Refining Docetaxel-Containing Therapy for Gastric Cancer

ABSTRACT

Gastric cancer—the second most common cause of cancer-related deaths worldwide—is a global health problem. Most cases present at advanced stages and are incurable due to locally advanced or metastatic disease. Although advanced gastric cancer is relatively chemosensitive, a gold standard chemotherapy regimen has yet to emerge, and response rates are of short duration. Cisplatin and 5-fluorouracil (CF) have emerged as the backbone agents in treating this disease. The pivotal V325 trial demonstrated the efficacy benefit of adding docetaxel to CF (DCF). DCF, however, is associated with significant toxicity, making it less tolerable to patients. As a result, docetaxel-containing regimens have been extensively studied and improved upon to mitigate toxicity while maintaining efficacy. Various dosing and scheduling permutations of the original DCF regimen have emerged, and substitutions with other 5-fluorouraci and platinum analogs have been studied. In this review we highlight some of these studies using docetaxel-based regimens as well as new approaches using targeted therapy, including monoclonal antibodies and tyrosine kinase inhibitors. Continuing efforts to improve the efficacy and tolerability of docetaxel-based chemotherapy, combining pharmacokinetic parameters and pharmacogenetic correlates, will further assist in developing optimized regimens. Emerging data using targeted therapy and biologics in combination with chemotherapy are promising, but results of ongoing studies are required to establish the safety and efficacy of these regimens.

Gastric cancer, with an estimated 930 000 new cases reported each year and 700 000 associated deaths annually, is the second most common cause of cancer-related deaths worldwide.¹ In the United States, the overall incidence of gastric cancer has been declining, with an estimated incidence of 21 130 cases in 2009.² Despite this, gastric cancer remains a global health problem that carries a poor overall prognosis, as over 60% of cases are diagnosed at the locally advanced or metastatic stage, with 5-year survival rates of 26.6% and 3.4%, respectively.³ Although the overall incidence of gastric cancer has been declining, adenocarcinomas of the gastroesophageal junction (GEJ) are increasing in incidence.⁴ Cancers of the GEJ are associated with poor prognosis, with the majority of patients presenting with advanced disease, beyond surgery with curative intent.⁵

Advanced gastric cancer has been treated with an increasing armamentarium of chemotherapy agents, from various classes of drugs, including taxanes, anthracyclines, fluoropyrimidines, platinums, and the camptothecin irinotecan. Although gastric cancer is a relatively chemosensitive cancer, the response duration to chemotherapy is short, and a complete response is rare. Recent literature provides data on a multitude of doublet and triplet regimens that are under investigation in various stages of clinical development. Despite the large number of regimens under study, optimal treatment of patients with advanced gastric cancer is wrought with controversy. This disease continues to pose a challenge in treatment, with modest improvement in overall response rates (ORRs) and overall survival (OS), achieved at the cost of therapy-related side effects.

A gold standard chemotherapy regimen for the treatment of advanced gastric cancer has yet to be defined. Compared with best supportive care, the addition of combination chemotherapy with 5-fluorouracil (5-FU) and either etoposide or an anthracycline plus methotrexate improved OS from 3–5 months to 9–12.3 months, respectively.^6–8 Subsequent randomized studies comparing single-agent 5-FU with various combinations of 5-FU, cisplatin, mitomycin, and doxorubicin demonstrated an ORR, progression-free survival (PFS) and toxicity profile favoring the 5-FU plus cisplatin regimen.^9–11 Consequently cisplatin/5-FU has emerged as a comparison standard and backbone for the development of more efficacious regimens. Both the epirubicin/cisplatin/5-FU (ECF) and the docetaxel/cisplatin/5-FU (DCF) regimens have been extensively tested and improved upon in recent times.

Docetaxel, a semisynthetic taxane, has demonstrated significant activity in many solid tumors including gastric cancer. The results of single-agent studies of docetaxel in Europe, Japan, and the United States have shown consistent ORRs of approximately 20%, similar to those reported by most active agents in advanced gastric cancer.^12–16 The taxanes mediate cytotoxicity by inhibiting tubulin depolymerization, thereby facilitating the formation of microtubule bundle aggregates, ultimately leading to cell death. This mechanism of action is unique, and in vitro studies have shown lack of cross-resistance with other chemotherapeutic agents.¹⁷ Furthermore, preclinical studies have shown synergy between docetaxel and platinum compounds.¹⁸

Experiments in gastric cancer xenografts have shown enhanced tumor activity of docetaxel in combination with 5-FU compared with docetaxel alone.¹⁹ The individual pharmacokinetic profiles of docetaxel, cisplatin, and 5-FU are not affected by their coadministration.²⁰ Given the absence of cross-resistance and the potential for synergistic combinations, there has been much interest in studying docetaxel in combination with other chemotherapeutic agents for the treatment of advanced gastric cancer.

The pivotal phase III V325 multinational trial compared DCF with cisplatin and 5-FU (CF) in patients with locally advanced or metastatic gastric adenocarcinoma, 22% of whom had GEJ primary tumors.²¹ The results demonstrated a significant improvement in all efficacy end points in favor of the DCF arm, including improved ORR (37% compared with 25%), time to progression (TTP) (hazard ratio [HR] 1.473), and OS (HR 1.293). Subsequent analyses have demonstrated a clinical benefit with improvements in performance status, weight loss, appetite, and quality of life.^22,23 Despite these benefits, DCF has been widely criticized and held under scrutiny for its toxicity profile.

In the V325 study, patients in the DCF arm experienced more grade 3/4 neutropenia (82% vs 57%), febrile neutropenia (29% vs 12%), and diarrhea (19% vs 8%) compared with patients in the CF arm. Strategies to improve treatment-related side effects without compromising efficacy have included changes in the dose and schedule, as well as the substitution of 5-FU and cisplatin with comparable analogs.

DOSE AND SCHEDULE

Weekly dosing schedules for docetaxel—compared with every-3-weeks schedules—have demonstrated comparable efficacy with lower rates of neutropenia when used as treatment for non–small-cell lung cancer or breast cancer.^24,25 Likewise, 5-FU infusion schedules administered weekly rather than via a protracted regimen have resulted in decreased mucosal-related toxicities when used to treat patients with gastrointestinal tumors.²⁶ Phase I and II studies have explored these strategies to minimize the frequency of DCF-related side effects (Table 1).^27–35

Table 1.

Outcomes of studies of docetaxel and platinum combinations

Author	Regimen(s)	No. of patients	Study design, phase	Tumor type and stage	Grade 3/4 neutropenia, %	Other grade 3/4 AEs (%)	Median OS, months	ORR, %
Hejna et al27	Docetaxel 80 mg/m2 + oxaliplatin 100 mg/m2, q3w (prophylactic G-CSF administered)	35	II	Advanced gastric or GEJ adenocarcinoma	17	Anemia (17) Nonhematologic toxicity mainly mild to moderate	11.6	34.0
Kim et al28	Docetaxel 65 mg/m2 + oxaliplatin 120 mg/m2, q3w	42	II	Advanced gastric adenocarcinoma	26.1	Grade 1/2 fatigue (61.9), grade 1/2 nausea (47.7)	9.9	45.2
Park et al29	Docetaxel 75 mg/m2 + oxaliplatin 130 mg/m2, q3w	50	I/II	Advanced gastric adenocarcinoma	8.0	Febrile neutropenia (14), diarrhea (10), neurotoxicity (10)	NR	26.0
Richards et al30	Docetaxel 60 mg/m2 + oxaliplatin 130 mg/m2, q3w	71	II	Advanced gastric or GEJ adenocarcinoma	70	Vomiting (17), nausea (16), dehydration (13), diarrhea (13), fatigue (13)	8.5	36.0
Quintero et al31	Docetaxel 50 mg/m2 + cisplatin 50 mg/m2, q2w (maximum 12 cycles)	52	II	Advanced gastric adenocarcinoma	5.9 per cycle	Anemia (1.8), asthenia (1.8), vomiting (1.0)	8.9	37.0
Kim et al32	Docetaxel 70 mg/m2 + cisplatin 70 mg/m2, q3w	39	II	Metastatic squamous cell esophageal cancer	Grade 3: 21 Grade 4: 10	Grade 2/3 anemia 26%/3%, grade 3 infection 5%, grade 2/3 nausea 18%/3%	10.5	33.3
Park et al33	Docetaxel 75 mg/m2 + cisplatin 75 mg/m2, q3w	92	II	Metastatic gastric adenocarcinoma	17.4	Nausea/vomiting (13.0), diarrhea (7.6)	11.5	43.5
Sym et al34	Docetaxel 35 mg/m2 days 1 and 8, q3w + cisplatin 60 mg/m2 day 1 (Arm A) or oxaliplatin 120 mg/m2 day 1 (Arm B)	61	Randomized II	Unresectable and/or metastatic adenocarcinoma	Arm A: 32.3 Arm B: 36.6	No between-group difference in overall grade 3/4 toxicity, one treatment-related death in Arm B	PFS: 4.4 (Arm A) vs 4.3 (Arm B)	34.5 (Arm A) vs 39.2 (Arm B)
Shankaran et al35	Docetaxel 50 mg/m2 + oxaliplatin 85 mg/m2 + 5-FU 2400 mg/m2 CI over 46 hours, q2w	44	II	Metastatic or unresectable gastric or GEJ adenocarcinoma	7 patients (15.9)	Neurologic (8 patients), mucositis (4 patients), diarrhea (4 patients), anemia (3 patients), no cases of complicated neutropenia	10	74.2
Wang et al36	Docetaxel 33.3 mg/m2 + cisplatin 30 mg/m2 + dose-escalating 5-FU (starting at 1000 mg/m2) for 3 consecutive weeks, q4w	21	I	Advanced gastric cancer	2 patients (9.5)	Diarrhea/ mucositis (2 patients), cardiac ischemia (1 patient)	NR	26.0

Abbreviations: AE = adverse event; CI = confidence interval; 5-FU = 5-fluorouracil; G-CSF = granulocyte-macrophage colony-stimulating factor; GEJ = gastroesophageal junction; NR = not reached; ORR = overall response rate; OS = overall survival; q2w = once every 2 weeks; q3w = once every 3 weeks; q4w = once every 4 weeks.

In a phase I trial in 21 patients with advanced gastric cancer, patients received a weekly regimen of docetaxel 33.3 mg/m², cisplatin 30 mg/m², and dose-escalating 5-FU starting at 1000 mg/m² for 3 consecutive weeks every 4 weeks.³⁶ The maximum tolerated dose of 5-FU was 1750 mg/m² with grade 3/4 hematologic and nonhematologic toxicity occurring in less than 10% of patients. The ORR was 26%.³⁶ Variable levels of toxicity have been shown for docetaxel plus oxaliplatin-based regimens for advanced or metastatic gastric adenocarcinoma (Table 1), ranging from a grade 3/4 neutropenia rate of 8.0% with docetaxel 75 mg/m² plus oxaliplatin 130 mg/m², q3w,²⁹ to 70.0% with docetaxel 60 mg/m² plus oxaliplatin 130 mg/m², q3w.³⁰ These regimens were associated with similar ORRs (Table 1).

A study by Shankaran et al,³⁵ however, has reported both low toxicity (grade 3/4 neutropenia: 15.9%) and a high ORR of 74.2% with docetaxel 50 mg/m² plus oxaliplatin 85 mg/m² plus 5-FU 2400 mg/m², q2w (Table 1). Phase II studies of docetaxel plus cisplatin regimens have consistently shown relatively low toxicities, with ORRs of between 33.3% and 43.5% (Table 1). Survival rates are typically about 10% for both docetaxel plus cisplatin or oxaliplatin combinations in patients with advanced gastric cancer (Table 1).

A low-dose weekly regimen of docetaxel 20 mg/m², cisplatin 20 mg/m², and 5-FU 350 mg/m² given weekly for 6 weeks of 8 was associated with minimal hematologic toxicity and produced a partial response rate of 27%; 45% of patients had stable disease.³⁷ In this study of 57 patients with advanced gastric or esophageal cancer, PFS was 4 months and OS was 8.9 months. Fatigue was the most common nonhematologic toxicity, reported in 51% of patients. A retrospective review of this regimen in 95 patients demonstrated similar findings.³⁸

A schedule of docetaxel 40 mg/m² and cisplatin 40 mg/m² given at weeks 1, 3, and 5 with weekly 5-FU 2000 mg/m² and leucovorin 200 mg/m² for 6 of 8 weeks, was associated with rates of grade 3/4 neutropenia of 22%, diarrhea of 20%, and lethargy of 18%.³⁹ In this study of 24 patients with locally advanced cancer and 36 patients with metastatic gastric cancer or GEJ adenocarcinoma, the ORR was 47%, TTP was 9.4 months, and OS was 17.9 months. Twenty-one patients with locally advanced tumors ultimately underwent complete resection.

A different approach was undertaken in a study of 32 patients, of whom 18 had locally advanced disease and 14 had metastatic disease.⁴⁰ Administration of docetaxel 75 mg/m² on day 1 with cisplatin 30 mg/m² and 5-FU 500 mg/m² on days 1–3 every 3 weeks produced grade 3 neutropenia in 32% and nausea in 40% of patients but was associated with an impressive ORR of 66.7% and median survival of 10.5 months.

A three-arm randomized phase II study of 119 patients compared the standard ECF regimen (epirubicin 50 mg/m² day 1, cisplatin 60 mg/m² day 1 plus infusional 5-FU 200 mg/m² on days 1–21 every 3 weeks) with DC (docetaxel 75 mg/m² plus cisplatin 75 mg/m² on day 1 every 3 weeks) and a modified DCF regimen (in which the dose of infusional 5-FU was reduced to 300 mg/m² on days 1–14 every 3 weeks).⁴¹ The rates of grade 3/4 neutropenia were 34%, 49%, and 57%, respectively. Efficacy was demonstrated with ORRs of 25%, 18.5%, and 36.6%, respectively, and median survival times of 8.3, 11.0, and 10.4 months, respectively. Given the acceptable toxicity profile and the demonstration of superior activity, it was concluded that the modified DCF regimen would be a reasonable therapy to pursue in a phase III randomized comparison with ECF.

POTENTIAL INTERACTIONS OF DOCETAXEL WITH OTHER AGENTS

A pharmacokinetic study was undertaken to evaluate potential interactions of the antiemetics aprepitant and palonosetron, commonly administered with cisplatin, on docetaxel clearance.⁴² Aprepitant and palonosetron are both CYP3A4 inhibitors, while docetaxel is both a substrate and an inhibitor of CYP3A4, the enzyme responsible for its clearance. Toxicity and pharmacokinetic data were available for 13 patients, 8 of whom received standard DCF and 5 of whom received modified DCF. Seven of 8 patients who received standard DCF had grade 3/4 toxicity during cycle 1 compared with 1 of 5 patients who were treated with modified DCF.

Pharmacokinetic data were suggestive of a higher clearance and reduced docetaxel exposure in patients who received the modified DCF regimen. Liver microsome studies demonstrated no difference in docetaxel metabolism in the presence or absence of cisplatin or 5-FU, suggesting that the observed differences were the result of the drugs being coadministered with cisplatin. Further studies are needed to evaluate the significance of these findings on efficacy.

PROPHYLAXIS WITH GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

In the original V325 phase III study, granulocyte-macrophage colony-stimulating factor (G-CSF) was used only as secondary prophylaxis once evidence of complicated neutropenia had been established.²¹ It was noted that by using G-CSF the rate of febrile neutropenia and neutropenic complications in the DCF group was reduced from 27% to match the 12% observed in the CF group.²¹ In a phase II trial in which a 5-day course of prophylactic G-CSF was administered, grade 3 and 4 neutropenia was observed in only 17% of patients, and there were no episodes of febrile neutropenia. Neutrophil counts recovered within 7 days for the majority of patients, thus facilitating timely chemotherapy infusions without delay in cycles.²⁷

COMBINATION THERAPY WITH DOCETAXEL AND OXALIPLATIN

Oxaliplatin inhibits DNA synthesis in a manner similar to cisplatin and has shown a wide spectrum of antitumor activity, lower incidence of nausea, and no renal toxicity. Four phase II studies assessing oxaliplatin and docetaxel in patients with advanced gastric cancer, including some with GEJ adenocarcinoma, in the first-line setting with doses of docetaxel ranging from 60–80 mg/m² and oxaliplatin from 100–130 mg/m², given every 3 weeks, have been reported (Table 1).^27–30 Three of these regimens reported rates of grade 3/4 neutropenia in the range of 18%–26%, and one at 70%, with a 7% febrile neutropenia rate. The ORRs ranged from 26% to 45% with median OS in the range of 5.7–11.6 months.

These efficacy results are comparable with those of docetaxel and cisplatin doublets with ORRs of 33.3%–43.5% and median OS of 8.9–11.5 months.^31–33 Grade 3/4 toxicity rates, including neutropenia, were also comparable. One study, in which docetaxel at 50 mg/m² and cisplatin at 50 mg/m² were given every 2 weeks, reported a grade 3/4 neutropenia rate of 5.9% per cycle and less than 2% nonhematologic toxicity.³¹

In a randomized phase II study in which docetaxel was administered at 35 mg/m² on days 1 and 8 of a 3-week regimen with either cisplatin 60 mg/m² or oxaliplatin 120 mg/m² on day 1,³⁴ the rate of grade 3/4 neutropenia was the same in both arms (32.3% and 36.6%, respectively), as was PFS (4.4 months and 4.3 months, respectively) and ORR (34.5% and 39.2%, respectively).

A phase II study in 44 patients with metastatic or unresectable gastric or GEJ adenocarcinomas investigated a triplet combination of docetaxel 50 mg/m², oxaliplatin 85 mg/m², and 5-FU 2400 mg/m² continuous infusion over 46 hr administered every 2 weeks.³⁵ The rate of grade 3/4 neutropenia was 16% with no complicated neutropenia, and the only significant nonhematologic toxicity was cumulative neurotoxicity of incidence 18%. The ORR was 74% with a median OS of 10.4 months.

COMBINATION THERAPY USING ORAL 5-FU ANALOGS

In a 2 × 2 trial design, 1002 patients were randomly assigned to receive triplet therapy with either epirubicin plus cisplatin plus the oral fluoropyrimidine capecitabine (ECX), the standard 5-FU–containing regimen of ECF, or epirubicin plus oxaliplatin plus either 5-FU or capecitabine.⁴³ The median OS was 9.9 months both for patients who received ECX and for those who received ECF, establishing noninferiority of capecitabine and offering it as a more convenient alternative to infusional 5-FU.

Three phase I studies in advanced gastric or gastroesophageal cancer have been conducted to determine the maximum tolerated dose of triple therapy comprising docetaxel, oxaliplatin, and capecitabine. Dose-limiting toxicities (DLTs) of neutropenia, febrile neutropenia, and diarrhea were reported.^44–46 Results of a phase II study of docetaxel 40 mg/m² and oxaliplatin 50 mg/m² administered on days 1 and 8 with capecitabine 625 mg/m² administered twice daily on days 1–14 showed that this regimen was associated with a rate of 43% for grade 3 diarrhea and abdominal pain and 24% for hematologic toxicity.⁴⁷ The ORR was 31%, and median OS was 9 months.

S-1 is a novel oral dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine (DIF) that was developed based on a biochemical modulation of 5-FU; S-1 contains tegafur and two types of enzyme inhibitor—5-chloro-2,4-dihydroxypyridine and potassium oxonate—in a molar ratio of 1:0.4:1. In pharmacokinetic studies, S-1 maintained high 5-FU concentrations. S-1 is approved for use throughout Asia.

Phase II trials using S-1 as a single agent for the treatment of gastric cancer have demonstrated ORRs in the range from 44%–49%, with a median OS of approximately 7 months (207 days).^48,49 Several phase I or II studies have evaluated S-1 in combination with docetaxel (Table 2).^50–55 A phase I study of this compound in combination with docetaxel in advanced gastric cancer revealed that neutropenia was the DLT. The ORR was 57%.⁵⁰ Phase II studies^51–54 with S-1 at a dose of 40 mg/m² twice daily on days 1–14 and docetaxel at doses ranging from 35–60 mg/m² have demonstrated rates of grade 3 and 4 neutropenia of between 29.4%⁵¹ and 67%.⁵³ The ORRs in these studies ranged from 46% to 87%.

Table 2.

Outcomes of studies of docetaxel and S-1 combinations

Author	Regimen(s)	No. of patients	Study design, phase	Tumor type	Grade 3/4 neutropenia, %	Other grade 3/4 AEs, n (%), and safety conclusion	Median OS, months	ORR, %
Kunisaki et al50	Docetaxel 20–45 mg/m2 days 1 and 15 + S-1 oral 80–120 mg/day, days 1–7 and days 15–21	21	I	Advanced gastric adenocarcinoma	n/a (DLT = neutropenia)	n/a	n/a	57.1
Park et al51	Docetaxel 35 mg/m2 days 1 and 8 + S-1 oral 40 mg/m2 bid days 1–14, q3w	52	II	Metastatic gastric adenocarcinoma	29.4	Febrile neutropenia (19.6)	13.7	66.7
Sato et al52	Docetaxel 60 mg/m2 day 8 + S-1 oral 40 mg/m2 bid days 1–14, q3w	31	II	Advanced or unresectable gastric adenocarcinoma	51.6 (grade 4: 32)	Anorexia (29), nausea (26.6)	n/a	87.1
Yamaguchi et al53	Docetaxel 40 mg/m2 day 1 + S-1 oral 40 mg/m2 bid days 1–14, q4w	46	II	Advanced gastric adenocarcinoma	67	Leukopenia (41), anemia (22), anorexia (22), hyponatremia (17)	14.0	46
Yoshida et al54	Docetaxel 40 mg/m2 day 1 + S-1 oral 40 mg/m2 bid days 1–14, q3w	48	II	Advanced or recurrent gastric adenocarcinoma	58.3	Febrile neutropenia (8.3), leukopenia (41.7), appetite loss (14.6)	14.3	56.3
Nakayama et al55	Docetaxel 40 mg/m2 + cisplatin 60–80 mg/m2 day 1 + S-1 40 mg/m2 bid days 1–14, q4w	14	I	Advanced gastric adenocarcinoma	n/a	DLT: grade 3 diarrhea, febrile neutropenia, delayed resumption of treatment	n/a	n/a

Abbreviations: AE = adverse event; bid = twice daily; DLT = dose-limiting toxicity; n/a = not available; ORR = overall response rate; OS = overall survival; q3w = once every 3 weeks; q4w = once every 4 weeks.

A phase I trial of S-1 40 mg/m² given twice daily on days 1–14, docetaxel 40 mg/m², and dose-escalating cisplatin given on day 1, has demonstrated DLTs of grade-3 diarrhea and febrile neutropenia, with an ORR of 69.2%.⁵⁵ A randomized phase II study of docetaxel given in combination with S-1 or cisplatin demonstrated ORRs of 43.6% and 24.3%, respectively.⁵⁶ Given the demonstrated efficacy of S-1, further studies of this agent as part of combination therapy are warranted. In this regard, a phase III collaborative study comparing S-1 alone and in combination with docetaxel is underway by the Japan Clinical Cancer Research Organization and Korean Cancer Study Group [NCT00287768].⁵⁷

As demonstrated with other fluoropyrimidines, it is imperative to establish the efficacy and toxicity profile of S-1 in various geographic populations, as the metabolism of S-1 may differ between patients.⁵⁸ The maximum tolerated dose of S-1 in Japanese studies is 80 mg/m²⁵⁹; however, the same dose is not well tolerated by Western patients.⁶⁰ This interindividual variation perhaps relates to genetic polymorphisms in the CYP2A6 enzyme involved in the prodrug conversion. It is postulated that the efficacy of CYP2A6 enzyme is higher in white populations than in Asians, owing to specific polymorphism frequencies that confer variable ability to assimilate the drug.^60,61

DOCETAXEL COMBINATIONS WITH OTHER CYTOTOXIC AGENTS

Investigation of non–5-FU–containing regimens has been pursued in an attempt to decrease rates of gastrointestinal toxicity. A retrospective review of a biweekly schedule of docetaxel 25 mg/m², irinotecan 40 mg/m², and cisplatin 20 mg/m² used as second-line therapy demonstrated a grade 3/4 neutropenia rate of 20.6%, an ORR of 34.5%, and median survival of 11.1 months.⁶² Two phase II studies in patients with metastatic gastric or GEJ adenocarcinoma evaluated docetaxel at a dose of 60 mg/m² every 3 weeks: one in combination with irinotecan 150 mg/m² and oxaliplatin 85 mg/m²⁶³ and the other in combination with epirubicin 50 mg/m² and oxaliplatin 100 mg/m².⁶⁴ The rates of grade 3/4 neutropenia were comparable (47.5% and 53%, respectively) as were the ORRs (50% and 48.5%, respectively).

DOCETAXEL AND MOLECULAR TARGETED AGENTS

The role of monoclonal antibodies and small-molecule tyrosine kinase inhibitors is undefined in the treatment of gastric cancer at this time. The results of preclinical studies and preliminary clinical trials appear promising; however, ongoing studies will establish the safety and efficacy of these combinations.

Three bevacizumab and docetaxel-based combinations have been reported in studies of patients with advanced gastric or GEJ cancer (Table 3). In a study of bevacizumab administered at a dose of 7.5 mg/kg in combination with docetaxel 70 mg/m² and oxaliplatin 75 mg/m² every 3 weeks, considerable toxicity was observed.⁶⁵ Overall, 38% of patients experienced grade 3/4 neutropenia, 13% had hypertension, and gastrointestinal perforation occurred in 2 of 8 patients following the second treatment cycle. No efficacy data were available, though a partial response was observed in 4 patients. Preliminary analysis of a phase II study of bevacizumab in combination with docetaxel in patients who had previously received treatment for esophageal and gastric cancer showed an ORR of 27%.⁶⁶ The rates of arterial thrombosis and gastrointestinal hemorrhage were 10% and 15%, respectively.

Table 3.

Outcomes of studies of docetaxel with targeted agents

Author	Regimen(s)	No. of patients	Study design, phase	Tumor type	Grade 3/4 neutropenia, %	Other grade 3/4 AEs (%) and safety conclusion	Median OS, months	ORR, % or no. of patients
El-Rayes et al65	Bevacizumab (7.5 mg/kg) + docetaxel (70 mg/m2) + oxaliplatin (75 mg/m2 on day 1 of 21-day cycle)	8	II	Locally advanced or metastatic gastric or GEJ adenocarcinoma	38	Gastrointestinal perforation in 2 patients after 2nd cycle, fever (13), acute neuropathy (13)	n/a	PR (N = 4), SD (N = 4)
Enzinger et al66		20	II	Metastatic gastric, esophageal, or GEJ cancer	10	Fatigue (15), gastrointestinal bleeding (15), anemia (15), arterial thrombosis (10)		PR: 4/15 (27%) (evaluable patients)
Enzinger et al67	Bevacizumab (10 mg/kg day 1, q3w) + docetaxel (30 mg/m2) + cisplatin (25 mg/m2) + irinotecan (50 mg/m2 on days 1 and 8, q3w)	35	II	Metastatic gastroesophageal	29	Diarrhea (34)	n/a	n/a
Jhawer et al68	Bevacizumab (10 mg/kg), docetaxel (40 mg/m2), 5-FU (400 mg/m2), leucovorin (400 mg/m2 day 1), 5-FU (1000 mg/m2/day × 2 days) + cisplatin (40 mg/m2 day 3) q2w	42	II	Metastatic gastroesophageal	49	Febrile neutropenia (7), thrombocytopenia (15), anemia (12), fatigue (15) Venous thromboembolism (29), gastrointestinal perforation (1 patient)	NR 6-month PFS: 83%	Of 36 patients, PR: 64 (23 patients), SD: 25 (9 patients)
Pinto et al73	Cetuximab (400 mg/m2 [loading dose], 250 mg/m2 iv [maintenance dose]) + cisplatin (75 mg/m2 iv) + docetaxel (75 mg/m2 iv day 1), q3w (max 6 cycles)	48	II	Locally advanced or metastatic gastric or gastroesophageal	45.8	Thrombocytopenia (2.1), asthenia (22.9), anemia (6.25), febrile neutropenia (22.9) Greater toxicity limited to neutropenia	n/a	40.5
Sun et al70	Sorafenib (400 mg bid orally) + docetaxel (75 mg/m2 iv day 1) + cisplatin (75 mg/m2 iv day 1), q3w	44	II	Metastatic or advanced unresectable gastric and GEJ adenocarcinoma	26 patients	Neutropenia, fatigue, anorexia, hand-foot reaction, nausea, diarrhea, dehydration	14.9	38.6
Tebbutt et al74	Cetuximab (400 mg/m2 [loading dose] + 250 mg/m2 [weekly]) + docetaxel (30 mg/m2 days 1 and 8), q3w	38	II	Docetaxel-refractory gastroesophageal	n/a	Diarrhea (11), stomatitis (3), acneiform rash (5)	5.3	PR: 6 SD: 43

Abbreviations: AE = adverse event; 5-FU = 5-fluorouracil; GEJ = gastroesophageal junction; iv = intravenous; n/a = not available; NR = not reached; ORR = overall response rate; OS = overall survival; PFS = performance-free survival; PR = partial response; q2w = once every 2 weeks; q3w = once every 3 weeks; SD = stable disease.

The combination of bevacizumab 10 mg/kg every 3 weeks given in combination with docetaxel 30 mg/m², cisplatin 25 mg/m², and irinotecan 50 mg/m² on days 1 and 8 every 3 weeks has been studied in 35 patients with metastatic esophagogastric cancer.⁶⁷ This regimen was better tolerated than the regimen described by El-Rayes and colleagues⁶⁵; the main toxicities were grade 3/4 neutropenia (29%) and diarrhea (34%). It was recommended that patients take 81 mg of aspirin daily unless contraindicated. Three patients developed thromboembolic complications and were not taking aspirin. In the 32 evaluable patients, 69% were reported to have a partial response and 25% to have stable disease.

Higher toxicity was reported for a regimen of bevacizumab, docetaxel, leucovorin, 5-FU, and cisplatin, with 49% of patients experiencing grade 3/4 neutropenia, 29% of patients developing thromboembolism, and one patient developing gastrointestinal perforation.⁶⁸ The efficacy for this regimen, however, was promising, with a 6-month PFS of 83% and partial response rate of 64%.

The addition of bevacizumab to standard chemotherapy seems promising; however, until the safety has been confirmed, this approach should not be used as a treatment for gastric or GEJ cancer outside of clinical trials. The present data highlight concerns surrounding the high risk of thromboembolic, bleeding, and gastrointestinal perforation complications.

Aflibercept is a potent antivascular endothelial growth factor angiogenesis inhibitor that is in development for gastric cancer; a phase I study in combination with docetaxel is now under way in Japan.⁶⁹ Sorafenib is a potent multikinase inhibitor of several receptor tyrosine kinases implicated in gastric cancer. A phase II trial in patients with metastatic or advanced unresectable gastric or GEJ adenocarcinoma combining sorafinib with docetaxel and cisplatin revealed an ORR of 38.6%.⁷⁰ This study failed to meet its primary end point and was suspended based on these results. However, continued follow-up revealed a median PFS of 5.8 months and median OS of 14.9 months. The most common grade 3 or higher toxicity was neutropenia, with two deaths thought to be related to study drug. Given the observed prolonged survival, sorafinib in combination with docetaxel-based therapy is being considered as the basis of a randomized study by the Eastern Cooperative Oncology Group.

The monoclonal epidermal growth factor receptor inhibitor cetuximab, administered in combination with 5-FU, leucovorin, and irinotecan (FOLFIRI schedule) or with weekly 5-FU, leucovorin, and oxaliplatin (FUFOX), has shown favorable results as a first-line treatment for advanced gastric or GEJ adenocarcinoma in phase II studies.^71,72 A study evaluating cetuximab in combination with docetaxel 75 mg/m² and cisplatin 75 mg/m² every 3 weeks in patients with locally advanced or metastatic gastric or GEJ adenocarcinoma demonstrated a rate of grade 3/4 neutropenia of 45.8% (22.9% febrile neutropenia).⁷³ The ORR was 40.5%, and although survival data were premature, PFS at 3 months was 80%. For docetaxel-refractory disease, cetuximab with docetaxel 30 mg/m² on days 1 and 8, every 3 weeks, demonstrated low toxicity rates, and median PFS and OS of 2.1 months and 5.3 months, respectively.⁷⁴ There was a clear trend toward improved survival correlating with an increased grade of acne-like rash.

Other molecular targeting agents, such as the mTOR inhibitor RAD001,⁷⁵ the multitargeted tyrosine kinase inhibitor sunitinib,⁷⁶ and the erbB2 inhibitors, are under investigation. A multicenter phase II study designed to assess the effectiveness of trastuzumab, cisplatin, and docetaxel therapy in patients with metastatic gastric or gastroesophageal cancer with HER2 overexpression is currently under way.⁷⁷

CHEMOTHERAPY FOR GASTROESOPHAGEAL CANCERS

Many of the studies considered in this review included patients with cancers of the GEJ. In the studies reporting such information,^{21,28,30,35,37,38,43,45,63–66,68,73} the proportion of enrolled patients with primary cancer of the GEJ ranged between 10% and 50%. In the registrational randomized phase III V325 multinational trial previously mentioned,^19,21 22% of patients had primary GEJ tumors. In their phase III study, comparing different triplet regimens based on either capecitabine or oxaliplatin, Cunningham et al⁴³ stated that median OS was unaffected by the origin of the primary tumor (22%–29% of patients had primary GEJ cancer across the four study arms in this study). In a phase II study evaluating the combination of irinotecan, docetaxel, and oxaliplatin reported by Di Lauro et al⁶³ ORR and TTP were not different in patients with GEJ cancer (n = 10; ORR 50%, TTP 6.3 months) and those with gastric cancer (n = 30; ORR 50%, TTP 6.5 months). Ongoing studies to identify effective treatment regimens for gastric cancers include patients with cancers of GEJ origin.^{35,37,38,45,64,65,68}

DISCUSSION

To improve tolerability while maintaining the efficacy of docetaxel-based doublet and triplet regimens, the optimal dosing and scheduling of chemotherapy need to be refined. Phase I and II studies have demonstrated that the tolerability profile of docetaxel can be improved markedly when it is administered on a weekly or split schedule. Furthermore, sufficient data exist showing the reduced rates of neutropenia and neutropenic fever associated with these regimens with the routine use of G-CSF as secondary prophylaxis.

Recent guidelines highlight the benefits associated with the use of primary prophylactic G-CSF in conjunction with chemotherapy agents that have an associated risk for development of neutropenic infections.⁷⁸ Phase III studies in patients with breast cancer receiving docetaxel-based chemotherapy have shown the beneficial role of primary prophylactic G-CSF with significant reductions in the incidence of febrile neutropenia and neutropenia-associated hospitalization observed.^79,80 Future trials need to consider incorporating G-CSF as primary prophylaxis with the hope of preventing hematologic toxicities.

The rising incidence of cancers of the GEJ in the Western world^4,5 makes it likely that future trials will include an ever-increasing proportion of patients with this subtype of gastric cancer. The distinct pathophysiology of GEJ cancer^4,5 suggests that prospective evaluation of outcomes specifically in this subpopulation should be part of the design of future trials evaluating docetaxel-based and other chemotherapy in gastric cancer.

Various permutations of the original DCF regimen have been investigated, either substituting drugs within the same category, adding newer fluoropyrimidines, or combining targeted therapy with docetaxel-based regimens. Despite modifications, the toxicity profile of doublet or triplet regimens containing docetaxel remains high in patients with advanced gastric cancer. Given the availability of only limited data from small studies, targeted therapy and biologics should remain under the auspices of clinical trial investigation. Combining more sophisticated pharmacokinetic parameters as well as pharmacogenetic correlates, while taking into account population-based differences, will further assist in developing optimized regimens geared toward providing maximum efficacy while maintaining a tolerable toxicity profile.