Critical Reviews in Oncology/Hematology 37 (2001) 47–51

The treatment of undifferentiated neuroendocrine tumors

Emmanuel Mitry *, Philippe RougierSer6ice d’Hepato-Gastroenterologie et Oncologie Digesti6e. Hopital Ambroise Pare, 9 A6enue Charles de Gaulle, 92104 Boulogne Cedex, France

Accepted 10 May 237

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483.1. Etoposide+cisplatin combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483.2. Other chemotherapy regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

4. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

5. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Abstract

The aggressiveness of poorly-differentiated neuroendocrine tumors is similar to small-cell lung cancer within a median survivalof 6 months without treatment. Most patients have metastatic disease and poor condition at the time of diagnosis, and cannotbe approached surgically with curative intent. Moertel et al. [Treatment of neuroendocrine carcinomas with combined etoposideand cisplatin, Cancer 1991;68:227–232] reported an objective response rate of 67% with a chemotherapy regimen combiningetoposide plus cisplatin, with a median survival of 19 months and a median time to progression of 11 months. Since thispublication, this regimen has been considered as the reference treatment for poorly-differentiated neuroendocrine tumors. AFrench retrospective study has recently confirmed the high chemosensitivity of those tumors. However, the prognosis remainspoor with a 2-year survival lower than 20% and other therapeutic approaches should be developed. © 2001 Elsevier ScienceIreland Ltd. All rights reserved.

Keywords: Neuroendocrine tumors; Drug therapy; Pathology; Etoposide; Cisplatin; Survival analysis

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1. Introduction

Despite common pathological features, neuroen-docrine tumors (NET) are a heterogeneous group oftumors arising from diverse sites, presenting with differ-ent clinical syndromes or biological activity, differentaggressiveness and prognosis. According to the second

* Corresponding author. Tel.: +33-1-49095878; fax: +33-1-49095880.

E-mail address: emmanuel.mitry@apr.ap-hop-paris.fr (E. Mitry).

1040-8428/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.PII: S 1 0 4 0 -8428 (00 )00073 -1

E. Mitry, P. Rougier / Critical Re6iews in Oncology/Hematology 37 (2001) 47–5148

World Health Organization classification [1], well-dif-ferentiated and poorly-differentiated NET should bedistinguished. This distinction according to tumoraldifferentiation is important since it has a therapeuticand prognostic impact.

Poorly differentiated endocrine carcinoma–small cellcarcinoma is defined as ‘‘a malignant epithelial tumorcomposed of highly atypical, small- to intermediate-sized tumour cells growing in the form of large, ill-defined aggregates, often with necrosis and prominentangioinvasion and/or perineural invasion’’ [1].

In contrast to well-differentiated NET, which areusually slow-growing tumors, the aggressiveness ofpoorly-differentiated NET (PDNET) is similar to small-cell lung cancer (SCLC), resulting in a median survivalof 6 months without treatment [2,3].

2. Epidemiology

Epidemiological data about PDNET are rare andtheir incidence, probably less than 10% of all the NET,is difficult to estimate precisely. PDNET seem morefrequent in males [4–6] and the median age at the timeof diagnosis is around 50 years of age [5,6]. But cases ofPDNET before the age of 30 years have been reported[7,8]. PDNET are rarely functional tumors with hor-monal hypersecretion [6] but a pathological ACTH,somatostatinoma or serotonin hypersecretion [9], orhypercalcemia are possible with pancreatic PDNET[10].

3. Treatment

3.1. Etoposide+cisplatin combination

Surgery is the only curative modality of NET but, incases of unresectable tumor, many options areavailable.

In well-differentiated NET, careful observation maybe the best attitude for patients with indolent, nonfunc-tional and slow-growing metastatic tumor. In case ofprogressive well-differentiated NET, chemotherapyand/or biotherapies (interferon, somatostatin ana-logues) and/or local treatments (arterial ligation,chemoembolization) may provide an effective palliationof symptoms, and allow improvements in the quality oflife in symptomatic tumors and in survival in pancreaticNET [11].

In contrast, most patients with a PDNET havemetastatic disease and poor condition at the time ofdiagnosis, and cannot be approached surgically withcurative intent [5,12].

The rarity of PDNET does not allow for prospectiverandomized trials evaluating chemotherapy regimens,

and only small nonrandomized prospective or retro-spective studies have been published.

Etoposide is a drug with known single-agent efficacyin the treatment of SCLC [13]. Etoposide plus cisplatinhave a synergic action in vitro [14] and on tumors ofmice [15]. This combination is actually considered asthe reference treatment for SCLC [16]. Because ofcommon features between PDNET and SCLC, thecombination of etoposide+cisplatin has been evalu-ated in the treatment of PDNET.

In 1987, Davis et al. reported activity with thiscombination in a small group of patients with carcinoidtumors [17]. In 1989, Morant et al. reported the case ofa patient with a polymetastatic pancreatic PDNETprogressing after initial chemotherapy with strepto-zocin, 5-fluorouracil (5-FU) and methotrexate, doxoru-bicin, cyclophosphamide and lomustine (MACC) whoremained in complete remission 26 months after achemotherapy with etoposide (150 mg/m2/day intra-venously on days 1–3) and cisplatin (50 mg/m2 onintravenously on day 2) [18]. Hainsworth et al. reported72% of major objective responses (OR) among 23 pa-tients with PDNET of unknown primary site treated bythe etoposide+cisplatin combination or other cis-platin-based regimens [5]. Updated results recently pub-lished have confirmed more than 75% of OR withalmost 25% of complete responses (CR) [19].

In 1991, Moertel et al. reported their experience witha regimen combining etoposide 130 mg/m2/day for 3days plus cisplatin 45 mg/m2/day on days 2 and 3, bothdrugs given by continuous intravenous infusion, in agroup of 45 patients with metastatic NET [6] (Table 1).In the subgroup of 18 patients with a PDNET, a majortherapeutic activity was found with an OR rate of 67%(with 17% of CR) and a median duration of response of8 months (range up to 21 months). The median survivalwas 19 months and the median time to progression 11months. In contrast, the OR rate in 27 patients withwell-differentiated NET was only 7%. Since this publi-cation, the association of etoposide and cisplatin hasbeen considered as the reference treatment formetastatic poorly-differentiated NET.

In 1995, Seitz et al. observed 75% of OR with 25% ofmajor responses among eight patients [20].

A retrospective analysis of 41 patients withmetastatic poorly differentiated NET treated at theGustave-Roussy Institute with a etoposide–cisplatincombination had recently confirmed the highchemosensitivity of those tumors [21]. Patients receivedthe following chemotherapy every 21 days: cisplatin,100 mg/m2 intravenously on day 1 in a 2-h infusion,and etoposide, 100 mg/m2/day intravenously from days1 to 3 in a 2-h infusion. The OR rate was 41.5% (fourcomplete responses, 13 partial responses). The medianduration of tumoral response was 9.2 months (range,4.5–23.5 months). The median survival was 15 months

E. Mitry, P. Rougier / Critical Re6iews in Oncology/Hematology 37 (2001) 47–51 49

(range, 11.7–25 months) and the median progressionfree survival was 8.9 months (range, 6.7–13.4 months)(Table 1).

Cisplatin is a platinum compound that producesinter-strand and intra-strand cross-links of cellularDNA in a similar manner to bifunctional alkylatingagents. Major dose-limiting toxicities of cisplatin aresevere nausea-vomiting and renal toxicity. Acutenephrotoxicity was highly frequent in the past but hasbeen greatly reduced by intravenous hydration andforced diuresis. Cumulative nephrotoxicity remains aproblem and may be severe. Cisplatin may also causeserious electrolyte disturbances, mainly represented byhypomagnesemia, hypocalcemia, and hypokalemia.Myelosuppression often occurs but is mostly mild tomoderate and reversible at the usual doses. Ototoxicityappears to be dose-related and cumulative, and is usu-

ally reversible. Peripheral neuropathies occur infre-quently with the usual doses and are generally sensoryin nature

Etoposide is a semisynthetic derivative of podophyl-lotoxin that exhibits cytostatic activity in vitro by pre-venting cells from entering mitosis or by destroyingthem at a premitotic stage. The major dose-limitingtoxic side effect is myelosuppression, mainly neutro-topenia and thrombocytopenia. Mild to moderate nau-sea and vomiting are the main gastrointestinal toxiceffects. Alopecia and hypotension following rapid intra-venous administration may occur.

Severe hematological and neurological toxicity was amajor problem in Moertel et al.’s study, and dosagereductions or cessation of therapy were frequently re-quired [6]. Seitz et al. failed to avoid the hematologicalcomplications by the systematic use of granulocytecolony-stimulating factor [20]. The regimen we usedwas less intensive and better tolerated with less acutetoxic effects but more frequent cumulative toxicity [21].

3.2. Other chemotherapy regimens

Objective responses have also been observed in fewpatients included in phase II studies evaluating otherchemotherapy regimens.

Three patients with a metastatic PDNET of un-known primary site had an objective tumoral responsewith a combination of paclitaxel, carboplatin andetoposide [22]. Seven of the 24 patients included in aphase II study evaluating 5-FU in continuous infusionin association with a-2b interferon had a PDNET (sixof unknown primary site and one originating for thecolon). Two patients had a partial response during 2.5and 24.5 months, respectively, whereas the other pa-tients had a stabilization of their disease [23].

4. Prognostic factors

Age, tumor size, stage and primary site may berelated to the outcome of NET [2,24–26]. Biologicalactivity of NET may also have an impact on survival[27,28]. Tumor differentiation remains, however, themain factor related with survival.

For the subgroup of PDNET, no significant relation-ship was found between tumoral response or patientsurvival and patient age or gender, primary tumor site,stage, hormonal secretions, prior treatment orchemotherapy line [6,21]. In the IGR study, the re-sponse rate for tumors of unknown primary site waslower compared with tumors with a known primary site(14.3% versus 47.1%, P=0.2) [21] and contrasted withthe results from Hainsworth et al. [5], who observed a72% major responses rate with cisplatin-based regimensin PDNET of unknown primary site.

Table 1

IGR [21]Mayo Clinic [6]

Total number of patients 18 41Male/female 32/910/8

52 (24–74)Median age in years (range) 53.4 (20–76)

Primary tumor site

55.5%Foregut 78%Pancreas 6 13Stomach 3 3

0Gallbladder 25Respiratory tract 1

Mediastinum 0 5Head and neck 0 4

Midgut 16.7% 4.9%Small bowel 2 0Right colon 21

Hindgut 011.1%2 0Rectum

Unknown Primary site 16.7% 17.1%

Prior chemotherapy 17% 32%Median number of courses 6 (1–9)5 (2–22)

(range)

Tumoral response3 (17%)Complete response 4 (9.8%)

Partial response 139 (50%)(31.7%)

6 (33%)Stabilization 14(34.1%)

Progression 0 10(24.4%)

9.24 [4.5–23.5]Median duration of response 8 (3–21)(range)

Sur6i6al19 (5–36+)Median survival (range) 15 (11.7–25)

8.9 (6.7–13.4)Median time to progression 11 (2–21)(range)

E. Mitry, P. Rougier / Critical Re6iews in Oncology/Hematology 37 (2001) 47–5150

5. Conclusion and perspectives

In conclusion, NET differentiation is a main progno-sis factor that should be clearly specified when deter-mining a therapeutic strategy. Poorly-differentiatedNET are characterized by rapid tumor growth and highchemosensitivity. The combination of etoposide andcisplatin provides 40–70% of objective responses and isactually the reference treatment for inoperable tumors.Response to treatment occurred early and it is probablyunnecessary to continue chemotherapy for patients whohave not responded after three courses. Nevertheless,considering the aggressiveness of this type of tumor andthe absence of alternative efficient therapy, a stabiliza-tion for patients with progressive disease could beconsidered as a positive result. In this situation, contin-uing the chemotherapy, if it is well tolerated, may bebeneficial. Chemotherapy probably improves the sur-vival of patients with such tumors but the prognosisremains poor with quick relapses and a 2-year survivallower than 20%.

There is clearly a need to develop new and moreactive chemotherapy regimen to improve these results.Recently, phases I and II studies with new chemother-apy combinations with taxoids or topoisomerase I in-hibitors in the treatment of SCLC have been presented(ASCO Meeting, 1999). An OR rate of 60% with 21%of CR has been observed with paclitaxel plus topote-can. Objective response rates higher than 50% were alsoobserved with paclitaxel plus carboplatin plus ifos-famide, paclitaxel plus cisplatin, docetaxel plus cisplatinor irinotecan+etoposide. A future randomized phaseII study of the European Neuro Endocrine Tumorgroup (ENET) will evaluate the combination of cis-platin and docetaxel versus etoposide plus cisplatine inthe first-line treatment of inoperable PDNET.

Reviewers

Prof. Kjell O8 berg, Chairman, Department of MedicalSciences, Internal Medicine, University Hospital, 75185 Uppsala, Sweden.

Prof. Michel Mignon, Chef de Service, Serviced’Hepato-Gastroenterologie et de Nutrition, HopitalBichat-C. Bernard, 46 rue de Henri Huchard, 75877Paris Cedex 18, France.

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Biographies

Emmanuel Mitry is a medical doctor, specialist ingastroenterology and digestive oncology. He is MD

assistant at the Rene Descartes Faculty (Paris V) andthe Service of Hepatogastroenterology and DigestiveOncology of the Hospital Ambroise Pare-Boulogne,France. He is member of SNFGE and FFCD.

Philippe Rougier is a medical doctor, specialist in gas-troenterology and digestive oncology. He was MD as-sistant at the Institut Gustave Roussy (IGR)-Villejuif,France between 1981 and 1988, and the head of theGastrointestinal Unit at IGR between 1988 and 1997.He is currently Professor of Medicine at the ReneDescartes Faculty (Paris V) and the Service of Hepato-gastroenterology and Digestive Oncology of the Hospi-tal Ambroise Pare-Boulogne, France. He is member ofASCO, AACR, EORTC, ESMO, and the French gas-troenterology Association (SNFGE), and is vice-presi-dent of the French foundation for digestive cancerology(FFCD).

.