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Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities

Author: Robert Maki, MD, PhD

Section Editor: Thomas F DeLaney, MD
Deputy Editor: Diane MF Savarese, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2018. | This topic last updated: Aug 21, 2017.

INTRODUCTION — Soft tissue sarcomas (STS) are uncommon malignant tumors that arise from extraskeletal
connective tissues, including the peripheral nervous system. They can arise at any body site, but are most
common in the extremities, particularly the lower limbs. (See "Clinical presentation, histopathology,
diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical presentation'.)

In treating STS of the extremities, the major therapeutic goals are long-term survival, avoidance of a local
recurrence, maximizing function, and minimizing morbidity. Surgical resection is the cornerstone of
potentially curative treatment. For nearly all patients with extremity sarcomas >5 cm, the addition of radiation
therapy (RT) improves local control, and it has also had a significant impact on limb salvage. There are
advantages to preoperative (neoadjuvant) as compared with postoperative (adjuvant) administration of RT,
and for neoadjuvant therapy utilizing combinations of RT and chemotherapy, particularly for recurrent and
large, high-grade primary tumors. These topics are discussed in detail elsewhere. (See "Overview of
multimodality treatment for primary soft tissue sarcoma of the extremities and chest wall" and "Treatment of
locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

Systemic chemotherapy is a routine component of treatment for several sarcomas that occur predominantly
in children (eg, rhabdomyosarcoma, Ewing sarcoma, and osteogenic sarcoma). However, the value of
adjuvant chemotherapy in patients undergoing resection of the adult-type localized extremity STS (eg,
leiomyosarcoma, liposarcoma, synovial sarcoma) remains controversial due to the complexity of the group of
diagnoses involved.

This topic review will discuss the use of adjuvant and neoadjuvant chemotherapy in the treatment of adult-
type extremity STS. The role of chemotherapy in the treatment of retroperitoneal STS, rhabdomyosarcoma
and the Ewing sarcoma family of tumors, and neoadjuvant combined modality approaches for patients with
large, high-grade or recurrent extremity STS are discussed in detail elsewhere. (See "Clinical features,
evaluation, and treatment of retroperitoneal soft tissue sarcoma", section on 'Adjuvant chemotherapy' and
"Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment" and "Treatment of the Ewing
sarcoma family of tumors" and "Surgical treatment and other localized therapy for metastatic soft tissue
sarcoma".)

ADJUVANT CHEMOTHERAPY

Pediatric-type sarcomas — The addition of systemic chemotherapy to local therapy significantly improves

outcomes for the common pediatric types of sarcoma (rhabdomyosarcoma, osteogenic sarcoma, and the
Ewing sarcoma family of tumors of both soft tissue and bone). Most modern treatment plans utilize initial
(induction or neoadjuvant) chemotherapy followed by local treatment and additional (adjuvant)
chemotherapy.
 Rhabdomyosarcoma — The vast majority of patients with rhabdomyosarcoma are children. The routine
use of multiagent chemotherapy (typically vincristine, dactinomycin, and cyclophosphamide, VAC, or
regimens used for Ewing sarcoma), in addition to surgery and radiation therapy (RT), has contributed
significantly toward increasing cure rates among those with localized disease. The rare cases of
rhabdomyosarcoma that arise in adults are managed similarly. (See "Rhabdomyosarcoma in childhood,
adolescence, and adulthood: Treatment".)

Ewing sarcoma — Among children, Ewing sarcoma is much more common in bone than in soft tissue,
while in adults, it more often presents in soft tissue. Regardless of whether it arises in bone or soft tissue, the
tumor is treated in the same multidisciplinary manner in adults as in children. A combination of neoadjuvant
and adjuvant chemotherapy using vincristine, doxorubicin, and cyclophosphamide (VAC), with alternating
cycles of ifosfamide and etoposide, is a US standard of care in addition to local therapy; in Europe a
somewhat different combination of many of these agents is recommended (vincristine, ifosfamide,
doxorubicin, etoposide [VIDE]). (See "Treatment of the Ewing sarcoma family of tumors", section on
'Treatment for localized disease'.)

Extraosseous osteogenic sarcomas — Osteosarcomas rarely arise in the soft tissue rather than bone
(image 1 and image 2). In contrast to Ewing sarcoma, when osteogenic sarcomas arise in soft tissue rather
than bone, management has to date followed the principles established for soft-tissue tumors rather than
primary bone tumors.

While adjuvant chemotherapy is a standard component of treatment for primary bone osteosarcomas in all
age groups, it has been thought to be much less effective for tumors of extraosseous origin [1]. However, at
least one study suggests that outcomes may be better when children with extraosseous osteosarcoma are
treated with the same combination chemotherapy protocols as used for bone-primary osteogenic sarcoma
[2]. (See "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology" and
"Chemotherapy and radiation therapy in the management of osteosarcoma".)

Sarcomas more commonly seen in adults — The remainder of this discussion will focus on the use of
adjuvant chemotherapy for the more common adult-type STS, such as liposarcomas, leiomyosarcomas, and
synovial sarcomas.

Over 20 randomized trials and two meta-analyses have addressed the potential benefit of adjuvant
chemotherapy for resected extremity STS in adults. Unfortunately, these have yielded conflicting data, and as
a result, the benefit of adjuvant chemotherapy remains uncertain.

Early randomized trials — The majority of early trials used doxorubicin alone or with dacarbazine but did
not employ ifosfamide, a compound only developed in the mid-1980s. Among the first 14 published
randomized trials of adjuvant doxorubicin-based therapy versus surgery alone, two reported a significant
survival advantage for combination chemotherapy, three found higher survival in the observation arm, and the
remainder showed no difference in outcome in the treated group [3].

SMAC meta-analysis — Individual patient data from these trials, which involved 1568 adults with localized
resectable STS (only some of which were localized to an extremity), were analyzed by the Sarcoma Meta-
Analysis Collaboration (SMAC) and published in 1997 [4,5]. All evaluated studies that randomly assigned
patients postoperatively to receive or not receive adjuvant doxorubicin-containing chemotherapy; fewer than 5
percent of patients received a chemotherapy regimen that included ifosfamide. The following benefits were
noted in the chemotherapy group:

● Significantly longer local recurrence-free interval — hazard ratio [HR] for local recurrence 0.73 (95% CI
0.56-0.94).

● Significantly longer distant recurrence-free interval — HR 0.70 (95% CI 0.57-0.85).

 ● Significantly higher overall recurrence-free survival — HR for any recurrence 0.75 (95% CI 0.64-0.87). This
corresponded to an absolute 6 to 10 percent improvement in recurrence free survival at 10 years.

● There was a trend towards better overall survival that favored chemotherapy, but it was not statistically
significant (HR for death 0.89, 95% CI 0.76-1.03).

There was no consistent evidence of a difference in any endpoint according to age, sex, stage, site, grade,
histology (although there was no central pathology review), extent of resection, tumor size, or exposure to RT.
However, the strongest evidence of a beneficial effect on survival was shown in the subset of patients with
extremity and truncal sarcomas. Among these patients who received adjuvant doxorubicin-containing
chemotherapy, there was a modest but statistically significant benefit for chemotherapy (HR for death 0.80, p
= 0.029), which translated into a 7 percent absolute benefit in overall survival at 10 years.

The updated meta-analysis from this group, which includes many later trials, is presented below. (See
"Clinical features, evaluation, and treatment of retroperitoneal soft tissue sarcoma", section on 'Adjuvant
chemotherapy' and 'Updated meta-analyses' below.)

Later randomized trials — Given the suggestion of a survival benefit for extremity and truncal STS in the
SMAC meta-analysis, later randomized trials largely focused on these sites. There are few randomized trials
addressing the benefit of adjuvant chemotherapy for visceral or head and neck STS.

Four additional randomized trials explored the benefit of anthracycline and ifosfamide-based combination
adjuvant chemotherapy in extremity STS [6-10], two of which suggest a possible survival benefit for adjuvant
chemotherapy [6-8]:

● In an Italian trial in which 46 percent of the enrolled patients had either synovial sarcoma or liposarcoma
(two relatively chemosensitive histologies), 104 patients with high grade large (≥5 cm) or recurrent
spindle cell sarcomas involving the extremities or girdles were randomly assigned to no postoperative
therapy or to five cycles of chemotherapy [6,7]. Chemotherapy consisted of a dose intensive
epirubicin/ifosfamide combination (epirubicin 60 mg/m2 on days 1 and 2 plus ifosfamide 1.8 g/m2 on
days 1 to 5) with mesna and granulocyte colony-stimulating factor support. Accrual was prematurely
discontinued at two years, when a significant difference in the cumulative incidence of distant
metastasis was found (45 versus 28 percent), favoring the chemotherapy group.

Four-year overall survival was significantly greater in favor of chemotherapy (69 versus 50 percent), but
the difference that favored the chemotherapy group lost statistical significance with median follow-up of
over seven years, a finding that was attributed to the limited number of enrolled patients. Curiously,
overall relapse rates (local and distant) were similar in the two groups (44 and 45 percent).

It is difficult to interpret these results, since the main expected benefit of adjuvant systemic
chemotherapy is to reduce the rate of distant relapse. However, this may have reflected a preponderance
of patients with local recurrence later amenable to local surgical salvage approaches.

● A follow-up Italian trial randomly assigned 88 patients with high-risk extremity sarcoma to surgery with or
without RT (n = 43) or to surgery plus chemotherapy (n = 45, 26 with epirubicin alone, and 19 to epirubicin
plus ifosfamide) with or without RT [8]. The five-year survival rate of patients treated with chemotherapy
was significantly higher than that of patients who did not receive chemotherapy (72 versus 47 percent).
However, the large number of treatment variables and the small number of studied patients makes
interpretation of this result difficult.

In contrast to these results, a survival benefit from adjuvant doxorubicin and ifosfamide-containing
chemotherapy could not be shown in two other trials [9,10]:

● The European Organisation for Research and Treatment of Cancer (EORTC) randomly assigned 351
patients with completely resected STS (67 percent extremity tumors, 60 percent high-grade, 40 percent
≥10 cm) to observation versus five cycles of adjuvant chemotherapy (doxorubicin 75 mg/m2 and
 ifosfamide 5 g/m2 per cycle) [10]. The estimated five-year relapse-free survival was similar in both arms
as was overall survival (67 versus 68 percent, HR 0.94, 95% CI 0.68-1.31). Interpretation of these results
is limited by the inclusion of patients with nonextremity, small, and low/intermediate-grade primaries, as
well as the relatively low ifosfamide dose.

● An Austrian trial of 59 patients assigned to perioperative chemotherapy or surgery alone was also
negative, but the small number of patients makes it likely that the study was underpowered to detect a
small difference between the arms, if one were present [9].

Updated meta-analyses — An updated 2008 meta-analysis was conducted on published data from 18
randomized trials of 1953 patients with localized and potentially resectable STS that were reported between
1973 and 2002, including the Austrian and both Italian trials discussed above, but not the most recent large
EORTC trial [11]. Five of the trials used doxorubicin plus ifosfamide, while the others used doxorubicin alone
or in combination with other agents.

The odds ratio (OR) for local recurrence was 0.73 (95% CI 0.56 to 0.94) in favor of chemotherapy; the
corresponding value for distant and overall recurrence was 0.67 (95% CI 0.56 to 0.82), again favoring
chemotherapy. These values are nearly identical to those found in the earlier meta-analysis. (See 'SMAC
meta-analysis' above.)

However, in contrast to the earlier analysis, the use of doxorubicin with ifosfamide was associated with a
statistically significant overall survival benefit (OR for death 0.56, 95% CI 0.36 to 0.85). The absolute risk
reduction for doxorubicin in combination with ifosfamide was 11 percent (30 versus 41 percent risk of death).
Benefit could not be shown for doxorubicin alone (OR 0.84, 95% CI 0.68 to 1.03), implying the fundamental
importance of ifosfamide in the adjuvant treatment of sarcomas overall.

Pooled analysis of the EORTC trials — In contrast to this result, a pooled analysis of individual patient data
from the two largest adjuvant trials of doxorubicin and ifosfamide-based chemotherapy (both performed by
the EORTC [10,12] and totaling 819 patients) was negative [13]. Compared with surgery alone, the use of
postoperative adjuvant chemotherapy was not associated with a significant survival benefit, except in the
subset of patients undergoing incomplete (R1) resection. In multivariate analysis, tumor size, histologic
subtype, and grade were not associated with any progression-free or overall survival benefit from adjuvant
chemotherapy.

Impact of histology — Adjuvant clinical trials in adult sarcomas have, out of necessity, included patients
with multiple histologies, in contrast to pediatric studies, which focus on one specific sarcoma subtype. It is
well recognized that myxoid/round cell liposarcomas and synovial sarcomas are relatively chemosensitive
subtypes of STS, at least in the setting of metastatic disease. (See "Systemic treatment of metastatic soft
tissue sarcoma", section on 'Histology-driven treatment'.)

Although it has been proposed that the benefit of adjuvant chemotherapy may be preferentially seen when
patients are selected based upon tumor histology, grade [14] or tumor size, this hypothesis has never been
validated in a prospective clinical trial in adult sarcoma patients, nor in any of the pooled analyses of
randomized trial data [11,15].

Furthermore, the results from retrospective reports evaluating adjuvant chemotherapy in patients with the
more chemotherapy-sensitive histologic subtypes are conflicting [16-20]. While three contemporary
retrospective series suggest a potential survival benefit for adjuvant chemotherapy in patients with the
liposarcoma and synovial sarcoma subtypes of extremity STS [16,17,19], two others do not [18,20]. As
examples:

● Benefit for adjuvant chemotherapy was suggested in a single-center Italian report of 251 patients (aged 5
to 87 years) with a localized synovial sarcoma [17]. Adjuvant chemotherapy was administered to 61 of
215 patients who had a macroscopically complete resection (28 percent), while the remainder received
no adjuvant systemic therapy. Five-year metastasis-free survival was greater for those treated with
 chemotherapy (60 versus 48 percent), and benefit appeared to be greatest for patients aged 17 or older
who had tumors measuring >5 cm (five-year metastasis-free survival 47 versus 27 percent, respectively).

● On the other hand, a lack of long-term benefit from adjuvant chemotherapy was suggested in a report of
the combined experience of two major cancer cancers (Memorial Sloan Kettering Cancer Center
[MSKCC] and MD Anderson) that included 674 consecutive adults undergoing resection of a high-grade,
≥5 cm extremity STS between 1984 and 1999 [18]. Adjuvant doxorubicin-based chemotherapy was
administered to 336 (50 percent), while the remainder received local therapy only.

Although not a randomized trial, there were no statistically significant differences between the
chemotherapy and local therapy alone groups with respect to tumor size, anatomic site, histopathologic
subtype, or resection margin status. With a median follow-up of 6.1 years, the effect of chemotherapy
appeared to vary over time. During the first year, the HR for disease-specific survival for chemotherapy
versus no chemotherapy was 0.37 (95% CI 0.20-0.69); thereafter, the HR was 1.36 (95% CI 1.02-1.81) and
did not vary according to histology or tumor size.

Interpretation of retrospective data such as these is hampered because several biases are operative that
favor the control arm:

• Chemotherapy was likely recommended for those patients whose tumors were thought to have the
highest risk of recurrence, while those thought to have more favorable outcomes were not offered
chemotherapy.

• Although none of the differences were statistically significant, there were differences in tumor
histology and size between the two groups. In the combined report from MSKCC and MD Anderson,
50 percent of the patients who did not receive chemotherapy had 5 to 10 cm primary tumors, while
only 42 percent of those receiving chemotherapy had this relatively favorable tumor size. It is well
recognized that the risk of metastasis increases for every centimeter increase in the size of a
primary sarcoma. In addition, 21 percent of the control patients had liposarcoma histology
compared with 14 percent in the treatment group.

These data can be interpreted positively or negatively; the negative view is that overall survival was not
improved with the use of chemotherapy. The positive view is that patients with inferior prognosis had their
survival improved to that of lower risk patients with the use of systemic chemotherapy in the adjuvant setting.

Summary — The role of chemotherapy for patients with a resected extremity STS remains uncertain and
controversial [21,22]. The updated meta-analysis from the Sarcoma Meta-Analysis Collaboration [11]
suggests that use of an optimal, adequately dosed anthracycline/ifosfamide-containing regimen significantly
prolongs survival in patients with resected extremity STS [11] with the ifosfamide component as the more
important of the two drugs. However, the analysis did not include data from the single largest negative trial,
which so far has been reported only in abstract form [12]. A preliminary report of a pooled analysis of this trial
and another European large trial, both of which tested the value of an anthracycline and ifosfamide-
containing regimen, indicated no benefit from adjuvant anthracycline-ifosfamide chemotherapy [15].

Taken together, despite the most recent positive meta-analysis, it is difficult to recommend adjuvant
chemotherapy as a standard practice for all patients with extremity STS. If there is a survival benefit for
doxorubicin-based adjuvant chemotherapy, it appears to be small, no more than 5 percent absolute increase
in survival at 5 to 10 years [11]. Conversely, the positive meta-analysis from 2008 is arguably the strongest
evidence in support of the use of adjuvant chemotherapy. The challenge wrought by treating many different
sarcoma subtypes with one particular therapeutic plan has not worked in other cancers, and should be not be
expected to apply to what are 50 or more sarcoma subtypes.

In keeping with the consensus-based guidelines of the National Comprehensive Cancer Network (NCCN) and
the European Society of Medical Oncology [23], which encompass adjuvant chemotherapy as an option for
high-risk patients, our present approach is to individualize therapy, taking into consideration the patient's
performance status, comorbid factors (including age), site of disease, and histologic subtype (eg, younger
patients with synovial sarcoma or the round cell version of myxoid liposarcoma). The potential for benefit
from adjuvant chemotherapy must be discussed in the context of expected treatment-related toxicities,
including potential sterility in younger people, cardiomyopathy, renal damage, second cancers, and overall
impairment of quality of life.

Even for those patients in whom the decision has been made to administer adjuvant chemotherapy, the
optimal regimen is undefined. We prefer five to six cycles of doxorubicin (usually 75 mg/m2 per cycle in split
bolus doses or continuous infusion over three days), ifosfamide (9 to 10 g/m2 in split doses over three hours
per day for three to four days), with mesna [AIM (table 1 and table 2)] rather than MAID (mesna, doxorubicin,
ifosfamide, and dacarbazine [24]) since this permits the administration of maximal doses of the two most
active drugs for sarcoma (doxorubicin and ifosfamide), rather than adding myelotoxicity with dacarbazine.
Three cycles of chemotherapy may suffice, although the data supporting this statement are limited to a single
trial of three versus five cycles of chemotherapy in 328 patients with high-risk (deeply seated, high grade, or
large [≥5 cm] primary, or locally recurrent) extremity sarcomas [25]. Given the limitations of the available data,
with the understanding that microscopic metastatic disease may ultimately require more, rather than fewer,
cycles of chemotherapy, we still consider that five or six cycles of chemotherapy represents the preferred
approach. (See "Treatment protocols for soft tissue and bone sarcoma".)  

Given that the benefit of chemotherapy appears to be dependent upon the use of ifosfamide, at least from the
most recent meta-analysis, and the known age-dependent toxicities of ifosfamide, it makes a decision to use
adjuvant chemotherapy in older patients even more difficult. In view of the uncertainty of long-term benefit for
patients with most sarcoma subtypes, extreme caution is indicated in treating elderly patients with adjuvant
chemotherapy.

NEOADJUVANT CHEMOTHERAPY — Neoadjuvant (induction) therapy is most often considered in the setting

of a large or recurrent high-grade tumor, particularly if limb salvage is an issue. In these situations, radiation
therapy (RT) is most commonly selected, with or without chemotherapy. The optimal neoadjuvant regimen
and how best to integrate RT, chemotherapy, and surgery are unknown. (See "Overview of multimodality
treatment for primary soft tissue sarcoma of the extremities and chest wall", section on 'Initial
chemoradiotherapy for large high-grade STS' and "Treatment of locally recurrent and unresectable, locally
advanced soft tissue sarcoma of the extremities", section on 'Preoperative chemoradiotherapy'.)

The benefit of induction chemotherapy alone in this setting is uncertain. However, National Comprehensive
Cancer Network (NCCN) guidelines indicate that preoperative RT alone, preoperative chemotherapy (with
postoperative RT), or preoperative chemoradiotherapy are all acceptable options. Where available, another
option is neoadjuvant chemotherapy combined with regional hyperthermia. (See "Treatment of locally
recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on
'Chemotherapy with regional hyperthermia'.)

There are no data to support one approach over the other, and the specific neoadjuvant approach chosen
typically depends upon institutional expertise and experience. If possible, we prefer that these patients be
treated in the context of a clinical trial.

Theoretical advantages to neoadjuvant approaches to therapy include tumor cytoreduction, immediate

treatment of micrometastases, and an early indication as to the effectiveness of chemotherapy/radiotherapy.
Cytoreduction may allow less radical surgical resection to be performed, and this approach is often
considered in patients with large extremity sarcomas, particularly if the patient is a borderline candidate for
limb salvage surgery.

Most often, when induction therapy is considered for a patient with a large or recurrent extremity sarcoma,
particularly if limb salvage is an issue, RT is chosen with or without chemotherapy. Adjuvant RT with and
without chemotherapy is discussed in detail elsewhere. (See "Overview of multimodality treatment for
primary soft tissue sarcoma of the extremities and chest wall", section on 'Initial chemoradiotherapy for large
high-grade STS' and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of
the extremities", section on 'Preoperative chemoradiotherapy'.)

The benefit of induction chemotherapy alone in this setting is uncertain. Adequately powered, randomized
phase III trials are not available, and the results of uncontrolled studies are conflicting [26,27]. A randomized
phase II European Organisation for Research and Treatment of Cancer (EORTC) study in which 150 patients
were randomly assigned to three cycles of neoadjuvant doxorubicin (50 mg/m2 per cycle) plus ifosfamide (5
g/m2 per cycle) versus surgery alone failed to show better survival in the chemotherapy arm, and the trial was
stopped before expansion into a phase III study [28]. The low chemotherapy intensity used in this study may
have contributed to the negative result.

Histotype-driven therapy — Increasingly, treatment for advanced STS is histotype driven. (See "Systemic
treatment of metastatic soft tissue sarcoma", section on 'Histology-driven treatment'.)

At least some data supports the use of neoadjuvant trabectedin, where available, in patients with locally
advanced myxoid liposarcoma. In an uncontrolled study of 23 patients, seven had an objective partial
response, and at surgery, three had a pathologic complete response after three to six cycles of trabectedin
(1.5 mg/m2 over 24 hours, once every 21 days) [29]. (See "Systemic treatment of metastatic soft tissue
sarcoma", section on 'Trabectedin'.)

On the other hand, benefit for histotype-tailored versus standard neoadjuvant chemotherapy could not be
shown in an international, open-label, randomized, phase III, multicenter trial conducted in 287 patients with
high-risk (deep seated, high grade, or ≥5 cm) extremity or truncal STS [30]. Patients with five different
histologic subtypes of STS were randomized 1:1 to standard chemotherapy (full-dose epirubicin plus
ifosfamide) or histotype-tailored therapy (trabectedin for high-grade myxoid liposarcomas [n = 64], high-dose
ifosfamide alone for synovial sarcoma [n = 70], etoposide plus ifosfamide for malignant peripheral nerve
sheath tumor [n = 27], gemcitabine plus dacarbazine for leiomyosarcoma [n = 28], and gemcitabine plus
docetaxel for undifferentiated pleomorphic sarcoma [n = 97]). In an interim analysis at a median follow-up of
12.3 months, the projected disease-free survival (DFS) at 46 months was 62 percent for standard
chemotherapy and 38 percent for histotype-specific therapy (hazard ratio [HR] for DFS 1.95, 95% CI 1.12-
3.19). In exploratory subset analysis, the difference in DFS favoring standard therapy was seen in all
histologic subtypes, with the exception high-grade myxoid liposarcoma, in which DFS was similar (HR 1.03,
95% CI 0.24-4.39).

Given these data, the use of neoadjuvant histotype-driven therapy in these settings is still considered
experimental.

Chemotherapy with regional hyperthermia — Another option is regional hyperthermia plus systemic

chemotherapy. A European randomized trial reported benefit from the addition of regional hyperthermia to
neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone among patients with large high
grade tumors, or initially unresectable disease. This approach, which is not widely used outside of Europe, is
discussed in detail elsewhere. (See "Treatment of locally recurrent and unresectable, locally advanced soft
tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
 ● Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

Surgical resection is the cornerstone of treatment for virtually all patients with an extremity soft tissue
sarcoma (STS). The combination of surgery and radiation therapy (RT) achieves better outcomes than either
treatment alone for nearly all STS more than 5 cm in greatest dimension. (See 'Introduction' above.)

● Systemic chemotherapy is a routine component of treatment for several STS that occur predominantly in
children (ie, rhabdomyosarcoma, Ewing sarcoma). (See 'Pediatric-type sarcomas' above.)

However, despite many randomized trials, the role of adjuvant chemotherapy for the more common adult
subtypes of STS (such as liposarcoma, synovial sarcoma, and leiomyosarcoma) remains uncertain:

• The most recent analysis from the Sarcoma Meta-Analysis Collaboration (SMAC) suggests a
significant 11 percent improvement in survival for doxorubicin and ifosfamide-based adjuvant
chemotherapy compared with resection alone [11].

• However, a pooled analysis of individual patient data from the two largest adjuvant trials of
doxorubicin and ifosfamide-based chemotherapy (both performed by the European Organisation for
Research and Treatment of Cancer (EORTC) [10,12], only one of which was included in the SMAC
meta-analysis) presented at the 2008 American Society of Clinical Oncology (ASCO) meeting was
completely negative [15]. (See 'Pooled analysis of the EORTC trials' above.)

• There is no evidence that adjuvant chemotherapy is relatively more beneficial for the chemotherapy-
sensitive subtypes of STS. (See 'Impact of histology' above.)

Thus, in our view, this approach cannot be adopted as a standard treatment for all extremity STS, regardless
of histology.

● In keeping with the guidelines of the National Comprehensive Cancer Network (NCCN) and the European
Society for Medical Oncology [23], we suggest that the appropriateness of adjuvant chemotherapy be
addressed on a case by case basis, taking into consideration the patient's performance status, comorbid
factors (including age), disease location, tumor size, and histologic subtype. The potential for benefit
must be discussed in the context of expected treatment-related toxicities including sterility in younger
individuals, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life.

For patients who decide to undergo adjuvant chemotherapy despite the uncertainty of benefit and the
potential for treatment-related toxicity, we recommend using a regimen that contains both ifosfamide
and doxorubicin (Grade 1A). We prefer doxorubicin plus ifosfamide and mesna [AIM (table 2 and table 1)]
rather than the MAID regimen. (See 'Summary' above and "Treatment protocols for soft tissue and bone
sarcoma".)

● Neoadjuvant therapy is most often considered in the setting of a large or recurrent high-grade tumor,
particularly if limb salvage is an issue. In these situations, RT is most commonly selected, with or without
chemotherapy. The optimal neoadjuvant regimen and how best to integrate RT, chemotherapy, and
surgery are unknown. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the
extremities and chest wall", section on 'Initial chemoradiotherapy for large high-grade STS' and
"Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the
extremities", section on 'Preoperative chemoradiotherapy'.)

The benefit of induction chemotherapy alone in this setting is uncertain. However, NCCN guidelines
indicate that preoperative RT alone, preoperative chemotherapy (with postoperative RT), or preoperative
chemoradiotherapy are all acceptable options. Where available, another option is neoadjuvant
chemotherapy combined with regional hyperthermia. (See "Treatment of locally recurrent and
 unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with
regional hyperthermia'.)

There are no data to support one approach over the other, and the specific neoadjuvant approach chosen
typically depends upon institutional expertise and experience. If possible, we prefer that these patients
be treated in the context of a clinical trial.

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Topic 7720 Version 24.0

GRAPHICS

Extraosseous osteosarcoma with metastatic disease to the lungs

The patient is a 38-year-old female found to have a calcified nodule in the left breast (A, arrow). The CT scan of the
chest in the transverse projection reveals three densely calcified nodules in the left lung (B, arrowheads). Following
surgical excision of the breast mass, pathological evaluation revealed a diagnosis of extraosseous osteosarcoma. The
morphological similarity of the lung nodules to the primary tumor on CT suggests metastatic extraosseous
osteosarcoma to the lungs.

Courtesy of Richard Waite, MD.

Graphic 83187 Version 2.0

Mammogram and x-ray of surgical specimen of an extraosseous osteosarcoma arising in
the breast

(A) The mammogram of the left breast reveals a 2 cm mass with dense calcifications (arrow).
(B) X-ray of the surgical specimen showing a densely calcified mass with the needle localizer traversing the mass. The
x-ray confirms the heavy calcification, and histopathology confirmed the diagnosis of an extraosseous osteosarcoma.

Courtesy of Richard Waite, MD.

Graphic 83419 Version 1.0

Doxorubicin (Adriamycin), ifosfamide, and mesna (AIM 75/9) for advanced soft tissue sarcoma and as
neoadjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma [1]

Cycle length: 21 days.

Drug Dose and route Administration Given on days

Doxorubicin 25 mg/m 2 per day IV Dilute with 50 mL normal saline (NS) or 5% Days 1, 2, and 3
dextrose in water (D5W) and administer over one to
five minutes.

Ifosfamide 2000 to 3000 mg/m 2 Dilute with 250 to 500 mL of NS or D5W to a final Days 1, 2, and 3
per day IV* concentration of 0.6 to 20 mg/mL and administer
over three hours daily.

Mesna ¶ 1200 to 1800 mg/m 2 Dilute one-third of the total daily dose in NS or D5W Days 1, 2, and 3
per day IV (60% of the (total concentration of mesna should not exceed
total daily ifosfamide 20 mg/mL) and administer over 15 minutes prior to
dose), given in three each daily dose of ifosfamide. Repeat at four and
divided doses eight hours after the initiation of each dose of
ifosfamide daily.

Pretreatment considerations:

Hydration Adequate hydration (at least two liters of oral or IV fluids per day) should be maintained with
ifosfamide to reduce the risk of bladder toxicity. [2]
Refer to UpToDate topic on "Cystitis in patients with cancer".

Emesis risk HIGH (>90% risk of emesis). ¶

Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting
in adults".
Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity; [3-5] its use
is avoided at some institutions.

Prophylaxis for There is no standard premedication regimen.

infusion reactions Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".

Vesicant/irritant Doxorubicin is a vesicant; avoid extravasation.

properties Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic
vesicants".

Infection The incidence of febrile neutropenia was not reported in the study; however, severe neutropenia is a
prophylaxis frequent adverse event. [1] Primary prophylaxis with hematopoietic growth factors should be
considered on an individual basis, particularly for high-risk patients such as those with preexisting
neutropenia, advanced disease, poor performance status, or age over 50 years.
Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in adult patients with
chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic
syndrome, and hematopoietic cell transplantation".

Dose adjustment for A lower initial ifosfamide dose may be needed for patients with preexisting renal or liver impairment. A
baseline liver or lower starting dose of doxorubicin may be needed for patients with preexisting liver impairment. [6]
renal dysfunction Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver
disease" and "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency:
Conventional cytotoxic agents".

Cardiac issues Doxorubicin is associated with cardiomyopathy, the incidence of which is related to the cumulative
dose. Assess baseline LVEF prior to administration. Doxorubicin is contraindicated for patients with
recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy
with high cumulative doses of doxorubicin or any other anthracyclines. [6]
Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents".

Monitoring parameters:

CBC with differential and platelet count weekly during treatment.

Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 g/m 2. Clinical manifestations may
include hypophosphatemia, renal potassium wasting, metabolic acidosis with a normal ion gap, and rarely, polyuria due to
 nephrogenic diabetes insipidus. Assess creatinine and electrolytes, including potassium and phosphate, daily during treatment
and prior to each subsequent treatment cycle.
Refer to UpToDate topic on "Ifosfamide nephrotoxicity".

Mesna does not prevent hemorrhagic cystitis in all patients. [7] Monitor a morning specimen of urine for hematuria daily, on
days 1 through 3.
Refer to UpToDate topic on "Cystitis in patients with cancer".

Monitor for ifosfamide neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction)
daily on days 1 to 3. Central nervous system side effects may be especially problematic for those over age 60.
Refer to UpToDate topic on "Overview of neurologic complications of non-platinum cancer chemotherapy".

Assess liver function tests prior to each treatment cycle.

Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated.

Suggested dose modifications for toxicity:

Myelotoxicity No defined dose alterations for myelosuppression were outlined in this study. [1] However, treatment
should be delayed until white blood cell count is >4000 cells/microL and platelet count is
>100,000/microL. Reduce doses of ifosfamide and doxorubicin by 25% for failure to recover platelets
to >100,000/microL by day 28, or for grade 4 neutropenia or febrile neutropenia despite prophylaxis
with hematopoietic growth factors, or for platelet count <50,000/microL during any cycle.

Neurologic toxicity Although formal guidelines are not provided by the manufacturer, ifosfamide dose adjustment (lower
dose, or administering the same dose over a greater number of days) should be considered for
patients with reversible grade 2 or 3 neurologic toxicity. [2] Discontinue for ≥grade 3 toxicity.
Refer to UpToDate topic on "Overview of neurologic complications of non-platinum cancer
chemotherapy".

Bladder toxicity For microscopic hematuria (greater than 10 RBC per high power field), withhold ifosfamide until
complete resolution. Although formal guidelines are not available, ifosfamide dose adjustment may be
needed for patients with grade 3 or worse urotoxicity that has not responded to increases in IV fluids
or mesna. [2]

Renal toxicity A 50% reduction in ifosfamide dose is suggested for creatinine increase up to 1.5 times ULN during
therapy, with treatment discontinuation for any increase >1.5 times ULN. [8] In addition, for patients
with a normal baseline serum creatinine level, reduce ifosfamide dose for a day 1 serum creatinine of
1.8 mg/dL or greater.
Refer to UpToDate topic on "Ifosfamide nephrotoxicity".

If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen
must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the
context of individual circumstances to make adjustments, as necessary.

IV: intravenous; LVEF: left ventricular ejection fraction; CBC: complete blood count; RBC: red blood cells; ULN: upper limit of normal.
* The ifosfamide dose (6000 or 9000 mg/m 2 per cycle) should be chosen based upon clinical judgment. While generally well tolerated, AIM
chemotherapy may be associated with severe, potentially fatal neutropenia, thrombocytopenia, and anemia as well as nephrotoxicity and
neurotoxicity. A lower dose of ifosfamide may be preferred for patients over the age of 60. [2]
¶ If necessary, oral mesna may be used; however, oral mesna is not recommended for the initial dose. [9] If the oral route is chosen, patients
should receive an initial IV dose of mesna (at 20% of the daily dose of ifosfamide) prior to the day 1 ifosfamide administration, followed by
oral mesna tablets at 40% of the daily ifosfamide dose per dose, administered at two and six hours after the initiation of each dose of
ifosfamide. This same dosing schedule is repeated on each day that ifosfamide is administered. The total daily mesna dose is 100% of the
ifosfamide dose when the oral route is used. If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or
receive an IV dose of mesna. [10]

References:
1. Grobmyer SR, et al. Ann Oncol 2004; 15:1667.
2. Ifosfamide injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov,
accessed January 3, 2012).
3. Durand JP, et al. Ann Oncol 2007; 18:808.
4. Jarkowski A. Am J Health-Syst Pharm 2008; 65:2229.
5. Howell JE, et al. J Oncol Pharm Practice 2008; 14:157.
6. Doxorubicin hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at
dailymed.nlm.nih.gov, accessed January 3, 2012).
 7. MESNA injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov,
accessed January 3, 2012).
8. Worden FP, et al. J Clin Oncol 2005; 23:105.
9. Hensley ML, et al. J Clin Oncol 2009; 27:127.
10. Mesna tablets. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov,
accessed January 3, 2012).

Graphic 67985 Version 14.0

Doxorubicin (Adriamycin), ifosfamide, and mesna (AIM 75/10) for advanced soft tissue sarcoma [1]

Cycle length: 21 days until disease progression or maximum of six cycles.

Drug Dose and route Administration Given on days

Doxorubicin 25 mg/m 2 per day IV Dilute with 1000 mL normal saline (NS) and Days 1 through 3
administer as a continuous IV infusion over 24
hours daily.

IV mesna* 0.5 g/m 2 IV bolus prior Dilute 0.5 g/m 2 bolus dose in NS (total Days 1 through 4
to each day's dose of concentration of mesna should not exceed 20
ifosfamide, then 1.5 mg/mL) and administer over 15 minutes prior to
g/m 2 IV concurrently each daily dose of ifosfamide. Dilute mesna 1.5
with ifosfamide (mix in g/m 2 dose in same 1000 mL NS bag as ifosfamide
same bag) dose and deliver over four hours.

Ifosfamide 2.5 g/m 2 per day IV After mesna bolus (500 mg/m 2), dilute with 1000 Days 1 through 4
mL NS and administer concurrently with mesna
(1.5 g/m 2) in the same bag over four hours daily.

Oral mesna 1 g/m 2 Orally at two and six hours after completion of Days 1 through 4
each day's ifosfamide infusion (round to nearest
tablet size).

Pegfilgrastim 6 mg subcutaneously Single injection. Day 6, at least 24 hours

after completing
chemotherapy

Pretreatment considerations:

Hydration Adequate hydration (at least two liters of oral or IV fluids per day) should be maintained with
ifosfamide to reduce the risk of bladder toxicity. [2]
Refer to UpToDate topic on "Cystitis in patients with cancer".

Emesis risk HIGH (>90% risk of emesis). ¶

Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting
in adults".
Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity; [3-5] its use
is avoided at some institutions.

Prophylaxis for There is no standard premedication regimen.

infusion reactions Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".

Vesicant/irritant Doxorubicin is a vesicant; avoid extravasation. Administer infusional regimens through a central
properties venous line.
Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic
vesicants".

Infection The risk of febrile neutropenia with this regimen was >20%, [1] even with primary prophylaxis with
prophylaxis granulocyte colony stimulating factor in all patients.
Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in adult patients with
chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic
syndrome, and hematopoietic cell transplantation".

Dose adjustment for In the original protocol, patients were excluded if they had a baseline total bilirubin of greater than 30
baseline liver or micromol/L (1.8 mg/dL) or a serum creatinine of greater than 120 micromol/L (1.4 mg/dL) or
renal dysfunction creatinine clearance (by Cockroft and Gault method) less than 65 mL/min. [1] A lower initial ifosfamide
dose may be needed for patients with preexisting renal or liver impairment. A lower starting dose of
doxorubicin may be needed for patients with preexisting liver impairment. [6]
Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in patients with liver
disease" and "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency:
Conventional cytotoxic agents".

Cardiac issues Doxorubicin is associated with cardiomyopathy, the incidence of which is related to the cumulative
dose. Assess baseline LVEF prior to administration. Doxorubicin is contraindicated for patients with
recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy
with high cumulative doses of doxorubicin or any other anthracyclines. [6]
 Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents".

Monitoring parameters:

CBC with differential and platelet count weekly during treatment.

Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 g/m 2. Clinical manifestations may
include hypophosphatemia, renal potassium wasting, metabolic acidosis with a normal ion gap, and rarely, polyuria due to
nephrogenic diabetes insipidus. Assess creatinine and electrolytes, including potassium and phosphate, daily during treatment
and prior to each subsequent treatment cycle.
Refer to UpToDate topic on "Ifosfamide nephrotoxicity".

Mesna does not prevent hemorrhagic cystitis in all patients. [7] Monitor a morning specimen of urine for hematuria daily, on
days 1 through 4.
Refer to UpToDate topic on "Cystitis in patients with cancer".

Monitor for neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily on
days 1 through 5. Central nervous system side effects may be especially problematic for those over age 60.
Refer to UpToDate topic on "Overview of neurologic complications of non-platinum cancer chemotherapy".

Assess liver function tests prior to each treatment cycle.

Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated.

Suggested dose modifications for toxicity:

Myelotoxicity In the original protocol, patients had to have an absolute neutrophil count greater than 2000
cells/microL and platelet count greater than 100,000/microL prior to initiating therapy. [1] The original
protocol specified a one week delay for subsequent cycles for incomplete hematologic recovery. [8] A
20% dose reduction was performed for repeated neutropenic septic episodes despite growth factor
support per protocol. [8] If the ifosfamide dose is adjusted, the mesna dose should also be modified to
maintain the mesna-to-ifosfamide ratio.

Neurologic toxicity Formal guidelines are not provided for dose reduction in the event of neurotoxicity in the United States
Prescribing Information. The original protocol recommended discontinuation of treatment for ≥grade 3
toxicity. [8] The United States Prescribing Information recommends discontinuation of treatment for
encephalopathy. [2] Some centers advocate IV alkalinization to reduce the incidence of
encephalopathy, but this is not a standard practice.
Refer to UpToDate topic on "Overview of neurologic complications of non-platinum cancer
chemotherapy".

Renal toxicity In the original protocol, treatment was discontinued if serum creatinine was >2.5 upper limit of normal
or creatinine clearance (by Cockroft and Gault method) was <60 mL/min. [8] If ifosfamide dose is
adjusted, the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio.

Bladder toxicity If microscopic hematuria (greater than 10 RBC per high power field) is present, withhold ifosfamide
until complete resolution. [2] Although formal guidelines are not available, reduced ifosfamide dose
may be needed for patients with grade 3 or worse cystitis that has not responded to increases in IV
fluids or mesna.

Cardiotoxicity In the original protocol, treatment was discontinued if LVEF dropped below 45% or if there was a drop
of >20% from baseline (confirmed three to five days later). [8]

If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen
must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the
context of individual circumstances to make adjustments, as necessary.

IV: intravenous; LVEF: left ventricular ejection fraction; CBC: complete blood count; RBC: red blood cells.
* If the patient vomits within two hours of taking a dose of oral mesna, he or she should repeat the dose or receive an IV dose of mesna (at
one-half of the dose, ie, 0.5 g/m 2). [7,9]
¶ The original protocol included only IV dexamethasone 8 mg and a 5HT3 receptor antagonist as antiemetics, and reported 78% nausea and
56% vomiting. [1]

References:
1. Judson I, et al. Lancet Oncol 2014; 15:415.
2. Ifosfamide injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov,
accessed May 12, 2014).
 3. Durand JP, et al. Ann Oncol 2007; 18:808.
4. Jarkowski A. Am J Health-Syst Pharm 2008; 65:2229.
5. Howell JE, et al. J Oncol Pharm Practice 2008; 14:157.
6. Doxorubicin hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at
dailymed.nlm.nih.gov, accessed May 12, 2014).
7. MESNA injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov,
accessed May 12, 2014).
8. Judson I, et al. Lancet Oncol 2014; 15:415. (Protocol available online at http://www.eortc.be/services/download/Protocols/62012.pdf,
accessed May 19, 2014).
9. Mesna tablets. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.gov, accessed
May 13, 2014).10.

Graphic 81370 Version 17.0

Contributor Disclosures
Robert Maki, MD, PhD Grant/Research/Clinical Trial Support: Immunocore [Medical oncology (IMCgp100
and related compounds)]; Regeneron [Medical oncology (REGN3767, REGN2810)]; Presage [Medical oncology
(CIVO device)]; Tracon [Medical oncology (TRC105)]; Lilly [Medical oncology (Olaratumab)]; Daiichi [Medical
oncology (Pexidartinib)]. Consultant/Advisory Boards: AADi [Medical oncology (Investigational agent)]; Arcus
[Medical oncology (Multiple investigational agents)]; Bayer [Medical oncology (Sorafenib, regorafenib)];
Deciphera [Medical oncology (Investigational agent)]; Janssen [Medical oncology (Trabectedin, liposomal
doxorubicin)]; Pharma Mar [Medical oncology (Trabectedin)]; Karyopharm [Medical oncology (Selinexor)];
Lilly/Imclone [Medical oncology (Olaratumab)]; SARC [Medical oncology (Multiple commercial agents under
clinical trials)]; Tracon Pharmaceuticals [Medical oncology (TRC105)]; Presage [Medical oncology (CIVO
device)]. Thomas F DeLaney, MD Nothing to disclose Diane MF Savarese, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy