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No consensus on treatment for advanced gastric cancer
Benefit vs. toxicity may be best parameter for determining optimal treatment.
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The only consensus about the optimal treatment for advanced gastric cancer is that there is no consensus. The incidence of gastric adenocarcinoma varies significantly worldwide, so it is no surprise clinicians have to wade through an alphabet soup of often toxic chemotherapy regimens to treat a disease that, ultimately, is most often diagnosed in the advanced stage and carries a poor prognosis for survival.
Comparisons of one multidrug regimen with another have yielded few significant differences among them, apart from varying degrees of toxicity. Superiority of one regimen compared with another has not been clearly shown. Some clinicians believe extending a patient’s life by only a month or two is worth the added effort, toxicity and cost often associated with complicated, multidrug regimens; other clinicians disagree.
With only palliative care, patients may live only three to four months. Single-agent therapy with intravenous 5-fluorouracil may extend survival for up to seven months. Doublet therapy, such as high-dose platinum cisplatin and 5-FU — also known as CF, the standard treatment in the United States — may increase survival a month or more, whereas multiagent therapy DCF (docetaxel, cisplatin and 5-FU) has been shown to prolong patient life for up to two additional months.
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Photo by Memorial Sloan-Kettering Cancer Center, Manhattan |
Research in the United States has focused on aggressive multidrug combinations.
Given the poor prognosis and the limited increase in survival rates, it is unclear whether or not clinicians should eschew prolonging patient survival in favor of less toxic treatment.
HemOnc Today has spoken with a group of experts about the current research and treatment paradigms for advanced gastric cancer.
Current standard treatment
“We have not made much progress in [treating] gastric cancer. If you compare the progress made in colon cancer or breast cancer, gastric cancer is way behind in terms of incorporating new treatments and doing a lot of phase-3 trials,” said Jaffer A. Ajani, MD, professor of gastrointestinal medical oncology, the University of Texas M.D. Anderson Cancer Center.
David H. Ilson, MD, PhD, associate attending physician at Memorial Sloan-Kettering Cancer Center, considers the standard combination CF very toxic. “Results of recent phase-2 and -3 studies indicated that if we model the schedule and dosing of these drugs on colon cancer schedules where we give the treatment every two weeks and use lower doses of platinum or taxanes, we get much better tolerance.
“Adverse events drop dramatically, gastrointestinal toxicities fall below 10% and neutropenia toxicities decrease. Results of recent phase-2 and -3 trials indicated comparable degrees of efficacy, response rates, time to progression and survival,” Ilson said.
“If we are going to promote CF as a standard regimen, there are many caveats that we have to be aware of, including the modest increment in benefit and the severity of toxicity. This is not a regimen that most patients with metastatic gastric cancer would tolerate,” he said.
DCF may be too toxic
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For advanced local and metastatic gastric cancers, three-drug regimens are more commonly used in the United States. Docetaxel (Taxotere, Sanofi Aventis) has emerged as the key in multidrug regimens to prolonging survival. However, clinicians and patients have to weigh its adverse effects on quality of life, and the relatively short extension of life, and they must decide if it is worth the cost.
Jonathan D. Cheng, MD, attending physician at Fox Chase Cancer Center in Cheltenham, Pa., said that the extension of life “may not merit the toxic effects.
“Often, we’ll see some chemotherapy regimens show a higher response rate, but that doesn’t necessarily translate into improved survival and other important parameters. There are a number of active chemotherapies but no clear superiority,” he said.
Cheng pointed to positive results in the V-325 Study Group, which compared DCF with CF, but DCF “hasn’t gained widespread use in my practice because the toxicities are substantial, and it’s still somewhat of a cumbersome regimen.”
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“There was a lot of push to use DCF, but I never advocated its use. I don’t see anyone using it,” said Tanios S. Bekaii-Saab, MD, assistant professor of hematology and oncology at Ohio State University.
Ajani, who assessed quality-of-life issues in the V-325 Study Group, acknowledged that despite its benefits, DCF can be intensely toxic. He does not routinely recommend it. Complicated neutropenia topped the list of adverse events reported in the V-325 study.
Docetaxel combined with 5-FU can benefit some patients, compared with 5-FU alone. “The problem is, you don’t know who these patients are going to be, so you end up treating everybody. In the [V-325] trial, we showed that docetaxel benefited few patients, but it benefits them tremendously,” Ajani said.
“For example, the two-year survival rate doubled. It provides better quality of life, better clinical benefit, longer time to progression and reduction in risk for death by 22%. But it’s not the right combination,” he said.
“The toxicity of the three-drug regimen was quite prohibitive [in the V-325 study] — the 80%+ rate of grade-3 neutropenia, 30% rate of complicated febrile neutropenia and severe GI toxicities in excess of 20% of stomatitis and diarrhea. … Roughly half of the patients in this study were taken off treatment either due to treatment refusal or toxicity,” Ajani said.
Working with docetaxel
Because advanced gastric cancer is not a common cancer in the United States, experience with treatment is very limited. “A general oncologist may only see a couple of cases of gastric cancer a year. So it’s difficult to get used to a tough regimen like DCF, which really requires a lot of support and experience using the regimen,” Bekaii-Saab said. “This is one of the reasons why oncologists shy away from this even more-toxic-than-usual regimen.”
Ajani agreed that part of the difficulty with developing an optimal treatment regimen is that there are few patients of this tumor type at the advanced stage. In the United States, “oncologists are familiar with docetaxel because they use it in breast and prostate cancer. But they’re not familiar with this patient population.”
He believes some modification of the DCF regimen may address toxicity problems while still maintaining efficacy. He noted at least 15 modifications in the literature. “These modifications are much better tolerated and ought to be used by those unfamiliar with this patient population. If you modify the dosing schedule and turn it into a weekly regimen, reduce the number of days you give 5-FU or give it every two weeks, it becomes easier.”
Finding optimal, less toxic treatment
Ajani said that many more phase-3 trials are needed before an optimal treatment is found, but he acknowledged that the disease is a relatively low priority for research. “Pharmaceuticals are not focusing on those tumors that are not common in the West,” he said.
But the profit-making ability of drugs to target advanced gastric cancer is just one side of the story. “Funding agencies like NCI don’t worry too much about gastric cancer because that’s not what is killing Americans.”
Cheng said that he tells patients that there are “certain trial results that indicated that giving more chemotherapy shows a survival advantage compared with less chemotherapy.”
“If you’re fit and healthy and want to be more aggressive, then that’s an option. I’ve given DCF, ECF [epirubicin, cisplatin and 5-FU] and EOF [epirubicin, oxyplatin and 5-FU]; I’ve given the randomized trial ‘winners,’ so to speak.
“For patients who are more frail or do not want to tolerate the toxicity associated with polychemotherapy, I give the alternatives, either single agents or doublets, to try to preserve their quality of life,” Cheng said.
“These probably have less toxicity but possibly less efficacy. In general, younger people want to be more aggressive and choose the polychemotherapy that gives them the best survival chance,” he said.
Bekaii-Saab said that he has safely used ECF in patients aged up to 84 years. “ECF ends up being safer than CF because CF uses higher doses of the cisplatin and 5-FU, which can increase toxicity. In fact, some preliminary safety data from a large phase-3 study suggests that ECF may be at least as safe as 5-FU administered daily for five days every four weeks.”
Bekaii-Saab also frequently uses FOLFIRI (irinotecan, 5-FU and leucovorin). “In a phase-3 international study, FOLFIRI compared with CF showed the same amount of efficacy, but the toxicity favored FOLFIRI. Any time you have a regimen that gives you the same results in terms of efficacy and survival and seems to be less toxic, then that is what you favor,” Bekaii-Saab said.
There currently is no one-size-fits-all chemotherapy recommendation for advanced gastric cancer, Ilson said.
“Combination regimens have the potential to preserve quality of life, but not many of these studies have shown improved quality of life. They seem to maintain and stabilize it. That’s why toxicity of these regimens is so important. Patients may be on this treatment for four to eight months a year. If their survivorship is measured in a year, toxicity of treatment has to be a strong consideration,” Ilson said.
Continuing the same chemotherapy treatment after a patient develops the maximum response is overreaching. If the cancer continues to grow, the same agents become ineffective and potentially harmful. This is when oncologists should consider another, perhaps simpler, alternative.
“If you listen to the patient and make dose reductions, and if they’re responding, they’re apt to continue it,” said Ilson. But with DCF, “even if you lower the individual doses over time, the cumulative toxicity is still going to be substantial.”
According to Bekaii-Saab, treatment options are further complicated simply because so many different agents are used in a variety of combinations in phase-2 studies. “It ends up being an institutional preference. In the absence of comparative data, it’s impossible to establish a true standard of care.”
Different standard treatments
In South America and parts of Eastern Europe and Asia where gastric cancer is far more common than it is in the United States, oncologists take a much more cautious approach to treatment and toxicity issues, according to Ajani. “They use more oral treatments. They rarely use docetaxel, and research focuses on single or double agent regimens using drugs not approved for use in the United States,” he said.
Clinicians in Europe use CF or ECF as standard treatment. But researchers are taking another direction in multidrug therapy, noting positive results with capecitabine.
According to data presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, patients receiving a combination of capecitabine and cisplatin showed a similar time to progression as those treated with the standard IV 5-FU and cisplatin (5.6 months in the capecitabine arm compared with five months in the CF arm).
Patients in the capecitabine group also showed a greater response rate (41% vs. 29%) and had similar survival rates (10.5 months vs. 9.3 months).
Because of the relatively quick path of disease progression, ease of use and convenience have been key factors that clinicians abroad consider when prescribing treatment. In the study, treatment only required that patients take oral capecitabine once, compared with receiving 5-FU for five days every three weeks.
In the phase-3 REAL 2 study, researchers found longer survival rates in advanced gastric cancer patients receiving COX (epirubicin, oxaliplatin and capecitabine), compared with CF or ECF. Also, patients treated with ECX (epirubicin, cisplatin and capecitabine) had comparable response and survival rates as the ECF arm, with fewer adverse events and less overall toxicity.
Oral capecitabine is recommended to replace IV 5-FU as first-line treatment in parts of Europe. It is now used more often in the United States, but is not considered part of a standard treatment regimen.
Another option gaining ground in the United States is oral fluoropyrimidine (S-1, Taiho Pharmaceutical Co. Ltd), used widely in Japan, where the incidence of gastric cancer is also much higher than it is in the United States.
Future treatments ahead
Taking a cue from researchers abroad, oncologists in the United States are researching less toxic, more patient-friendly treatment.
The researchers of the phase-2 GASTRO-TAX-1 trial, whose data were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, sought to reduce toxicity of DCF while maintaining efficacy. The researchers used split doses of docetaxel, cisplatin, leucovorin and fluorouracil (T-PLF). In 60 patients, the median overall survival was 17.9 months, whereas median time to progression was 9.4 months. The combination was shown to be highly active with a reasonable toxicity profile.
Ajani believes that in the near future, there will be treatments that are universally recognized as being safer and just as effective, which will serve as a foundation upon which to build more patient-targeted treatment.
“We’re extrapolating from more common tumor types. The role model for gastric cancer is colon cancer. We basically don’t do our own research trials; we pick up the drugs already studied in colon cancer and then study them in gastric cancer,” Ajani said.
“Biochemotherapy will be developed in gastric cancer because it’s been successful in colon cancer,” he said. Results of studies have indicated that biochemotherapy may shrink tumors more effectively than single-agent or combination chemotherapy.
Following the European lead, other drugs can be combined with 5-FU instead of docetaxel, such as capecitabine, oxaliplatin and S-1.
“Two-drug regimens tend to be better tolerated than three-drug regimens. I think doublets are going be a better foundation to add targeted agents, because with targeted agents you’ll also add greater toxicity,” Ilson said.
Bekaii-Saab believes the fluoropyrimidines will form the backbone of future chemotherapy treatment, but he predicts that capecitabine or S-1 will one day replace IV 5-FU. “S-1 has a long way to go in the United States; in Asia, it’s replacing 5-FU and is even taking over a lot of the capecitabine market for gastric cancer.”
Targeting treatment
The next stage of research points to using targeted inhibitors and then identifying the next generation of targets. “That’s what my lab and other investigators are interested in pursuing,” Cheng said. Preliminary research into targeted VEG-F inhibitors suggested the next wave in treatment development. Bevacizumab has shown strong promise in phase-3 studies.
Ilson said that in a phase-2 trial, he and his colleagues “combined bevacizumab with weekly irinotecan and cisplatin, and results suggested a higher response rate, about 70% improvement in time to progression, and a one-year survival.
“Larger follow-up phase-2 studies and phase-3 trials will evaluate capecitabine and cisplatin with or without bevacizumab as a global study in metastatic gastric cancer,” he said.
Another alternative is the EGF pathway. “The EGF receptor tyrosine kinases have been inactive in gastric cancer. But the monoclonal antibodies, like matuzumab or rituximab when combined with chemotherapy, suggested higher response rates and better rate to progression but also more toxicity,” Ilson said.
According to Cheng, researchers have done all they can with various permutations of chemotherapy regimens. “I think DCF was kind of the last hurrah. The ability to get more benefit out of the chemotherapies we currently have has more or less passed.”
“We have to move the field forward,” Ilson said, “and not just focus on rearranging these cytotoxic chemotherapy agents. We must also get new drugs into development, targeted agents, and try to identify patients who will respond to new treatments with molecular techniques like pharmacogenomics and pharmacogenetics, which can more specifically tailor treatment to each individual patient.” – by Carey Cowles
Adding docetaxel to cisplatin and 5-FU in gastric cancer: too toxic?
For more information:
- Ajani, J, Moiseyenko V, Tjulandin S, et al. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a Phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007;25:3210-3216.
- Cunningham D, Rao S, Starling N, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: the REAL 2 trial. J Clin Oncol. 2007;24(Suppl 18S).
- Ilson, D. Docetaxel, cisplatin, and fluorouracil in gastric cancer: Does the punishment fit the crime? J Clin Oncol. 2007;25:3188-3190.
- Kang Y, Kang WK, Shin DB, et al. Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): efficacy and safety results. J Clin Oncol. 2007;24(Suppl 18S).
- Lorenzen S, Weigert N, Heinemann V, et al. Docetaxel, cisplatin and leucovorin/fluorouracil in first-line advanced gastric cancer and adenocarcinoma of the esophagogastric junction: results of the phase II GASTRO-TAX-1trial. J Clin Oncol. 2007;24(Suppl 18S).
- National Cancer Institute website. Gastric cancer treatment. http://www.cancer.gov/cancertopics/pdq/treatment/gastric/healthprofessional/.