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Thalidomide in Solid Tumors: The London Experience

Thalidomide in Solid Tumors: The London Experience

ABSTRACT: Investigators at the Royal Marsden Hospital and University College in London have studied thalidomide (Thalomid) as both low-dose (100 mg orally, every night) and high-dose (600 mg, given as 300 mg twice per day) therapy for patients with a variety of solid tumors. In the phase II low-dose study, responses were disappointing in patients with melanoma, ovarian cancer, and breast cancer. Results for patients with renal-cell carcinoma were more encouraging. A case study of a patient with metastatic renal-cell carcinoma in the lung and lymph nodes in the low-dose thalidomide study illustrates that (1) responses may be very slow; (2) the palliative response is separate from the overall response, occurs much earlier, and is not consistent with an antiangiogenic action; and (3) peripheral neuropathy is a manageable side effect. Besides peripheral neuropathy, patients can experience severe constipation (even on low doses) as well as headache, edema, and skin rash for which treatment recommendations can be made. Anecdotal benefits of thalidomide include enhanced or maintained appetite, improved sleeping, and reduced sweating. The high-dose study has been submitted for publication. [ONCOLOGY 14(Suppl 13):17-20, 2000]

Introduction

Tumors secrete growth factors that help them to grow and
metastasize.[1] Some of these factors are angiogenic, some immunomodulatory, and
several fall into both categories.[2] Angiogenesis is an important new target
for anticancer drugs. As shown in Figure 1,
thalidomide (Thalomid) may interfere with the expression or release of several
angiogenic factors,[3-6] including tumor necrosis factor-alpha (TNF-alpha) and
interleukin-6 (IL-6), from renal carcinoma cells, and may interfere indirectly
with vascular endothelial growth factor (VEGF) and basic fibroblast growth
factor (bFGF).[7,8]

These factors may stimulate cell growth in a paracrine or
autocrine manner.[9] For example, the combined activity of TNF-alpha and IL-6 is
quite potent as an autocrine and paracrine growth factor, at least in vitro. A
number of patients with renal cell carcinoma appear to have metastatic bone
disease and little or no disease in other soft tissue. It is interesting to
speculate that IL-6 may be an important factor in this pattern of disease, since
it is often expressed at high levels in bone.

Data are also accumulating for thalidomide’s effects on growth
factor suppression and immunomodulation.[10]

Low-Dose Study

Earlier this year, we published data in the British Journal of
Cancer, reporting on work done primarily at the Royal Marsden Hospital.[11] The
study investigated the use of low-dose thalidomide (100 mg orally, every night)
in patients with a variety of advanced malignancies, including melanoma,
renal-cell carcinoma, ovarian, and breast cancers. The aims of the study were to
assess the toxicity and gain an early indication of the efficacy of continuous
low-dose thalidomide. We also attempted to assess biological responses by serial
measurements of TNF-alpha, VEGF, and bFGF concentrations in stored serum
samples.

Thalidomide was administered on a continuous schedule rather
than a shorter, higher-dose regimen because data suggest that an antiangiogenic
agent may have optimum effect if given over a long period. Using thalidomide
over a long period, however, increases the risk of peripheral neuropathy.[12] We
therefore started our study at an extremely cautious dose of 100 mg every night.

Patients and Methods

All patients in the study had histologically confirmed,
measurable, progressive disease. None of them had had any anticancer therapy,
including surgery, in the previous 4 weeks because of our concern that patients
receiving thalidomide might have some interference with their ability to heal
after surgery. Using our standard criterion, women of childbearing age agreed to
use adequate contraception for the duration of the study and for 6 months
afterwards. Patients showing any signs of peripheral neuropathy were excluded to
avoid exacerbation.

Patients were assessed initially and at 1 month, then at 3, 6,
9, and 12 months, until they showed evidence of disease progression or they
experienced unacceptable toxicity. Assessments included full blood count, serum
biochemistry, and the sensory nerve action potential (SNAP) test for peripheral
neuropathy. We also froze serum and urine for later enzyme-linked immunosorbent
assay (ELISA) of biomarkers (bFGF, VEGF, and TNF-alpha). We also asked patients
to complete symptom distress scales (Hospital Anxiety and Depression [HAD] and
Rotterdam scores).

A total of 66 patients (37 women and 29 men; median age: 48
years, range: 33-62 years) with advanced measurable cancer (19 ovarian, 18
renal, 17 melanoma, 12 breast cancer) were enrolled in the study (Table
1
). Several patients had poor performance status and most had received
cancer treatment prior to enrollment.

Complete response was defined as the disappearance of all known
disease determined by two observations not less than 4 weeks apart. Partial
response was defined as a decrease by at least 50% of the sum of the products of
the largest perpendicular diameters of all measurable lesions as determined by
two observations not less than 4 weeks apart.

Progressive disease was defined as a more than 25% increase in
the size of the lesion or the appearance of a new lesion. Stable disease was
defined as where there had been a less than 50% decrease and a less than 25%
increase in the sum of products of the largest perpendicular diameters of all
measurable lesions for two observations not less than 4 weeks apart.

Results

Three partial responses were seen in the 18 patients with
renal-cell carcinoma. Two of these patients had had extensive pretreatment. One
response lasted 5 months, and the other two partial responses continued after 5
and 11 months of follow-up. Thirteen patients with renal-cell carcinoma
experienced stabilization of their previously progressive disease. Three had
stable disease for 3 months or longer; 10 had stable disease for only 1 to 3
months.

Objective results (partial response or stable disease) in the
remaining 48 patients were disappointing. However, three patients had a
differential response; one patient with rapidly progressive skin deposits of
melanoma on his leg experienced symptomatic improvement and was able to walk
more than 100 yards, having been previously confined to a chair. Thalidomide may
be of more interest as part of a multiple modality regimen in melanoma.

Of 15 patients who completed serial HAD and Rotterdam scores, 11
experienced improvements in sleeping and 14 experienced a maintained or enhanced
appetite. Both findings were statistically significant (P < .05), although
based on a small number of patients.

Case Report

One patient’s case serves to illustrate the results of our
low-dose study. This man had progressed on treatment for renal-cell carcinoma,
with deteriorating performance status 2 months after receiving a combination of
interleukin-2 (IL-2), interferon alfa, and fluorouracil. He had several large
pulmonary and lymph node mestastases and had developed increasingly severe night
sweats and weight loss.

The patient was started on 100 mg of thalidomide at night. At
his first assessment at 1 month, he denied feeling any different. However, his
wife said that he was, in fact, a changed man. The patient’s appetite had
returned, his sweats had stopped, and he was more active. Over the next 4 months
of treatment with thalidomide he had a gradual disease response, which resolved
to a single residual lung mass in the right lung showing only necrotic tissue on
bronchoscopy.

It is well recognized that rarely, spontaneous or late responses
to immunotherapy may be seen in patients with renal-cell carcinoma. This is
unlikely to be the explanation for this man’s response for two reasons: first,
the patient had rapidly progressive disease following biochemotherapy, and
second, he obtained significant palliative benefit within a short time of
starting thalidomide.

After 9 months in the study, a SNAP test detected peripheral
neuropathy and the thalidomide was stopped, according to the study protocol. The
patient did not want to stop treatment then because he was feeling much better
and had not noticed the peripheral neuropathy. After 1 month without
thalidomide, his SNAP improved and he was restarted at a lower dose (50 mg). He
developed peripheral neuropathy again after a month, at which time treatment was
stopped. Eleven months later progressive disease was noted in the right lung.
Restaging showed no evidence of relapsed disease at other sites and a
pneumonectomy was performed. The patient remains well now, 3 years after
starting thalidomide.

This case illustrates several points. First, responses to
thalidomide may be slow. Second, the palliative response is separate from the
objective tumor response, and is much faster and not consistent with an
antiangiogenic action. Third, although peripheral neuropathy is a problem, it
can be managed safely by appropriate dose reduction and where necessary,
cessation of treatment. Fourth, responses and palliative benefit may be obtained
in patients with metastatic renal-cell carcinoma who have progressed on
immunotherapy.

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