Clinical Trial Reports: October 2007

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â–º PHASE III

Is Combination or Sequential Treatment for Metastatic Colorectal Cancer More Effective?

Optimal treatment of advanced colorectal cancer is still very much a dynamic question. In order to determine whether combination treatment is better than sequential administration, researchers from The Netherlands conducted a study of 820 patients with advanced colorectal cancer who received the same chemotherapeutic drugs.

All of the subjects had advanced colorectal cancer. After randomization to receive either first-line treatment with capecitabine, second- line irinotecan, and third-line capecitabine plus oxaliplatin (dubbed sequential treatment; N = 410) or first-line treatment with capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (called combination treatment; N = 410). Overall survival was the primary endpoint.

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Seventeen patients were determined ineligible for study inclusion. During the trial period, 675 (84%) subjects died (336 in the sequential group, 339 in the combination group). A median overall survival of 16.3 months (95% confidence interval [CI], 14.3—18.1 mo) was noted for patients in the sequential treatment group compared with 17.4 months (95% CI, 15.2–19.2 mo) for the combination treatment group ( = .3281). The combination treatment versus sequential treatment hazard ratio was 0.92 (95% CI, 0.79—1.08; = .3281). No significant difference was seen in the frequency of grade 3 or 4 toxicity over all lines of treatment between the two groups, except for grade 3 hand—foot syndrome (13% sequential group vs. 7% combination group; = .004).

Overall survival was not significantly improved by using a combination treatment instead of the sequential use of cytotoxic drugs in patients with advanced colorectal cancer, acknowledged the researchers. Therefore, they added, sequential therapy is still a valid treatment option.

Koopman M, Antonini NF, Douma J, et al: Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): A phase III randomized controlled trial

2007;370:135-142.,

. Lancet

Cervical Cancer Vaccines Do Not Work Like Investigational Cancer Vaccines, Study Confirms

The FDA-approved human papillomavirus (HPV) vaccine Gardisil is currently indicated for use in girls before they become sexually active, to prevent HPV infection. It is not known whether this vaccine may also be useful in women who already have HPV infection, and thus might work in a manner similar to investigational vaccines intended for other cancers (i.e., to treat rather than to prevent them).

Researchers from the National Cancer Institute, Bethesda, MD; Costa Rica; and the manufacturer conducted a study to determine whether an investigational HPV vaccine (bivalent HPV 16/18 virus-like particle AS04) will also treat pre-existing infections.

The phase III, masked, community-based randomized study conducted in Costa Rica involved 2,180 women aged 18 to 25 years who were positive for the presence of HPV at enrollment. The first group of 1,088 individuals received three doses of the HPV vaccine, and the control group of 1,101 infected young women received a hepatitis A shot.

Six months postvaccination, clearance rates for HPV-16/18 infections were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%). At 12 months, clearance rates of HPV-16/18 were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, —2.0%).

The human immune system naturally clears some HPV infections over time, the researchers noted, as experienced in the control group. No added benefit was provided by giving women the HPV vaccine and no differences were seen between the groups in terms of viral antibody load, the extent of HPV-linked disease, or the results of cervical cell tests performed in the laboratory.

Hildesheim A, Herrero R, Wacholder S, et al:

2007;298:743-753.

JAMA

Docetaxel to Improve Clinical and Quality of LifeImprovement in the Treatment of Advanced Gastric or Gastroesophageal Cancer

Patients diagnosed with advanced gastric or gastroesophageal cancer are generally in need of not only clinical response but symptomatic relief. A phase III study was undertaken to determine if docetaxel, added to a regimen of fluorouracil and cisplatin (CF), improved not only clinical response but also patient’s symptoms.

Clinicians from the M.D. Anderson Cancer Center, Houston, Texas, reported the results of a multinational study comprising 445 patients with the conditions. The patients were randomly assigned to receive CF or docetaxel plus fluorouracil and cisplatin (DCF). Clinical benefit was measured as “time to definitive worsening” by one or more categories of Karnofsky performance status (KPS). Patient symptom relief was determined through changes in quality-of-life(QoL) measures.

Throughout the study, clinical benefit assessments were performed (from over 75% of patients). Compared with CF, the time to definitive worsening by KPS was significantly prolonged with DCF (median, 6.1 vs. 4.8 mo; hazard ratio, 1.38;

P = .009). Time to definitive worsening of appetite and time to definitive weight loss favored DCF, although it was not statistically significant. Results for painfree survival and the time until a patient first needed an opioid to treat cancer-related pain were comparable in the two groups.

At baseline, more than three-quarters of both the DCF and CF groups completed validated QoL questionnaires. The group receiving docetaxel experienced a longer duration of QoL, demonstrated by a slower 5% deterioration of global health status (P = .01).

The addition of docetaxel to CF significantly improved the clinical benefit in these patients with gastric or gastroesophageal cancer, stated the researchers. It also had a favorable effect on time to progression, QoL, and overall survival compared with CF.

Ajani JA, Moiseyenko VM, Tjulandin S, et al: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: The V-325 study group

2007;25:3205- 3209.

Ajani JA, Moiseyenko VM, Majlis A, et al: Quality of lifewith 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

2007;25:3210-3216.

. J Clin Oncol . J Clin Oncol

â–º PHASE II

Two-Drug Combination Fights Metastatic Kidney Cancer

Metastatic renal cancer is a deadly disease that is extremely difficult to treat. However, a two-drug combination seems to offer real hope to a significant proportion of patients, according to researchers from Duke University, the University of North Carolina, Chapel Hill, and the National Cancer Institute, Bethesda, MD.

The researchers assessed the utility of sorafenib and interferon alfa-2b in metastatic renal cell cancer in 40 patients enrolled at two sites. The treatment consisted of eightweek cycles of sorafenib 400 mg orally bid and interferon alfa-2b 10 million U subcutaneously three times a week. The cycle was repeated after a two-week break if the patient’s tumor had not grown or had shrunk until the tumor vanished or the cancer worsened.

Patients experienced a 33% response rate, including a 28% partial response rate. Two patients (5%) demonstrated complete responses. After a median follow-up of 14 months, median progression-free survival was 10 months. Median overall survival was not reported. Common toxicities included fatigue, diarrhea, anemia, anorexia, rash, nausea, hypophosphatemia, and weight loss.

The researchers concluded that one-third of patients with metastatic kidney cancer benefit from the use of this drug combination. Although the toxicity exceeded that of either drug alone, they added, dose reductions and breaks between cycles allowed for chronic therapy.

Gollob JA, Rathmell WK, Richmond TM et al: Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer

. J Clin Oncology 2007;25:3288-3295.

Intensify the Dose to Treat Metastatic Testicular Cancer

After first-line chemotherapy fails metastatic testicular tumors, patients may be effectively treated by intensifying the dose of anticancer drugs followed by stem-cell rescue, reported Indiana University researchers.

They conducted a retrospective review of 184 patients with metastatic testicular cancer whose disease had progressed despite receiving cisplatin-containing chemotherapy. Two consecutive courses of high-dose chemotherapy (700 mg carboplatin/m² of body-surface area and 750 mg etoposide/m²) were given to 173 patients for three consecutive days, followed by an infusion of autologous peripheral-blood hematopoietic stem cells. Another 11 patients received only a single course of the same treatment. The high-dose chemotherapy was preceded in 110 patients by cytoreduction with one or two courses of vinblastine plus ifosfamide plus cisplatin.

Disease-free results when combinationtherapy with stem-cell rescue was used.

Percentage Disease Free

Therapy Timing

Second Line 70% ≥ Third Line 45%

Platinum Sensitivity

Sensitive 69% Resistant 45%

With the median follow-up of 48 months, complete remission was seen in 116 of the 184 subjects without relapse. Of the 135 individuals who were given the therapy second line, 94 were disease-free at follow-up. Eighteen of 40 patients with cancer that was refractory to standard-dose platinum were disease-free, as well as 98 of 144 who had platinum-sensitive disease. Disease-free status was also achieved by 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors. There were three drug-related deaths during therapy among the 184 patients.

High-dose chemotherapy with hematopoietic stem-cell rescue can potentially cure testicular tumors, the researchers commented, even when that regimen is utilized as thirdline or later treatment or in patients with platinum-refractory disease.

Einhorn LH, Williams SD, Chamness A, et al: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors

2007;357:340-348.

. N Engl J Med

Vaccination Plus Chemotherapy for Advanced Colorectal Cancer Offers Hope

Therapeutic cancer vaccines may be an effective new mode of management of difficult-to-treat cancers, motivating the body’s immune system to centrally attack tumor cells. In an open-label phase II study of patients with metastatic colorectal cancer researchers from the United Kingdom, evaluated the safety and immunogenicity of the vaccine known as modified vaccinia Ankara-encoding 5T4 (TroVax) when used with treatment cycles of standard chemotherapy with 5-fluorouracil, folic acid, and oxaliplatin (i.e., FOLFOX).

The patients were monitored for an immune response to the protein 5T4, which is found in the membrane of neoplastic cells but not normally in healthy tissue. Eleven of 17 patients with metastatic colorectal cancer who received the vaccine were evaluated for immunologic responses after receiving six injections. The injections were given before, during, and after treatment with FOLFOX. Of these subjects, six had displayed signs of significant tumor shrinkage, and one patient did not exhibit any detectable tumors.

There is no evidence of enhanced toxicity or reduced immunologic efficacy by adding TroVax to chemotherapy regimens, stated the researchers. The overall median survival rate for the 17 vaccinated patients was 68 weeks and 118 weeks in the 11 patients who received all six vaccinations, although they acknowledged the study was not designed to prove that patients survived longer than would normally be expected.

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Harrop R, Drury N, Shingler W, el al: Vaccination of colorectal cancer patients with modified vaccinia Ankara encoding the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune responses

2007;13:4487-4494.

Clin Cancer Res

Testing Sequential Therapy in Patients With Poor-Risk Acute Myelogenous Leukemia

A previous phase I study of flavopiridol, followed by 1-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone, yielded an overall response rate of 31% in patients with acute myelogenous leukemia (AML). A phase II study of this sequential regimen was recently completed for the treatment of patients with poor-risk AML has recently been completed by Maryland researchers.

The 62 subjects with poor-risk AML received three cycles of flavopiridol (50 mg/m²) infused over one hour daily starting at day 1 followed by ara-C 2 g/m2/72 hr beginning day 6 and mitoxantrone 40 mg/m² on day 9.

After receiving flavopiridol, the researchers noted at least a 50% decrease in peripheral blood blastocytes in 44% of patients by median day 2. This was reduced by at least 80% in one-quarter of the patients by the third day. Tumor lysis was self-limited in 53% of patients. Over the course of therapy, three (5%) of the individuals died (2 owing to multiorgan failure, 1 due to fungal pneumonia). Twelve of 15 (75%) patients with newly diagnosed secondary AML achieved complete remission. Disease-free survival after two years of follow-up for all patients demonstrating a complete remission was 40%. Subjects who were newly diagnosed had a 50% disease-free survival rate after two years.

Either directly or combined with ara-C and mitoxantrone, flavopiridol has anti-AML activity, noted the researchers. The timed sequential course of therapy induces complete remissions in a considerable percentage of the cohort with newly diagnosed secondary AML, they added, as well as in adults with AML in first relapse.

Karp JE, Douglas Smith B, Levis MJ, et al: Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: A phase II trial in adults with poor-risk acute myelogenous leukemia

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2007;13:4467-4473.

Clin Cancer Res