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REVIEW |
Department of Medical Oncology, Vall d’Hebron University Hospital, Ps. Vall d’Hebron, 119-129, Barcelona 08035, Spain
1 Department of Medical Oncology, Institut Català d’Oncologia, Barcelona, Spain
2 Department of Endocrine Oncology, University Hospital, 751 85 Uppsala, Sweden
(Requests for offprints should be addressed to E Vilar; Email: evilar{at}vhebron.net)
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Abstract |
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 Top Abstract IntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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The WHO classification of 2000 divided neuroendocrine malignancies into three groups: well-differentiated NET, well-differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine carcinoma. Distinction between groups relies on several pathological and clinical data such as invasion of muscularis propria, histological differentiation (well-differentiated versus poorly differentiated), tumor size ( < 2 vs 2 cm), angioinvasion, Ki-67 index ( < 2, > 2, and > 30%), biological behavior (benign, low-grade and high-grade malignant), presence of metastases, and presence of hormonal symptoms. However, a sub-classification according to tumor localization distinguished several origins: gastric, duodenum, ileum, appendix, colon–rectum, and pancreas. In this review, we have included both well-differentiated pancreatic NETs and carcinomas under the term of PETs, and both well-differentiated NETs and carcinomas from any other localization of the gastrointestinal tract (including gastric, duodenum, upper jejunum, ileum, cecum, colon–rectum, and appendix tumors) under the term of CT. Poorly differentiated tumors are characterized by extensive angioinvasion, increased necrosis, nuclear atypia, and high mitotic activity measured by mitotic count or by Ki-67. Although a clear cut-off value for Ki-67 has not been established, several authors placed it between 20 and 30% (Kloppel et al. 2004, Rindi et al. 2006).
NETs are rare as they constitute < 2% of all gastrointestinal malignancies (Oberg et al. 2004b); CTs are the most frequently occurring NETs with an adjusted incidence rate of approximately four cases per 100 000 population per year, which appears to have increased over the past 30 years (Modlin et al. 2003). Incidence of PETs is estimated from indirect data based on the largest series reported (Jensen & Norton 1995).
Most of the cases have low growth rates with survival times longer than other gastrointestinal tumors, site by site. Thus, use of chemotherapy in cases of unresectable locoregional or advanced disease is usually preferred only after treatment with locoregional techniques and biological therapies have failed.
Several studies have tried to better define the prognosis of patients using several immunohistochemistry markers in biopsies from primary tumors or metastases; nevertheless, there is a lack of prospective trials assessing the role of these markers in the advanced setting, and misleading interpretations of retrospective results may lead to an inappropriate use of them.
In this review, our objective is to analyze the role of the expression of the proliferation marker Ki-67 and review the relevant studies of chemotherapy in the digestive NETs with a view to identify specific subgroups of patients that derive the largest benefit from this therapeutic option.
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Role of KI-67 proliferation index in digestive NETs |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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, would represent better options (Rougier & Mitry 2000, Kaltsas et al. 2004, Oberg et al. 2004a). An alternative approach is to try to identify the pathological features to assist in characterizing subgroups with similar biological behavior that may lead to a better patient selection for chemotherapy treatments. The combination of microscopic structural analysis and immunohistochemical detection of cell cycle-related antigens may distinguish the level of aggressiveness in NETs. There are several antibodies against different cell cycle proteins available in the market to quantify the proliferation by immunohistochemistry in formalin-fixed paraffin-embedded tissue, such as proliferation cell nuclear antigen (PCNA) and Ki-67. PCNA is a protein found in the nucleus that acts as a cofactor of DNA polymerase and increases the processivity of leading strand synthesis during DNA replication. The antibody against it recognizes a 36 kDa protein that is present during the S phase (Lloyd 1998); however, in response to DNA damage, it is ubiquitinated and associated in the RAD6-dependent DNA repair pathway, so its detection will mark cell proliferation and DNA repair processes (Hoege et al. 2002). The Ki-67 protein is a proliferation antigen, which is present in G1, S, G2, and M phases of the cell cycle. Quiescent or resting cells in the G0 phase of the cell cycle do not express the Ki-67 antigen. Probably, the Ki-67 index is the best available marker of proliferation because it is not involved in DNA repair process as PCNA; MIB-1 monoclonal antibody is the most commonly used because it is readily available and compares well with other antibodies against Ki-67 due to the high specificity of nuclear versus background staining (Lloyd 1998).Inthe majority ofpublications,Ki-67 proliferation index is assessed by scanning the stained slide to determine the area of maximum staining intensity. The number of positive cells in a total of 2000 or more tumor cells observed in ten or more representative high-power fields (HPF) is counted (Rindi et al. 2006).
There are several studies in PETs as well as in CTs that attempt to determine the role of PCNA and Ki-67 as predictors of biological behavior (Table 1
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With regard to CTs, several authors (Chaudhry et al. 1992, Sokmensuer et al. 2001, Kawahara et al. 2002) have demonstrated a similar correlation between low Ki-67 values and longer survival, although a clear cutoff value is not defined. In addition, one publication reported in the literature includes the analysis of both CTs and PETs (Canavese et al. 2001). This paper reports on the results of Ki-67 along with other immunochemistry markers of 109 gastrointestinal NETs from the University of Parma. The authors reviewed the primary specimens of 46 PETs, 51 CTs and 12 poorly differentiated tumors. Malignancy was defined according to WHO criteria as evidence of invasion of surrounding tissues and/or metastasis to lymph nodes or distant sites. Mean Ki-67 value was found to be significantly different between benign and malignant tumors (0.05 vs 1.99%, P < 0.0001). Poorly differentiated tumors were characterized by a very high Ki-67 index that was > 14% in all cases. Interestingly, midgut carcinoids presented low Ki-67 values, despite they met malignancy criteria (median 0.1%).
In summary, these studies include patients affected by locoregional or advanced PETs, CTs, or both who have undergone surgery. They are retrospective and their common objective is to evaluate whether Ki-67 proliferation index could be a prognostic factor of metastasis or survival. The evidence is convincing in that Ki-67 evaluation yields prognostic information of added value to the classical pathological report whenever it is performed in laboratories, where the test has been validated. In fact, in the last TNM staging proposal for foregut NETs Ki-67 is determined to asses the tumor grade and three groups are defined: %2%, between 3 and 20%, and > 20% (Rindi et al. 2006). However, there are several caveats to consider in the interpretation of the results from these studies. First, most of these studies have reviewed a single-institution experience with PETs or CTs that have been surgically resected (Pelosi et al. 1992, La Rosa et al. 1996, Clarke et al. 1997, Hochwald et al. 2002, Jorda et al. 2003). Secondly, patients were considered to have advanced disease if they presented with either locoregional lymph node or distant metastasis (La Rosa et al. 1996, Clarke et al. 1997, Hochwald et al. 2002, Jorda et al. 2003). Thirdly, prognostic factors are derived from the clinicopathological and immunohistochemical characteristics of the primary tumor and they are retrospectively correlated with patient outcome independently of the initial staging. Fourthly, only two studies includes both tumor primary types, PETs and CTs (Canavese et al. 2001, Panzuto et al. 2005), so comparison of Ki-67 prognostic value against primary site type or location in large series is lacking.
Based on the former studies that state the role of Ki-67 as a prognostic factor, several authors and guidelines (Öberg 2002, Oberg et al. 2004b) have proposed that the Ki-67 value could be a valid surrogate marker of biological behavior, and it could possibly substitute for clinical course surveillance to establish the indication of chemotherapy. Given the current evidence, it is sensible to hypothesize that tumors with high Ki-67 may respond better to chemotherapy, but this should be tested in prospective clinical studies that assess the role of Ki-67 as a predictive factor of responsiveness to chemotherapy or other biological therapies. One limitation to this approach is the potential intratumoral heterogeneity and the differential expression between metastasis and primary tumors, when faced with a biopsy sample in a metastatic setting, which could jeopardize the clinical validation of Ki-67 as a predictive factor in this group of patients (Chaudhry et al. 1992), as it has been showed in other neoplasms (Dodd et al. 1997, Yasui et al. 2006).
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Chemotherapy in PETs |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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There are a number of solid arguments that support the indication of chemotherapy as an effective treatment in PETs. First, it is well established that streptozocin (STZ) selectively targets pancreatic islet cells (Murray-Lyon et al. 1968), possibly through a transport system that is present on pancreatic ß-cells and recognizes the glucose moiety of STZ (Kawada et al. 1987). Secondly, Ki-67 is, on average, higher in PETs than in CTs (Canavese et al. 2001), which may render them candidates for chemotherapy earlier in the treatment plan. High Ki-67 values may relate to other poor prognostic features such as higher tumor size (mean 5–6 cm), local extension, perineural or angioinvasion, and lymph node or distant metastasis (Clarke et al. 1997, Gentil Perret et al. 1998, Rindi et al. 1998, Pape et al. 2004). In addition, the majority of well-differentiated PETs are non-functioning, which in some reports have higher Ki-67 than functioning tumors (Clarke et al. 1997). Finally and most importantly, data from phase II and III trials show that PETs respond to a number of chemotherapeutic agents, and that combination regimens are better than mono-therapy (Moertel et al. 1980, 1992).
Several cytotoxic agents have been evaluated in monotherapy (Table 2). In a phase II trial, doxorubicin (DOX) showed an response rate (RR) of 20% in 20 patients previously treated (Moertel et al. 1982). A phase II trial conducted by the ECOG tried to assess the efficacy of dacarbazine (DTIC; Ramanathan et al. 2001). The RR was 34% in 50 patients included, with a median survival of 19.3 months and a mild toxicity profile. High-dose paclitaxel with G-CSF support has been analyzed in a phase II trial (Ansell et al. 2001). Nine patients with advanced PETs were included showing no radiological and only one biochemical response. Therefore, taxanes are considered inactive for this group of tumors. Likewise, gemcitabine showed no radiological or biochemical responses among seven patients with PETs (Kulke et al. 2004b).
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) produced much of the evidence of what is still considered the standard of care. A total of 103 patients were randomized to receive STZ and 5-fluorouracil (5-FU) or STZ in a phase III trial conducted by Moertel et al.(1980). The combination treatment was better than the single-agent arm in terms of response, 63 and 36% respectively, and also yielded a survival advantage, although this did not reach statistical significance. These results led the ECOG to design a new phase III trial to compare STZ and DOX versus STZ and 5-FU versus chlorozotocin (CLZ) in monotherapy (Moertel et al. 1992). The DOX combination group showed a significant increase in RR (69 vs 45 vs 30% respectively). Additionally, this benefit was also translated into a statistically significant increase in time to progression (TTP; 18 vs 14 vs 17 months) and median overall survival (mOS; 26.4 vs 16.8 vs 18 months). The SWOG group has published its experience on 47 patients treated with CLZ and 5-FU (Bukowski et al. 1992). This combination showed an RR of 36% and an mOS of 25 months. Thirteen patients developed renal toxicity secondary to CLZ, which explains the limited use of this agent in subsequent trials. Subsequent retrospective reports of the use of the STZ plus DOX combination in two different institutions have been published. Both the Dana Farber Cancer Institute (McCollum et al. 2004) and the Memorial Sloan Kettering Cancer Center (Cheng & Saltz 1999) have reported their experience, with an RR of 6%, much lower than the activity reported earlier. This disparity of results may be explained by the methodology used to assess response in the old studies, where clinical measurement of hepatomegaly on physical examination, radionuclide liver–spleen scanning, and biological response were considered for response evaluation. It may also be partially explained by tumor heterogeneity in terms of biological behavior and responsiveness to chemotherapy. Another potential explanation is the fact that in the last decade biological therapies have been progressively introduced as first- or second-line treatment, starting chemotherapy only after the progression of those therapies (Vilar et al. 2005).
In an intent to improve the efficacy results with doublets obtained in these two modern series, and as it has been done in other malignancies, triple cytotoxic combinations with 5-FU, DOX, and STZ have also been retrospectively reviewed in 84 patients treated at MD Anderson Cancer Center (Kouvaraki et al. 2004). The majority of patients had non-functioning (n = 64) and metastatic tumors (n = 76), although some locally advanced were also included in the analysis (n = 8). The overall RR was 39%, and 50% achieved a stable disease (SD). In terms of response, no differences were observed between locally advanced and metastatic tumors. Median progression-free survival (PFS) and PFS at 2 years were 18 months and 41% respectively; mOS and overall survival (OS) at 2 years were 37 months and 74% respectively. Multivariate analysis showed that replacement of more than 75% of the liver was independently associated with inferior PFS.
Due to the disagreement concerning the therapeutic effect of the classical chemotherapy regimens used in PETs, several groups have studied other combinations. The Italian Trials Medical Oncology group evaluated the efficacy of a combination of 5-FU, DTIC, and epirubicin and its dose intensification (Bajetta et al. 2002). Their pooled data published in 2002 included 28 patients with pancreatic tumors. Among these, one complete response (CR), seven partial responses (PR), and eight stabilizations were observed. The ECOG performed a phase II trial in advanced NETs to assess the efficacy of the combination of temozolomide and thalidomide (Kulke et al. 2006a). Temozolomide is an oral prodrug of DTIC with better bioavailability profile. Thalidomide is postulated to have an antiangiogenic effect and, as NETs are characterized by abundant vasculature, therapies related to these pathways may be especially relevant. Eleven patients affected by PET were treated; 1 (CR) and 4 (PR) were observed in this group. This regimen seems to be especially active in pancreatic tumors. Another phase II study of the combination of temozolomide and bevacizumab was reported (Kulke et al. 2006c) during the 2006 ASCO Meeting. The authors enrolled 18 patients with PETs who had received several prior treatment lines. Four patients experienced PR (24%) and 12 SD (70%), thus this combination has shown promising activity that has not been confirmed in patients with CT (n = 12, 0 PR and 11 SD). Experience with temozolomide and capecitabine has been reviewed retrospectively in 17 patients with PETs. One patient achieved a (CR), and nine a (PR) with a median duration of partial response of 284 days; therefore, this combination has a promising activity that should be evaluated in further studies (Isacoff et al. 2006).
One old study by Moertel et al.(1994) analyzes the combination of chemotherapy with a locoregional treatment. A total of 46 patients with PETs and liver metastasis were treated with hepatic artery occlusion followed by a non-randomized investigator’s choice of sequential chemotherapy or observation. Arterial occlusion was done by surgical ligation or by catheterization and embolization. The chemotherapy regimen included DOX and DTIC and, 4 weeks later, STZ and 5-FU, and cycles were administered until the patient had reached the stabilization of the disease or at a maximum tumor regression or had reached the accumulated dose limit in the case of DOX or had experienced intolerable toxicity. Twenty-nine patients were given the combined treatment and 17 with hepatic artery occlusion alone. The regression rate and median TTP were 78% and 20 months, and 43% and 3.6 months respectively. Despite the limitations and potential bias of this study, due to its non-randomized design, its results suggest that locoregional treatment of liver metastasis may enhance the efficacy of subsequent chemotherapy and supports the rationale for exploring combined sequential treatments.
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Chemotherapy in gastrointestinal CTs |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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Several drugs have been evaluated as single-agent regimens (Table 3). A phase II trial (Moertel et al. 1986) tested the efficacy of cisplatin (CDDP). Fifteen patients were treated showing only one (PR). STZ has shown very little activity in monotherapy (Oberg et al. 1987). DTIC (Bukowski et al. 1994) was evaluated in a phase II trial with 63 patients, exhibiting an RR of 16%. Two studies assessed the efficacy of gemcitabine (Kulke et al. 2004b) and docetaxel (Kulke et al. 2004a) in monotherapy; both treatments were considered inactive because neither of them induced any radiological response. Likewise, 14 patients were enrolled in a trial with high-dose paclitaxel (Ansell et al. 2001) in the Mayo Clinic showing minimum clinical activity despite severe toxicities, mainly hematological. In summary, single-agent chemotherapy should not be considered as a therapeutic option.
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The two studies from the ECOG stimulated the design of a phase III trial (study E1281; Sun et al. 2005) which randomized 163 patients to receive 5-FU plus DOX or STZ plus 5-FU. Results in terms of RR (15.9 vs 16%, P = 0.82) or PFS (4.5 vs 5.3 months, P = 0.17) did not show any differences; however, STZ plus 5-FU was superior to 5-FU plus DOX in mOS (24.3 vs 15.7 months, P = 0.02). The authors concluded that for selected patients the combination of STZ and fluoropyrimidines would be an appropriate option if systemic chemotherapy is considered.
In the Cleveland Clinic Foundation (Bukowski et al. 1987), 65 patients were randomized to 5-FU plus cyclophosphamide plus STZ with or without DOX showing an RR of 31 and 22% respectively. Another combination chemotherapy including 5-FU plus DTIC plus epirubicin (Bajetta et al. 1998) has been evaluated by an Italian collaborative group. In this trial, only two responses (10%) out of 20 patients were observed. In a more recent study, the same regimen at intensified doses slightly increased the response to 17% with a remarkable increase in toxicity (Bajetta et al. 2002). Another combination with DTIC plus 5-FU and leucovorin (Ollivier et al. 1998) had poor results, with only one (PR) out of nine CTs treated. A recently published multi-institutional phase II trial has evaluated the combination of temozolomide and thalidomide (Kulke et al. 2006a) in patients with advanced NETs of several origins; among 15 patients with CT, there was only one response. Therefore, this combination does not seem to be active for patients with CT, either.
The main prognostic factors that have correlated with better response to chemotherapy are a good performance status and age under 60 years.
None of the regimens analyzed has demonstrated enough efficacy to consider chemotherapy upfront in the systemic treatment in patients with advanced CT. Hence, other forms of systemic antitumoral treatment based on the presence of somatostatin receptors and other molecular characteristics as expression of vascular endothelial growth factor in CT are being used and explored. One of the options that has been explored is the combination of biological agents with target therapies and, as a consequence, a planned phase III study will randomize patients into two different treatment arms, octreotide plus bevacizumab versus octreotide plus IFN. Other strategy is the use of radiolabeled SAs which has shown interesting results in terms of tumor responses associated with low rates of toxicity in heavily pretreated patients (Kwekkeboom et al. 2005).
Locoregional treatments also show higher antitu-moral activity in terms of RR than systemic treatments, as it has been observed in a prospective study comparing chemotherapy with STZ plus 5-FU, transcatheter arterial embolization, and SAs in digestive NETs (Skinazi et al. 1996, Roche et al. 2003). In addition, Moertel et al.(1994) analyzed the combination of hepatic arterial occlusion and sequential chemotherapy. Sixty-five patients affected by advanced CTs with liver metastasis were included. Twenty-three patients were treated with hepatic arterial occlusion and 42 patients with the combined modality treatment that was stated in the well-differentiated PET section. The RR and median duration of response were 56% and 6.6 months, and 75% and 19.8 months respectively. However, a recent report has yielded conflicting results, where a sequential effect between embolization and chemotherapy has not been confirmed. In this study, the OS of patients who received postembolization chemotherapy was 38 months, whereas in the group that did not receive chemotherapy it was 44 months (Strosberg et al. 2006).
Multiple studies have demonstrated that locoregional techniques in CT render a higher benefit than chemotherapy in terms of RR; but despite this evidence, they are generally used as an alternative treatment after failure to systemic therapies rather than upfront which would seem a sensible approach. Studies of sequential or concomitant combination of both strategies in first-line treatment are needed to decide what the best sequence is, in order to improve the outcome in this subgroup of digestive NETs.
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Poorly differentiated gastroenteropancreatic NETs or anaplastic gastroentero-pancreatic tumors |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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Moertel et al initially reported an RR of 67% (CR 17%, PR 50%, and SD 33%) with the combination of CDDP and etoposide (VP-16) in 18 patients with poorly differentiated tumors of gastrointestinal and pancreatic origin. The RR for patients with well-differentiated tumors was 7% (n = 27, PR 7%), emphasizing the fact that this regimen is less effective for this group (Moertel et al. 1991). Mitry et al.(1999) observed a RR for poorly (n = 41) and well-differentiated (n = 11) NETs of 41.5 and 9% respectively, thus confirming the results obtained by the Mayo Clinic group.
In contrast, another study with this regimen in second- and third-line treatments does not confirm the relationship between the grade of differentiation and RR. A possible explanation is that patients with well-differentiated tumors included in these trials had a rapidly progressing clinical course and some of them were atypical lung carcinoids, which are more responsive to cisplatin-based chemotherapy (Fjallskog et al. 2001).
A recent phase II trial of the combination of paclitaxel, carboplatin, and VP-16 has been reported by Hainsworth et al.(2006). Seventy-eight patients with histologically proven poorly differentiated neuro-endocrine carcinoma with a variety of known primary sites with the exception of lung were included. A majority of them were from an unknown primary site, and nine patients had primaries located in the colon, rectum, esophagus, and stomach. Fifty-three percent showed major responses with a complete RR of 15% and median OS of 14.5 months. PFS and OS were not significantly different when unknown and known primary sites were compared. Nevertheless, toxicity was important, grade 3/4 neutropenia being present in 82% of patients and three patients died as a consequence of neutropenic sepsis. This remarkable toxicity rate counterbalances the efficacy results of this combination, thus CDDP plus VP-16 regimens continue being the standard treatment in this population. Kulke et al. (2006b) have reported the efficacy of the combination regimen of CDDP and irinotecan among 18 patients with advanced NETs. Only one radiological response was observed among four patients with poorly differentiated NETs and no radiological responses were observed in 14 patients with well-differentiated tumors. Efficacy of the oxaliplatin-based regimen FOLFOX-4 in 16 patients (8 low-grade and 8 high-grade) has been reported at the 2006 ASCO meeting by Wiedenmann et al. SD was observed in 62.5% patients, despite of the fact that the majority of patients (n = 13) had a Ki-67 value 10% (Pape et al. 2006), suggesting that this regimen may be an option in tumors with highly aggressive potential.
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Conclusions |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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) would favor chemotherapy as first choice in tumors with Ki-67 > 10% and as second or further – if at all indicated – line of treatment after failure of biotherapy and other forms of treatment in low proliferating tumors with Ki-67 lower than 5% (Öberg 2002), but this approach needs to be validated in prospective trials. Furthermore, validation of Ki-67 and other clinical and pathological prognostic factors is urgently needed for better patient stratification in future clinical trials. This approach will help identifying which patient subgroups obtain the largest therapeutic benefit from the different old and new treatments potentially available in NETs. In the meantime, Ki-67 should only be considered a prognostic factor and a valid surrogate of biological behavior that could guide therapeutic decisions, but its predictive value of responsiveness to treatment is unknown.
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In light of the results achieved with the current treatment approaches, a logical therapeutic and investigational approach should include sequential treatments with aggressive locoregional strategies and systemic treatment, a better candidate selection based on predictive validated clinical, pathological, and molecular factors, development of new targeted therapies, and the combination of these with chemotherapy or with other targeted therapies. These strategies should derive in the continuous progress on survival improvements of the patients affected by NETs.
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Acknowledgements |
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References |
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TopAbstractIntroductionRole of KI-67 proliferation...Chemotherapy in PETsChemotherapy in gastrointestinal...Poorly differentiated...ConclusionsReferences |
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