Advances in the Pharmacological Treatment of Gastro-Oesophageal Cancer
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Despite a sharp decline in the incidence of gastric cancer during the second half of the 20th century, this malignancy remains the second leading cause of cancer mortality in the world. The incidence and mortality rate of gastric cancer increase with age; at present, the median ages at diagnosis are 67 years for men and 72 years for women in the US. This article reviews and discusses current medical treatment options for both the general population and elderly gastric cancer patients.
Management of localized gastric cancer has changed significantly over recent years. Adjuvant chemoradiation is not generally recommended outside the US. After decades of trials of adjuvant chemotherapy with inconclusive results, a significant survival benefit for perioperative combination chemotherapy — as compared with surgery alone — in patients with resectable or locally advanced gastro-oesophageal cancer was recently demonstrated in the UK MAGIC trial. A further large, randomized trial from Japan demonstrated a significant survival benefit for adjuvant chemotherapy with S-1 after D2 resection for gastric cancer. However, both trials are applicable only to the population in which the trials were conducted. Specific data on elderly patients are missing.
For patients with metastatic disease, oral fluoropyrimidines, such as capecitabine, have been developed. In Asian patients, treatment with the oral fluoropyrimidine S-1 is safe and effective. Docetaxel, oxaliplatin and irinotecan have demonstrated activity against gastric cancer in appropriately designed, randomized, phase III trials and have increased the available treatment options significantly. In addition, according to preliminary data, trastuzumab in combination with chemotherapy has significantly improved activity when compared to chemotherapy alone in patients with human epidermal receptor (HER)-2-positive gastric and gastro-oesophageal cancers. Thus, therapeutic decisions in patients with advanced gastric cancer may be adapted to the molecular subtype and co-morbidities of the individual patient. Data from retrospective analyses suggest that oxaliplatin seems to be better tolerated than cisplatin in elderly patients.
Despite a sharp decline in its incidence during the second half of the 20th century, gastric cancer remains the second leading cause of cancer mortality in the world, with substantial variation internationally. In Europe, 78 114 new stomach cancer cases were diagnosed and 63 381 stomach cancer deaths occurred in 2000. The incidence and mortality rates for gastric cancer are increasing with age. The median age at diagnosis is 70 years for men and 75 years for women in Germany; in the US, median ages at diagnosis for men and women are 67 and 72 years, respectively. Currently, people aged 65 years and older account for 61% of all new cancer cases and 70% of all cancer deaths. As a consequence of the demographic changes we have to face in the coming decades, the absolute number of cancer patients will increase significantly; elderly patients will mainly be affected. This will involve gastric cancer as well as many other malignancies. In contrast to clinical reality, the age of patients treated in clinical trials is well below the abovementioned figures. Lewis et al. reported the relative frequency of patients aged ≥65 years treated in clinical trials conducted by the US National Cancer Institute and compared these data with US data for patients with the same disease. In early stage cancer, 42% of patients in clinical trials were aged ≥65 years compared with 75% in the overall incident population of the US. The respective data for late-stage disease were 39% compared with 66%. Even if clinical trials do not exclude elderly patients via inclusion or exclusion criteria, elderly patients who are recruited in clinical trials for chemotherapy are highly selected.
This article has two main aims: (i) to review current medical treatment for patients with gastro-oesophageal cancer; and (ii) to analyse relevant trials and other available literature for the inclusion of elderly patients with gastro-oesophageal cancer. On this basis, treatment options for this special population are discussed. We focus on recent phase III trials of drug treatment, i.e. chemotherapy and targeted agents, in gastric adenocarcinoma. These trials usually include carcinomas of the gastro-oesophageal junction. Some of these trials also include patients with squamous cell cancer of the oesophagus and are discussed separately. A review of the published literature including the MEDLINE database as well as relevant abstracts was performed in October 2008. The search strategy included the terms ‘chemotherapy’, ‘elderly’, ‘cancer’ and ‘gastric’ or ‘stomach’.
1. Demography, Epidemiology and Age as Prognostic Factors
Is the tumour biology different? Tumour biology might differ between younger and elderly patients with gastro-oesophageal cancer: Saito et al. observed more blood vessel invasion and more well differentiated tumours in elderly patients. Buffart et al. identified different genomic profiles in younger versus elderly gastric cancer patients.
Do elderly patients receive the same treatment? Again, Saito et al. reported that in elderly patients fewer lymph nodes are dissected and less postoperative chemotherapy is applied.
Does the analysis include parameters of Comprehensive Geriatric Assessment (CGA) that reflect the individual aging process, such as functional limitations, co-morbidities, dementia, depression, reduced mobility and others? The pivotal question, whether age remains a prognostic factor after adjustment for age-associated changes in CGA has not been addressed in gastro-oesophageal cancer patients to date.
2. Geriatric Assessment
CGA is an established method in geriatric medicine for recognizing individual deficits and resources, especially in areas missed by standard history taking and physical examination. It covers the following areas: ability to self-care; mobility and risk of falls; cognition and dementia; depression and mood; social support; and co-morbidity. In elderly patients with cancer, a structured geriatric assessment detects changes missed by traditional work-up of the patients[11,12] and is more sensitive than a physician’s judgement in rating a patient’s fitness for chemotherapy. For example, mild to moderate cognitive impairment is often missed by routine history taking and clinical examination. Completion of a standard form for assessing cognitive function is therefore a fundamental part of a geriatric assessment, which is of particular importance when oral chemotherapies are administered.
A CGA is recommended for patients aged ≥70 years. A two-step approach is useful: screening patients to identify those without deficits and applying a complete CGA only to those patients with deficits observed in screening.[15,16]
Medically fit patients can be treated with protocols established in younger patients as standard treatment, vulnerable patients need specific treatment approaches and frail patients should receive primarily palliative care. In the geriatric setting, indicators of frailty are an inability to perform one or more basic activities of daily living, a stroke in the past 3 months, depression, dementia, a history of falls, one or more unplanned hospital admissions in the past 3 months, difficulty in walking, malnutrition, prolonged bed rest, incontinence, pressure sores, sensory impairment and polypharmacy. However, the significance of these indicators for decision making in medical oncology must currently be considered unclear.
3. Treatment of Localized Disease: Adjuvant and Perioperative Therapy
For patients with localized disease (International Union against Cancer [UICC] stage 0–II), surgery offers the only chance for cure. However, success rates of surgery are limited by high recurrences rates. Both local and systemic recurrences decrease 5-year survival rates in stage II gastro-oesophageal advanced cancer to between 30% and 50%, and in stage III–IV disease to between 10% and 30% in a large Western series.[18,19] Principally, medical treatment aimed at increasing survival in patients with resectable gastric cancer may be delivered before, after, or before and after surgery.
Adjuvant therapy is generally defined as a treatment that is administered after curative surgery (R0 resection) to improve the chances of long-term survival. Depending on the type of disease, adjuvant treatment may consist of drug treatment, radiotherapy or both. Some major issues regarding surgical therapy need to be considered before any discussion of adjuvant therapy is possible. Continuing controversy over the treatment of gastric cancer and resultant international differences in surgical management of the disease mean it is difficult to compare the results of adjuvant treatment from different settings. There is no doubt that a more extensive lymphadenectomy improves the accuracy of staging and reduces locoregional recurrences, but its impact on survival is probably limited to a subset of patients. The so-called D1 resection consists of removal of the stomach, the lesser and greater omentum and associated N1 lymph nodes. In contrast, a D2 resection includes a more extensive dissection with removal of N2 lymph node stations. In Japan, the D2 lymphadenectomy is considered the standard of care and is performed with impressively low morbidity, mortality and local recurrence rates; conversely, D2 lymphadenectomy is not generally recommended in Europe or the US.[20,21]
Neo-adjuvant treatment is performed with the same goal as adjuvant therapy, but differs in that it is administered preoperatively. In addition, neo-adjuvant treatment may be applied to patients with locally advanced, primary unresectable disease to achieve secondary resectability.
Perioperative therapy has only recently been introduced in gastric cancer treatment and consists of a combination of both pre- and postoperative therapy for resectable gastric cancer.
Chemotherapy is feasible in a significantly greater proportion of patients when applied preoperatively. This was impressively demonstrated in the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial, in which only 54% of the patients assigned to receive perioperative chemotherapy did in fact commence postoperative chemotherapy.
(Radio)chemotherapy is delivered earlier in the course of the disease when given preoperatively and may, therefore, be more effective against disseminated tumour cells, which have been shown to be significantly associated with the risk of relapse.
For patients diagnosed at a stage where curative resection is unlikely (UICC stage III, T3–4, N+), effective preoperative therapy offers a chance of downsizing the tumour and increasing the rate of R0 resections.
In the Intergroup 0116 trial, 556 patients with stage Ib–IV M0 adenocarcinoma of the stomach were randomized to either adjuvant treatment with one cycle of fluorouracil/leucovorin (folinic acid), followed by fluorouracil-based adjuvant chemoradiation and two cycles of adjuvant systemic fluorouracil/leucovorin or surgery alone. Median survival was 36 months in the patients who received adjuvant therapy, as compared with 27 months with observation alone (p = 0.005). On this basis, adjuvant radiochemotherapy has been widely introduced in clinical practice in the US. However, this trial has attracted substantial criticism, mainly because of the type of surgery used; more than half of the patients in this trial had less than a D1 resection, which is clearly insufficient according to current surgical standards. In addition, with 1% of patients experiencing toxicity-related deaths, toxicity was substantial. Toxicity and the minimal lymphadenectomy used are the main reasons that adjuvant radiochemotherapy is not generally recommended outside the US.
Adjuvant chemotherapy has been the focus of a large number of clinical trials in recent decades, the results of which have been summarized in several meta-analyses.[25, 26, 27] Although these meta-analyses found a small relative reduction in the risk of death for adjuvant chemotherapy versus observation, adjuvant chemotherapy alone has not become an accepted standard treatment.
3.2 Recent Advances: Adjuvant and Perioperative Chemotherapy
Sakuramoto et al. randomized 1059 patients with stage II or III gastric cancer after D2 resection to adjuvant treatment with S-1 (6-week cycles of 80 mg/m2/day for 4 weeks, followed by 2 weeks rest, for 1 year) versus observation. The primary endpoint was overall survival. Three years after randomization, overall survival was 80.1% in the S-1 group and 70.1% in the surgery-only group, with a hazard ratio (HR) for death of 0.68 (95% CI 0.52, 0.87; p = 0.003) for patients treated with adjuvant S-1. The most common grade III or IV adverse events in the S-1 group were anorexia (6%), nausea (3.7%) and diarrhoea (3.1%). Comparable results (5-year overall survival rates of 86% vs 73%; p = 0.017) were achieved in another Japanese trial that randomized 188 patients after D2 or greater lymph node dissection to adjuvant tegafur/uracil (UFT) [360 mg/m2 for 5 days with a 2-day rest, beginning 6 weeks and ending 16 months after surgery] or surgery alone. However, although these two trials show convincing results in East Asian patients, these findings are not applicable to countries where D2 surgery is not routinely performed. In addition, differences in the toxicity of S-1 for Japanese versus Western patients have been observed, and both UFT and S-1 have been insufficiently studied in Western patients with gastric cancer. Adjuvant chemotherapy may, therefore, only be recommended to Asian patients.
The pivotal MAGIC trial, which compared three cycles of ECF (epirubicin 50 mg/m2, cisplatin 60 mg/m2 and fluorouracil 200 mg/day for 21 days every 3 weeks), administered before and after surgery, with surgery alone, showed a significant survival benefit (5-year survival rates 36.3% vs 23%, HR for death 0.74 [95% CI 0.59, 0.93; p = 0.009]) for patients treated with this regimen and established a new standard of care in Europe. As noted in the previous section, this combined pre- and postoperative approach is also referred to as perioperative therapy. The trial included a total of 503 patients with stage II or higher adenocarcinoma of the stomach or lower oesophagus. The median age of the trial population was 62 years (range 23–85). Approximately 20% of the patients were aged >70 years. In patients treated with surgery alone, surgery was performed within 6 weeks of randomization. Patients treated with surgery plus perioperative chemotherapy had surgery 3–6 weeks after completion of the third cycle of chemotherapy. Apart from 13% and 17% of patients in the perioperative chemotherapy and surgery-alone groups, respectively, who had nonresectional surgery, all other patients had either an oesophagogastrectomy or at least a D1 resection, which must be considered adequate according to Western standards. The incidence of postoperative complications was similar in the two groups, as was the number of deaths within 30 days. The fact that only 42% of the patients who were randomized to perioperative therapy completed all six cycles of therapy, mainly because of disease progression/early death, patients’ choice or postoperative complications, provides important insights into the feasibility of any postoperative therapy: postoperative therapy is in fact not feasible in about one-half of patients undergoing gastric cancer surgery. The results of this trial have been replicated almost exactly in a French trial (5-year survival rate of 38% vs 24%; p = 0.021 for patients with vs without preoperative chemotherapy), which used a two-drug (cisplatin/fluorouracil) regimen instead of ECF.
4. Treatment of Advanced and Metastatic Disease: Palliative Therapy
In patients with advanced gastric cancer, chemotherapy clearly improves survival and quality of life compared with best supportive care. A Cochrane review and meta-analysis identified an HR of 0.39 for the comparison of chemotherapy versus best supportive care, which translates into an absolute benefit in weighted mean average survival of approximately 6 months. Combination chemotherapy has been shown to be associated with a significant survival benefit over single-agent chemotherapy, albeit at the expense of increased toxicity. Furthermore, three-drug combinations including fluorouracil/cisplatin and an anthracycline have shown superior results for survival when compared with two-drug combinations of either fluorouracil and an anthracycline or fluorouracil/cisplatin. Therefore, in the absence of contraindications, combination chemotherapy should be used as initial treatment. Nevertheless, the question of whether a two-drug (fluorouracil/platinum) or three drug (fluorouracil/platinum/anthracycline or fluorouracil/cisplatin/docetaxel) combination should be used as first-line therapy for patients with good performance status and adequate organ function remains a matter for debate.
Fluoropyrimidines are the backbone of any chemotherapy regimen for gastric cancer. Fluorouracil has been used most frequently in the past, either as a bolus or infusional regimen. Infusional fluorouracil regimens are preferentially used in combination chemotherapies because of their lower haematological toxicity. In addition, they are associated with a lower rate of toxic deaths. To avoid complications and inconvenience associated with implantable catheters and portable pumps, as well as because of patient preference for oral versus intravenous chemotherapy, several oral fluoropyrimidines have been developed. Capecitabine and S-1 have mainly been used in recent phase III clinical trials of advanced gastric cancer.
Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil in three enzymatic steps. The last two steps involve the enzymes cytidine deaminase and thymidine phosphorylase, which have a 2- to 3-fold higher activity in gastric cancer tissue compared with adjacent normal tissue. This results in an increased concentration of fluorouracil at the site of the tumour. Capecitabine is rapidly and extensively absorbed as an intact molecule through the gastrointestinal mucosa, with its bioavailability estimated to be nearly 100%. The rate and extent of absorption of capecitabine are significantly reduced by food intake. Greater than 90% of the administered dose is recovered in urine. Caution is therefore advised in patients with mild or moderate renal impairment, and the drug is contraindicated in patients with severe renal impairment. Calculation of creatinine clearance is, therefore, necessary before administration of capecitabine in elderly patients. Age, sex, body surface area and hepatic dysfunction have no significant impact on the pharmacology of capecitabine.[39,40]
In addition to numerous phase II trials using capecitabine as first- and second-line treatment in different combinations in advanced gastric cancer, two large, well designed, randomized, phase III trials have established the non-inferiority of capecitabine versus infusional fluorouracil in combination with cisplatin, and in combination with epirubicin and cisplatin or oxaliplatin. In the first study, 316 patients (median age 56 years, range 22–74) with advanced or metastatic gastric adenocarcinoma were treated with oral capecitabine 1000 mg/m2 twice daily on days 1–14, or with fluorouracil 800 mg/m2 continuous infusion on days 1–5 in combination with cisplatin 80 mg/m2 on day 1 every 3 weeks. The primary outcome measure was non-inferiority of capecitabine when compared with infusional fluorouracil. This trial met its primary endpoint and confirmed the non-inferiority of capecitabine. The median duration of overall survival in capecitabine/cisplatin recipients was non-inferior to that for fluorouracil/cisplatin recipients (10.5 vs 9.3 months, HR 0.85 [95% CI 0.64, 1.13]), while the remission rate was significantly superior (41% vs 29%; p = 0.03) for capecitabine. Toxicity was as expected, with a higher rate of hand-foot syndrome (22% vs 4%) in patients treated with capecitabine. Other grade III/IV toxicities, such as neutropenia, vomiting, diarrhoea, anaemia and stomatitis, had comparable incidences in both treatment arms.
The second, pivotal REAL-2 (Randomised ECF for Advanced and Locally Advanced Esophagogastric Cancer-2) trial used a 2 × 2 factorial design to evaluate capecitabine versus infusional fluorouracil in a triplet combination with cisplatin or oxaliplatin and epirubicin. The results of this study are discussed in section 4.4.1. Of interest, a recent meta-analysis of both trials demonstrated significant benefits in terms of overall survival (HR 0.87; 95% CI 0.77, 0.98) as well as response rate for capecitabine compared with fluorouracil.
S-1 is another oral fluoropyrimidine which contains tegafur (a fluorouracil prodrug) combined with 5-chloro-2,4-dihydroxypyridine (gimeracil, an inhibitor of dihydropyridine dehydrogenase, which degrades fluorouracil) and oteracil (a pyrimidine phosphoribosyltransferase inhibitor, which reduces phosphorylation of fluorouracil in the gastrointestinal tract, thereby reducing the gastrointestinal adverse effects of fluouracil) at a molar ratio of 1 : 0.4 : 1. Although phase III studies in combination with cisplatin (SPIRITS [S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer] trial) and as a single agent in Japanese patients have been published only recently, S-1 (as a single agent or in combination) is an established treatment for gastric cancer in Japan. While a dosage of 80 mg/m2/day is widely used in single and combination chemotherapies in Asian patients, a phase I pharmacokinetic study in Western patients established S-1 50 mg/m2/day, given on day 1–21 every 28 days, in combination with 75 mg/m2 of cisplatin on day 1 as the recommended schedule. This difference in tolerability is attributed to polymorphic differences in the cytochrome P450 2A6 (CYP2A6) gene between Japanese and non-Japanese patients. The schedule has been evaluated in a phase III trial, for which results have recently been published in abstract form, in comparison with cisplatin/infusional fluorouracil (FLAGS [First-line Therapy in patients with Advanced Gastric Cancer] study). This trial randomized a total of 1053 patients (median age 59 years, range 18–85, 41% performance status = 0) to treatment with S-1 or cisplatin/fluorouracil. Median survival was equal in both treatment arms (8.6 months for cisplatin/S-1 vs 7.9 months for cisplatin/fluorouracil). However, significant safety advantages could be demonstrated for cisplatin/S-1: rates of grade III/IV neutropenia were 18.6% for cisplatin/S-1 versus 40% for cisplatin/fluorouracil; febrile neutropenia occurred in 1.7% of patients treated with cisplatin/S-1 and 6.9% of those treated with cisplatin/fluorouracil. Grade III/IV stomatits occurred in 1.3% of patients treated with cisplatin/S-1 and 13.8% of patients treated with cisplatin/fluorouracil. All-grade renal adverse events occurred in 18.6% of patients treated with cisplatin/S-1 versus 33.5% of patients treated with cisplatin/fluorouracil. Rates of treatment-related deaths were 2.5% for cisplatin/S-1 and 4.9% for cisplatin/fluorouracil (p < 0.05). However, successful application of an oral chemotherapy requires more than an effective drug; adequate cognitive function and compliance are also crucial and both should be carefully evaluated before starting treatment.
4.3 Two-Drug Combinations
4.3.1 Platinum/Fluoropyrimidine Combinations
While cisplatin has been used in combination chemotherapies for gastric cancer for many years, the role of oxaliplatin in the treatment of gastric cancer was only recently established, mainly through the results of two randomized, phase III trials.[42,48] The REAL-2 trial is discussed in detail in section 4.4.1. The second trial (n = 220, median age 64 years, range 27–86) aimed to demonstrate the superiority of FLO (fluorouracil 2600 mg/m2 via 24-hour infusion, leucovorin 200 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks) over FLP (fluorouracil 2000 mg/m2 via 24-hour infusion, leucovorin 200 mg/m2 weekly and cisplatin 50 mg/m2 every 2 weeks) in terms of progression-free survival. This trial did not meet its primary endpoint. Although there was a trend for a longer progression-free survival of nearly 2 months with FLO, the difference was statistically nonsignificant. In addition, patients treated with the oxaliplatin-based compared with the cisplatin-based combination had a more favourable toxicity profile; significantly fewer any-grade toxicities were observed for anaemia (54% vs 72%), nausea (53% vs 70%), vomiting (31% vs 52%), alopecia (22% vs 39%), fatigue (19% vs 34%), renal toxicity (11% vs 34%) and thrombembolic events (0.9% vs 7.8%) in patients treated with FLO compared with FLP. In contrast, the incidence of peripheral neuropathy was higher in patients treated with oxaliplatin (63% vs 22%) compared with cisplatin.
4.3.2 Irinotecan/Fluorouracil Combinations
Irinotecan has shown promising activity in several randomized, phase II trials of patients with gastric cancer.[49, 50, 51] However, a subsequent phase III trial (n = 333, median age 58/59 years, range 28–77), which compared IF (irinotecan 80 mg/m2, folinic acid 500 mg/m2 and fluorouracil 2000 mg/m2) for 6/7 weeks with cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2/day, days 1–5, every 4 weeks did not meet its primary endpoint, which was a superiority of progression-free survival for the IF versus cisplatin/fluorouracil combination. In addition, this trial failed to establish non-inferiority for the experimental IF combination. Time-to-progression for IF and cisplatin/fluorouracil were 5.0 and 4.2 months, respectively. Median survival in patients treated with IF was 9.0 months compared with 8.7 months with cisplatin/fluorouracil. One-year overall survival rates for IF and cisplatin/fluorouracil were 37% and 31%, respectively. According to the protocol, to be considered non-inferior, the lower limit of the 95% confidence interval for the Cox model HR of time to progression in the control arm to the test arm was to be ≥0.93 in both the intent-to-treat (ITT) and per-protocol analyses. This criterion was met only in the ITT population. Thus, although neither superiority nor non-inferiority could be formally established for the IF combination, a clinically significant inferiority of irinotecan/fluorouracil as compared with cisplatin/fluorouracil is unlikely. In fact, both regimens showed comparable results for efficacy, albeit differences in toxicity. While patients treated with cisplatin had higher rates of neutropenia, stomatitis and nausea, patients treated with irinotecan — as expected — had higher rates of diarrhoea. In addition, the rate of treatment-related deaths (0.6% vs 3%) was lower in patients treated with irinotecan. The finding of a nonsignificant difference in survival between irinotecan- and non-irinotecan combination chemotherapy regimens was confirmed in a recently published meta-analysis. Thus, in clinical practice, irinotecan should be considered an alternative treatment option in patients in whom use of cisplatin is contraindicated because of concomitant medical problems, such as pre-existing neuropathy. Regimens that use fluorouracil as a bolus in combination with irinotecan should generally be avoided because of their higher rates of toxic deaths.
4.4 Three-Drug Combinations
4.4.1 Combinations Including Fluorouracil, a Platinum Derivate and an Anthracycline: The REAL-2 Trial
ECF (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1 and fluorouracil 200 mg/m2/day days 1–21 every 3 weeks), which served as the reference treatment;
ECX (epirubicin and cisplatin as above, with capecitabine 625 mg/twice daily days 1–21 every 3 weeks);
EOX (epirubicin and capecitabine as above, with oxaliplatin 130 mg/m2 instead of cisplatin on day 1);
EOF (epirubicin, oxaliplatin and fluorouracil as above).
4.4.2 Taxanes: Docetaxel/Cisplatin/Fluorouracil (DCF) and Docetaxel/Cisplatin Regimens
Taxanes are naturally derived chemotherapeutic agents that prevent microtubule depolymerization during mitosis. Both paclitaxel and docetaxel have demonstrated clinical activity in metastatic gastric cancer in preliminary trials.[57, 58, 59] In contrast, only docetaxel was the subject of two recently published, phase III studies. The first study (V325) [n = 445, median age 55 years, range 25–79], which was a large, international phase III study, compared the three-drug combination of docetaxel/fluorouracil/cisplatin (DCF) versus the two-drug combination of cisplatin/fluorouracil. A second study evaluated the two-drug combination of docetaxel/cisplatin versus cisplatin/fluorouracil. V325 demonstrated a statistically significant benefit in overall survival (8.6 vs 9.2 months; p = 0.02) for the three-drug combination of DCF compared with the two-drug combination of cisplatin/fluorouracil, which became apparent especially after 1 and 2 years (1-year survival rate 40% vs 32%, 2-year survival rate 18% vs 9% for patients treated with DCF vs cisplatin/fluorouracil). However, the absolute benefit in median survival for the three-drug combination was not more than 20 days, and its clinical relevance is a matter of debate.[33,61] Furthermore, this benefit has to be weighed against a significantly higher toxicity: rates of grade III/IV neutropenia were 82% versus 57%, diarrhoea 19% versus 8% and lethargy 19% versus 14%, in patients treated with DCF compared with cisplatin/fluorouracil. Rates of complicated neutropenia in the DCF arm with and without colony-stimulating factor prophylaxis were 27% and 12%, respectively. Elderly patients were also clearly underrepresented in this trial.
The other, recently published phase III trial that included docetaxel found no significant differences, including in time to progression and survival, between groups treated with docetaxel/cisplatin or cisplatin/fluorouracil. As expected, docetaxel/cisplatin had higher incidences of grade III and IV leukopenia as compared with cisplatin/fluorouracil (45.2% vs 8.2%), but gastrointestinal toxicity and nausea were less frequent in patients treated with docetaxel/cisplatin (18.5% and 29.2% for gastrointestinal toxicity, 17.3% vs 22.2% for nausea). The median age of patients in this trial was 62 years. Overall, the incidences of grade III and IV toxicities with docetaxel/cisplatin were much lower than those reported for DCF in V325. A further randomized, phase II trial evaluated the combination of docetaxel and continuous-infusion fluorouracil versus ECF. Again, this regimen was relatively well tolerated, but its efficacy was not relevantly different to that of ECF. In summary, the efficacy of docetaxel in gastric cancer has been clearly demonstrated in two randomized trials.[53,60] Unfortunately, the three-drug combination of DCF is associated with significant toxicity. Two-drug regimens of either docetaxel/cisplatin or docetaxel/fluorouracil are better tolerated, but do not seem to have any advantage in efficacy over the reference regimens cisplatin/fluorouracil or ECF.
5. Chemotherapy in Elderly Patients with Gastro-Oesophageal Cancer
In elderly patients, chemotherapy is generally associated with an increase in toxicity, mainly haematological toxicity. Because specific, prospective data on chemotherapy in elderly patients with gastro-oesophageal cancer are rare, some results obtained in patients with other types of cancer, e.g. breast or colorectal carcinoma, may also be helpful in decision-making for elderly patients with gastro-oesophageal carcinoma.
Fluorouracil regimens are well studied in the adjuvant treatment of elderly patients with colorectal carcinoma. Apart from an increased rate of neutropenia in patients aged ≥70 years, Sargent et al. did not observe increased toxicity in elderly patients treated with adjuvant chemotherapy for colorectal cancer. Tumour-specific survival was identical in patients aged <70 years and those aged ≥70 years. Folprecht et al. analysed 22 European trials of chemotherapy for metastatic colorectal cancer. They found that age ≥70 years is not a negative prognostic factor for remission rate, progression-free survival or overall survival. However, only 629 (16%) of all 3825 patients were aged ≥70 years. Toxicity was not reported. Goldberg et al. performed a retrospective analysis of four randomized trials that used the FOLFOX (fluorouracil/folinic acid/oxaliplatin) regimen in patients with colorectal cancer; 614 (16%) of 3742 patients were aged ≥70 years. These investigators found an increase in grade III or higher haematological toxicity (neutropenia 43% in patients aged <70 years vs 49% in those aged ≥70 years; p = 0.04; thrombocytopenia 2% in patients aged <70 years vs 5% in those aged ≥70 years; p = 0.04); however, the rates of non-haematological toxicities and 60-day mortality were comparable. These investigators also found no differences in dose-intensity, remission rate, progression-free survival, recurrence-free survival and overall survival between patients aged <70 years and those aged ≥70 years.
IF-based combination chemotherapy for metastatic colorectal cancer was analyzed for age-associated changes in toxicity and efficacy by Folprecht et al. These investigators compared data from 599 patients aged ≥70 years with data from 2092 patients aged <70 years treated in four prospective randomized trials with first-line therapy for advanced colorectal carcinoma. In this analysis, remission rates and progression-free survival were identical in patients aged ≥70 years compared with those aged <70 years. Interestingly, improved response rates and progression-free survival for patients treated with the IF combination as compared with fluorouracil/folinic acid alone were correlated with a benefit in survival in patients aged <70 years and those aged 70–74 years, but not in patients aged ≥75 years. There were no significant differences in toxicity between patients aged <70 years and those aged ≥70 years.
If oral chemotherapy is selected, compliance needs to be carefully evaluated. To reduce compliance problems in the elderly, cues that assist them to remember to take doses (time of day, meal-time or other daily rituals) and devices to simplify remembering doses (medication boxes) might be helpful.
5.2 Adjuvant and Perioperative Therapy in Elderly Patients
Apart from a subgroup analysis of 105 patients in the trial by Cunningham et al., which showed a comparable benefit from perioperative therapy for patients aged >70 years as compared with younger patients, specific data on adjuvant/perioperative therapy for elderly gastro-oesophageal cancer patients are lacking. Therefore, the drawbacks of adjuvant treatment and risk of relapse need to be balanced against life expectancy, health status and the preferences of each older individual. Many elderly individuals have substantial life expectancies, even in the setting of significant illness. For example, a person in average health surviving to the age of 75 years has a life expectancy of 11 years. Gastric cancer recurrences in current Western series occur in >50% of patients within 2 years of primary treatment. They are generally incurable and associated with rapid development of clinical symptoms. Therefore, elderly patients with adequate organ function and performance status, without any criteria for frailty, should undergo validated oncological treatment options, such as perioperative therapy for resectable gastric cancer. Prognostic indices for 2- and 4-year mortality[68,69] may also be helpful for estimation of the individual life expectancy.
5.3 Palliative Chemotherapy in the Elderly
The largest dataset on chemotherapy of elderly patients with gastro-oesophageal cancer is a pooled, retrospective analysis of three clinical trials that includes data for 257 patients aged ≥70 years who met the standard criteria for clinical trials. However, among these 257 patients, 160 patients were in the age group 70–74 years, 78 were in the age group 75–79 years, and only 19 were in the group aged ≥80 years. According to this analysis, the overall incidence of grade III/IV toxicities in patients aged ≥70 years undergoing chemotherapy for oesophagogastric cancer did not differ significantly from that for patients aged <70 years. However, these were highly selected patients, and data on patients aged ≥80 years were scarce. For elderly patients with co-morbidities, in whom combination chemotherapy is not considered feasible, single-agent chemotherapy with a fluoropyrimidine alone is a reasonable alternative treatment option. A symptomatic benefit, as measured by improvements in pain control, weight loss, dysphagia and oesophageal reflux, was demonstrated for protracted venous infusion (PVI) of fluorouracil 300 mg/m2/day as a single agent compared with the combination of fluorouracil/mitomycin C in over 64% of patients in a randomized trial that included 254 patients with a median age of 72 years (range 52–84) and a performance status of 0–2. Median survival was 6.3 months for PVI-fluorouracil and 5.3 months for PVI-fluorouracil/mitomycin. A benefit arising from addition of mitomycin could not be demonstrated.
An unplanned subgroup analysis of the trial by Al-Batran et al., which compared FLO with FLP, provided interesting insights into the efficacy and tolerability of these regimens in elderly patients. In patients aged >65 years (n = 94), treatment with FLO resulted in significantly superior progression-free survival (6.0 vs 3.1 months; p = 0.29) and overall survival (13.9 vs 7.2 months) compared with FLP, which is most likely to be attributable to the earlier treatment discontinuation for FLP compared with FLO (after a median of 1.7 vs 3.3 months, respectively). Although the results of any unplanned subgroup analysis need to be interpreted with caution, the finding of a higher dose-intensity of cisplatin in patients aged <70 years compared with patients aged ≥70 years is consistent with data from other trials in gastric cancer. On this basis, FLO should be considered a favourable treatment option for elderly gastric cancer patients. In contrast, DCF was associated with a higher rate of treatment-related grade 3–4 infection (20%) versus (9%) for DCF and cisplatin/fluorouracil in patients aged >65 years, and infection was the main cause of toxic deaths (seven of eight patients in the DCF arm) in the abovementioned phase III trial. Furthermore, the median age of patients included in this trial was 55 years. Only 24% of patients treated with DCF were aged ≥65 years. Therefore, further data on the tolerability of this regimen in elderly patients are warranted before widespread use in this population may be recommended.
6. Targeted Therapies
In contrast to colorectal cancer, targeted therapies in patients with gastric cancer have mainly been evaluated in phase II trials; however, several subsequent phase III trials are currently ongoing. Inhibition of vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor-1 (EGFR-1) [human epidermal receptor, HER-1] are the two principal strategies.
Inhibition of tumour angiogenesis is a therapeutic approach that has been introduced in clinical practice only recently. Expression of VEGF in gastric cancer increases with increasing stage and tumour burden. Bevacizumab, a humanized monoclonal antibody against VEGF, is an established treatment in colorectal cancer. A single-arm, phase II trial of bevacizumab in combination with irinotecan and cisplatin for gastric cancer has been reported recently. The objective response rate was 65%, time to progression was 8.3 months and median survival was 12.3 months. Possible bevacizumab-related toxicity included hypertension, gastric perforations in 6% and grade III/IV thromboembolic events in 25% of patients. A randomized, phase III trial (the AVAGAST [Avastin in Combination With Capecitabine and Cisplatin as First-Line Therapy in Patients With Advanced Gastric Cancer] trial) of bevacizumab in combination with capecitabine and cisplatin in the advanced setting is ongoing, together with a UK Medical Research Council phase II/III study of ECX, with or without bevacizumab, in the perioperative setting.
HER-1 is another target that promotes cell proliferation and is overexpressed in 18–81% of primary gastric cancers and/or metastases.[79,80] In contrast to studies that evaluated tyrosine-kinase inhibitors that block EGFR, such as erlotinib and gefitinib, preliminary data from other phase II trials of cetuximab, a chimeric monoclonal antibody targeting EGFR-1, have yielded promising results. Two single-arm, phase II trials of cetuximab in combination with irinotecan and fluorouracil[83,84] reported response rates of 44% and 55%, respectively. In the first trial, the median time to progression was 8 months and, after a median follow up of 11 months, 55.3% of patients in the study were still alive. In the trial by Moehler et al., the tumour control rate at 7 weeks was 100%; further results are still pending. A third phase II trial of cetuximab in combination with weekly oxaliplatin/fluorouracil/folinic acid for first-line metastatic gastric cancer observed 39.1% confirmed responses. On this basis, a randomized phase III trial of capecitabine in combination with cisplatin, with or without cetuximab (the EXPAND [Erbitux in combination with Xeloda and cisPlatin in AdvaNceD esophago-gastric cancer] trial), is ongoing. In addition to HER-1, HER-2 is overexpressed in a subset of gastric cancers. Again, the highest rates of overexpression are observed in patients with advanced disease, and inhibitors of HER-2, such as lapatinib and trastuzumab, are being evaluated in randomized trials. Most recently, data from a randomized, phase III trial (the ToGA [Trastuzumab fOr GAstric cancer] trial) in patients with advanced gastric cancer have been reported as an oral presentation. In this study, patients with HER-2-positive gastro-oesophageal or gastric adenocarcinoma (locally advanced, recurrent or metastatic) were randomized to receive either trastuzumab in combination with chemotherapy (fluorouracil or capecitabine and cisplatin) every 3 weeks for six cycles or chemotherapy alone. HER-2 positivity was detected in 22% of all patients screened. Trastuzumab was given until disease progression. The primary endpoint was overall survival; secondary endpoints included overall response rate, progression-free survival, time to progression, duration of response and safety. An interim analysis was planned at 75% of deaths and the Independent Data Monitoring Committee recommended release of the data. At the time of the interim analysis, 594 patients had been randomized. Median overall survival was significantly improved with trastuzumab in combination with chemotherapy compared with chemotherapy alone: 13.5 versus 11.1 months, respectively (HR 0.74; 95% CI 0.60, 0.91; p = 0.0048). The overall response rate was 47.3% in the trastuzumab plus chemotherapy arm compared with 34.5% in the chemotherapy alone arm (p = 0.0017). The safety profiles in the two treatment groups were similar with no unexpected adverse events. There was no difference in symptomatic congestive heart failure between treatment arms. Asymptomatic decreases in left ventricular ejection fraction were reported in 4.6% of patients in the trastuzumab plus chemotherapy arm compared with 1.1% in the chemotherapy alone arm.
Important advances in the treatment of both resectable and advanced gastric cancer have been made in recent years. For patients with resectable disease, perioperative combination chemotherapy with ECF was associated with a significant benefit in overall survival compared with surgery alone in a recently published landmark study (MAGIC trial), which was conducted mainly in Europe. This study has changed the standard of care in patients with resectable disease. In a further, large, randomized trial conducted in Japan, adjuvant treatment with S-1, given for 1 year after D2-lymphadenectomy, achieved a comparable advantage in overall survival. Although the results of these trials are valid only in the settings in which they were conducted, both studies confirm that, even when optimal surgery is performed, medical treatment is necessary and able to improve on the results of surgery alone.
For patients with metastatic disease, several new drugs, such as oxaliplatin, capecitabine, irinotecan and docetaxel, have importantly increased the systemic treatment options for gastric cancer. The major advantages of these new treatment options are patient convenience and a reduction in toxicity: for example, infusional fluorouracil may be replaced by oral capecitabine, and cisplatin by oxaliplatin. According to preliminary data, oxaliplatin seems to be better tolerated than cisplatin in elderly patients. Irinotecan is an alternative treatment option in situations where platinum combinations should be avoided. Nevertheless, median survival in randomized trials for advanced gastro-oesophageal cancer remains <12 months. Other targeted therapies are currently being evaluated in clinical trials for both resectable and advanced disease. According to phase III data reported recently as an oral presentation, trastuzumab has significant activity in patients with HER-2-positive tumours. Whether other targeted therapies will be able to alter the prognosis of patients with gastric cancer must be considered unclear at present.
In elderly patients, a systematic geriatric assessment will help to identify patients with an increased risk of adverse effects from surgery and chemotherapy, and who are therefore less likely to experience a treatment benefit for this reason. Medically fit patients should be treated according to the abovementioned standards. In vulnerable patients with advanced disease, single-agent chemotherapy, e.g. protracted infusion of fluorouracil, provides a symptomatic benefit. In frail patients with advanced disease, symptom-orientated supportive care should be the treatment of choice.
No sources of funding were used to assist in the preparation of this review. Ulrich Wedding has received lecture fees from Roche, Amgen, Ortho-Biotec, Novartis and GlaxoSmithKline, has acted as a consultant to Ortho-Biotec and has received study support from Ortho-Biotec. Anna Wagner has no conflicts of interest that are directly relevant to the content of this review.
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