Current approaches and perspectives in the therapy of medullary thyroid carcinoma

Current Approaches and Perspectives in the Therapyof Medullary Thyroid Carcinoma

Giovanni Vitale, M.D.1

Michele Caraglia, M.D.2

Antonio Ciccarelli, M.D.1

Gelsy Lupoli, M.D.1

Alberto Abbruzzese, M.D.2

Pierosandro Tagliaferri, M.D.3

Giovanni Lupoli, M.D.1

1 Department of Molecular and Clinical Endocrinol-ogy and Oncology, School of Medicine, Universityof Naples “Federico II,” Naples, Italy

2 Department of Biochemistry and Biophysics,Second University of Naples, Naples, Italy.

3 Department of Experimental and Clinical Medi-cine, “Magna Graecia” University, Catanzaro, Italy.

The authors thank Ms. Gabriella Granata and Mr.Philip Sands for their help in preparation of thearticle.

Address for reprints: Giovanni Lupoli, M.D., De-partment of Molecular and Clinical Endocrinologyand Oncology, Via Pansini S, 80131 Naples, Italy;Fax: (39) 81-7462427; E-mail: [email protected]

Received August 7, 2000; revised December 4,2000; accepted January 2, 2001.

BACKGROUND. Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor

derived from parafollicular cells. At present, surgery is the most important treat-

ment for MTC.

METHODS. We describe the current approaches of MTC treatment (surgery, che-

motherapy, radiation therapy, and biologic therapy).

RESULTS. MTC is currently approached surgically in the main part through total

thyroidectomy and compartment-oriented microdissection of cervicomediastinal

lymph nodes. Substitutive l-thyroxine administration together with close clinical

monitoring and the measurement of basal and stimulated serum calcitonin are

subsequently performed. Radiotherapy and chemotherapy play a marginal role in

advanced MTC. Recently, it has been found that somatostatin analogs and type I

interferon are able to control the neuroendocrine symptoms induced by advanced

MTC and that they provide clinical benefit by improving the lifestyle of these

patients.

CONCLUSION. Although these agents are poorly active in inducing a shrinkage in

tumor mass, the combined use of different biologic agents and cytotoxic drugs

needs to be explored in advanced MTC. However, at present, surgery is the only

curative treatment for MTC. Cancer 2001;91:1797– 808.

© 2001 American Cancer Society.

KEYWORDS: medullary thyroid carcinoma, therapy, surgery, chemotherapy, soma-tostatin analog, interferon.

Medullary thyroid carcinoma (MTC), a malignant neoplasm ofparafollicular C cells, represents about 5–10% of thyroid tumors.

Unlike endodermally derived thyroid follicular cells, the C cells orig-inate from the embryonic neural crest. MTC releases calcitonin (CT)and carcinoembryonic antigen (CEA) and occasionally releases neu-ron-specific enolase, serotonin, chromogranin, gastrin-releasing pep-tide, substance P, pro-opiomelanocortin– derived products, and so-matostatin.1–2

MTC occurs in the sporadic form in about 70 – 80% of cases,whereas the remaining 20 –30% is represented by three familial forms:multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrineneoplasia type 2B (MEN 2B), and familial MTC not associated withMEN (FMTC). These familial forms are inherited as an autosomaldominant trait. Distinct germ-line mutations in the RET protoonco-gene have been identified in patients who are affected by familialMTC (Table 1).3–12

Clinical symptoms generally are correlated to local invasion andhormonal secretion. Local mass-associated symptoms include dys-phagia, stridor, or recurrent laryngeal nerve injury. Hormone-relatedsymptoms, including flushing, diarrhea, and the ectopic corticotropin

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© 2001 American Cancer Society

syndrome often are associated with an advanced stageof the disease. The clinical course of patients withMTC is variable, ranging from indolent to extremelyaggressive,13 and it is related to the stage of the diseaseat the time of diagnosis. Survival rate at 10 years is 95%for patients with tumor limited to the thyroid (StagesI and II, International Union Against Cancer [UICC,1987] staging system), whereas it is 55% for patients atStages III and IV.14

SurgeryAll patients with a preoperative diagnosis of MTCshould be screened for pheochromocytoma and hy-perparathyroidism with the 24-hour measurement ofurinary metanephrines and catecholamines and withthe determination of serum parathormone and cal-cium levels. If one or more pheochromocytomas arefound, adrenalectomy should precede thyroidectomy.15

Controversy exists about the kind of adrenalectomy tobe performed. A few clinicians have advocated bilat-eral adrenalectomy in those patients with MEN 2, evenwhen a pheochromocytoma involves one gland only.This has been suggested because of the frequent bi-lateral involvement caused by adrenal disease at thecellular level, even when it appears unilateral at radio-graphic imaging studies, and in consideration of apossible development of malignant pheochromocy-toma.16,17 Most experts have recommended unilateraladrenalectomy in patients with MEN 2 who show ra-diographic evidence of unilateral pheochromocytomafor the following reasons: 1) Approximately 50% ofpatients treated by unilateral adrenalectomy do notdevelop a pheochromocytoma in the opposite gland;2) The occurrence of malignant pheochromocytoma israre; 3) A more conservative approach avoids the riskof an Addisonian crisis, related to bilateral adrenalec-tomy.18 –21 If hyperparathyroidism is diagnosed, bothMTC and hyperparathyroidism are treated surgically,and these surgeries may be done simultaneously.22

Surgery is the most effective treatment for MTC(Fig. 1). However, the rarity and the generally lowbiologic aggressiveness of MTC make the extension ofsurgical dissection still controversial. Total thyroidec-tomy should be performed on all patients with MTC.In fact, bilateral cancer foci have been reported in20 –30% of the sporadic form and in almost 100% offamilial forms.23–26 In addition to total thyroidectomy,prophylactic central neck lymph-node dissection isadvised during primary surgery for the early and fre-quent involvement of locoregional nodes. In patientswith palpable, unilateral, intrathyroidal tumors, Moleyand De Benedetti27 recently have observed lymphnode metastases in 81% of central node dissections, in81% of ipsilateral functional dissections, and in 44% ofcontralateral functional dissections. In patients withbilateral intrathyroid tumor, lymph node metastaseswere present in 78% of central node dissections, in71% of ipsilateral functional dissections, and in 49% ofcontralateral functional node dissections. However,intraoperative palpation of nodes is not an accuratemethod for the detection of nodal metastatic involve-ment (sensitivity 5 64%, specificity 5 71%).27 There-fore, the strategy of resecting only macroscopicallyinvolved nodes (selective therapeutic lymphadenec-tomy) may not be successful in MTC.

Dralle et al.28 –30 have demonstrated in retrospec-tive studies that systematic lymphadenectomy, usingthe technique of a compartment-oriented microdis-section of cervicomediastinal lymph nodes, representsthe most suitable surgical treatment in MTC. In fact, innode-positive MTC, the rate of biochemical cure washigher after systematic lymphadenectomy (29.2%)than after selective lymphadenectomy (8.5%). More-over, survival was significantly better for patients aftersystematic instead of selective lymphadenectomy.28

Therefore, the rationale for a more extensive, com-partment-oriented, cervical lymphadenectomy ap-pears to be a useful strategy in approaching MTC.

Systematic lymphadenectomy consists of the “enbloc” microdissection of anatomically defined com-partments (central, mediastinal, and lateral regions)that contain lymph nodes, adipose, and connectivetissue. This type of surgery preserves, when possible,muscles, vessels, and nerves.28

The central compartment is bordered superiorlyby the hyoid bone, inferiorly by the brachiocephalicvein, and laterally by the carotid sheaths, including thesubmandibular lymph nodes.28 In some classifica-tions, the submandibular nodal group is excludedfrom the central compartment.27 Otherwise, Ellenhornet al.31 do not advise submandibular triangle dissec-tion unless nodes are palpated at that site, given the

TABLE 1Familial Forms of MTC

Type Associated lesions RET mutationsa Clinical behavior

MEN 2A Pheochromocytoma exons 11, 10 IntermediateHyperparathyroidismCutaneous lichen amyloidosis

MEN 2B Pheocromocytoma exon 16 AggressiveGanglioneuromatosisMarfanoid habitus

FMTC None exons 10, 11, 13,14

Mild

a See references 3–12.

1798 CANCER May 1 2001 / Volume 91 / Number 9

absence of metastases in submandibular lymph nodesas reported in a study of 32 MTCs.

The mediastinal compartment is made up oflymph nodes on both sides of the trachea from the leftbrachiocephalic vein down to the tracheal bifurcationwithin the anterior and posterior part of the medias-tinum, including any visible thymic tissue. Dralle etal.28 have used a trans-sternal approach. However,several authors recommend the dissection of the up-per thymus gland through a standard cervical incision.When mediastinal adenopathy is identified preopera-

tively, a complete mediastinal dissection by means ofa median sternotomy is a more complete opera-tion.27,32 A mediastinal dissection also is very impor-tant to detect abnormal parathyroid glands and tocure hyperparathyroidism in MEN 2A.33

The lateral compartment includes the area fromthe carotid sheath medially to the trapezius musclelaterally, and from the subclavian vein anteriorly tothe hypoglossal nerve posteriorly, and between thefascicles of the cervical plexus.28 However, in relationto the low incidence of involvement of posterior tri-

FIGURE 1. Therapeutic approaches of

medullary thyroid carcinoma.

Treatment of Medullary Thyroid Carcinoma/Vitale et al. 1799

angle nodes,31 Moley et al.34 do not routinely performan extensive dissection of the posterior triangle lymphnodes in the absence of palpable adenopathy.

During surgical procedures, recurrent nerves andparathyroid glands should be identified to avoid com-plications. However, the inferior parathyroid glandsoften are inseparable from the surrounding lymphnodes. In these cases, the balance between aggressivenodal resection and parathyroid preservation shouldfavor nodal resection. Therefore, the parathyroidglands should be left in situ when possible and shouldbe autotransplanted when they cannot be preservedon a vascular pedicle. A few experts suggest removingall parathyroid glands and performing autotransplan-tation into muscle of the nondominant forearm (inpatients with MEN 2A) or into the sternocleidomas-toid muscle (in patients with sporadic MTC, MEN 2B,and FMTC) after histologic verification (so as not toautograft lymph node metastases).23,27,34

At present, although most surgeons agree withroutinely performing total thyroidectomy and centralcompartment resection in MTC, the technique oflymph node dissection and its extension to lateral andmediastinal compartments are still debated. However,a thorough and complete cervical lymphadenectomyin addition to total thyroidectomy and central neckdissection, performed early in the course of this dis-ease, appear to decrease rates of locoregional recur-rence and to improve patient survival.

Genetic Counseling and DNA TestingThe RET protooncogene is located on chromosome10q11.2 and encodes a transmembrane protein ty-rosine kinase. It is made up of an extracellular domainthat includes a cysteine-rich region, a short trans-membrane domain, and a cytoplasmic tyrosine kinasedomain.6 The glial-derived neurotrophic factor(GDNF) is one of the RET ligands. Physiologic re-sponses to GDNF require the presence of a novelglycosyl-phosphatidylinositol-linked protein, calledGDNF receptor-alpha. GDNF promotes the formationof a physical complex between GDNF receptor-alphaand RET, thereby inducing its thyrosine phosphoryla-tion.35,36 RET expression has a role in the developmentand migration of neural crest and neuroendocrinetissue and in kidney organogenesis. Moreover, specificmutations convert RET into a dominant transforminggene with oncogenic activity in MTC.12,37

In fact, mutations in the RET protooncogene arefound in the germ line and in the tumor cell DNA ofmost patients with hereditary MTC, although they oc-cur only in the tumor tissue of approximately 30% ofsporadic forms. All of these patients must receive ge-netic counseling by expert personnel before blood

DNA testing, to be informed appropriately about theirdisease, its genetic aspects, and their therapeutic op-tions. The possibility of performing genetic testingshould be explained, including the benefits, and ne-cessity to identify the RET mutations. Possible impli-cations or problems should be discussed with pa-tients, including the following: the need to involveother family members for genetic testing; the possibil-ity of identifying no mutations; the implication andpossible impact of testing on insurance; strong feel-ings of guilt of affected gene carriers about transmit-ting the gene to their children; and a reluctance to-ward genetic tests because of the possibility ofdiscovering adultery. After patients give a written in-formed consent, specifically for the use of genetictesting for clinical management and for the disclosureof the test result to other family members for thispurpose, leukocyte DNA analysis should be performedto identify RET mutations and familial forms of MTC.When the mutation is found, the genetic counselingand testing must be performed as soon as possible inall first-degree relatives of the index case. In a familywith a known mutation of the RET protooncogene,members not carrying the mutation do not need bio-chemical testing and no test is required for their de-scendants. Furthermore, kindred with RET germ-linemutations should be considered at high risk of devel-oping MTC, if not already present; biochemicalscreening for MTC and other tumors associated withMEN syndromes should be considered. Currently,about 5% of MTC patients with a negative genetic testhave familial disease with unknown RET mutations.Therefore, pentagastrin screening usually is per-formed on all first-degree relatives of MTC patientswho have histologic features suggestive of a hereditarytumor. If the pentagastrin test is normal in three first-degree relatives, the probability of hereditary MTCreduces to an insignificant level.38 – 41 When pentagas-trin is not available, other substances (calcium, thyro-tropin-releasing hormone [TRH], omeprazole) can beused to stimulate CT levels. However, provocativetesting with pentagastrin remains the most efficaciousbiochemical test.42,43

Prophylactic thyroidectomy in asymptomatic at-risk patients, found to be carriers of RET mutations,appears to be the preferred therapy because of thehigh penetrance of familial MTC. Most experts recom-mend performing preventive surgery before age 6years in MEN 2A and FMTC gene carriers and as soonas possible in children with MEN 2B. The latter pa-tients have an earlier onset of MTC, which also is moreaggressive. For RET oncogene-positive patients whohave an elevated basal CT or who are older than 6years, a total thyroidectomy combined with central


neck dissection is recommended. This also is true forpatients who have tumors with or without palpablelymphadenopathy.44 –51

In this way, an early total thyroidectomy, basedexclusively on the genetic test result, removes nor-mal and malignant C cells before metastases candevelop.44,45 Wells et al.44 reported 13 patients (6 withnormal and 7 with elevated plasma CT levels) who hadinherited a mutation in the RET protooncogene. Aftereach of these patients had a timely thyroidectomy andcentral compartment dissection, only 4 of the 13 pa-tients (31%) had macroscopic evidence of MTC. Therewere no metastases to regional lymph nodes, andpostoperative stimulated CT levels were normal.

Therefore, genetic counselors play an importantrole in the management of familial MTC because theyare responsible for informing kindred of the theoreti-cal and practical aspects of the genetic tests and ther-apeutic options, including prophylactic thyroidec-tomy.

PostSurgery Therapy and Follow-upAfter thyroidectomy, postsurgical hypothyroidismmust be corrected (Fig. 1). Since MTC is not a TSH-dependent tumor, the administration of l-thyroxinemust be substitutive and not suppressive (l-thyroxine1.5–1.8 mg/kg/day).52

Follow-up of MTC is based on basal and stimu-lated plasma CT measurements. In fact, CT is the mainbiochemical marker for predicting the presence oftumor. Measurement of serum CEA levels also is use-ful during follow-up because high concentrations orrapidly increasing levels indicate disease.53–55

All patients should repeat CT determination 2months after surgery: if basal CT becomes undetect-able, a pentagastrin stimulation test is advisable. Pa-tients with normal stimulated CT levels are likely to beconsidered as surgically cured; neck palpation andplasma CT determination should be performed every6 –12 months. Conversely, elevated serum CT levelsafter surgery occur when a persistent or recurrentdisease is present. To detect the sites of the cancer,several techniques have been used including ultra-sound of the neck and liver, computed tomography ormagnetic resonance imaging of neck mediastinum,chest and liver, and radionuclide scanning using99mtechnetium methylene diphosphonate, 123I- or 131I-MIBG, 99mtechnetium (V) dimercaptosuccinic acid,201thallium, thallium and technetium subtraction,111indium pentetreotide, and 111indium-labeled anti-CEA monoclonal antibodies.14,52,56 –58

Selective venous sampling catheterization is usedfor localizing the origin of high serum-CT levels, butthis is a laborious, invasive, and expensive tech-

nique.58 Finally, laparoscopic liver examination in pa-tients with high CT levels has been considered for thediagnosis of liver metastases. Tung et al.59 identifiedliver metastases in 8 of 14 patients, 7 by laparoscopyand 1 by open examination. Seven of these patientsshowed no evidence of hepatic involvement by rou-tine laboratory tests, computed tomography, or mag-netic resonance imaging.59

Therapy of Persistent, Recurrent or Advanced DiseaseSurgerySurgery is again highly recommended when the dis-ease is well localized and isolated. Conversely, thereare two different views regarding the approach to pa-tients with high CT levels that are caused by persistentlocoregional or distant disease undetectable by con-ventional radiologic imaging (occult metastatic MTC)(Fig. 1). Some authors have suggested taking an ag-gressive approach to localize and treat occult meta-static MTC. A selective venous catheterization withstepwise collection of blood from the superior venacava, jugular, and mediastinal veins, hepatic vein, anda peripheral vein may be useful to detect the site of theneck that has the presumed MTC metastases and toexclude occult metastases in the mediastinum and theliver by evaluating the CT gradient. This procedurecan be improved by pentagastrin stimulation. Tisell etal.,60 Buhr et al.,61 and Moley et al.34 have recom-mended an aggressive microsurgical neck dissectionin these patients, with normalization of serum-CT lev-els in 15–36% of patients. The second approach ismore conservative. van Heerden et al.62 have studied31 patients with elevated CT levels in the absence of aclinically or radiologically detectable disease after pri-mary surgery for MTC. Eleven (36%) of these patientsunderwent additional surgical treatment after the clin-ical or radiologic localization of the tumor. None ofthese had normal basal-CT levels after the operation.However, the 5- and 10-year survival rates of all 31patients were excellent (90% and 86%, respectively).Therefore, van Heerden et al.62 have suggested thatreoperation should be deferred until clinical and ra-diologic signs of recurrence show in patients withoccult metastatic MTC, in relation to the often indo-lent course of the disease. However, multicenter stud-ies with a longer follow-up are deemed necessary todefine the optimum management of patients with oc-cult advanced MTC.

Radiation therapyNonsurgical approaches to MTC treatment have metwith inconsistent results. The role of external beamradiotherapy is controversial. Although most investi-gators agree that MTC is poorly radiosensitive and that


external beam radiation leads to some complications(cervical fibrosis, chronic dysphagia, radiation trache-itis, paraplegia),52,63 others64 have reported a reduc-tion in locoregional recurrences in high-risk patients.However, radiotherapy presently is used as a palliativefor symptomatic bone, central nervous system andmediastinal metastases, and as an adjunct to surgeryin patients with incomplete resections, direct extra-thyroidal invasion, recurrent disease, and extensivenode disease.65

Radioactive iodine does not heap up in patientswith persistent or metastatic MTC because C cells donot originate from thyroid follicles, and, therefore,they do not trap iodine.66

Recent studies have proposed the use of a newand specific radiotherapy for MTC, which is based onthe selective uptake of 131I-MIBG, and 111In-pentet-reotide.67– 69 Other nuclear medicine approaches withradionuclide-labeled monoclonal antibodies againstCEA have aroused interest in targeted radiotherapy foradvanced MTC.70,71 At present, these studies are lim-ited to a small number of patients and the preliminaryresults indicate only their mild palliative role.

ChemotherapyBecause of the indolent clinical course of MTC and thehigh survival rates of many patients despite the pres-ence of distant metastases, chemotherapy generally isused in patients with rapidly progressive, measurable,metastatic disease, but, to date, none of the regimensreported have been found to be particularly effective,and the response rate has been generally low (Table2). Adriamycin (60 –75 mg/m2 every 3– 4 weeks, or 15mg/m2 every week) is the most active drug used as asingle agent or in combination with others with a bestestimate of 37% partial remission (PR) rate. However,myelo- and cardio-toxicity were reported for these

patients, and all responses were limited and tempo-rary.72–76 Similar results were obtained with a 3-drugregimen: cyclophosphamide (750 mg/m2, Day 1), vin-cristine (1.4 mg/m2, Day 1), and dacarbazine (600mg/m2, Days 1 and 2). This regimen induces PR in 2 of7 patients with moderate or severe gastrointestinalside effects.77 Orlandi et al.78 reported PR in 3 of 5patients with metastatic MTC treated with the admin-istration of bolus dacarbazine (250 mg/m2/day) and5-fluorouracil (450 mg/m2/day) by a 12-hour constantinfusion over 5 days, administered every 4 weeks. Theauthors78 also reported Grade 1 leukopenia in 1 pa-tient and Grade 2 nausea and vomiting in 4 patients.Petturson79 used a similar schedule and reported onecomplete remission (CR).79 In a larger series of pa-tients, dacarbazine (200 mg/m2/day) and 5-fluoroura-cile (400 mg/m2/day) were administered for 5 days,followed, 3 weeks later by streptozocin (500 mg/m2/day) and 5-fluorouracil (400 mg/m2/day) for 5 days.This schedule was repeated every 6 weeks. PR in 3 of20 patients, stable disease (SD) in 11 of 20 patients,and progressive disease (PD) in 6 of 20 patients werereported. Grade III (World Health Organization[WHO]) toxicity occurred in 20% of patients (10% car-diotoxicity and 5% nephrotoxicity).80 Conversely, mi-toxantrone at 12 mg/m2 intravenously every 3 weeks ispoorly active in MTC.81 Garcia-Pascual et al.82 ob-served no response following short-term administra-tion of tamoxifen in advanced MTC.

The resistance of MTC to chemotherapy could becaused, at least in part, by the overexpression of theproduct of the mdr-1 gene by the tumor cells. In fact,mdr-1 encodes a transmembrane glycoprotein p-170that antagonizes intracellular accumulation of cyto-toxic agents of natural derivation and confers the mul-tidrug resistance phenotype to the tumor cells.83 Themdr-1 reverting agents (verapamil, cyclosporin A, and

TABLE 2Results of Chemotherapy in MTC

Schedule CR PR SD 1 PD Ref

ADM (60 mg/m2/day) 0 1 3 73ADM (60 mg/m2/day) 1 CDDP (40 mg/m2/day) 0 2 4 73ADM (15 mg/m2/week) 1 0 0 74BLM (Days 1–3: 30 mg/day 1 ADM (Day 5: 60 mg/m2) 1 CDDP (Day 5: 60 mg/m2) 0 3 5 75ADM (50 mg/m2) 1 CDDP (60 mg/m2) 1 VDS (3 mg/m2) 0 1 9 76CTX (Day 1: 750 mg/m2) 1 VCR (Day 1: 1.4 mg/m2) 1 DAC (Days 1–2: 600 mg/m2/day) 0 2 5 77DAC (250 mg/m2/day) 1 5-FU (450 mg/m2/day) 0 3 2 78DAC (200 mg/m2/day) 1 5-FU (400 mg/m2/day) 3 STZ (500 mg/m2/day) 1 5-FU (400 mg/m2/day) 0 3 17 80DHAD (12 mg/m2/day) 0 1 4 81TAM (20 mg 3 2/day) 0 0 2 82

ADM: adriamycin; CDDP: cisplatin; BLM: bleomicin; VDS: vindesine; CTX: cyclophosphamide; VCR: vincristine; DAC: dacarbazine; 5-FU: 5-fluorouracil; STZ: streptozocin; DHAD: mitoxantrone; TAM: tamoxifen; CR:

complete remission; PR: partial remission; SD 1 PD: stable disease 1 progressive disease.


SDZ PSC 833) enhance the activity of chemotherapeu-tic agents in vitro but they are highly toxic in vivo.84,85

Moreover, it must be borne in mind that all reporteddata are derived from small Phase II studies, and,therefore, considerable selection bias might have oc-curred. However, the results of the above-mentionedclinical studies indicate that the activity of chemother-apy is only marginal, and its side effects may reducethe quality of life in MTC patients. Therefore, chemo-therapy should be used only in patients with rapidprogression of the disease.

Biological therapyThere is now growing interest in the possible clinicaladvantages induced by the treatment of highly symp-tomatic human tumors even in the absence of objec-tive tumor regression. This means that, in the clinicalbenefit-based approach, a treatment that induces asignificant reduction in symptoms even in the absenceof objective tumor regression is valued more than atreatment that induces transient tumor shrinkage withconsiderable side effects and poor control of symp-toms. The emerging medical approaches must beevaluated for their impact on the functional, psycho-logical, and social health of the individuals. Althoughtumor response, disease-free interval, time to progres-sion, and overall survival remain the main endpointsof cancer clinical trials, the quality of life has beenincluded, quite rightly, as a parameter in the evalua-tion process. In fact, it is now recommended thatfuture research approaches should explore the qualityof life domains throughout all the stages of cancertreatment.86,87 On the basis of these considerations,biologic drugs appear to be suitable agents in thetreatment of symptomatic MTC.

An interesting possibility is that chemoresistanttumors, such as MTC, could be responsive to biologicresponse modifiers or biologic drugs. These agentscan act by direct antiproliferative effects (inhibition oftumor cell growth without cytolysis) and can stimulatethe antitumor immune response without considerableside effects. In fact, over the last few years somatosta-tin analogs (octreotide and lanreotide) and interferon-a

(IFNa) have been used in the therapy of advanced andsymptomatic MTC.

Somatostatin analogs inhibit neuroendocrine tu-mor cell growth through the inhibition of the releaseand activity of growth-promoting hormones or fac-tors, inhibition of angiogenesis, modulation of immu-nologic activity, and direct antimitotic effects by wayof somatostatin receptors.88 Octreotide appears tohave an impact on the symptoms and on the produc-tion of CT in MTC patients. However, it has not been

demonstrated that octreotide reduces the tumor massor improves the patient survival rate.88 –92

Mahler et al.93 treated 3 patients who had ad-vanced MTC with high-dose octreotide (600 –2,000 mg/day) for 3–17 months. The symptoms induced by thetumor (diarrhea, asthenia, and weight loss) improvedin all the patients and side effects were negligible. Themaximum decrease in serum CT was 2 47%, 2 52%and 2 81% of the basal values, and it was observed inthe 1–3 month period after the beginning of the treat-ment. A long-lasting effect was observed in two pa-tients. Modigliani et al.94 treated 14 patients affectedby MTC with 500 mg/day octreotide for 90 days byconstant subcutaneous infusion. Octreotide producedno major side effect, and, in 4 of 14 patients, CT levelsdecreased during treatment (2 43%, 2 50%, 2 15%and 2 20%). After completion of the treatment, CTincreased in 9 patients (1 22% to 1 130%). A slightregression of cervical node metastases was observedin one patient during the treatment, and asthenia wasreduced in eight patients. Raue et al.95 treated 7 MTCpatients with 200 –1,000 mg/day octreotide for 3–9months. In this study, no symptom improvement wasdetected, and CT serum levels decreased in 1 patientonly (2 61% of the basal values).

IFNa has antiproliferative activity against neu-roendocrine tumors through mechanisms differentfrom, and sometimes complementary to, octreotide.In fact, IFNa increases the non-MHC restricted cyto-toxicity against tumor cells. It also increases the secre-tion of immunoglobulins at low doses by plasma cellsand exerts a direct cytotoxic effect on tumor cells. Themolecular mechanisms of the direct antitumor effectof IFNa still are not completely clear. It has beensuggested that IFNa may deprive tumor cells of essen-tial metabolites such as glucose or tryptophane. More-over, IFNa activates a series of transcriptional factorsthat elicit the arrest of DNA synthesis.96 –100

Bajetta et al.101 have found that IFNa-2a (6 3 106

international units/day for 8 weeks and then 3 times aweek) has a remarkable activity in the treatment ofneuroendocrine tumors (49 patients). They observedan improvement in the symptoms of 64% of patients,1 CR in a patient with MTC with mediastinal involve-ment, and 4 PRs in the 34 patients with carcinoidsincluded in the series.

An interesting tool for the treatment of refractorytumors may be the use of combined biologic agents.In fact, we treated six patients affected by advancedMTC with a combination of octreotide and IFNa. Oc-treotide was administered subcutaneously at a dailydose of 150 mg for 6 months and subsequently at adaily dose of 300 mg for 6 more months. IFNa wasadministered intramuscularly at 5 million interna-


tional units 3 times a week for 12 months. The maxi-mum decrease of CT was reached after 1 month in 2patients ( 2 56% and 2 34% from the basal CT values)and after 3 months in 4 patients (2 88%, 2 34%,2 36% and 2 42% from the basal CT values). There-after, CT values increased moderately in all patients.CEA levels decreased in all patients. Preexisting diar-rhea and flushing significantly improved during long-term treatment. All patients expressed a feeling of wellbeing.102

In a recent report, we have described the effects ofthe slow-release lanreotide (30 mg, intramuscularly,every 10 –14 days) in combination with interferon-a-2b (5,000,000 international units, intramuscularly, 3times a week) in 7 patients with advanced and symp-tomatic MTC. To provide unbiased and objective cri-teria for the definition of response to systemic treat-ment of symptomatic MTC, a structured algorithm forthe assessment of clinical benefit and biochemicalresponse has been defined. Our algorithm is based onthe comparison between parameters such as diarrhea,flushing, fatigue, weight, performance status, and CTlevels. During the therapy, the number and intensityof bowel movements and flushing episodes decreasedin 5 of 6 and 2 of 2 patients, respectively. Decrease infatigue and improvement in performance status wereobserved in 5 of 7 and 6 of 7 patients, respectively.Weight gain was recorded in 3 of 4 patients. Plasmalevels of CT decreased significantly in 6 of 7 patients.Clinical benefit was achieved in 6 of 7 patients andwas coupled with a biochemical response in 3 of 7patients. Disease stabilization and minor tumor re-gression were observed in 3 of 7 and 2 of 7 patientsrespectively.103

Therefore, biologic therapy of MTC appears tohave a symptom-relief effect and low toxicity with avery good compliance. Also, it can be administeredeasily as an outpatient regimen.

In vitro and in vivo studies have proposed the useof interleukin-2 (IL-2) in the treatment of MTC. Tu-mors caused by implanted MTC cells in animals canbe inhibited in their growth and even eradicated bylocal secretion of IL-2. This cytokine leads to the de-velopment of antitumoral immunity by stimulatingthe proliferation of cytotoxic and helper T cells, caus-ing the activation of natural killer cells and enhancingtheir cytolytic function as lymphokine-activated killercells.104 –107 Conversely, severe side effects due to sys-temic administration of high doses of IL-2 have lim-ited its clinical use in the treatment of cancer. Toovercome this problem, some investigators trans-fected IL-2 complementary DNA into tumor cells. Theresults have shown that IL-2-secreting tumor cells losttheir tumorigenicity and induced an efficient immune

response after implantation into syngeneic ani-mals.104,105 Retroviruses and adenoviral vectors mayrepresent an alternative approach to the use of xeno-geneic cells for local interleukin delivery. In smallMTCs, (# 30 mm3), intratumoral injection of replica-tion-defective adenoviral vectors containing murineIL-2 complementary DNA (AdCMVmIL2) induced tu-mor regression in 69% of animals. The treatment oflarge tumors (. 30 mm3) with AdCMVmIL2 led to thestabilization of the tumor size in 71% of cases, but itdid not completely treat them.106,107

These data demonstrate the ability of IL-2 to elicitspecific antitumor immune response and offer hopefor the use of this therapy on humans, which shouldlead finally to a vaccine for the protection of familymembers at risk of developing the disease. Also, itcould be used as adjuvant therapy after surgery and asa cure in patients with advanced MTC. However, vac-cine strategies deserve further investigation and, pres-ently, should be considered a strictly experimentalapproach.

Conclusions and Perspectives in the Therapy of MTCMTC has a slow and progressive clinical course withfrequent involvement of blood vessels and lymphnodes in the neck. Surgery is the only treatment thatcan be curative. Therefore, the main objective of MTCtherapy is the radical ablation of the tumor masses,that is, total thyroidectomy with bilateral central, me-diastinal, and lateral neck dissection. Our experiencesuggests taking an extremely aggressive approachright from the first surgery. However, reoperationshould be performed in the presence of elevated post-operative plasma-CT levels when the site of the MTChas been defined.108

In advanced MTC, chemotherapy, along with itspotential toxicity, induces major responses only in alow percentage of treated patients and has only neg-ligible effects on neuroendocrine symptoms (flushing,diarrhea, electrolytic disorders, Cushing syndrome).Therefore, chemotherapy should be used only in pa-tients who have rapidly progressing metastatic MTC.Conversely, somatostatin analogs and IFNa are welltolerated, and they readily improve tumor symptomsand quality of life. However, these studies are limitedto a small series of patients, and there are no consis-tent data available on the effects of the biologic agentson the inhibition of tumor growth and patient sur-vival. The introduction of an objective algorithm, pro-posed by our group to evaluate the efficacy of thetherapy with valid interobserver possibility of repro-ducibility, is necessary for multiinstitutional studieson rare diseases such as MTC. Therefore, it would beuseful to evaluate the efficacy of biologic therapy.103


Medical treatment of advanced MTC will requirefurther attention in the near future. On the basis of theresults currently available, we believe that the com-bined use of chemotherapy, endocrinotherapy, andbiologic therapy could be beneficial. A better under-standing of the immunologic and endocrine microen-vironment of medullary thyroid tumor cells is essen-tial for devising new therapeutic strategies againstMTC. Future experimental approaches will have toinclude the use of biologic response modifiers withimmunomodulatory capacities, such as IL-2, also incombination with other agents (drugs or biotechno-logic products), targeted radiotherapy, and gene ther-apy aimed at inhibiting the effects of RET activation.

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Current approaches and perspectives in the therapy of medullary thyroid carcinoma

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