NcXHF

AHMAD A. TARHINI
patients; neoadjuvant and locoregional therapeutic approaches
appear to be very promising in terms of improving the surgical
outcome and the risk of relapse and mortality.
NEOADJUVANT TREATMENT OF POTENTIALLY
RESECTABLE LOCOREGIONAL METASTASES OF
CUTANEOUS MELANOMA
Neoadjuvant therapy has improved the outcome of patients
with multiple different solid tumors, including head and
neck, breast, bladder, esophageal, and rectal cancers. 14-17
Benefıts include improvements in survival, surgical resectability,
local control, and organ preservation. Other advantages
of neoadjuvant therapy are the ability to evaluate the
clinical and pathologic responses and the potential to identify
immunologic and histologic correlates of tumor response.
Access to tumor tissue before and after neoadjuvant therapy
also may allow a better understanding of the antitumor
mechanisms of action that may enable more selective application
of therapeutic agents to those patients who are more
likely to benefıt. Such fındings would improve the therapeutic
index and cost-effectiveness of these agents. Neoadjuvant
studies of chemotherapy, BCT, and immunotherapy have
been investigated in melanoma, with several important fındings.
Table 1 provides a summary of these studies.
Neoadjuvant Chemotherapy and Biochemotherapy
Studies in Patients with Melanoma with Locoegional
Metastases
A phase II study tested neoadjuvant temozolomide (TMZ) in
chemotherapy-naive patients who had melanoma with surgically
resectable, locoregionally advanced disease. 18 Two cycles
of 75 mg/m 2 /day oral TMZ were given preoperatively for
6 weeks of every 8-week cycle. The response rate, which included
one partial response and two complete responses, was
KEY POINTS
Patients with locoregionally advanced melanoma continue
to experience a high risk of relapse and death despite the
best available standard management approaches.
Neoadjuvant biochemotherapy demonstrated high tumor
response rates but was eventually abandoned after failure
to deliver survival benefits in randomized trials of
metastatic disease.
Neoadjuvant immunotherapy with interferon alfa and
ipilimumab have yielded several important clinical and
mechanistic findings.
In drug development, biomarker and mechanistic studies
can be accelerated through neoadjuvant studies because of
the access to biospecimens before and during therapy.
Newer targeted and immunotherapeutic agents and
combinations currently are being translated into the
neoadjuvant setting at an accelerated pace and carry
significant promise.
16%. Four patients had stable disease, and 12 experienced
disease progression. Overall, the observed clinical activity
with neoadjuvant TMZ was not different from what is known
in metastatic melanoma.
Neoadjuvant BCT demonstrated high tumor response
rates in phase II studies but eventually was abandoned because
of the failure of BCT to deliver survival benefıts in randomized
trials of metastatic disease. A neoadjuvant phase II
study of concurrent BCT was conducted in patients with resectable
locoregional metastases of cutaneous melanoma
(stage III; nodal, satellite/in-transit metastases and/or local
recurrence). 19 In total, 65 patients were treated with two to
four cycles of BCT before surgery, as summarized in Table 1.
Two additional postoperative courses were given to patients
who experienced tumor response after two preoperative
courses. Among patients whose responses were assessed histologically,
a partial response was reported in 27 patients
(43.5%), and a pathologic complete remission (pCR) was reported
in 6.5%; the overall response rate was 50%. Patients
who experienced pCR had a signifıcantly lower tumor burden
(p 0.02). 19 In a second phase II study that enrolled 48
patients, two cycles of BCT were administered before and after
complete lymph node dissection using a BCT regimen
similar to the prior study. Clinical responses were observed
in 14 (38.9%) of 36 patients who had measurable disease; 13
(36.1%) experienced partial responses, and one patient
(2.8%) experienced a complete response. A pCR was noted in
four patients (11.1%). At a median follow-up of 31 months,
38 (79.2%) of the 48 patients were alive, and 31 patients
(64.6%) remained free of disease progression. 20
The phase II BCT studies indicated that neoadjuvant BCT is
clinically active in patients who have melanoma with locoregional
metastases. However, BCT has failed to demonstrate a
survival advantage versus chemotherapy alone in phase III randomized
trials in patients with stage IV disease. 21,22 Furthermore,
chemotherapies as single agents or in combinations have
not been shown to have a survival impact in patients with metastatic
melanoma. IFN alfa and interleukin-2 (IL-2) used in the
BCT regimens were administered at potentially suboptimal low
dosages; also, in combination with chemotherapy, there is the
potential for interactions of IFN alfa or IL-2 with chemotherapeutic
agents, some of which have been shown to be immunosuppressive.
23 These factors may potentially antagonize or alter
the immunotherapeutic effects of IFN alfa and IL-2. Of note, a
phase III trial of adjuvant BCT in patients with high-risk, surgically
resected melanoma (S0008) reported improved relapsefree
survival but no difference in overall survival and more
toxicity than HDI. 24
Neoadjuvant Immunotherapy Studies
Several observations support the adjuvant and neoadjuvant
evaluation of immunotherapeutic agents in patients with
surgically resectable melanoma at high risk for death as a result
of melanoma recurrence. Host immune resistance of
melanoma plays a key role in disease control in the adjuvant
and advanced disease settings and appears to have important
implications for neoadjuvant immunotherapy of patients
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