3099
`
`Treatment of Metastatic Carcinoids and
`Other Neuroendocrine Tumors with
`Recombinant Interferon-Alpha-2a
`A Study by the Italian Trials in Medical Oncology Group
`
`Emilio Bajeffa, M.D., Nicoleffa Zilembo, M.D., Maria Di Barfolomeo, M.D.,
`Angelo Di Leo, M.D., Silvana Pilotfi, M.D., Anna Maria Bochicchio, M.D.,
`Rita Castellani, M.D., Roberto Buzzoni, M.D., Luigi Celio, M.D.,
`Luigi Doglioffi, M.D., Gabriella Pinotti, M.D., Enrico Aitini, M.D.,
`Roberfo Labianca, M.D., Adriano Fornasiero, M.D., Piefro Riva, M.D.,
`Giuseppe Schieppafi, M.D., Patrizia Nelli, and Luigi Mariani, M.D.,
`for the Italian Trials in Medical Oncology (ITMO) Group, ITMO Scientific Service
`
`Background. Using a wide range of interferon (IFN)
`doses and schedules, a number of authors have found
`them to be active against neuroendocrine tumors.
`Methods. To verify the clinical activity of IFN, 49
`evaluable patients with advanced stage low- and inter-
`mediate-grade neuroendocrine tumors were treated with
`
`Presented in part at the 28th Annual Meeting of the American
`Society of Clinical Oncology, San Diego, California, May 17-19,
`1992.
`From the Istituto Nazionale per o Studio e la Cura dei Tumori,
`Milan, Italy.
`The following investigators participated in this study: Marco At-
`tard, M.D., Ospedale Cervello, Palermo; Mario Barduagni, M.D., Isti-
`tuto Regina Elena, Roma; Francesco bell^, M.D., Ospedale Regionale,
`Bolzano; Franco Buzzi, M.D., Ospedale S. Maria, Terni; Modesto
`D’Aprile, M.D., Ospedale S. Maria Goretti, Latina; Elvira De Marino,
`M.D., Ospedale Vito Fazzi, Lecce; Cosimo Epifani, M.D., Ospedale S.
`Anna, Como; Gabriella Farina, M.D., Ospedale Fatebenefratelli, Mi-
`lano; Pier Paolo Fattori, M.D., Ospedale degli Infermi, Rimini; Bruno
`Ferrero, M.D., Casa Cura Villa Gerani, Trapani; Vinicio Fosser, M.D.,
`Ospedale S. Bortolo, Vicenza; Antonio Iirillo, M.D., Ospedale Civile,
`Legnago, Verona; Vito Lo Russo, M.D., Istituto Oncologico, Bari; Giu-
`seppe Maifredi, M.D., Ospedali Riuniti, Bergamo; Paola Merozzi,
`M.D., Ospedale Cervello, Palermo; Felice Pasini, M.D., Ospedale Ci-
`vile, Verona; Enrico Luigi Sarti, M.D., Ospedali Riuniti, Bergamo;
`Albert0 Scanni, M.D., Ospedale Fatebenefratelli, Milano; Claudio
`Verusio, M.D., Milano; Eugenio Villa, M.D., 1st Scient. S. Raffaele,
`Milano; and Moscatelli Giovanni Ospedale Bufalini, Cesena, Foeli,
`Italy.
`The authors thank Dr. K. Oberg for reviewing the manuscript
`and Hoffman La Roche for providing interferon-alpha-2a.
`Address for reprints: Emilio Bajetta, M.D., Division of Medical
`Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, via
`Venezian 1, 20133 Milan, Italy.
`Accepted for publication June 28, 1993.
`
`recombinant IFN-alpha-Za at a daily dose of 6 X lo6 IU
`intramuscularly for 8 weeks, and 3 times weekly thereaf-
`ter. The predominant histotype was carcinoid, although
`a few cases had malignant islet cell tumors, medullary
`thyroid carcinoma, Merkel cell carcinoma, or other neu-
`roendocrine tumors. All of the patients had measurable
`lesions and most had multiple sites. Carcinoid syndrome
`was present in 14 cases.
`Results. After a median treatment duration of 6
`months, complete regression was achieved in 1 of the 7
`cases of medullary thyroid carcinoma, and partial re-
`sponse was observed in 4 of 34 carcinoids. Response dura-
`tion ranged from 1-11 months. Control of the syndrome
`was obtained in nine patients and a greater than or equal
`to 50% reduction of 5-hydroxyindoleacetic acid in eight
`patients. The treatment was well-tolerated. The most fre-
`quently observed side effects were fever, flu-like syn-
`drome, and leukopenia. After 1 2 months of recombinant
`IFN-alpha-Za, 15 cases in progression and 4 with stable
`disease or partial response received another treatment
`(either radiometabolic therapy with 113* metaiodobenzyl-
`guanidine or polychemotherapy with streptozotocin plus
`epirubicin).
`Conclusions. The use of recombinant IFN-alpha-Za
`at these doses is well-tolerated and effective in control-
`ling carcinoid syndrome (complete remission plus partial
`remission, 64%), although it has limited activity on tu-
`mor growth inhibition. No definitive data can be given
`for the other protocol treatments. Cancer 1993; 72:
`3099-105.
`
`Key words: carcinoid tumor, neurosecretory system, in-
`terferon-alpha-Za, biologic tumor markers.
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 1 of 7
`
`

`

`3100
`
`CANCER November 15, 2993, Volume 72, No. 10
`
`Neuroendocrine neoplasms make up a large, heteroge-
`neous spectrum of lesions whose common denominator
`is a histopathologic "organoid" growth pattern, the ar-
`gyrophilia of the cells, the immunocytochemical detec-
`tion of endocrine markers, and the ultrastructural evi-
`dence of secretory granules. Their heterogeneity is a
`result of differences in their histogenesis, structure,
`functional activity, and clinical behavior. Carcinoid tu-
`mors are the most frequent neuroendocrine neoplasms
`and account for 0.05-2.09'0 of all tumors.',' According
`to the World Health Organization clas~ification,~ the
`term carcinoid refers to tumors of the diffuse endocrine
`system, excluding those of the pancreatic islets and
`medullary thyroid carcinomas (MTC). In Italy, the inci-
`dence of carcinoid tumors accounts for 13% of all small
`bowel tum01-s.~ Clinical outcome is related to tumor pro-
`gression and the symptoms induced by some sub-
`stances secreted by the tumor itself. Tumor progression
`often leads to the onset of liver metastasis, lymph nodes
`and lung being other frequent sites of involvement. It is
`the release of serotonin, tachykinin, and bradykinin
`from the neoplasm that causes the carcinoid syndrome,
`and 24-hour urinary 5-hydroxyindoleacetic acid (5-
`HIAA), the metabolite of serotonin, is an appropriate
`marker for following the effectiveness of treatment or
`disease progression.
`Surgery is the treatment of choice for local disease,
`but systemic therapy is required during the progressive
`metastatic phase or in the presence of uncontrolled hor-
`monal symptoms. The goal of medical treatment is to
`inhibit tumor growth and control the clinical symptoms
`due to hormonal secretion. The results of chemother-
`apy studies are discordant. Moerte15 reported a re-
`sponse rate of 26% when fluorouracil was used in cases
`of malignant carcinoid tumors. Streptozotocin (STZ)
`alone has been shown to be active against islet cell carci-
`noma,6 although polychemotherapy is responsible for
`the highest response rates.7,* In carcinoid tumors, no
`clear advantage for the use of combined drugs has been
`documented. 9-11
`In an attempt to improve both tumor control and
`symptom relief, other treatment approaches using non-
`cytotoxic agents, such as interferons (IFN), have been
`adopted. Although the antineoplastic mechanisms of
`IFN are not fully known, alpha-interferon has been
`shown to have inhibitory effects on oncogene expres-
`sion, DNA replication, and protein synthesis. Tumor
`cell division is mainly blocked in the Go-G, phase, but a
`definite cytotoxic effect has not yet been demonstrated;
`control could also be indirect and occur through the
`activation of the immunoregulatory sy~tem.'~,'~
`On the basis of these biologic data, various authors
`have already investigated the clinical activity of a wide
`range of different doses and schedules of IFN in neuro-
`
`endocrine tumor^.'^-'^ Given that no definitive conclu-
`sions have yet been drawn as far as the antitumor activ-
`ity and proper dose of IFN are concerned, it was de-
`cided to test the activity of recombinant IFN-alpha-2a
`(rIFN-alpha-2a) using an original schedule adminis-
`tered for a maximum of 12 months.
`
`Patients and Methods
`
`Patients
`
`The 53 patients entering this ITMO Group study came
`from 23 different centers, coordinated by the Division
`of Medical Oncology B, Istituto Nazionale Tumori, Mi-
`lan, Italy. To be included, the patients had to have histo-
`logic diagnosis of carcinoid or other neuroendocrine tu-
`mor with progressive metastatic disease. In cases of his-
`tologic uncertainty, the Division of Pathology, Istituto
`Nazionale Tumori, undertook pathologic reviews. In all
`cases, diagnosis was based on the examination of tis-
`sues routinely fixed on hematoxylin and eosin stained
`slides without immunocytochemical phenotyping. Pre-
`treatment with surgery and/or limited radiation ther-
`apy fields was allowed, as was any previous chemother-
`apy discontinued for more than 1 month (excluding
`STZ and anthracyclines). None of the patients had pre-
`viously received any biologic response modifiers, and
`all of them had to be younger than or equal to 78 years
`of age and have a performance status less than or equal
`to two (Eastern Cooperative Oncology Group scale).
`Adequate renal (serum creatinine < 1.5 mg/dl), hepatic
`(bilirubin < 3 mg/dl), and hematologic functions
`(white blood count 2 4000/mm3 and platelet count 2
`120,000/mm3) were also required, and at least one le-
`sion had to be measurable. The exclusion criteria were
`the presence of severe concomitant illness, active heart
`disease, and a life expectancy of less than 3 months
`with rapidly progressive life-threatening metastases.
`The nature of the program was explained to each
`patient, and informed consent was obtained according
`to the standard procedures followed by each of the
`participating institutions. The staging procedures per-
`formed before starting therapy included physical exami-
`nation, a biochemical profile, chest X-ray, electrocar-
`diogram, and abdominal ultrasound/computed tomog-
`raphy scan; additional procedures (percutaneous liver
`biopsy, laparoscopy, gastrointestinal series) were used
`according to each clinical presentation.
`
`Tumor Marker Analysis
`
`The level of 5-HIAA was evaluated by means of high-
`performance liquid chromatography of a 24-hour urine
`sample. Calcitonin, human chorionic gonadotropin
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 2 of 7
`
`

`

`Treatment of Neuroendocrine TumorslBajetta et al.
`
`beta subunit, and neuron-specific enolase (NSE) serum
`levels were determined by radioimmunoassay. Serum
`samples, drawn immediately before the start of treat-
`ment and every 2 months thereafter, were collected in
`ordinary plastic tubes, frozen, and stored at -20°C.
`
`Treatment
`
`Patients received rIFN-alpha-2a (Roferon-A, Hoffman
`La Roche Basel, Switzerland) at a daily dose of 3 X lo6
`IU for the first 3 days. The dose was then increased to 6
`X lo6 IU, administered daily for the first 8 weeks and
`three times per week thereafter. The rIFN-alpha-2a was
`given intramuscularly into one of the gluteus muscles.
`Patients were admitted to the hospital for the beginning
`of treatment; the drug was then self-administered in an
`outpatient setting, the patients being carefully moni-
`tored to ensure they took it regularly. At the time of
`every response evaluation, the physician questioned
`the patient directly and, during physical examination,
`special care was taken to investigate injection sites. Al-
`lowance was made for dosage reduction or treatment
`interruption in the event of persistent or severe toxicity,
`classified according to World Health Organization
`grading. Acetaminophen was routinely used for pallia-
`tion of fever and myalgia. Therapy continued until ob-
`jective tumor progression or for a period of 12 months.
`In the presence of persistent disease, patients received a
`different treatment. Radiometabolic therapy with 113'
`metaiodobenzyl-guanidine was activated in cases
`where an intensive scan uptake correlated with disease
`extension. In other cases, polychemotherapy with STZ
`(500 mg/m2 intravenously on days 1, 2, and 3) plus
`epirubicin (75 mg/m2 intravenously on day 1) was ad-
`ministered. The cycles were repeated every 3 weeks.
`
`Evaluation of Response
`
`History, physical examination, hemogram, blood bio-
`chemistry, and tumor measurement by ultrasound/
`computed tomography and radiograph were performed
`every 2 months. Flushing and diarrhea were checked
`monthly. The intensity of clinical symptoms was as-
`sessed by means of a three-grade scale (mild, moderate,
`and severe), and the number of flushing and/or diar-
`rhea attacks was recorded. Three categories of response
`were assessed: (1) tumor, (2) biochemical, and (3) symp-
`tomatic. Tumor response was defined according to In-
`ternational Union Against Cancer criteria: complete re-
`mission (CR), defined as complete disappearance of all
`known disease for a minimum of 1 month; partial re-
`mission (PR), defined as greater than or equal to 50%
`decrease in the sum of the products of the two largest
`perpendicular diameters of all tumor masses for at least
`
`Table 1. Patient Characteristics
`Characteristic
`Evaluable
`M/F
`Age (yr)
`Median
`Range
`Performance status 0-1
`Carcinoid syndrome
`Flushing
`Diarrhea
`Flushing and diarrhea
`Abnormal urinary 5-hydroxyindoleacetic
`acid excretion
`Histologic type
`Carcinoid
`Malignant islet cell tumors
`Medullary thyroid carcinoma
`Merkel cell carcinoma
`Well-differentiated neuroendocrine carcinoma
`of the lung
`Neuroendocrine carcinoma of the breast
`
`3101
`
`~
`
`No. of patients
`49
`24/25
`
`60
`39-77
`49
`14
`4
`4
`6
`
`15
`
`34
`4
`7
`2
`
`1
`1
`
`1 month; stable disease, defined as less than 50% de-
`crease or less than 25% increase in the size of measur-
`able lesions; and progressive disease, defined as greater
`than or equal to 25% increase in any tumor lesion or the
`appearance of new sites. For biochemical response, CR
`was defined as the return of the elevated tumor markers
`to within the normal range for at least 1 month, and PR
`was defined as greater than or equal to 50% decrease
`for at least 1 month. For symptomatic response, CR was
`defined as the complete relief of ail symptoms, and PR
`was defined as a reduction of at least 50% in both the
`frequency and intensity of flushing and/or diarrhea at-
`tacks.
`
`Results
`
`Between August 1989 and December 1991, 53 eligible
`patients were sequentially enrolled in this multicenter
`trial; 49 were evaluable for response. Of the four non-
`evaluable patients, there was a lack of adequate infor-
`mation for three and one dropped out for severe toxicity
`(fatigue and leukopenia) within the first month. The
`main characteristics of the evaluable patients are listed
`in Table 1. The predominant histologic type was carci-
`noid (diagnosed in 34 patients). The primary sites of the
`19 foregut carcinoids were: pancreas (n = lo), bronchus
`(n = 5), stomach (n = 3), and thymus (n = 1). Five
`patients affected by pancreatic carcinoids had abnor-
`mal 5-HIAA excretion. In addition, there were four islet
`cell tumors (three insulinomas and one glucagonoma),
`seven medullary carcinomas of the thyroid gland, two
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 3 of 7
`
`

`

`3102 CANCER November 15, 1993, Volume 72, No. 10
`
`Table 2. Characteristics of Patients Who Responded to Treatment
`
`Age
`(yr)
`63
`56
`54
`39
`72
`
`Histologic
`type
`Medullary
`Carcinoid
`Carcinoid
`Carcinoid
`Carcinoid
`
`Primary
`site
`Thyroid
`Lung
`Midgut
`Foregut
`Midgut
`
`Disease
`extension
`Mediastinal nodes
`Lung, abdominal nodes
`Liver, abdominal nodes
`Lung, pancreas, liver
`Liver, ileum, abdominal nodes
`
`Objective
`response
`Complete
`Partial
`Partial
`Partial
`Partial
`
`Time to
`response
`(mo)
`
`Response
`duration
`(mo)
`
`4
`11
`4
`10
`2
`
`11
`1
`10
`5+
`2
`
`neuroendocrine (Merkel cell) carcinomas of the skin,17
`one well-differentiated neuroendocrine carcinoma of
`the lung," and one neuroendocrine carcinoma of the
`breast." Thirty-six patients had multiple sites and 4 had
`bulky disease (defined as a mass diameter of 10 cm or
`greater). The most frequent site of metastasis was the
`liver. Abnormal 5-HIAA urinary excretion was present
`in 15 patients (median, 21.8 mg/24 h; range, 11.5-
`243.0), carcinoid syndrome in 14 patients, and both in 7
`patients. Regarding previous treatments, 20 patients
`had been treated with radical surgery and 6 had re-
`ceived palliative resection. Cytotoxic drugs, including
`fluorouracil and cisplatin (CDDP), had been adminis-
`tered in 11 cases. Fourteen patients had not received
`any previous therapy, and 7 had been given more than
`1 treatment. After a median treatment duration of 6
`months (range, 2-12), five patients (10%) showed an
`objective response. Stable disease was documented in
`16 patients, 9 of whom received rIFN-alpha-2a for 12
`months. Progressive disease was observed in 28 pa-
`tients. The main characteristics of the responders are
`listed in Table 2. In particular, one patient affected by
`MTC with 3-cm diameter mediastinal nodes assessed
`by computed tomography scan experienced a CR. It is
`noteworthy that a long period of treatment was re-
`quired before obtaining a response in two patients. The
`responding patient with a lung carcinoid obtained PR
`after 11 months of treatment and, in accordance with
`the protocol, received chemotherapy 1 month later.
`None of the responders had been pretreated with che-
`motherapy.
`Our results of carcinoid syndrome are listed in Ta-
`ble 3. Nine patients (64%) had a symptomatic response,
`with the complete disappearance of symptoms for a
`median duration of 5 months in five patients. In all
`patients, the response was obtained within the first 2
`months of treatment. The 5-HIAA levels in the eight
`patients with biochemical response are shown in Figure
`1. The reduction generally occurred after 8 weeks of
`treatment, with a median duration of 4 months. In three
`of the four patients with carcinoids who had an objec-
`tive response, their 5-HIAA levels also returned to nor-
`mal; the remaining patient showed a reduction of more
`
`than 50%. There was also a concomitant biochemical
`response in four patients who experienced subjective
`relief of symptoms. Six patients had abnormal NSE val-
`ues, but we have no further data to assess their behav-
`ior during the treatment. No abnormal baseline human
`chorionic gonadotropin beta subunit values were found
`in any of our patients. All of the seven patients affected
`by MTC had high-baseline calcitonin values. No reduc-
`tion in the tumor marker was observed, not even in the
`patient with a clinically documented objective CR.
`Side effects were analyzed according to World
`Health Organization grade and are listed in Table 4.
`The most frequent side effects observed in about 65%
`of patients during IFN treatment were fever, myalgia,
`and fatigue. The fever, which rarely exceeded 39"C, as
`well as the myalgia and fatigue were short-lasting.
`Chills, nausea, and headache were less frequent. In five
`patients, the treatment was administered at lower dos-
`ages. Four patients experienced grade 3 flu-like syn-
`drome, and treatment was continued at 75% of the ini-
`tial dose in one patient and 50% in three patients.
`Grade 3 liver toxicity requiring a 25% dose reduction
`was documented in one patient. No patient died of tox-
`icity.
`Nineteen patients in progression or with persistent
`disease after 12 months of rIFN-alpha-2a received an-
`other treatment. A polychemotherapeutic schedule
`with STZ plus epirubicin was administered in 15 pa-
`tients, l of them experiencing a PR lasting 5 months.
`Four patients were treated with I'31 metaiodobenzyl-
`guanidine therapy, three being evaluable because one is
`still on treatment. In one patient, a PR lasting 5 months
`was reported. The results of the treatment programs are
`listed in Table 5. No severe side effects were observed
`during either the polychemotherapy or radiometabolic
`treatment.
`
`Discussion
`
`The medical treatment of neuroendocrine tumors is still
`questionable. The control of tumor growth and a reduc-
`tion in the clinical symptoms due to hormonal secretion
`by the tumor itself are the main objectives for clinicians.
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 4 of 7
`
`

`

`Treatment of Neuroendocrine TumorslBajetta et al.
`
`3103
`
`Table 3. Results of Carcinoid Syndrome
`
`No. of
`eligible
`patients
`
`Features
`Carcinoid syndrome
`Flushing
`Diarrhea
`Abnormal urinary 5-hydroxyindoleacetic
`acid
`*Median baseline value: 21.8 mg/24 h (range, 11.5-243).
`
`14
`10
`10
`
`15
`
`Response
`Complete +
`partial
`9
`7
`7
`
`Complete
`5
`5
`3
`
`6
`
`8
`
`Percent
`
`64
`70
`70
`
`53
`
`Reports on the use of active antineoplastic drugs in such
`tumors regard fluorouracil, doxorubicin, dacarbazine,
`STZ, and CDDI'.Zo,Z' However, chemotherapy is of
`marginal value in reducing clinical symptoms and ob-
`taining objective responses. The use of rIFN has been
`tried in many types of tumors and has been shown to
`possess some therapeutic effects on neuroendocrine tu-
`mors with distant spread."
`The activity of natural human leukocyte IFN was
`documented by the Swedish
`which, when us-
`ing IFN at a dose of 3-6 X lo6 IU three times a week,
`
`5-HIAA (mg/24 hr)
`
`100
`
`1 2 0 L
`
`obtained objective tumor regressions in 11 9'0 of patients
`and biochemical responses in 53%.
`In an attempt to reduce the side effects associated
`with human leukocyte IFN, Smith et a1.16 tested the
`activity of rIFN-alpha at a dose of 10 X lo6 IU/m2. No
`objective tumor regressions were observed, but 36% of
`the patients had a reduction of at least 50% in 5-HIAA
`excretion, and 67% achieved symptomatic relief of car-
`cinoid syndrome. The treatment was well tolerated.
`High-dose rIFN-alpha-2a (ie., 24 X lo6 IU intra-
`muscularly three times a week) induced more objective
` regression^.'^ However, the responses only persisted
`for a median of 7 weeks. Because of the side effects
`encountered, the schedule was not recommended for
`the routine treatment of carcinoid tumor or syndrome.
`With the aim of achieving significant tumor re-
`sponse rates with fewer side effects than those previ-
`ously encountered, we treated 53 patients affected by
`neuroendocrine tumors with rIFN-alpha-2a at a daily
`dose of 6 X lo6 IU for the first 8 weeks, reduced to 3
`times per week thereafter. We included one patient
`with well-diff erentiated neuroendocrine carcinoma of
`the lung, which is characterized by a biologic behavior
`falling somewhere between that of a carcinoid and
`small-cell carcinoma, thus underlining the heterogene-
`
`Table 4. Side Effects of Interferon Treatment
`in 49 Evaluable Patients
`World Health
`Organization
`grade
`Fever
`Chills
`Myalgia
`Leukopenia
`Liver dysfunction
`Anorexia
`Nausea
`Fatigue
`Headache
`
`Grade 3
`3
`3
`6
`3
`1
`9
`1
`9
`2
`
`Overall
`32
`15
`30
`33
`2
`30
`16
`33
`14
`
`No. of patients
`
`Grade 1
`20
`7
`14
`18
`-
`11
`14
`14
`8
`
`Grade 2
`9
`5
`10
`12
`1
`10
`1
`10
`4
`
`0'
`
`2
`
`4
`
`6
`
`8
`
`10
`
`Months
`Figure 1. Behavior of 5-HIAA (mg/24 h) urinary levels in eight
`patients with a biochemical response.
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 5 of 7
`
`

`

`3104
`
`CANCER November 15, 1993, Volume 7 2 , No. 10
`
`Table 5. Responses to the Protocol Programs
`Response
`No. of
`evaluable Complete +
`partial
`cases
`
`Treatment
`
`Complete
`
`Interferon
`1’31 MIBG
`Streptozocin + epirubicin
`MIBG: metaiodobenzyl-guanidine.
`
`49
`3
`15
`
`5
`1
`1
`
`1
`-
`
`-
`
`ity of this type of neoplasm. We observed five objective
`tumor responses. Four PR occurred in patients with car-
`cinoid tumors affected by carcinoid tumors with liver
`metastasis and high-urinary 5-HIAA levels. A CR was
`observed in one patient affected by MTC with medias-
`tinal nodes.
`Previous experience in the treatment of MTC with
`chemotherapeutic agents remains extremely limited,
`and the results are subject to debate. A review of re-
`ports, including cases treated with doxorubicin alone or
`in combination with other agents, indicated that about
`20% of patients with MTC can be expected to obtain an
`objective re~ponse.’~ Experience in the treatment of
`MTC with other drugs is even more limited than experi-
`ence with doxorubicin, and no conclusions can be
`drawn. Grohn et al. used low-dose rIFN-alpha-2a to
`treat two patients with previously treated advanced
`MTC.25 No change in the size of measurable metastases
`was observed, despite a decrease in calcitonin values
`and a clear subjective improvement. However, given
`the small number of investigated patients, further stud-
`ies are necessary to evaluate the efficacy of IFN in MTC.
`Our study confirms the efficacy of rIFN-alpha-2a
`in patients with carcinoid syndrome, with subjective
`relief of symptoms being obtained in 64% of patients.
`Noteworthy is the correlation among objective re-
`sponses, symptomatic control, and a reduction in 5-
`HIAA levels. The side effects of our schedule were toler-
`able in most patients, and there was no life-threatening
`toxicity.
`After IFN treatment, the activity of polychemo-
`therapy was evaluated. The low-response rate obtained
`might be explained by the large number of treatments
`given before chemotherapy. Given the small number of
`treated patients, no conclusions can be drawn in rela-
`tion to radiometabolic therapy, although our results ap-
`pear interesting and worthy of further confirmatory
`studies.
`We conclude that our schedule is effective in con-
`trolling carcinoid syndrome and that it can be recom-
`mended because of its good patient compliance. How-
`ever, no significant impact on tumor growth was ob-
`served. It might be useful to combine IFN therapy with
`
`conventional cytotoxic chemotherapy to improve ob-
`jective responses in neuroendocrine tumors; some re-
`cent reports have suggested the activity of high doses of
`long-acting somatostatin analogues in the management
`of such tumors,26-28 although the best dose and the
`most adequate schedule of administration have not yet
`been defined. In our institute, a study is in progress to
`evaluate the efficacy of such an agent on tumor growth
`inhibition.
`
`References
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`Berge T, Line11 F. Carcinoid tumors: frequency in a defined popu-
`lation. Acta Pathol Microbiol Immunol Scand 1976; 84:322-30.
`Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer
`1975; 36:560-9.
`Williams ED, Siebenmann RE, Sobin LH. Histological typing of
`endocrine tumours. International histological classification of
`tumours. Geneva: World Health Organization, 1980: 23.
`Distribuzione per sesso, eth, sede del tumore e diagnosi morfolo-
`gica CIM-0. In: Lega Italiana per la Lotta Contro i Tumori-Asso-
`ciazione Italiana di Epidemiologia. Cancer in Italy: incidence
`data from Cancer Registries 1983-1987. Torino: Zanetti and
`Crossignani, 1992: 106-24.
`Moertel CG. Treatment of the carcinoid tumor and the malig-
`nant carcinoid syndrome. J Clin Oncol 1983; 1:727-40.
`Broder LE, Carter SK. Pancreatic islet cell carcinoma: results of
`therapy with streptozotocin in 52 patients. Ann Intern Med 1973;
`79:108-18.
`Moertel CG, Lefkopoulo M, Lipsitz S, Hann RG, Klaassen D.
`Streptozotocin-doxorbicin, streptozotocin-fluorouracil, orchloro-
`zotocin in the treatment of advanced islet-cell carcinoma. N Engl
`J Med 1992; 326519-23.
`Kvols LK, Buck M. Chemotherapy of endocrine malignancies: a
`review. Sernin Oncol 1987; 14:343-53.
`Bukowski RM, Johnson KG, Peterson RF, Stephens RL, Rivkin
`SE, Neilan B, et al. A phase I1 trial of combination chemotherapy
`in patients with metastatic carcinoid tumors: a Southwest Oncol-
`ogy Group Study. Cancer 1987; 60:2891-5.
`Moertel CG, Hanley JA. Combination chemotherapy trials in
`metastatic carcinoid tumor and the malignant carcinoid syn-
`drome. Cancer Clinical Trials 1979; 2:327-34.
`Engstrom PF, Levin FT, Moertel CG, Folsch E, Douglas HO.
`Streptozotocin plus fluorouracil versus doxorubicin therapy for
`metastatic carcinoid tumor. J Clin Oncol 1984; 2:1255-9.
`Strander HA. Clinical effects of interferon therapy with special
`emphasis on antitumor efficacy. Acta Oncol 1989; 28:355-62.
`Gresser IA. Antitumor effects of interferon. Act0 Oncol 1989;
`28:347-53.
`Oberg K, Funa K, Alm G. Effects of leukocyte interferon on
`clinical symptoms and hormone levels in patients with midgut
`carcinoid tumors and carcinoid syndrome, N Engl J Med 1983;
`309329-33.
`Moertel CG, Rubin J, Kvols LK. Therapy of metastatic carcinoid
`tumor and the malignant carcinoid syndrome with recombinant
`leukocyte a-interferon. J Clin Oncol 1989; 7365-8.
`Smith DB, Scarffe JH, Wagstaff J, Johnston RJ. Phase I1 trial of
`rDNA a-2b interferon in patients with malignant carcinoid tu-
`mor. Cancer Treat Rep 1987; 71:1265-6.
`Pilotti S, Rilke F, Bartoli C, Grisotti A. Clinicopathologic Corre-
`lations of Cutaneous Neuroendocrine Merkel Cell Carcinoma. J
`Clin Oncol 1988; 6:1863-73.
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 6 of 7
`
`

`

`Treatment of Neuroendocrine Tumors/Bajetta et al.
`
`3105
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`Pilotti S, Patriarca C, Lombardi L, Scopsi L, Rilke F. Well-differ-
`entiated neuroendocrine carcinoma of the lung: a clinicopatho-
`logic and ultrastructural study of 10 cases. Tumori 1992; 78:
`121-9.
`Scopsi L, Andreola S, Pilotti S, Testori A, Baldini MT, Leoni F, et
`al. Argyrophilia and granin (chromogranin/secretogranin) ex-
`pression in female breast carcinomas. Am ] Surg Pathol 1992;
`16(6):561-76.
`Kessinger A, Foley JF, Lemon HM. Therapy of malignant APUD
`cell tumors: effectiveness of DTIC. Cancer 1983; 51:790-4.
`Moertel CG, Rubin J, O’Connell MJ. A phase I1 study of cisplatin
`therapy in patients with metastatic carcinoid tumor and the ma-
`lignant carcinoid syndrome. Cancer Treat Rep 1986; 70:1459-60.
`Hanssen EL, Schrumpf E, Kolbenstvedt AN, Tausjo J, Doha 0.
`Recombinant 01-2 interferon with or without hepatic artery em-
`bolization in the treatment of midgut carcinoid tumors. Actn On-
`C O ~ 1989; 28:439-43.
`Eriksson B, Oberg K, Alm G, Karlsson A, Lundquist G, Magnus-
`son A, et al. Treatment of malignant endocrine pancreatic tu-
`
`mors with human leukocyte interferon. Cancer Treat Rep 1987;
`71:31-7.
`24. Shimaoka K, Schoenfeld DA, Dewys WD, Creech RH, De Conti
`R. A randomized trial of doxorubicin versus doxorubicin plus
`cisplatin in patients with advanced thyroid carcinoma. Cancer
`1985; 56~2155-60.
`25. Grohn P, Kumpulainen E, Jakobsson M. Response of medullary
`thyroid cancer to low dose alpha-interferon therapy. Acta Oncol
`1990; 29~950-1.
`26. Wynich D, Bloom SR. The use of the long-acting somatostatin
`analog (octreotide) in the treatment of gut neuroendocrine tu-
`mors. J Clin Endocrinol Metab 1991; 73:l-3.
`27. Anthony LB, Winn S, Johnson DH, Russell A, Jones, Hande K.
`Continuous subcutaneous octreotide infusions for carcinoid tu-
`mors/syndrome. Proc A m SOC Clin Oncol 1992; 11:168.
`28. Souquet JD, Sassolas G, Forichon J, Champetier P, Partensky C,
`Chayuialle JA. Clinical and hormonal effects of a long-acting
`somatostatin analogue in pancreatic endocrine tumors and in
`carcinoid syndrome. Cancer 1987; 59:1654-60.
`
`NOVARTIS EXHIBIT 2047
`Par v. Novartis, IPR 2016-01479
`Page 7 of 7
`
`