Incidence of low grade well-differentiated neuroendocrine tumors (NET) is on the rise. The North American Neuroendocrine Tumor Society estimates that the United States has more than 150,000 gastroenteropancreatic NET patients. About 10% of metastatic NETs can be unknown primary, and due to their rarity, dedicated treatment algorithms and regimens are not defined. Combination of capecitabine and temozolomide (CAPTEM) is one of the systemic treatments used in gastroenteropancreatic NETs. We explored clinical activity of CAPTEM in NET of unknown primary.
Better diagnostics, recognition, and knowledge of neuroendocrine tumors (NETs) have led to consistent growth in their incidence and prevalence. SEER data suggests a 6-fold increase in the incidence from 1 per 100,000 patients in 1973 to almost 7 per 100,000 patients in 2012 [
Patients with neuroendocrine tumor of unknown primary were identified from the Markey Cancer Center’s database over a period of five years (2012–2016). IRB approval was obtained for retrospective chart review prior to starting the study. Neuroendocrine tumor of unknown primary was defined by lack of visual evidence of primary tumor on CT scan and or Octreoscan. Neuroendocrine tumors were histopathologically graded based on 2010 WHO classification. Grade 1 was defined as Ki-67 < 2%, grade 2 had Ki-67 index between 2% and 20%, and grade 3 was defined as Ki-67 index more than 20%. Patients treated with CAPTEM regimen were analyzed for radiologic response in the first scan, time to progression on treatment, and toxicity. We used 1500 mg/m2 capecitabine and 200 mg/m2 temozolomide for treatment of our patients. Capecitabine was administered continuously from days 1 to 14 daily in two divided doses (q 12 hours). Temozolomide was administered on days 10–14 in two divided doses (q12 hours). Eastern cooperative oncology group performance status criteria were utilized to assess the fitness of patient. Grade 0 was defined as fully active and being able to perform all activities without restrictions. Grade 1 was defined as restricted strenuous physical activity but able to carry out light work. Grade 3 was defined as being able to perform limited self-care. Grade 4 was completely disabled and grade 5 was defined as deceased. We used common terminology criteria for adverse events (CTCAE 4.03) to define toxicity. We did not use RECIST criteria to assess radiological response. Radiological response was categorized into progressive disease, stable disease, partial response, and complete response based on descriptive reading of radiological report.
A total of 56 patients with neuroendocrine tumors were identified. Twelve of these patients were treated with capecitabine and temozolomide. The median age of the patients 12 patients was 62 and 6 of them were women and 6 were men. Three patients had an ECOG Performance Status (ECOG PS) of 0 and remaining 9 patients had an ECOG PS of 1. A specific Ki-67 was available in two patients, the solitary grade 1 NET was 1%, and a grade 2 NET was 15%. The remaining patients were graded as I, II, and III as per the current guidelines that classify grade 1 as a Ki-67 of less than 2%, grade 2 between 2 and 20%, and grade 3 as more than 20%. One patient had a grade 1 NET, 7 with grade 2 NET, and 4 with grade 3 NET. Ten patients were classified as well-differentiated NET and two patients were poorly differentiated NET. Three patients had received previous treatments; one of them a grade 2 NET received carboplatin with etoposide and everolimus prior to the use of CAPTEM, the second patient a grade 3 NET received cisplatin with etoposide followed by carboplatin with paclitaxcel, and a third patient with grade 3 NET received carboplatin and etopside. The chromogranin A level was available at the time of starting CAPTEM in 8 of the 12 patients and ranged from 3.8 to 1505 (median 221). The most common sites of metastasis were to liver (10 patients), peritoneum (4 patients), bone (2 patients), brain (1 patient), and the heart (1 patients). Five patients received concomitant somatostatin analogs at the time of treatment with CAPTEM. Eight patients had an Octreoscan performed at the time of start of CAPTEM and four of them demonstrated uptake.
CAPTEM was used as front-line systemic therapy in 9 out of 12 patients. Median progression-free survival (PFS) on CAPTEM in grade II and grade III NET of unknown primary was 10.8 and 7 months, respectively. Figure
Patient characteristics.
Characteristic | Number |
---|---|
Total patients with NET | 56 |
Total patients treated with CAPTEM | 12 |
Median age | 62 years |
Male : female ratio | 1 : 1 |
Mean duration of treatment before progression | 10.8 months |
CAPTEM used as front-line systemic therapy | 9 patients |
Median chromogranin A | 221 |
Concomitant Somatostatin analogues use | 5 patients |
Grade I | 1 |
Grade II | 7 |
Grade III | 4 |
Kaplan-Meier curve depicting progression-free survival while on CAPTEM.
Following were the rates of common side-effects: Four patients developed grade II thrombocytopenia, three patients developed grade I lymphocytopenia, two patients developed hand and foot syndrome (one each, grades I and III), and six patients developed grade I fatigue (Table
Rates of common side-effects.
Side-effect | Grade | Number |
---|---|---|
Thrombocytopenia | II | 4 |
Lymphocytopenia | I | 3 |
Hand and foot syndrome | I | 1 |
Hand and foot syndrome | III | 1 |
Fatigue | I | 6 |
Neuroendocrine tumors are considered an orphan disease due to low incidence, but despite this fact, the prevalence of neuroendocrine tumors is on the rise. The North American Neuroendocrine Tumor Society estimates that there are over 150,000 gastroenteropancreatic neuroendocrine tumor patients in the United States alone. This imbalance between incidence and prevalence is due to indolent history of disease progression. Because of its orphan status, therapeutic clinical trials are few and the treatment options for progressive disease are limited.
CAPTEM is one of the suggested treatment regimens for progressive well-differentiated neuroendocrine tumors. Capecitabine is a prodrug that is converted from fluoropyrimidine to 5-fluorouracil upon oral intake. 5-Fluorouracil has anticancer activity that induces damage to DNA by inhibiting thymidylate synthase [
The rationale for combining capecitabine and temozolomide came from the hypothesis that the effects of capecitabine would enhance NET cell sensitivity to the lipophilic methylator, temozolomide [
There is very limited literature that observes the outcomes of CAPTEM as treatment for well-differentiated neuroendocrine tumors. Table
Outcomes and results of CAPTEM.
Primary site, % | Pts (n) | Prior treatment | CAP/TEM dosage (mg/m2) | Results (%) | PFS (months) | Observed toxicities, % |
---|---|---|---|---|---|---|
Peixoto et al. [ | ||||||
Pancreatic, 48.3 | 29 | (i) Octreotide | Cap: 750 | N/A | 4.7 | N/A |
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Fine et al. [ | ||||||
Pancreatic, 39 | 18 | (i) Octreotide | Cap: 600 | CR: 6 | 14 | Thrombocytopenia (grade 3 toxicity), 11 |
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Fine et al. [ | ||||||
Pancreatic, 39 | 28 | (i) Octreotide | Cap: 750 | CR: 11 | 22 | Lymphopenia (grade 3/4), 32 |
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Crespo et al. (abstract only) [ | ||||||
Pancreatic, 70.8 | 65 | N/A | N/A | CR: 3 | 16 | Grade 3/4 toxicity, 13.8 |
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Strosberg et al. [ | ||||||
Pancreatic, 100 | 30 | (i) Octreotide | Cap: 750 | PR: 70 | 18 | Grade 3/4 toxicity, 12 |
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Ramirez et al. [ | ||||||
Pancreatic, 52 | 29 | (i) Cytoreduction | Cap: 750 | PR: 17 | 12 | Thrombocytopenia grade 1 (3), grade 2 (3), grade 3 (1) |
| ||||||
Spada et al. [ | ||||||
Pancreatic, 55 | 58 | (i) Octreotide | Cap: 1,500 | PR: 22 | 13 | Thrombocytopenia (grade 3/4) |
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Fine et al. [ | ||||||
Metastatic NETs | 10 | (i) Octreotide | Cap: 750 | CR: 16 | NA | Hand-foot syndrome (grade 3), one case. |
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Saif et al. [ | ||||||
Pancreatic, 100 | 7 | (i) Octreotide | Cap: 1,000 | PR: 43 | 12 | Thrombocytopenia (grade 3), one case. |
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Abbasi et al. [ | ||||||
Pancreatic | 21 | (i) Octreotide | Cap: 600 | PR: 57 | 17 | No grade 4 toxicity |
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Ramirez et al. [ | ||||||
Pancreatic, 50 | 30 | N/A | N/A | PR: 33 | 11 | Cytopenia, 25 |
N/A: not available, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, Cap: capecitabine, and Tem: temozolomide.
The results from the studies in Table
Current literature on CAPTEM mainly stems from pancreatic neuroendocrine tumor patients [
Though various subtypes of NETs have been studied, there is a significant lack of data on the effectiveness of CAPTEM in NET of unknown primary. Only two studies mentioned in Table
CAPTEM shows activity in NET of unknown primary. Current FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus, both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grades I and II NET of unknown primary, especially in the case of visceral crisis or bulky disease. While a randomized trial would be optimal to confirm the benefit of CAPTEM in NET of unknown primary, the rarity of these tumors precludes the feasibility of a prospective trial.
Preliminary finding of our study was published in the proceedings of American Society of Clinical Oncology annual meeting in 2017; J Clin Oncol 35, 2017 (suppl; abstr e15691).
The authors have no potential commercial or financial conflicts of interest to disclose.
Statistical computation for this research was provided by the Markey Cancer Center’s Biostatistics and Bioinformatics Shared Resource Facility (NCI P30 CA177558).