitals
follow RCT participants closely in order to improve study follow-up and treatment
adherence. Following study conclusion, however, routine patients receiving routine
care may not achieve the same level of treatment adherence. Therefore study out-
comes and routine care outcomes for the same intervention may differ substantially.
Fourth, and perhaps most importantly, RCTs are restricted to a narrow patient
population and a limited number of study interventions and outcomes. These nec-
essary restrictions also restrict the broad applicability of RCT results.
Clearly investigators cannot rely solely on RCTs to address the unanswered
questions in surgical oncology. CER techniques offer multiple alternatives. We will
introduce these approaches here and then describe each technique in more detail
throughout the series.
3 Experimental Studies
The term “clinical trials” evokes images of blinded, randomized patients receiving
treatment from blinded professionals in a highly specialized setting. These RCTs
are highly sensitive to the efficacy of the intervention under investigation. In other
words, an intervention is most likely to demonstrate benefit in a setting where
patients have few confounding medical diagnoses, every dose or interaction is
monitored, and patients are followed closely over the study period. Unfortunately,
RCTs are often prohibitively expensive and require many years to plan and
complete. Furthermore, a medication that is efficacious during a highly-monitored
RCT may prove ineffective during routine care where patients more frequently
4 C.V. Kinnier et al.
Due to the constraints of an RCT, results may not be valid outside the trial
framework. Pragmatic trials attempt to address this limition in external validity by
testing an intervention under routine conditions in a heterogeneous patient popu-
lation. These routine conditions may include a broad range of adjustments. First,
pragmatic trials may have broad inclusion criteria; ideally trial patients are only
excluded if they are not intervention candidates outside of the study. Second, the
intervention may be compared to routine practice, and clinicians and patients may
not be blinded. This approach accepts that placebo effect may augment intervention
outcomes when used in routine practice. Third, pragmatic trials may use routine
clinic staff rather than topic experts, and staff may be encouraged to adjust the
medication or intervention as they would in routine practice. Fourth, patient-
reported outcomes may be measured in addition to—or instead of—traditional
outcomes. Finally, patients are usually analyzed according to their assigned inter-
vention arm; this is also known as intention-to-treat analysis. Pragmatic trials may
range anywhere along this spectrum: on one end, an otherwise traditional RCT may
use an intention-to-treat analysis; on the other, investigators may aim to conduct the
study under completely routine circumstances with the exception of intervention
randomization. The investigators must determine what level of pragmatism is
appropriate for their particular research question.
Pragmatic trials help determine medication or intervention effectiveness in a
more realistic clinical setting. The adjustments that make pragmatic trials more
realistic, however, also create limitations. Pragmatic studies are conducted under
routine clinical circumstances, so an intervention that is effective in a large, well-
funded private clinic may not be equally effective in a safety-net clinic. Therefore,
clinicians must consider the study setting before instituting similar changes in their
own practice. In addition, pragmatic trials include a broad range of eligible patients
and consequently contain significant patient heterogeneity. This heterogeneity may
dilute the treatment effect and necessitate large sample sizes and extended follow-
up periods to achieve adequate statistical power. This may then inflate study cost
and counterbalance any money saved by conducting the trial in a routine clinic with
routine staff.
Due to a history of unethical research, like the Tuskegee Syphilis Study, RCTs now
undergo multiple interim analyses [4]. These routine evaluations check for interim
results that may make trial continuation unethical, such as changes in routine care,
early and robust outcome differences, or failure to see outcome differences where
expected. Early termination prevents the inferior outcome group from suffering
further harm.
Simply initiating an RCT, however, requires significant time, funding, and
energy. Rather than terminating a trial, adaptive trials take advantage of interim
analyses to adjust the trial conditions or outcomes and address further treatment
questions. Changes to adaptive trials may include adjustments to eligibility criteria,
randomization procedure, treatment dose or duration, or the number of interim
analyses. They may also incorporate the addition of concomitant treatments or
6 C.V. Kinnier et al.
secondary endpoints. To prevent the introduction of bias, both the adjustments and
the circumstances under which they are introduced must be clearly delineated prior
to trial initiation.
Unblinding the data for interim analysis may introduce bias, so data and
resulting analyses must be sequestered from clinicians and patients still partici-
pating in the trial. Changing a study’s outcomes may also cloak long term results. A
medication that provides significant benefit after one year may have dangerous long
term side effects that will remain unknown if a study is adapted. The investigator
must therefore remember that any planned adaptations may affect important sec-
ondary outcomes.
4 Treatment-Response Heterogeneity
RCTs study the efficacy of a drug at a specific dose and frequency, but patients may
vary widely in their ability to metabolize a medication or their response to a
standard serum level. Furthermore, patient comorbidities may variably affect their
susceptibility to drug side effects. These variations in effectiveness are collectively
known as treatment-response heterogeneity.
There are three major techniques for addressing treatment-response heteroge-
neity. If the affected population and heterogeneity are already known, then a new
trial may stratify patients according to the groups that require investigation and
evaluate for outcome differences. If the affected population and heterogeneity are
unknown, then data from a previous trial may be divided into subgroups and
reanalyzed. This raises a number of analytical issues of which the investigator must
be aware. The original trial may be insufficiently powered to detect differences in
subgroups, especially when those subgroups are small segments of the larger study
population. If the study is sufficiently powered, the investigator must analyze the
subgroups appropriately. Evaluating the treatment effect within a subgroup is not
sufficient to draw conclusions about treatment-response heterogeneity within that
subgroup. Treatment effects within the subgroup must also be compared to
remaining subgroups in order to determine if treatment-response heterogeneity truly
exists within the subgroup of interest as compared to the general population. If
subgroups are too small for formal subgroup analysis, the investigator may simply
check for correlation between the concerning subgroup variable and the treatment.
High correlation between the two suggests treatment-response heterogeneity.
Health care studies have recently employed a fourth technique known as finate
mixture models [5]. These models allow certain covariate coefficients to vary for
patient variables containing treatment-response heterogeneity. While new, this
technique has been used with increasing frequency in health care cost modeling and
is likely to find other applications in coming years.
Approaches to Answering Critical CER Questions 7
Databases are an excellent data repository for large numbers of patients. Data may
be collected retrospectively or prospectively. While many institutions maintain their
own databases to facilitate single institution studies, we will focus here on some
commonly used and readily available national databases that are relevant to surgical
oncology.
The Nationwide Inpatient Sample (NIS) [6] is the largest all-payer, inpatient
database in the United States and is sponsored by the Agency for Healthcare
Research and Quality. Data elements are collected retrospectively from adminis-
trative billing data and include primary and secondary diagnosis codes, procedure
codes, total charges, primary payer, and length of stay. Data collection does not
extend beyond discharge, however, and patient data cannot be linked across
inpatient episodes. This means that even short-term variables like readmission and
30-day mortality cannot be measured. Limited information on patient demographics
and hospital characteristics may be obtained by linking to other databases where
permitted, but additional clinical details are unavailable. Consequently, patient-
level risk adjustment and investigation of clinical complications or intermediate
outcomes are largely impossible. Even with these limitations, the NIS is an all-
payer, inpatient database. This makes the NIS a valuable resource for investigators
interested in care and hospital cost differences associated with insurance coverage
or changes in procedure use over time. Furthermore, NIS data is relatively inex-
pensive and available to any investigator that completes the online training.
The American College of Surgeons National Surgical Quality Improvement
Program (ACS NSQIP) [7] maintains a database of 30-day outcomes for all qual-
ifying operations at ACS NSQIP hospitals. In contrast to the NIS, data elements in
ACS NSQIP are collected prospectively by a trained nurse registrar. This signifi-
cantly improves data quality by minimizing missing data elements and standard-
izing data entry. Data elements include patient demographics and comorbidities,
operative and anesthesia details, preoperative laboratory values and 30-day postop-
erative morbidity and mortality. Hospital participation in NSQIP is voluntary, so
unlike the NIS, ACS NSQIP data skews toward large, well-funded hospitals. Datasets
from the ACS NSQIP are free but only available to ACS NSQIP participants.
8 C.V. Kinnier et al.
Third-party, observational databases like those described above rarely contain the
precise data elements with the precise coding desired by the investigator. Investi-
gators may need to merge data elements to create a new study variable or define
parameters to categorize a continuous data element. These decisions may unin-
tentionally affect analytic results. Investigators can determine whether study results
are robust using sensitivity analysis. An analysis is first run using parameters and
specifications identified by the investigator, and the results are noted. Slight
changes to variable definitions are then made and the analysis is rerun. Substantial
changes in results suggest the results are largely dependent on investigator-selected
parameters and specifications. Conversely, unchanged or similar results suggest the
results are robust.
Approaches to Answering Critical CER Questions 9
As mentioned above, PSA corrects for measured confounders in a dataset, but there
is often reason to suspect that unmeasured confounders may be affecting the
analysis. Subgroup analysis is one way to identify whether results have been biased
by unmeasured covariates. There are multiple ways to use subgroup analysis to
identify bias caused by unmeasured covariates; two are described here.
10 C.V. Kinnier et al.
Given that instrumental variable analysis can mitigate the effects of unmeasured
confounders, it can be a powerful tool in observational research. Unfortunately, use
of the technique is highly dependent on having a reliable and unbiased instrumental
variable.
Large RCTs that produce definitive results are uncommon due to significant funding
and coordination barriers. Frequently, multiple small RCTs will address similar
research questions but produce conflicting or non-significant results. In this case, the
results of these RCTs can be aggregated to produce more definitive answers.
Multiple RCTs may address the same research topic with results published in
widely varying journals over many years. A systematic review disseminates these
research results more concisely through the methodical and exhaustive evaluation
of current literature on a specific research question. Investigators start with a
research question, or collection of related questions, that are not easily answered by
a single study or review. Medical databases are then searched using precise terms.
High quality systematic reviews search multiple databases covering multiple dis-
ciplines and use redundant and related search terms. While the number of search
terms must be brief enough to keep the number of results manageable, authors
commonly use too few search terms and therefore miss critical articles on the topic
of interest.
Once a list of articles is assembled, each article is carefully screened for eligi-
bility and relevance based on predetermined inclusion and exclusion criteria.
Results should summarize not only study results but also the quality of the study. In
addition to a traditional results section, systematic reviews typically include a table
of articles along with the study results and the level of evidence.
In the surgical community, the CHEST guidelines on venous thromboembolism
prophylaxis are perhaps the most well-known systematic review [12]. In addition,
the Cochrane collaboration is a not-for-profit, independent organization that pro-
duces and publishes systematic reviews on a wide range of healthcare topics, many
relevant to surgery [13]. Unfortunately, systematic reviews are limited by the
current data and they are unable to merge outcomes from multiple small RCTs.
Systematic reviews also become outdated quickly since they do not create any new
data. The quality of the conclusions is also highly dependent on the quality of the
underlying database review. Despite these limitations, systematic reviews are an
effective way to consolidate and disseminate information on a research topic and are
often able to reveal trends in study results that are not visible when presented across
multiple unique publications.
12 C.V. Kinnier et al.
6.2 Meta-Analysis
7 Decision Analysis
extreme cost and benefit values can be substituted for a questioned decision point. If
the optimal outcome is unaffected, then the decision point is superfluous.
Decision analysis highly depends on assignment of accurate probabilities as well
as costs and benefits. This is most challenging with non-monetary, analog outcomes
such as quality of life or emotional distress. Without realistic estimates, however,
the entire decision analysis will be inaccurate. The burden falls on the analyst to
thoroughly research each treatment branch and estimate costs and benefits based on
the best available data. If sufficient information is not available to develop an
accurate decision analysis, then preliminary studies may be needed before decision
analysis is attempted.
9 Conclusion
techniques and use them in their own research fields. Interest in effectiveness
research will only increase as policy makers attempt to rein in exponential
healthcare costs in the United States. If surgical oncologists begin using CER
techniques now, they will be well prepared for the culture shift that is already
mounting.
References
1. Pear R (2009) US to compare medical treatments. The New York Times, 16 Feb 2009
2. GovTrack HR (2009) Patient protection and affordable care act. In: 3590–111th congress.
Accessed 25 Feb 2014. http://www.govtrack.us/congress/bills/111/hr3590
3. Johnston S, Rootenberg J, Katrak S, Smith W, Elkins J (2006) Effect of a US national
institutes of health programme of clinical trials on public health and costs. Lancet 367
(9519):1319–1327
4. National Advisory Heart Council (1967) Organization, review and administration of
cooperative studies (Greenberg Report)
5. Hunsberger S, Albert PS, London WB (2009) A finite mixture survival model to characterize
risk groups of neuroblastoma. Stat Med 28(8):1301–1314
6. Overview of the Nationwide Inpatient Sample (NIS) (2014) http://www.hcup-us.ahrq.gov/
nisoverview.jsp. Accessed 25 Feb 2014
7. Welcome to ACS NSQIP (2014) http://site.acsnsqip.org/. Accessed 25 Feb 2014
8. National Cancer Data Base (2014) http://www.facs.org/cancer/ncdb/. Accessed 25 Feb 2014
9. Data and Software for Researchers (2014) Surveillance, epidemiology, and end results
program http://seer.cancer.gov/resources/. Accessed 25 Feb 2014
10. Taubman SL, Allen HL, Wright BJ, Baicker K, Finkelstein AN (2014) Medicaid increases
emergency-department use: evidence from Oregon’s Health Insurance Experiment. Science
(New York, NY) 343(6168):263–268
11. Tan HJ, Norton EC, Ye Z, Hafez KS, Gore JL, Miller DC (2012) Long-term survival
following partial versus radical nephrectomy among older patients with early-stage kidney
cancer. JAMA J Am Med Assoc 307(15):1629–1635
12. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ (2012) Executive
summary: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of
chest physicians evidence-based clinical practice guidelines. CHEST J 141(2_suppl):7S–47S
13. The Cochrane Collaboration (2014) http://us.cochrane.org/cochrane-collaboration. Accessed
25 Feb 2014
Leveraging Comparative Effectiveness
Research to Improve the Quality
of Multidisciplinary Care for Breast
Cancer Patients
Lane L. Frasier, Caprice C. Greenberg and Heather B. Neuman
Abstract
Breast cancer is the most commonly diagnosed cancer among women. To date,
the use of efficacy randomized controlled trials (RCTs) in breast cancer have
resulted in dramatic improvements in oncologic outcomes for this disease.
However, not every question pertinent to breast cancer is amenable to such
efficacy trials. This chapter will discuss some of the unique aspects of breast
cancer that make efficacy RCTs challenging and/or impractical, how comparative
effectiveness research can be used to address these issues, and identify several key
questions which would benefit from ongoing comparative effectiveness research.
Keywords
Comparative effectiveness research Breast cancer Breast conserving therapy
(BCT) Mastectomy Sentinel lymph node biopsy Axillary lymph node
dissection Hormonal therapy Hormone receptor status
Contents
1 Introduction ............................................................................................................................ 16
2 The Roles and Limitations of Randomized Controlled Trials in Breast Cancer Research.... 16
3 Breast Cancer-Specific Limitations to Efficacy Trials.......................................................... 19
4 Breast Cancer Clinical Questions Amenable to Comparative Effectiveness Research........ 22
5 Future Steps ........................................................................................................................... 28
References .................................................................................................................................... 29
1 Introduction
Breast cancer is the most commonly diagnosed cancer and the second leading cause
of cancer death for women in the United States. As a result of numerous randomized
controlled trials (RCTs) addressing key breast cancer questions, great strides have
been made in the detection, treatment, survival, and quality of life outcomes for this
disease. However, not every question pertinent to breast cancer is amenable to such
efficacy trials. There is also significant uncertainty in how the data generated in the
highly-controlled clinical trial setting translates into “real world” practice. Com-
parative effectiveness studies are the optimal means of addressing both of these
issues, and can generate critical evidence which complements the data generated
through efficacy trials, potentially improving the quality of care we provide breast
cancer patients. This chapter will begin with a brief representation of the critical role
efficacy RCTs have played in breast cancer management, followed by a discussion of
the unique characteristics of breast cancer which make some aspects of care difficult
to assess with a RCT. We will next identify several important issues amenable to
investigation with comparative effectiveness research (CER), and finally, discuss
potential approaches which might lead to high-quality evidence for these issues.
Efficacy RCTs have played a critical role in advancing breast cancer care. With the
enrollment of thousands of women across several decades, RCTs have been the
driving force behind current best-practice guidelines for the multidisciplinary
management of breast cancer. These studies were most commonly designed to
compare oncologic endpoints (survival, recurrence, treatment adverse events) in
selected patient populations receiving different therapies. The role of RCTs in
defining the surgical management of breast cancer is especially noteworthy, with
the evolution from the Halstead radical mastectomy to the current option of breast
conserving therapy (BCT) with sentinel lymph node (SLN) biopsy (Fig. 1). The
majority of these surgical trials have focused on overall survival and local recur-
rence. However, many surgical breast RCTs have increasingly incorporated alter-
native patient-centered outcomes, such as quality of life, [1] physical function, [2]
and arm range of motion. [3].
However, even as we acknowledge the important role of RCTs in defining the
management of modern breast cancer, it is important to recognize their limitations.
RCTs are conducted within a tightly controlled environment with strict inclusion
and exclusion criteria. Practically speaking, this may result in the exclusion of
patients with unfavorable baseline characteristics, such as significant comorbidities
or advanced age. As an example, in National Surgical Adjuvant Breast and Bowel
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SYLUANO Y SIRENO
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SIRENO
Vn ñudo ataste amor, que
no desatas,
es çiego, y çiego tú, y yo más
çiego,
y çiega aquella por quien tú
me matas.
Ni yo me vi perder vida y
sossiego:
ni ella vee que muero a causa
suya,
ni tú, que estó abrasado en
biuo fuego.
¿Qué quieres crudo amor,
que me destruya
Diana con ausençia? pues
concluye
con que la vida y suerte se
concluya.
El alegria tarda, el tiempo
huye,
muere esperança, biue el
pensamiento,
amor lo abreuia, alarga y lo
destruye.
Verguença me es hablar en
un tormento
que aunque me aflija, canse y
duela tanto,
ya no podria sin él biuir
contento.
SYLUANO
O alma, no dexeys el triste
llanto,
y vos cansados ojos,
no os canse derramar
lagrimas tristes:
llorad pues uer supistes
la causa prinçipal de mis
enojos.
SIRENO
La causa prinçipal de mis
enojos,
cruel pastora mia,
algun tiempo lo fue de mi
contento:
ay triste pensamiento,
quan poco tiempo dura vna
alegria.
SYLUANO
Quan poco tiempo dura vna
alegria
y aquella dulce risa,
con que fortuna acaso os ha
mirado:
todo es bien empleado
en quien auisa el tiempo y no
se auisa.
SIRENO
En quien auisa el tiempo y
no se auisa,
haze el amor su hecho,
mas ¿quién podra en sus
casos auisarse,
o quién desengañarse?
ay pastora cruel, ay duro
pecho.
SYLUANO
Ay pastora cruel, ay duro
pecho,
cuya dureza estraña
no es menos que la graçia y
hermosura,
y que mi desuentura,
¡quán a mi costa el mal me
desengaña!
SYLUANO
Pastora mia, más blanca y
colorada
que blancas[1269] rosas por
abril cogidas,
y más resplandesçiente,
que el sol, que de oriente
por la mañana assoma a tu
majada
¿cómo podré biuir si tú me
oluidas?
no seas mi pastora rigurosa,
que no está bien crueldad a
vna hermosa.
SIRENO
Diana mia, más
resplandesçiente,
que esmeralda, y diamante a
la vislumbre,
cuyos hermosos ojos
son fin de mis enojos,
si a dicha los rebuelues
mansamente,
assi con tu ganado llegues a la
cumbre
de mi majada gordo y
mejorado,
que no trates tan mal a vn
desdichado.
SYLUANO
Pastora mia, quando tus
cabellos
a los rayos del sol estás
peynando,
no vees que lo escuresçes,
y a mi me ensoberuesçes
que desde acá me estoy
mirando en ellos,
perdiendo ora esperança, ora
ganando?
assi gozes, pastora, esa
hermosura,
que des vn medio en tanta
desuentura.
SIRENO
Diana cuyo nombre en esta
sierra
los fieros animales trae
domados,
y cuya hermosura,
sojuzga a la ventura,
y al crudo amor no teme y
haze guerra
sin temor de occasiones,
tiempo, hados,
assi gozes tú tu hato y tu
majada,
que de mi mal no biuas
descuydada.
SYLUANO
La fiesta, mi Sireno, es ya
passada,
los pastores se uan a su
manida,
y la cigarra calla de cansada.
No tardará la noche, que
escondida
está, mientra que Phebo en
nuestro cielo
su lumbre acá y allá trae
esparzida.
Pues antes que tendida por
el suelo
veas la escura sombra, y que
cantando
de ençima deste aliso está el
mochuelo,
Nuestro ganado vamos
allegando,
y todo junto alli lo lleuaremos,
a do Diana nos está
esperando.
SIRENO
Syluano mio, vn poco aqui
esperemos,
pues aun del todo el sol no es
acabado
y todo el dia por nuestro le
tenemos.
Tiempo ay para nosotros, y
el ganado
tiempo ay para lleualle al claro
rio,
pues oy ha de dormir por este
prado;
y aqui cesse, pastor, el cantar
mio.
Os tempos se mudarão
a vida se acabará:
mas a fe sempre estara,
onde meus olhos estão.
Os dias, y os momentos,
as horas, con suas mudanças,
inmigas son desperanças,
y amigas de pensamentos:
os pensamentos estão
a esperança acabará,
a fe, me não deixará
por honrra do coraçon.