Februrary 2008 Clinical Trial Reports

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â–º PHASE III

What Factors Predict Prognosis in Patients With Malignant Pleural Mesothelioma?

Unlike other advanced types of cancer, little is known about patient-related symptoms or quality of life associated with malignant pleural mesothelioma (MPM), nor is there information about whether these patient-reported measures have prognostic value. Clinicians from Europe, Egypt, and Canada assessed the prognostic value of patient-related symptoms or quality-of-life information using data from a randomized, controlled phase III clinical trial of cisplatin and raltitrexed.

Patients were eligible to enter the trial if they had a histologically proven unresectable MPM that was not pretreated with chemotherapy; a World Health Organization (WHO) performance status score of no more than 2; and adequate renal, hematologic, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m² intravenously on day 1, with or without preceding infusion of raltitrexed 3 mg/m². The European Organisation for Research and Treatment of Cancer (EORTC) QLQC30/ Lung Cancer 13 tool was utilized to assess health-related quality of life.

P

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Of the 250 original participants (80% male; median age, 58 yr; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively) randomly assigned, 229 (91.6%) had a valid quality-of-life assessment. According to a Cox proportional hazards regression model, patient-reported pain ( < .0001), prognostic index (PI), and appetite loss ( = .01) were independent indicators of survival. These results suggest, the clinicians concluded, that pain, PI and appetite loss may be independent prognostic factors in patients with advanced MPM.

Bottomley A, Coens C, Efficace F, et al: Symptoms and patient-reported well-being: Do they predict survival in malignant pleural mesothelioma? A Prognostic factor analysis of EORTC-NCIC 08983: Randomized Phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma

2007;25:5770-5776.

. J Clin Oncol

Treatment for Patients With High-Risk Postoperative Breast Cancer

Patients with advanced, recurrent breast cancer have limited options to help manage tumor growth. High-dose chemotherapy (HDC) has been viewed as a possible alternative to moving to a palliative approach. Researchers from Japan have completed a randomized, controlled study to assess the efficacy of HDC as part of the treatment for high-risk postoperative breast cancer.

Patients younger than 57 years were invited to participate in this study. Each patient had stage I to IIIB breast cancer that involved 10 or more axillary lymph nodes (median, 16; range, 10—49). Ninety-seven patients (median age, 46 yr) were originally enrolled between May 1993 and March 1999, although two were later considered ineligible. A total of 72 (74%) of the subjects were premenopausal. Every patient had had a radical mastectomy.

Patients were randomized to receive one of two treatment arms; the treatment groups had similar demographic and clinical characteristics. Patients in the standard-dose treatment group (N = 48) were given six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. The other 49 patients in the HDC treatment arm were scheduled to receive cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil, after which tamoxifen was administered. However, the clinicians noted, 15 of those patients (31%) did not undergo HDC. In the remaining patients, they noted that HDC was well tolerated, and there was no treatment-related mortality.

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The five-year relapse-free survival was 37% for 47 eligible patients in the standard treatment arm and 52% for the 48 eligible patients in the HDC arm on an intent-to-treat basis (median follow- up, 63 mo [ = .17]). For all of the randomized patients, the five-year overall survival was 62% for the standard treatment arm and 63% for the HDC arm

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( = .78).

No advantage for the use of HDC was found, the researchers acknowledged. Nonsignificant differences in relapse-free survival and overall survival do not advocate for the use of HDC in this patient cohort.

Tokuda Y, Tajima T, Narabayashi M, et al: Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for highrisk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208

2008;99:145-151.

. Cancer Sci

â–º PHASE II

Epratuzumab Plus Rituximab Equals Non-Hodgkin’s Lymphoma Response

Epratuzumab, an anti-CD22 humanized monoclonal antibody, used in combination with rituximab has produced durable complete responses in patients with recurrent or refractory non-Hodgkin’s lymphoma (NHL), according to final clinical trial results presented by John P. Leonard, MD, Weill Cornell Medical College, at the 49th annual meeting of ASH in Atlanta, Georgia.

The investigators enrolled 49 patients (26 men, 23 women; median age, 61 yr) with recurrent or refractory low-grade CD20-positive B-cell NHL into this multicenter, open-label, single-arm study. Fourteen patients had had rituximab therapy, and the remainder was rituximab-naïve. Study participants received infusions of epratuzumab 360 mg/m² followed by rituximab 375 mg/ m² weekly for four consecutive weeks. After an infusion reaction, one patient discontinued rituximab but did complete epratuzumab treatment.

An objective response was achieved by 26 patients (54%), including 27% with complete responses and 27% with partial responses. The combination immunotherapy was active in 41 low-grade follicular patients (54% objective response, 24% complete response) as well as in seven patients with small lymphocytic lymphoma (57% objective response, 43% complete response). Comparable activity was observed in 34 rituximab-naïve patients (50% objective response, 26% complete response) and 14 patients who had responded previously to rituximab (64% objective response, 29% complete response).

The median duration of objective response was 14.7 months, reported the investigators, with a median progression- free survival (PFS) of 11.1 months. Durable responses with a median PFS of 10.0 months and median duration of response of 13.4 months was seen in patients with low-grade follicular NHL. Especially long-lived responses were observed in those with follicular NHL who experienced complete responses; their median PFS of 35.1 months and median duration of response of 33.4 months includes long-term responses still continuing for more than four years.

Leonard JP, Schuster SJ, Emmanoulides C, et al: Durable complete response following therapy with epratuzumab plus rituximab: Final efficacy results of a multicenter study in recurrent indolent non-Hodgkin’s lymphoma. Presented at the 49th annual meeting of the American Society of Hematology, Atlanta, December 10, 2008.

Topotecan Added to Twice-Daily Chemoradiation to Treat Limited-Stage, Small-Cell Lung Cancer Therapy

The use of early chemotherapy and twice-daily concurrent radiation has led to the longest survivals reported in randomized trials of localized small-cell lung cancer (SCLC). Even so, although tumor response is promising, five-year survival in patients with SCLC is disappointing, at best. Past experience shows that thoracic radiation therapy improves survival over the use of systemic chemotherapy alone and that twice-daily radiation therapy improves survival compared with daily fractionation. Furthermore, the use of prophylactic central nervous system radiation (prophylactic cranial irradiation) extends survival further.

Topotecan has been found to be active in patients with SCLC, both as first-line treatment as well as to treat recurrent disease. Danish researchers have conducted a new investigation into whether the addition of topotecan to existing concurrent twice-daily chemoradiation regimens would improve the outcomes of patients with limited-stage SCLC.

The multicenter trial utilized three cycles of two regimens: (A) intravenous topotecan 1.5 mg/m², day 1—5; cisplatin 50 mg/m², day 1, and (B) intravenous etoposide 120 mg/m2, day 1—3; carboplatin (reaching an area under the time–plasma concentration curve of 5), day 1; vincristine 1.3 mg/m², day 1). The treatments were given in the sequence of A-B-B-A-B-A every 21 days. Along with the first cycle of regimen B, twice-daily radiotherapy was administered at a dose of 1.5 Gyx30, 10fr/wk, 45Gy) was administered concurrently. Patients in complete remission were offered prophylactic cranial irradiation.

Survivals using the topotecan-added chemoradiation regime

Median Progression-free survival

11.8 mo

Median overall survival

22.9 mo

Five-year survival

21.0%

Individuals with limited disease SCLS were considered for study inclusion if they had not been previously treated for SCLC, had adequate organ function and a World Health Organization performance status (PS) of 2 or more. The study group consisted of 44 patients (median age, 60 yr; age range, 43—75 yr) at four centers.

Nonhematological toxicity was mild, but 26.5% of patients experienced grade 3 esophagitis. Grade 3 or 4 leukopenia and thrombocytopenia was seen in 82% and 75% of patients, respectively. One death, caused by neutropenic sepsis, was reported. Overall response rate was 77%, and 30% of patients had a complete response. The investigators found an 11.8-month median progression-free survival as well as median overall survival of 22.9 months. The five-year survival was 21%.

Topotecan combined with cisplatin and concurrent twice-daily chemoradiation was associated with a small increase in long-term survival, the clinicians commented, but with a high incidence of severe esophagitis.

Sorensen M, Lassen U, Palshof T, et al: Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small-cell lung cancer—A Danish oncological lung cancer group (DOLG) phase II trial

2007; Nov 22 [E-pub ahead of print].

. Lung Cancer

First-Line Therapy for Patients With Advanced or Metastatic Non—Small- Cell Lung Cancer

The standard of first-line therapy for advanced non— small-cell lung cancer (NSCLC) in patients with a good performance status is a platinum drug in combination with either gemcitabine, paclitaxel, vinorelbine, or docetaxel. The use of gemcitabine partnered with carboplatin is convenient to administer and has a favorable toxicity profile. Canadian and American researchers have recently evaluated the efficacy of the addition of cetuximab to first-line gemcitabine/platinum in patients with NSCLC.

Chemotherapy-naïve patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) were considered eligible for participation in the noncomparative, randomized clinical trial. Patients in one treatment arm (N = 65) received cisplatin (75 mg/m² IV every 3 weeks) or carboplatin (area under the plasma concentration—time curve of 5 intravenously q3wk), and gemcitabine (1,250 or 1,000 mg/m² IV, days 1 and 8) plus cetuximab (400 mg/m² IV day 1, followed by 250 mg/m²) weekly). Patients randomized to the second treatment arm (N = 66) received the same regimen without cetuximab.

The researchers set the study’s primary endpoint to be the response rate, whereas secondary endpoints included safety, progression-free survival, and overall survival.

Eighteen patients (28%) in the cetuximab arm experienced partial responses compared with 12 (18%) in the other treatment arm. Median progression-free survival was 5.09 and 4.21 months, respectively. Median overall survival was 11.99 months in the cetuximab arm compared with 9.26 months in the arm without cetuximab.

Response to the addition of cetuximab inpatients with non—small-cell lung cancer

Cetuximab Arm

Control Arm

Progression-free survival

5.09 mo

4.21 mo

Overall survival

11.99 mo

9.26 mo

Overall toxicity was considered acceptable, the clinicians reported, and consistent with the profiles of the individual agents. According to the investigators, first-line treatment with cetuximab plus gemcitabine/platinum can be given safely to patients with advanced NSCLC. The addition of cetuximab to platinum/gemcitabine may moderately improve clinical outcomes, as suggested by reasonable differences in response rate, progression-free survival, and overall survival, they added.

Butts CA, Bodkin D, Middleman EL, et al: Randomized phase II study of gemcitabine plus cisplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non—small-cell lung cancer

2007;25:5777-5784.

. J Clin Oncol

Radiotherapy for Nasal Squamous Cell Carcinoma

The use of radiotherapy (RT) either alone or in combination with surgery for treating nasal vestibule squamous cell carcinomas has been generally successful in producing positive outcomes. A study by clinicians from the University of Florida in 1999 found overall five-year survival of better than 85%. In this phase II extension study, the clinicians added to the patient database and provide data on follow-up lasting more than 25 years.

Of the 79 study participants with squamous cell carcinoma of the nasal vestibule treated at the University’s medical center, 71 received treatment with definitive RT. The remaining eight patients received surgery and RT. Follow-up ranged from four months to 27.7 years (mean 9.0 yr, median 7.9 yr). Follow-up on surviving patients ranged from six months to 27.7 years (mean, 10.0 yr, median, 8.1 yr).

Outcomes at five years included freedom from distant metastases, 94%; cause-specific survival, 90%; local control, 87%; local-regional control, 77%; and survival, 76%. Patients treated with definitive RT achieved 5-year local control rates of 95% for T1-T2 tumors; 71% for T4 tumors, 71%; and an overall survival of 86% (P = .0046). All of the eight patients treated with surgery and RT achieved local control.

A high cure rate for T1-T2 and favorable T4 tumors can result with RT treatment, concluded the researchers. Even patients with extensive T4 tumors can experience good outcomes if they are treated with both surgery and radiotherapy.

Wallace A, Morris C, Kirwan J, et al: Radiotherapy for squamous cell carcinoma of the nasal vestibule.

2007;30:612-616.

Am J Clin Oncol

â–º PHASE I/II

A New Combination Approach for Advanced-Stage Germ-Cell Tumors

The most studied regimens for patients with malignant, disseminated germ-cell tumors include bleomycin, etoposide, and cisplatin (BEP) and etoposide, ifosfamide, and cisplatin (VIP). However, past research indicates that neither holds a particularly compelling outcomes advantage over the other, and research into plausible treatments continue.

German researchers evaluated the feasibility and toxicity of sequential, dose-intensified VIP chemotherapy in combination with paclitaxel plus peripheral blood-derived hematopoietic stem-cell support (PBSC) as a new approach for individuals with untreated metastatic germcell tumors who are considered to have poor prognostic features, according to the International Germ Cell Consensus Cancer Group classification.

The clinicians added paclitaxel to the highdose VIP regimen (specifically with cumulative doses of etoposide 1,500 mg/m², ifosfamide 10,000 mg/m², and cisplatin 100 mg/m² per cycle) at the three dose levels of 135, 175 and 225 mg/m² applied on day 6. Granulocyte colonystimulating factor and hematopoietic stemcell support were provided during the cyclic treatment. Patients received one cycle of standard VIP before the start of high-dose VIP plus paclitaxel cycles in order to collect autologous stem cells.

Fifty-two patients were assessable for outcomes. Myelosuppression was a major adverse effect, as expected. Leukocyte counts of fewer than 1,000/μL and thrombocyte levels less than 25,000/μL occurred with median durations of six and four days, respectively, independently of the applied dose of paclitaxel. Five percent of patients experienced World Health Organization grade 2 neurotoxicity and grade 3 encephalopathy. Diarrhea, obstipation, and oral mucositis were other main adverse effects. A favorable response to chemotherapy plus secondary surgery was achieved by 79% of the subjects.

The researchers calculated two- and five-year survival rates as 77.6% (95% confidence interval, 65.4%—89.9%) and 75.2% (95% confidence interval, 62.5%–87.8%), respectively were seen after a median follow-up of 41 months in surviving patients.

For patients with poor prognosis germ-cell tumors, this represents a feasible but toxic approach, according to the researchers. Further investigation is warranted for this regimen, using high-dose VIP plus paclitaxel up to 225 mg/ m2 to examine the therapeutic potential in an expanded cohort of patients, they added.

Hartmann JT, Gauler T, Metzner B, et al: Phase I/ II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors by the German testicular cancer study group

2007;25:5742-5747.

. J Clin Oncol