2. GASTRO-ENTERO-PANCREATIC NEUROENDOCRINE TUMOURS

INTRODUCTION

Neuroendocrine tumors (NETs, Carcinoids, APUDOMAS) are derived from the diffuse neuroendocrine system, which is made up of peptide- and amine-producing cells with different hormonal profiles depending on their site of origin. Carcinoids synthesize bioactive amines and peptides, including neuron-specific enolase (NSE), 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP), synaptophysin, and chromogranins A and C, and other peptides like insulin, growth hormone, neurotensin, adrenocorticotropic hormone (ACTH), ß-melanocyte-stimulating hormone, gastrin, pancreatic polypeptide, calcitonin, substance P, other various tachykinins (neuropeptide K), growth hormone–releasing hormone, bombesin, and various growth factors such as transforming growth factor-ß platelet-derived growth factor, and fibroblast growth factor-ß.

Clinical Features
Signs and symptoms of carcinoid tumors vary greatly, depending on the location, size, and existence of metastasis. These range from no tumor-related findings to full symptoms of carcinoid syndrome.
The most common clinical presentation for a small intestinal carcinoid is periodic abdominal pain. This can be caused by fibrosis of mesentery, kinking of the bowel, or intestinal obstruction.

Table 1 Clinical features of pancreatic neuroendocrine tumours *

*Table from the journal: Gut 2005;54:iv1-iv16

Carcinoid syndrome is related to hormonal products of the tumor.

• An early and frequent symptom of carcinoid tumors, especially those of midgut with metastasis, is cutaneous flushing, typically of the head and neck, with striking color changes ranging from pallor or erythema to cyanosis. Other symptoms include a profuse and often colicky diarrhea, asthmatic wheezing, and symptoms of valvular heart lesion.
• Less common complaints include joint pain, arthritis, lacrimation, changes in mental status, ophthalmologic findings associated with flushing or secondary to vascular occlusion, and retroperitoneal fibrosis

The carcinoid crisis is characterised by profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure. It is thought to be due to the release of mediators which lead to the production of high levels of serotonin and other vasoactive peptides. It is usually precipitated by anaesthetic induction for any operation, intraoperative handling of the tumour, or other invasive therapeutic procedures such as embolisation and radiofrequency ablation

Work up

GENETICS

• Clinical examination to exclude complex cancer syndromes (for example, multiple endocrine neoplasia 1 (MEN1)) should be performed in all cases of neuroendocrine tumours (NETs), and a family history taken (grade C).
• In all cases where there is a family history of carcinoids or NET, or a second endocrine tumour, a familial syndrome should be suspected (grade C).
• Individuals with sporadic or familial bronchial or gastric carcinoid should have a family history evaluation and consideration of testing for germline MEN1 mutations. Management of MEN1 families includes screening for endocrine parathyroid and enteropancreatic tumours from late childhood, with predictive testing for first degree relatives of known mutation carriers (grade C).
• All patients should be evaluated for second endocrine tumours and possibly for other gut cancers (grade C)

Diagnosis
If a patient presents with symptoms suspicious of a gastroenteropancreatic NET:

• baseline tests should include chromogranin A (CgA) and 5-hydroxy indole acetic acid (5-HIAA) (grade C). Others that may be appropriate include thyroid function tests (TFTs), parathyroid hormone (PTH), calcium, calcitonin, prolactin, a-fetoprotein, carcinoembryonic antigen (CEA), and ß-human chorionic gonadotrophin (ß-HCG) (grade D);
• Specific biochemical tests should be requested depending on which syndrome is suspected (see table 2).
• Although detection of urinary 5-HIAA is the single best screening method for carcinoid tumors, it is not always elevated, and the measurement of other peptides (eg, SP, neuropeptide K, chromogranin) may be necessary for diagnosis and follow-up.

Table 2  Additional specific biochemical tests used in the diagnosis of neuroendocrine tumours (NETs) *

5-HIAA, 5-hydroxy indole acetic acid; GHRH, gonadotrophin releasing hormone; ACTH, adrenocorticotrophic hormone; ß-HCG, ß-human chorionic gonadotrophin.

*Table from journal: Gut 2005;54:iv1-iv16

Imaging

• For detecting the primary tumour, a multimodality approach is best and may include computed tomography (CT), magnetic resonance imaging (MRI), somatostatin receptor scintigraphy (SSRS), endoscopic ultrasound (EUS), endoscopy, digital subtraction angiography (DSA), and venous sampling (grade B/C).
• Based on the location of the tumor and metastasis, a combination of these may be used.
• In the large bowel, the disease often is detected by colonoscopy and does not provide an imaging challenge. Imaging diagnosis of small bowel carcinoids is more difficult. Small tumors in this location are difficult to detect by upper gastrointestinal (GI) series and CT scans and require other techniques.
• Computer tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US) detect <50% of NE small gut or pancreatic tumours, but CT and MRI have a higher sensitivity in visualizing NE thymic and bronchial tumours. Approximately 80–90% of liver metastases larger than 1–2 cm are revealed by these radiological techniques. By means of US (and CT) it is possible to take biopsies from tumours and metastases for histopathological evaluation.
• Endoscopic Ultrasonography: Tumors, local tumour invasion, and regional lymph node metastases are identified with a sensitivity and specificity of >80%. Furthermore, it is possible to perform a US guided fine needle aspiration of tumours and regional lymph nodes, which may increase the accuracy. EUS is indicated in patients suspected to have NE thymic, bronchopulmonary, gastro-duodenal, and pancreatic tumours. Rectal NE tumours are evaluated for local invasion and regional lymph node metastases by recto-vaginal US examinations with rigid probes.
• With advances in imaging studies, angiography is rarely used and is reserved for equivocal situations.
• PET scanning can be helpful and is increasingly used for diagnosis and follow-up of the tumors.
• Scintigraphy with MIBG and octreotide scanning have been used successfully for the detection of carcinoid tumors. MIBG is taken up by a host of neuroendocrine tumors and has been used extensively for the diagnosis and treatment of neuroblastoma. The sensitivity of this technique is less likely in the detection of carcinoid tumors than neuroblastoma.
• Somatostatin analogues attached to radioactive tracer (SSRS) can be used to advantage for diagnosis of carcinoid tumors.

• The current radiotracers used are indium 111 (111In)–diethylenetriamine pentaacetic acid (DTPA) and yttrium. Most neuroendocrine tumors have receptors for somatostatins. Five somatostatin receptor subtypes, SSTR-1 to SSTR-5, have been identified. For tumors larger than 1 cm in diameter, sensitivity of 111In-DTPA octreotide reaches 80-90%.

• Overall, SRS appears to be the imaging method of choice for localizing and evaluating the extent of carcinoid tumor. Octreotide appears to be more sensitive than MIBG. For assessing secondaries, SSRS is the most sensitive modality (grade B).
• When a primary has been resected, SSRS may be indicated for follow up (grade D).
• Bone metastasis is not uncommon in carcinoid tumors. In one study of 12 patients, 11 of whom had liver metastasis, 8 had bone involvement detected by SRS. Technetium-99m (99mTc) bone scanning also can aid in the detection of metastasis.

Stages of gastrointestinal carcinoid tumors

Depending on the results obtained from the work-up, the disease is classified as localized, locoregional, metastatic and recurrent.

Treatment
Surgical Care:

Treatment of gastrointestinal carcinoid tumor depends on the type of tumor, the stage, and the patient’s overall health.
• The treatment of choice for local and locoregional disease is surgical excision.

Localized Gastrointestinal Carcinoid tumors
Appendix:        < 2 cms - simple appendectomy
                        > 2 cms - right hemicolectomy

Metastatic Gastrointestinal Carcinoid tumors

Since carcinoid tumors are frequently indolent in growth, and asymptomatic, not all patients require treatment of metastatic disease at diagnosis. A period of observation may allow for a decision to be made concerning optimal supportive care or antitumor treatments. The goal is to relieve symptoms and slow the course of the disease.. If distant metastases are not causing symptoms, treatment may not be needed, although chemotherapy or immunotherapy (with interferon) may help delay the onset of symptoms in some patients.

Treatment options for distant metastasis:

1. Surgical treatment: Surgical treatment may frequently provide effective palliation (even in the presence of known distant metastasis with or without malignant carcinoid syndrome), particularly through bypass or palliative resection of obstructing small bowel tumors. Heroic attempts at surgical debulking, however, are not indicated except for hepatic resection in patients with the carcinoid syndrome.Although live metastases are usually multiple and neither bulky nor clustered, multiple wedge resections, cryosurgery, or radiofrequency ablation of the lesions can be considered in patients with carcinoid syndrome.

2. Chemotherapy: Cytotoxic treatment has been the gold standard for most NE tumours over the last three decades. However, the increasing awareness that low-proliferating NE tumours respond very poorly to cytotoxic treatment has stimulated the development of new biological treatments for slowly progressing NE tumours. Cytotoxic treatment is still to be considered as first-line treatment for high-proliferating tumours, i.e. metastatic disease with angio-invasion and proliferation index above 10%. Single-agent cytotoxic treatment has been of limited value in most trials producing response rates of less than 30%. The combination of streptozotocin (STZ) plus 5-FU and doxorubicin has shown response rates of more than 50% in malignant NE pancreatic tumours with a median duration of more than 2 years. Malignant pulmonary NE tumours, as well as colorectal carcinoids, respond poorly to this combination, as do the classical midgut carcinoids. Poorly differentiated NE tumours, particularly foregut (pulmonary, thymic) and small-cell colorectal NE tumours, might respond to a combination of cisplatinum/paraplatin plus etoposide. These tumours present a high-proliferation capacity, i.e. more than 15% Ki67 IR cells. The response rate has been reported to be 60–70% in poorly differentiated NE tumours with a duration of 8–9 months. Well-differentiated malignant tumours do not respond to this combination.

3. Chemoembolization: Hepatic artery infusion with fluorouracil, doxorubicin, mitomycin, or cisplatin, combined with embolization of the hepatic artery with collagen fibers or other material (i.e., gelfoam, lipiodol, or poly vinyl alcohol) has been reported to decrease tumor bulk of liver metastases from carcinoid tumors by 50% or more in as many as 60% of patients. Palliative embolizations that prove effective may be repeated if symptoms return.

4. Radiation therapy: The role of radiation therapy in the management of patients with carcinoid tumors with distant metastasis is restricted to symptomatic palliation. Although the tumor persists, painful bone metastases can be palliated.

5. I131-MIBG: Therapeutic doses of iodine131-labeled metaiodobenzylguanidine (MIBG) and unlabeled MIBG have been evaluated, with reduction of symptoms found in preliminary studies.

6. Biological modification (immunotherapy): Low-dose interferon alfa and octreotide, alone and in combination, have been reported to have activity.

Carcinoid syndrome

If carcinoid syndrome is causing bothersome symptoms, treatment options include chemotherapy, immunotherapy, treatment with octreotide or lanreotide, or removing the metastatic tumors by surgery. If metastatic tumors cannot be removed without causing severe side effects from removing essential organs and tissues, ablative methods (removal without surgery) are used to destroy as much of the tumor tissue as possible. These ablative methods, used mostly for liver metastases, include chemoembolization, radiofrequency ablation, cryosurgery, and alcohol injection. Patients should also be advised to avoid alcoholic drinks, stress, strenuous exercise, spicy foods, and certain medications that can make the symptoms of carcinoid syndrome worse.

Treatment options associated with metastatic carcinoid tumor:

1. Surgical treatment: Surgery may sometimes be of considerable value in the patient who has large or extensive hepatic metastases involving surgically accessible areas of the liver (single or multiple). Recurrent hepatic metastases (after previous resection) should be considered for resection if the lesions are placed in an area where resection can be done with minimal morbidity.

2. Hepatic artery ligation or embolization: For patients with bulky or symptomatic hepatic metastases, hepatic artery ligation or embolization can cause substantial tumor necrosis. Intra-arterial chemotherapy via the hepatic artery can cause regression of lesions in selected patients. These regressions tend to be durable as long as treatment is continued.

3. Pharmacologic management: Somatostatin analogue (octreotide) has been demonstrated to relieve symptoms of malignant carcinoid syndrome in the great majority of patients, with significant reduction of 5-hydroxyindoleacetic acid (5-HIAA) levels. Tumor reduction is rarely seen. Patients benefit from specific pharmacologic interventions that either suppress production of vasoactive amines or block their peripheral effects. These agents include cyproheptadine and H2-receptor blockers.
Monoamine oxidase inhibitors and adrenergic agonists are drugs to be specifically avoided in these patients since they will exacerbate the syndrome by inhibiting serotonin degradation or producing carcinoid syndrome crisis.

4. Interferon alfa preparations may have a role in controlling symptoms of the carcinoid syndrome or in arresting tumor growth. These benefits have generally been transient and accompanied by toxic effects that frequently outweigh therapeutic gains, although interferon alfa has been reported to reinduce symptom control in patients who did not respond to octreotide. The combination of interferon alfa and continuous-infusion fluorouracil has demonstrated antitumor and/or antihormonal activity and, similar to other drug regimens, can provide useful palliation. Combination of interferon alfa and octreotide has also been reported to have activity.

Recurrent Gastrointestinal Carcinoid tumors

The prognosis for any treated carcinoid patient with progressive or recurrent disease is poor. Deciding on further treatment depends on many factors, including prior treatment, site of recurrence, and individual patient considerations. Attempts at reresecting slow growing tumors (e.g., repeat or multiple liver resections) are worthy of consideration after extensive evaluation, since successful further reduction of tumor volume may provide long-term palliation. Recurrence in any single site may also be potentially resectable.

Prognosis:

These are slow growing tumours but survival depends on the histological type, degree of differentiation, mitotic rate, Ki67 or MIB-1 index, tumour size (>3 cm), depth, location, presence of liver or lymph node metastases, and age over 50 years. Following complete resection of the primary tumour and liver metastases if present, the overall five year survival is 83% but in cases where this is not possible survival ranges from 30% to 70% depending on the factors above and the treatment employed. The best prognosis is in bronchial and appendicular carcinoids with a five year survival for typical lung carcinoids and carcinoid tumours of the appendix being 80–90% whereas that for atypical lung tumours is 40–70%.

PATHOLOGY REPORT

The report should contain the following data for all tumour locations to allow the tumour to be classified according to the WHO classification:

• Gross description

              – nature of the specimen
              – description and dimensions of the specimen
              – description of lesion(s)—single or multifocal; solid or cystic, dimensions (of largest if multifocal)
              – extension into surrounding tissues
              – distant metastases

• Microscopic report

              – general morphological description
              – immunohistochemical profile, general neuroendocrine markers
              – vimmunohistochemical (and/or in situ hybridisation) profile, hormones
              – mitotic rate (per 10 high power fields (x40))
              – Ki-67 index (%) (at low levels of proliferation it is necessary to count a large number of cells to produce robust                  data for a Ki-67 index. To facilitate this, a grid might be used that allows the data to be calculated from counting                  only a subset of total cells212).
              – vascular, perineural, or lymphatic invasion
              – completely excised (with distance to margin) or present at excision margin
              – infiltration of surrounding tissues
              – lymph node status
              – distant metastases

• For gastrointestinal tumours

              – level of invasion
              – tumour on serosal surface or not
              – tumour on serosal surface or not
              – if not, level of invasion
              – depth of maximal wall invasion (mm)
              – distance to serosal surface (mm)

WHO classification of gastroenteropancreatic
endocrine tumours*

*Table from the journal : Gut 2005;54:iv1-iv16


Figure Algorithm for the treatment of malignant carcinoid tumors. LAR: Long acting Somatostatin analogues refers to the use of octreotide, lanreotide, depot formulations [octreotide LAR (long-acting release) or lanreotide SR (sustained release)].

ABSTRACT

1. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours . J K Ramage, A H G Davies, J Ardill et al. Gut 2005;54:iv1-iv16

A multidisciplinary group compiled these guidelines for the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland, as well as its Surgical Specialty Associations, and the United Kingdom Neuroendocrine Tumour Group (UKNET). Over the past few years there have been advances in the management of NETs, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there are few randomised trials in the field and the disease is uncommon; hence all evidence must be considered weak in comparison with other commoner cancers. It is our unanimous view that multidisciplinary teams at referral centres should give guidance on the definitive management of patients with gastroenteric and pancreatic NETs with representation that should normally include gastroenterologists, surgeons, oncologists, endocrinologists, radiologists, nuclear medicine specialists, and histopathologists. The working party that produced these guidelines included specialists from these various disciplines contributing to the management of gastrointestinal NETs. The purpose of these guidelines is to identify and inform the key decisions to be made in the management of gastroenteropancreatic NETs, including carcinoid tumours. The guidelines are not intended to be a rigid protocol but to form a basis upon which to aim for improved standards in the quality of treatment given to affected patients.

Recommendations (diagnosis)

If a patient presents with symptoms suspicious of a gastroenteropancreatic NET:

• Baseline tests should include CgA and 5-HIAA (grade C). Others that may be appropriate include TFTs, PTH, calcium, calcitonin, prolactin, a-fetoprotein, CEA, and ß-HCG (grade D).

• Specific biochemical tests should be requested depending on which syndrome is suspected.

Recommendations (imaging)

• For detecting the primary tumour, a multimodality approach is best and may include CT, MRI, SSRS, EUS, endoscopy, DSA, and venous sampling (grade B/C).

• For assessing secondaries, SSRS is the most sensitive modality (grade B).

• When a primary has been resected, SSRS may be indicated for follow up (grade D).

Recommendations (therapy)

• The extent of the tumour, its metastases, and secretory profile should be determined as far as possible before planning treatment (grade C).

• Surgery should be offered to patients who are fit and have limited disease-primary with or without regional lymph nodes (grade C).

• Surgery should be considered in those with liver metastases and potentially resectable disease (grade D).

• Where abdominal surgery is undertaken and long term treatment with SMS analogues is likely, cholecystectomy should be considered.

• For patients who are not fit for surgery, the aim of treatment is to improve and maintain an optimal quality of life (grade D).

• The choice of treatment depends on the symptoms, stage of disease, degree of uptake of radionuclide, and histological features of the tumour (grade C).

• Treatment choices for non-resectable disease include SMS analogues, biotherapy, radionuclides, ablation therapies, and chemotherapy (grade C).

• External beam radiotherapy may relieve bone pain from metastases (grade C).

• Chemotherapy may be used for inoperable or metastatic pancreatic and bronchial tumours, or poorly differentiated NETs (grade B).

2. Standardisation of imaging in neuroendocrine tumours: results of a European delphi process. J. Ricke, K. J. Klose, M. Mignon et al. European Journal of Radiology Volume 37, Issue 1 , January 2001, Pages 8-17

In 1998 and 1999, a delphi consensus procedure was performed to establish guidelines for standardised diagnostic imaging of neuroendocrine tumours. The procedure included four consecutive workshops of a European group of experts in neuroendocrine tumours as well as feedback given by specialists from the departments of radiology, nuclear medicine, surgery and internal medicine of the according home institutions. Diverging approaches among the centres, which became apparent during the discussion, reflect a lack of controlled studies specifically for rare subgroups of neuroendocrine tumours.

Central diagnostic modality for assessment of functional tumours of the pancreas is somatostatin-receptor-scintigraphy (SRS) with a sensitivity and specificity of up to 90 and 80%, respectively. In patients with suspected gastrinoma, endoscopy should precede the diagnostic workup of the pancreas to detect potential neoplastic manifestations in the duodenum. For disease limited to the pancreas or in cases where tumour localisation is pending but suspected in the pancreas, endosonography is regarded as the most sensitive modality. The use of computed tomography (CT) and magnetic resonance imaging (MRI) has been discussed controversially, with consensus regarding their advantages in routine tumour staging and monitoring of therapy. For somatostatin-receptor positive disease associated with MEN I, the diagnostic workup reflects established routines including MRI for recurrent hyperparathyroidism and tumour manifestation of the pituitary gland.

For local staging of Gastrinoma, endoscopy and endosonography of the stomach represent a sufficient workup. In case of suspected malignancy, SRS is seen as the most valuable staging modality; completion of diagnosis should be gained with abdominal CT.

In neuroendocrine tumours, patients often present with metastatic disease or clinical evidence, such as flush and diarrhoea in combination with elevated serum or urinary markers. To locate the primary tumour in these patients, SRS is seen as central diagnostic modality. Sensitivity for the detection of neuroendocrine gut tumours of foregut, midgut and hindgut into clinical use and significantly improved quality of life for patients with neuroendocrine tumors. Other means of medical treatment are alpha interferons, which have shown particular effect in patients with midgut carcinoid tumors giving both biochemical and tumor responses. Chemotherapy such as streptozotocin plus 5-fluorouracil (5-FU) or doxorubicin is still considered as first-line treatment in malignant endocrine pancreatic tumors but is combined with concomitant somatostatin analogue treatment. In the future a multimodal treatment will further develop combining different agents and also somatostatin receptor subtype specific analogues will come into clinical use.

4. Combination therapy with octreotide and á-interferon: Effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Margareta Frank , Klaus J. Klose , Matthias Wied et al. Am J Gastroenterol. 1999 May;94(5):1381-7.

OBJECTIVE: We investigated the antiproliferative efficacy of the addition of á-interferon to the somatostatin analogue octreotide in patients with metastasized gastroenteropancreatic tumors unresponsive to octreotide monotherapy. METHODS: In an open prospective trial, 21 patients with metastasized neuroendocrine gastroenteropancreatic tumors (nine patients with carcinoid syndrome, eight with nonfunctioning tumors, four with gastrinoma) were treated with 5 × 106 IU á-interferon tiw in addition to 200 ìg of octreotide tid. All patients, including 16 patients with preceding monotherapy with 200 ìg of octreotide tid, had tumor progression documented by computed tomography before entering the study. Growth response (computed tomography documented) and biochemical response were assessed at 3-month intervals. RESULTS: Inhibition of tumor growth was observed in 14 patients (67%), 11 of whom had preceding octreotide monotherapy; complete regression was observed in one patient lasting for 49 months and stable disease (stand-still) in 13 patients lasting for 3 to 52 months (median, 12 months). Seven patients failing this combination therapy exhibited a significantly shorter overall survival (median, 23 months; range, 5 to 42 months) than the 14 patients responding to this regimen (median, 68 months; range, 12 to 112 months; p=0.007). Two patients are still alive. Biochemical response was achieved in 69% of patients with functioning tumors: in three of four patients with gastrinoma and in six of nine patients with carcinoid syndrome. CONCLUSIONS: These data suggest that the addition of á-interferon to octreotide has antiproliferative efficacy in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy. Prolonged survival was seen in the responder group.

5. Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Oberg K. Ann Oncol. 2001;12 Suppl 2:S111-4

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 carcinoids. Streptozotocin-based combinations including 5-flourouracil 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 treatment 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 treatment of neuroendocrine gut and pancreatic tumours. The currently available somatostatin analogues particularly bind somatostatin receptor 2 and 5 and with low affinity 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 microg/day gives symptomatic responses in a medium of 60% of patients and biochemical responses in up to 70% of patients. Significant tumour responses 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 formulations. The quality of life has been significantly improved by using the long-acting formulations.