Review
`
`Annals of0nc0logy 12 (Suppl. 2): Slll—Sll4, 2001.
`O 200l Kluwer Academic Publishers. Printed in the Netherlands.
`
`Chemotherapy and biotherapy in the treatment of neuroendocrine tumours
`
`K. Oberg
`Department ofEndocrine Oncology, Medical Sciences, Internal Medicine, Uppsala University Hospital, Uppsala, Sweden
`
`Summary
`
`The medical treatment of neuroendocrine GEP tumours must
`be based on the growth properties of the tumour. Medical
`treatment includes chemotherapy, somatostatin analogues and
`alpha interferons. Chemotherapy has been particularly active
`in patients with high proliferating neuroendocrine tumours
`such as endocrine pancreatic tumours and lung careinoids.
`Streptozotocin-based combinations including 5-llourouracil
`and doxorubicin have generated partial remissions in 40%-
`60% of the patients giving a median survival of about two
`years in patients with advanced disease. Cisplatinum plus
`etoposide have demonstrated significant antitumour effects in
`anaplastic endocrine pancreatic tumours and lung carcinoids.
`However, in low proliferating tumours such as classical midgut
`carcinoids the response rates with the same combinations of
`cytotoxic agents have only generated short lasting responses
`in less than 10% of patients. In these patients, biological treat-
`ment has been of benefit. Alpha interferon at doses of 3-9
`million units three to seven times per week subcutaneously,
`has given biochemical response rates of 50% and significant
`
`tumour reduction in about 15% of patients with long duration,
`up to three years.
`Somatostatin analogues have been widely used in the treat-
`ment of neuroendocrine gut and pancreatic tumours. The
`cunently available somatostatin analogues particularly bind
`somatostatin receptor 2 and 5 and with low afiinity also
`receptor subtype 3. Octreotide is registered in most countries
`for the treatment of patients with carcinoid syndrome and also
`VIP and glucagon producing tumours. Regular octreotide at
`standard doses of 100-300 pg/day gives symptomatic re-
`sponses in a medium of 60% of patients and biochemical
`responses in up to 70% of patients. Significant tumour re-
`sponses are rare, less than 5%. Long-acting formulations of
`somatostatin analogues have been of significant benefit for the
`patients with similar response rates as for regular formula-
`tions. The quality of life has been significantly improved by
`using the long-acting formulations.
`
`Key words: alpha interferon, lanreotide, octreotide, somatos—
`tatin analogues, streptozotocin
`
`Introduction
`
`The medical treatment of neuroendocrine GEP tumours
`must be based on the growth properties of the tumour.
`Medical treatment includes chemotherapy, somatostatin
`analogues and alpha interferons. Because of the rarity
`of these tumours, clinical studies have frequently been
`reported in a very tenious fashion. Furthermore, many
`of the studies do not take into account diflerencies in
`biological behaviour between classical midgut carci-
`noids and endocrine pancreatic tumours. In addition,
`many clinicians are still reluctant to treat patients with
`neuroendocrine GEP tumours without clinical symp-
`toms since they have been assigned a good prognosis.
`However, a critical look at the survival data in patients
`with malignant neuroendocrine GEP-tumours showed a
`five-year survival rate of 20% and and average survival
`of two years when liver metastases are present in carci-
`noid tumour patients. For endocrine pancreatic tu-
`mours, the survival data are even worse [1, 2]. Today
`there is no medical treatment for ‘bulky’ disease that
`cures the patient. However, the quality of life for patients
`with functioning tumours has been significantly improved
`
`by the introduction of biological treatment, in particular
`somatostatin analogues and alpha interferons.
`
`Chemotherapy
`
`Chemotherapy has been considered ‘the gold standard’
`for treatment of most GEP tumours. However,
`it has
`usually been reported in studies involving a limited
`numbers of patients with variable criteria for assessing
`antitumour
`responses. Chemotherapy for endocrine
`pancreatic tumours has been of significant benefit [3—5].
`Streptozotocin based combinations including 5-flour-
`ouracil (5-FU) and doxorubicin have generated partial
`remissions in 40°/o—60°/o of the patients, giving a median
`survival of about two years in patients with metastatic
`disease. In contrast to the experience of chemotherapy
`for endocrine pancreatic tumours, classical midgut carci-
`noids have been rather resistant to various combinations
`
`of chemotherapeutic drugs. Combination chemotherapy
`trials,
`including streptozotocin, 5-FU, cyclophospha-
`mide or doxorubicin has only generated short-lasting
`responses in fewer than l0% of the patients [2, 5, 6].
`
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`However, in a subset of carcinoid tumours in particular
`forgut (lung,
`thymic), cytotoxic agents have produced
`remarkable remissions, in particular a combination of
`cisplatinum and etoposide. That is also true for ana-
`plastic endocrine pancreatic tumours but not for highly
`diflerentiated tumours [8].
`Liver targeted chemotherapy has been reported in
`some trials where objective responsed have been noticed
`in 60% of the patients with a median duration of 18
`months, in patients receiving embolization + DTIC +
`doxorubicin + 5-FU + streptozotocin [9]. Other trials
`including embolization + doxorubicin have generated
`response rates between 35"/o—78°/o with a duration of 17-
`24 months with significantly lower side-effects.
`Today, chemotherapy should be primarily reserved
`for patients with high proliferation capacity irrespective
`of the localisation ofthe primary tumour (see algorithm,
`Figure l). The precise level of the proliferation index
`(Ki-67) has not been determined but definitely prolifer-
`ation indices of about 10% and wide spread disease
`might support systemic chemotherapy as a first
`line
`[10, ll].
`
`Biotherapy
`
`SURGERY *
`
`T
`
`Mnrkers (CgA)
`Ocueoscun
`
`Cf, MRI, PET
`
`Low Prolif.
`Pmhf
`(m67<5 4blM
`Biological
`Cytotoxic
`Therapy
`Therapy *
`(1-[FN 1 SMS
`STZ at SFU, Doxo
`Embolimtion 1:
`
`Cispl + Etop.
`
`Owl
`
`Cyto-
`
`Chemo
`RF
`Laser
`
`Therapy
`
`Tumot Targeted
`Tmmnent
`
`(MIBG '”lnd-Ocun. “Y-DOTA-Octr.)
`
`* NB‘ SMS could be used during surgery and cytoreduczion to facilitate
`the procedure. Can also be used in 00lJJlJll1fl.ll0fl with cytotoxic
`therapy.
`
`Biological treatment of neuroendocrine tumours include
`alpha interferons and somatostatin analogues.
`
`Figure I. Neuroendocrine tumors.
`
`Interferon
`
`Alpha interferon was introduced by our group in the
`treatment of carcinoid tumours in I982, because of its
`ability to stimulate natural killer cell function and to
`control hormone secretion, clinical symptoms and tu-
`mour growth [l2}. Since then, more than 400 patients
`have been reported in the literature treated with alpha
`interferon [l3—l6]. Today recombinant alpha interferon
`are used (Intron, ot—interferon 2b and Roferon, c¢-inter-
`feron 2a). Alpha interferon 2b is the most commonly
`used on-interferon. The applied doses of at-interferon have
`been 3-9 MU 3-7 times/week subcutaneously. The dose
`has to be individually titrated in the patients and as a
`guide-line the leukocyte count should be reduced to 3.0
`X 109/l. By using such titration the biochemical response
`rate in carcinoid tumour has been reported to be 50%
`and significant tumour reduction 15%. The median du-
`ration response has been 32 months and 35% of the
`patients showed stabilisation of their disease with no
`further tumour growth. Only 15% of the patients con-
`tinued to progress. Survival data from our own center
`and from others, showed improved survival after treat-
`ment with ot-interferon in malignant classical midgut
`tumours with a carcinoid syndrome. The median sur-
`vival for patients with malignant carcinoids and liver
`metastases is at our institution more than eight years
`during continuous biotherapy [17]. Also in patients with
`low proliferating endocrine pancreatic tumours, a re-
`sponse rate of about 50% have been obtained lasting for
`
`more than two years. The mechanism of action of at-
`interferon is supposed to be a direct effect on the tumour
`cells but also trigging the immune system. It is known to
`inhibit
`the cell cycle in G-l
`to S-phase in carcinoid
`tumour cell and it
`inhibits the production of growth
`factor/receptors and other agents secreted by tumour
`cells. It is also known to induce class I antigens on the
`cell surface and thereby attract various response cells of
`the immune system. It is also assumed that on-interferon
`has an anti-angiogenetic effect, which has been explored
`in children treated for multiple hemangiomas.
`Alpha interferon has been combined with somatostatin
`analogues, especially octreotide, with significant poten-
`tiation of the clinical effect.
`In a group of patients resistant to somatostatin ana-
`logues, the addition of cz-interferon (median 5 MU three
`times/week) generated biochemical responses in 77% of
`the patients with 18% complete biochemical remission
`[18]. However, no significant tumour reduction was seen
`in this trial. Theoretical basis for using the combination
`of these two compounds is based on studies in vitro
`and in vivo in BON-cells, which are neuroendocrine
`differentiated cells. The combination of octreotide and
`at-interferon causes a significant growth inhibition com-
`pared to a single agent. Another recent study from our
`own group in malignant endocrine pancreatic tumour
`resistant to either on-interferon alone, somatostatin ana-
`logue alone or cytotoxic treatment, has generated 35%
`objective tumour reduction and 50% biochemical re-
`
`West-Ward Pharm.
`Exhibit 1025
`Page 002
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`sponses. These data are further supported by a recent
`publication from a German group, showing tumour
`reduction in more than 50% of patients receiving the
`combination of or-interferon and somatostatin analogue
`[19]. The adverse effects of at-interferon treatment in-
`clude mainly flu-like symptoms for the initial 3-4 days,
`which can be managed by paracetamol or aspirin. More
`severe adverse reaction is the chronic fatigue syndrome
`which occur in about 50% of the patients and sometimes
`also give mental depression. Another adverse reaction
`might be induction of autoimmune phenomenon with
`development of anti-nuclear,
`thyroid antibodies and
`sometimes development of thyroid dysfunction. Also
`neutralising antibodies
`to recombinant at-interferon
`might develop to which might abrogate the antitumour
`response.
`Interferon should be used in low proliferating tumours
`with limited tumour burden such as classical midgut
`carcinoids, where it has shown an antiproliferative effect
`(Figure 1). In the future,
`trials of adjuvant treatment
`after surgery with curative intent should be done to
`explore whether at-interferon can prevent the develop-
`ment of metastatic disease later on.
`
`Somatostazin analogues
`
`Somatostatin analogues have been widely used in the
`treatment of neuroendocrine gut- and pancreatic tu-
`mours. They can inhibit the release of peptides from the
`tumours and by that improving the clinical symptoms
`related to these tumours. The currently available soma-
`tostatin analogues are particularly seeing somatostatin
`receptor 2 and 5, and with low affinity also receptor type
`3 [20]. Octreotide is registered in most countries for the
`treatment of patients with carcinoid syndrome and also
`VIP and glueagon producing tumours. Today a large
`number of patients (more than a thousand) have been
`treated with somatostatin analogues. Regular octreotide
`at standard doses of 100-300 pg/day, give symptomatic
`responses in a median 60% of the patients [21]. Bio-
`chemical responses have been obtained in 70% of the
`patients and tumour responses in about 5%. When
`giving high-dose treatment (>3000 pg/day), the symp-
`tomatic and biochemical responses are similar but the
`tumour responses are slightly increased to 11% [22].
`Recently a slow release formulation has been developed
`for octreotide, Sandostatin-LAR, and the patients
`switch from regular octreotide to LAR at doses of 20-
`30 mg intramuscular per month, showing continuing
`biochemical response in more than 80% of the patients.
`Similar data has been obtained for a long-acting fonnu-
`lation of somatuline (lanreotide-PR) given 30 mg every
`two weeks intramuscular, where 50% of the patients
`showed biochemical response and a mean of 3% tumour
`responses. More interesting was the quality of life evalu-
`ation using QLQ-30, where a significant improvement in
`the quality oflife was obtained during treatment with a
`long-acting formulation [23].
`The average survival
`for patients with malignant
`
`113
`
`midgut carcinoids has been estimated at 36 months for
`somatostatin analogue treatment. The side-effects of
`octreotide treatment are generally mild and include fat
`malobsorption and sometimes gall bladder dysfunction
`and gall stones. The long-acting formulation is a real
`advantage for patients just taking one injection every
`three to four weeks, instead of three times/day.
`Somatostatin analogues will be the gold standard for
`management of hormonal clinical symptoms related to
`neuroendocrine GEP tumours for many years. Since
`there are five subtypes of somatostatin receptors, sub-
`type specific analogues might resolve the precise single
`transduction pathway and action from each subtype of
`receptor. It has also been recently shown that there is a
`cross-talk between somatostatin receptors within the
`same cell which can modulate response to a certain
`subtype of somatostatin analogue.
`
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`Page 003
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`
`Correspondence to:
`K. oberg, MD, PhD
`Department of Endocrine Oncology
`Uppsala University Hospital
`S—75l 85 Uppsala
`Sweden
`
`West-Ward Pharm.
`Exhibit 1025
`Page 004
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