| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
2b in the Treatment of Symptomatic Advanced Medullary Thyroid Carcinoma
Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II (G.V., P.T., E.R., A.C., A.R.B., G.L.), and Dipartimento di Biochimica e Biofisica, II Università di Napoli (M.C., A.A.), 80131 Naples, Italy
Address all correspondence and requests for reprints to: Prof. Giovanni Lupoli, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Via Pansini 5, 80131 Naples, Italy. E-mail: lupoli{at}unina.it
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
2b in
seven patients with advanced and symptomatic medullary thyroid
carcinoma. The frequency and intensity of daily flushing episodes and
bowel movements, the intensity of fatigue, weight, performance status,
calcitonin levels, and change in tumor masses were recorded before and
during treatment. No objective complete or partial responses were
recorded. However, disease stabilization and minor tumor regression
were observed in three of seven and two of seven patients,
respectively. The number and intensity of bowel movements and flushing
episodes decreased in five of six and two of two patients,
respectively. Decrease in fatigue and improvement in performance status
were observed in five of seven and six of seven patients, respectively.
Weight gain was recorded in three of four patients. Plasma levels of
calcitonin decreased significantly in six of seven patients. Clinical
benefit, evaluated by a structured algorithm, was achieved in six of
seven patients and was coupled with a decrease of 50% or more in serum
calcitonin levels in three of seven patients. In conclusion, the
combination of lanreotide with interferon had a major impact on
clinical symptoms and was well tolerated. |
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Different mechanisms can contribute to the tumor growth inhibitory effects of SMS analogs: inhibition of the release of mediators promoting growth, inhibition of angiogenesis, modulation of immunological activity, and direct antimitotic effects via SMS receptors on the tumor cells (6, 7, 8). The antitumor activity of SMS analogs often results in a symptomatic response in several neuroendocrine tumors. In fact, hormone hypersecretion and the related symptoms can be controlled by octreotide treatment in acromegaly, carcinoid, and some gastroenteropancreatic tumors (9, 10, 11, 12, 13, 14).
The therapeutic effects of octreotide have also been investigated in medullary thyroid carcinoma (MTC). Mahler et al. reported an improvement in symptoms (diarrhea, weight loss, and malaise) and a decrease in calcitonin (CT) levels in 3 of 3 patients treated with octreotide (15). Modigliani et al. administered octreotide to 14 patients with MTC. No significant improvement in diarrhea or flushing was observed; a beneficial effect on asthenia was obtained in 8 cases. CT levels decreased in 4 patients. An objective antitumoral effect was observed in only 1 patient (16).
The poor effects of SMS analogs on tumor burden and the need to
increase the symptom-relieving activity of such agents suggest that SMS
analogs should be combined with other anticancer agents in the
treatment of neuroendocrine tumors. We have reported that a combination
of octreotide and recombinant interferon- type 2b (rIFN-2b) is an
active treatment for advanced MTC. This combination led to the
stabilization of the disease, an improvement in tumor-associated
symptoms, and a decrease in the serum levels of CT and carcinoembryonic
antigen in all six patients (17).
Patients treated with octreotide usually receive two or three daily injections of the drug. To avoid multiple daily injections or the need for portable pumps, new formulations of SMS analogs have been recently developed. Lanreotide is a new cyclic octapeptide analog of SMS that is available in a slow release form thanks to the presence of microspheres containing polylactide-polyglycolide copolymer (18, 19, 20, 21).
In the present study we evaluated the toxicity profile, the antitumor
activity, and the symptom-relieving activity of the lanreotide depot in
combination with rIFN-2b in patients with advanced and symptomatic
MTC. Furthermore, we have attempted to define the effectiveness of the
treatment by a structured algorithmic approach.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Seven patients, three men and four women, ranging in age from
29–57 yr (mean ± SD, 43.86 ± 11.17 yr), with
symptomatic and advanced MTC were enrolled in this study. All patients
presented a sporadic form of MTC. The following criteria were required
for study selection: absence of symptomatic hearth disease and
gallstones, absence of significant ascites or other third space fluid
collection, normal liver and kidney biochemistry (total bilirubin,
1.5 mg/dL; aspartate aminotransferase and alanine aminotransferase,
3 times the normal limit; prothrombin and partial thromboplastin,
1.5 times the normal limit; creatinine, 1.2 mg/dL), adequate
hematological functions (white blood count,
4,000/mm3; platelet count,
120,000/mm3), a washout time of at least 4
weeks from any previous treatment with antitumor agents (chemotherapy,
biological therapy, and radiotherapy) and with drugs capable of
interfering with the evaluation of symptoms induced by the tumor and by
the toxicity of lanreotide and rIFN- (antidiarrheals, analgesics,
corticosteroids, antiemetics, and antipyretics), and expression of SMS
receptors in the tumor, demonstrated by positive
111indium-diethylenetriamine pentaacetic
acid-D-Phe1-octreotide scintigraphy.
All patients had previously undergone total thyroidectomy and lymphadenectomy. All of them presented nonresectable MTC, loco-regional and/or distant metastases (three patients with mediastinal metastases; one patient with mediastinal, pulmonary, and hepatic metastases; one patient with hepatic and pulmonary metastases; one patient with skeletal metastases; one patient with pulmonary and cervical metastases). Persistent and refractory diarrhea was observed in six patients, flushing episodes in two cases, and weight loss and fatigue in four and five patients, respectively. All patients had high plasma CT levels.
Treatment schedule
Slow release lanreotide (Ipsen, Milan, Italy) was
administered in a 30-mg im injection every 14 days for the first 6
months; the injection interval was then shortened from 14 to 10 days
for 6 more months. One month after the beginning of lanreotide
treatment, rIFN-2b (Schering-Plough Corp., Milan,
Italy) was administered im in doses of 5,000,000 IU three times
a week. The combined treatment was given for 11 consecutive months.
The protocol was approved by the institutional Review board. All patients gave informed consent according to institutional guidelines at the beginning of the therapy, and all treatments were self administered as home therapy.
Effectiveness evaluation
All patients underwent clinical examination at the beginning of the study and monthly during the therapy. Each visit included complete physical examination, evaluation of side-effects, assessment of tumor symptoms and Karnofsky performance status (KPS), weight measurement, determination of CT values, and routine biochemical profile. The toxicity of biological therapy was reported according to WHO grade (22). The frequency and intensity of daily flushing episodes and bowel movements, and the intensity of fatigue were calculated as the mean of the daily values for the 7 days preceding the visit. The intensities of flushing, diarrhea, and fatigue were self assessed by patients using three different 100-mm linear analog scales (0 = no flushing at all, 100 = the worst flushing; 0 = no diarrhea at all, 100 = the worst diarrhea; 0 = no fatigue at all, 100 = a great deal of fatigue). KPS was determined by two independent observers at baseline and then monthly thereafter. In the case of discrepancy between scores, the lower of the two values was used. CT levels were measured by an immunoradiometric, commercially available kit (Diagnostics Systems Laboratories, Inc., Webster, TX); intra- and interassay coefficients of variation were compatible with the criteria of validation of methods.
In all patients clinical benefit and tumor marker (biochemical)
response were evaluated according to a specific algorithm (Fig. 1
), which is based on the response to the
biological therapy of hormone-related symptoms (diarrhea and flushing),
general symptoms (fatigue and weight loss), KPS, and serum CT
levels.
|
The algorithm is based on the comparison between pairs of parameters
(Fig. 1
). If at least one parameter was negative, then the overall
category was considered to be negative. If one of the two parameters
was positive and the other was not negative or absent before the start
of and during the therapy, the overall category was considered
positive. If both parameters were stable or one was stable and the
other was absent before the start of and during the therapy, then the
overall category was considered stable. Therefore, patients were
considered to achieve symptom relief if a positive evaluation for at
least one hormone-related symptom or one general symptom had been
obtained, and if they had not been rated negative for any of the other
symptoms. A clinical benefit response was reached for the patients who
showed a positive classification for KPS or symptom relief without the
other parameter being negative. When symptom control occurred together
with a positive classification for CT levels, a clinical benefit and a
biochemical response were reached.
Disease staging was performed before the beginning of the treatment and then every 6 months throughout the treatment by chest x-ray, neck and abdominal ultrasound, technetium-99m diphosphonate bone imaging, total body computerized tomography and/or magnetic resonance, and response according to the WHO criteria (23).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
2b are summarized in Table 1. The
combined treatment was well tolerated, and only minor adverse events
were recorded (Table 1). Transient (1–2 days) erythema at the
injection site of lanreotide was reported in patients 4 and 7. The
induction of transient diarrhea for 1–2 days after lanreotide
injection was observed in patient 5 during the first 2 months of
therapy. Asymptomatic biliary sludge in the gallbladder was found on
ultrasound examination in patient 4 after 6 months of therapy. During
the first few days of rIFN-2b treatment, fever (WHO grade I–II)
occurred in patients 1, 2, 4, and 7. This symptom was always controlled
with paracetamol. Patients 2 and 3 experienced transient myalgia judged
as mild. Nausea was noted in patient 2, and transient vomiting occurred
in patient 5. Mild leukocytopenia occurred in patient 6. Side-effects
were never such as to stop the treatment in this series of
patients.
|
Table 2 describes the effects of
lanreotide and rIFN-2b combined treatment on diarrhea, flushing,
fatigue, weight loss, and KPS. A reduction in the number of bowel
movements was observed in five of six patients. The intensity of
diarrhea also decreased in five of six patients; two of them achieved
complete disappearance of the symptom. Two of two patients with
flushing experienced a decrease in frequency and intensity. In one of
these two cases the flushing disappeared completely. Amelioration of
fatigue was recorded in five of five patients. During treatment weight
gain was detected in three of four patients. An improvement in KPS was
observed in six of seven patients.
|
).
Subsequently, CT values increased in all patients. Therefore, after 12
months the CT level variations from the basal values were -22%,
-57%, +53%, -34%, -27%, and -31%, respectively. In patient 7,
CT levels increased during the therapy and after 12 months the CT level
variation from the basal value was +60%.
|
. Five of seven patients
(71%) and six of seven patients (86%) were classified as positive,
respectively, for hormone-related symptoms and general symptoms. Six of
seven patients (86%) achieved symptom relief. Four of seven (57%) and
two of seven patients (29%) were, respectively, positive and stable
for KPS. Therefore, six of seven patients (86%) were classified as
clinical benefit responders. Taking into account CT values, three of
seven patients (43%) achieved the clinical benefit and biochemical
response. |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Antiproliferative effects have also been observed in preclinical models, but tumor regression is less common than symptom control in patients treated with SMS analogs. In fact, major tumor responses (decrease of 50% or more in all tumor lesions) have been recorded in only 10% of the cases treated. However, several studies have shown that in a large number of patients treated with SMS analogs, the disease does not progress for several months (12, 26).
In the last few years, SMS analogs have been used in neuroendocrine
tumors in combination with other biological agents. Several studies
have investigated the clinical activity of the octreotide and IFN-
combination. In a case report, Joensuu et al. described a
patient, affected by carcinoid syndrome, who was in the terminal phase
of his disease when treated with IFN- alone. However, he experienced
a dramatic response, leading to the disappearance of all symptoms,
normalization of serum tumor markers, stabilization of tumor mass, and
restoration of his normal lifestyle when octreotide was added to
IFN- (27). A similar effect was subsequently described in a larger
study, in which 24 patients with metastatic carcinoid tumors received
octreotide. When response to the SMS analog did not occur, IFN- was
added. A normalization of serum tumor markers was recorded in 4 of 22
cases (18%), a reduction in serum tumor markers by 50% or more was
found in 13 of 22 (59%) patients, and a symptom improvement was noted
in 10 of 18 patients (56%). The disease remained stable in 15
patients. Nine of 17 patients responding to IFN- addition had
previously been treated with IFN- alone, but they showed tumor
progression or suffered from severe side-effects. Therefore, the
combined treatment did not lead to any significant reduction in tumor
mass, but had a significant effect on clinical symptoms and circulating
tumor markers and was also better tolerated than both agents
administered separately (28).
We first used the combination of rIFN-2b and octreotide in advanced
MTC. Six patients were administered octreotide (150 µg/day, sc, for 6
months and 300 µg/day for another 6 months) and rIFN-2b (5 mU, im,
three times a week) for 12 months. No significant change in tumor
lesions was observed. An amelioration in diarrhea and flushing was
recorded together with a decrease in serum CT and carcinoembryonic
antigen levels in all patients. The treatment was well tolerated in all
patients (17).
In the present study we have investigated the clinical activity of the
combination of slow release lanreotide and rIFN-2b in advanced and
symptomatic MTC. Six patients presented refractory diarrhea, not
responding to standard antidiarrheal preparations in conventional
dosages (loperamide up to 10–16 mg/day), and two patients reported
flushing. The number and intensity of diarrhea and flushing episodes
decreased in five of six and two of two patients, respectively, during
the treatment with lanreotide and rIFN-2b. Refractory diarrhea and
flushing episodes completely resolved in two and one patients,
respectively. An amelioration in fatigue, weight loss, and KPS was also
observed during biological therapy. Although no major tumor regression
was recorded in our patients, we observed a decrease in CT levels in
six of seven patients, five of whom remained free from progression. Two
of these patients experienced a reduction in tumor mass inferior to
less than 50% without the occurrence of new lesions (minor responses).
Lanreotide and rIFN-2b were well tolerated, and a progressive
reduction of side-effects occurred during treatment. Moreover, the use
of depot formulation of lanreotide, given every 10–14 days, strongly
reduced the number of injections compared to the octreotide formulation
used in the previous series (3 vs. 90 monthly injections),
increasing compliance with the treatment.
A clinical benefit response in symptomatic pancreas cancer has been defined to provide a systematic approach to evaluate the treatment effectiveness in a tumor poorly responsive to therapy in terms of cancer burden (29, 30, 31). In the same way, we have attempted to define an algorithmic approach for MTC to identify the patients who responded to the treatment in terms of tumor-related symptoms and hormone secretion. Clinical benefit is a valid parameter to assess the effectiveness of the therapy on tumor-related symptoms. However, it cannot completely account for the direct activity on the secreting functions of MTC. In fact, symptom-relief induced by SMS analogs could also be due to the drug activity on target organs, such as the bowel. Therefore, to evaluate the direct antitumor and antisecreting activities, we considered, in the case of MTC, the end point of clinical benefit and biochemical response, which includes the control of symptoms and a remarkable reduction in CT levels. According to our algorithmic evaluation, six of seven (86%) patients with MTC could be considered clinical benefit responders. After further comparison with response on CT tumor secretion, three of seven (43%) patients could be upgraded to clinical benefit and biochemical response.
In conclusion, in this series of patients the combination of rIFN-2b
and lanreotide depot has significantly contributed to the management of
advanced and symptomatic MTC. An advantage of our schedule is provided
by use of the long acting lanreotide formulation, which avoids the
discomfort of repeated injections. Moreover, we propose an algorithmic
evaluation of the response, because the availability of unbiased,
strict, and objective criteria with valid interobserver possibility of
reproducibility is mandatory for multiinstitutional studies of rare
diseases, such as MTC. This rigorous approach could be useful in future
trials to make a comparison between the effects of lanreotide used on
its own and those produced by the combination of rIFN-2b and
lanreotide.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received July 1, 1999.
Revised November 4, 1999.
Accepted November 11, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-2b and octreotide. Cancer. 78:1114–1118.[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  F. Tagliati, M. C. Zatelli, A. Bottoni, D. Piccin, A. Luchin, M. D. Culler, and E. C. degli Uberti Role of Complex Cyclin D1/Cdk4 in Somatostatin Subtype 2 Receptor-Mediated Inhibition of Cell Proliferation of a Medullary Thyroid Carcinoma Cell Line in Vitro Endocrinology, July 1, 2006; 147(7): 3530 - 3538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Zatelli, D. Piccin, F. Tagliati, A. Bottoni, A. Luchin, C. Vignali, A. Margutti, M. Bondanelli, G. C. Pansini, M. R. Pelizzo, et al. Selective Activation of Somatostatin Receptor Subtypes Differentially Modulates Secretion and Viability in Human Medullary Thyroid Carcinoma Primary Cultures: Potential Clinical Perspectives J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2218 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Vitale, W. W. de Herder, P. M. van Koetsveld, M. Waaijers, W. Schoordijk, E. Croze, A. Colao, S. W.J. Lamberts, and L. J. Hofland IFN-{beta} Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro Cancer Res., January 1, 2006; 66(1): 554 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Kaltsas, G. M. Besser, and A. B. Grossman The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors Endocr. Rev., June 1, 2004; 25(3): 458 - 511. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
