trial update clinical

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1 trial update clinical by John W. Mucenski, BS, PharmD, Director of Pharmacy Operations, UPMC Cancer Centers Recent advances in radiation therapy, such as intensity modulated radiation therapy (IMRT), have allowed for delivery of maximal homogenous doses of radiation to planned treatment volume while sparing radiation to normal tissue outside the target. This has led to shorter duration of therapy and improved cosmesis and comparable or improved outcomes to standard radiation therapy techniques. Title: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage smallcell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC , RTOG 0212, and IFCT 99-01): a randomized clinical trial. Authors: Le Pechoux C, Dunant A, Senan S, et al. Reference: Lancer Oncol. 2009;10: Purpose: Even though the incidence of small-cell lung cancer (SCLC) has declined over the past 10 years, survival for those patients with limited-stage (LS) disease has not changed. The five-year survival in studies combining chemotherapy and thoracic radiation remains at 20% to 25%. PCI following complete response (CR) to initial therapy has become the standard of care for these patients. Meta-analysis of this approach has shown a decrease in the risk for the development of brain metastases, 59% and 33% at three 38 managedcareoncology Quarter

2 years, as well as improved survival at three years, 15% to 21%. This study was designed to compare a standard dose (SD) of radiation with a higher dose (HD) of radiation and to assess the effect of PCI dose escalation on the incidence of brain metastases. Methods: Patients with histologically proven LS SCLC in complete remission following initial therapy were eligible for enrollment. Cerebral imaging had to be done during the month before randomization showing no evidence of brain or leptomeningeal metastases. Patients had to have a World Health Organization (WHO) performance status of 2. Patients were then randomized to receive PCI at either a standard dose, 25 Gy in 10 daily fractions of 2.5 Gy, or a higher dose of 36 Gy. Conventional or hyperfractionated accelerated PCI could be used in the higher-dose group. Conventional therapy consisted of 36 Gy in 18 daily fractions of 2 Gy or hyperfractionated accelerated PCI of 36 Gy in 24 fractions of 1.5 Gy given twice daily for 12 days with a minimum interval of six hours between courses. PCI was started as soon as possible after a CR and within 15 days of randomization. Patients were stratified according to age and interval between start of induction therapy and date of randomization for PCI. The primary endpoint of the study was the incidence of brain metastases at two years. Secondary endpoints included overall survival (OS) and neurological function following PCI. To detect brain metastases or treatment-related late sequelea, brain computed tomography (CT) or magnetic resonance imaging (MRI) scans were scheduled at specific intervals or at the onset of new neurological signs or symptoms. Results: A total of 720 patients were enrolled, 360 in each group. There were no significant baseline differences noted between the two groups in regards to median age, sex, method of imaging, etc. Nine patients did not receive PCI five in the SD group and four in the HD group. Full-dose radiation was administered to 341 patients in the SD group and 335 in the HD group. After a median follow-up of 39 months (range 0 to 89 months), 145 patients had developed brain metastases. There were 82 patients in the SD group and 63 patients in the HD group. This finding was not statistically significant, with a p value of p = The two-year OS was 42% in the SD group and 37% in the HD group. This was statistically significant (p = 0.05). The shorter OS survival in the HD group appeared to be secondary to an increase in cancer-related mortality. Only five serious adverse events were noted in the SD group vs. 0 in the HD group. The most common acute adverse events were fatigue (30% SD and 34% HD), headache (24% SD vs. 28% HD), and nausea and vomiting (23% SD vs. 28% HD). Conclusion: No significant reduction in total incidence of brain metastases was observed after HD PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in patients with LS SCLC who have achieved a complete response after initial induction therapy with chemotherapy and thoracic radiation. Managed Care Implications: Dose and duration of PCI in patients with LS SCLC is important. The results of this study show that more is not necessarily better. Title: Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. managedcareoncology.com 39

3 Authors: Zelefsky MJ, Eastham JA, Cronin AM, et al. Reference: J Clin Oncol [published online ahead of print on February 16, 2010, as / JCO ]. Purpose: The eradication of local disease in patients with clinically localized prostate cancer has been shown to decrease the risk for tumor dissemination and prostate cancer mortality. Radical prostatectomy (RP) and external beam radiotherapy (EBRT) represent the standard for managing these patients and are superior to watchful waiting. There has been a substantial improvement in surgical technique over the past two decades that has resulted in a reduced incidence of (+) margins and better cancer control. Radiation therapy has also improved in this time frame with improved delivery systems such as three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT). This has allowed for the delivery of high-dose EBRT to the prostate. This article is a retrospective study comparing RP and EBRT for localized prostate cancer at a single institution. Methods: Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT at a dose of 81 Gy or RP. Surgical treatment included bilateral pelvic lymphadenectomy removing the external iliac, obturator, and hypogastric lymph nodes. Short courses of androgen-deprivation therapy (ADT) were administered to 56% of the patients receiving EBRT before and concurrent with IMRT. ADT was required in only 1% of patients undergoing RP due to high-risk pathological features of their tumor at time of surgery. The endpoints of the study were distant metastasesfree survival (DM) and cause-specific mortality. Patients were observed in follow-up three months after therapy, then every six months until year five, then annually thereafter. The median follow-up for patients without metastases or cancer-specific death was 5.0 years for those treated with EBRT and 5.1 years for patients undergoing RP. Two methods were used to control for pretreatment tumor characteristics: the Kattan pretreatment nomogram risk probability and the National Comprehensive Cancer Network (NCCN) risk-group classification. Low risk was defined as patients with clinical stages T1-T2a, Gleason scores of 2 to 6, and a prostate-specific antigen (PSA) level <10 ng/ml. High risk was defined as clinical stage T3, Gleason scores of 8 to 10, or PSA level > 20 ng/ml. Results: A total of 2,380 patients meeting the clinical stages T1c-T3b biopsy-proven adenocarcinoma of the prostate were treated with either RP (n = 1,318) or EBRT (n = 1,062). As expected, patients undergoing EBRT were older (median 69 years vs. 60 years). These patients also had a higher serum PSA level, a higher clinical stage of disease, and a higher biopsy Gleason score (all p < 0.001). The eight-year probability of freedom from metastatic prostate cancer was 97% for RP patients and 93% for EBRT patients. After adjustment for the Kattan preoperative nomogram risk probability, age, and treatment year, RP was associated with a reduced risk for metastases (HR, 0.35; 95% CI, 0.19 to 0.65; p < 0.001). The most significant variable associated with metastatic progression was risk group (high vs. low) followed by treatment (RP vs. EBRT). Results were similar for prostatecancer-specific mortality favoring RP when adjusted for age and treatment year (HR, 0.32; 95% CI, 0.12 to 0.82; p = 0.018). Conclusion: Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higherrisk disease had a lower risk for metastatic progression and prostatecancer-specific deaths than EBRT patients. 40 managedcareoncology Quarter

4 Managed Care Implications: Appropriate initial therapy with RP or EBRT for the treatment of localized prostate cancer will depend upon the risk for progression at the time of diagnosis and patient preference for type of therapy. Title: A phase 2 study of yttrium-90 ibritumomab tiuxetan (Zevalin) in patients with chronic lymphocytic leukemia. Authors: Jain N, Wierda W, Ferrajoli A, et al. Reference: Cancer. 2009;115: Purpose: While chemoimmunotherapy produces high CR and durable remissions in patients with chronic lymphocytic leukemia (CLL), evaluation by more sensitive techniques, such as flow cytometry or polymerase chain reaction (PCR) assays, have shown these patients to have detectable disease. Radioimmunotherapy (RIT) with agents such as yttrium-90y ibritumomab tiuxetan (Zevalin) and iodine 131I tositumomab (Bexxar) combine a monoclonal antibody conjugated via a chelator to a radioactive nuclide. These agents have been approved by the U.S. Food and Drug Administration (FDA) for use in relapsed CD20(+) non-hodgkin s lymphoma (NHL). Myelosuppression was the main side effect seen with Y90 ibritumomab; however, this can be reduced only if administered to patients who have < 25% bone marrow involvement. Therefore, RIT has generally not been evaluated in patients with CLL since extensive marrow involvement is common with the disease. Small studies with various RIT have shown efficacy in treating patients with CLL with this type of therapy. The objective of this study was to evaluate whether 90Y ibritumomab given to patients with CLL after maximum response to chemotherapy could eliminate minimal residual disease (MRD) in patients who had achieved a CR or convert patients who had achieved a partial response (PR) to a CR. Methods: Patients were eligible for this phase 2 study if they were age 18 or older and had a diagnosis of CLL with either of the following disease characteristics: Patients who had achieved a CR with chemotherapy but had documented residual disease by immune-phenotyping or achieved a PR after chemotherapy but had < 25% bone marrow involvement. Other eligibility criteria included a WHO performance status 2 and normal end-organ function. Patients received an initial infusion of 250 mg/m 2 of rituximab followed immediately by a fixed dose of 5.0 mci of 111In 90Y. Biodistribution of 111In 90Y was determined from visual examination of whole-body gamma imaging at specific times following administration. If the biodistribution was acceptable, a second infusion of 250 mg/m 2 of rituximab and either 0.4 mci (platelet count 150,000/ mm 3 ) or 0.3 mci (platelet count between 100,000 and 150,000/mm 3 ) of 90Y ibritumomab was given one week later. The dose of the RIT was capped at 32 mci. A response rate of 20% was considered significant. At least 14 patients in each group were initially planned to be treated. If a response was observed, then 35 additional in each group would be added. If none of the first 14 patients responded, then the trial would be terminated. Results: Fifteen patients were registered on the trial, with 14 going through the biodistribution phase of the study and 13 treated with the RIT. One patient (7.7%) achieved a morphological CR but with a persistent MRD of the marrow; a second patient achieved a CR in the bone marrow with (-) flow cytometry but had worsening lymphadenopathy and was subsequently diagnosed with Richter transformation. Grade 3 or 4 hematologic toxicity was noted in 12 of 13 patients (92%) managedcareoncology.com 41

5 with grade 3 or 4 thrombocytopenia (TCP) noted in 11 (85%). Patients experiencing RIT-induced TCP had it for a median duration of 37 days, and five patients had persistent TCP lasting more than three months posttherapy. Conclusion: Even in patients with CLL and limited bone marrow involvement, the use of RIT results in unacceptable hematologic toxicity. Managed Care Implications: Patients with CLL are not candidates for RIT even if the bone marrow involvement is < 25%, even though activity in similar patients with other hematologic malignancies has been noted and FDA-approved. Title: Quantitative PCR analysis for bcl-2/igh in a phase 3 study of ytrrium-90 ibritumomab tiuxetan as consolidation of first remission in patients with follicular lymphoma. Authors: Goff L, Summers K, Iqbal S, et al. Reference: J Clin Oncol. 2009;27: Purpose: Follicular lymphoma (FL) is the second most common form of NHL, a disease characterized by initial responsiveness to therapy followed by almost inevitable recurrence. The median survival for patients with FL is nine to 10 years with conventional therapy. Approximately 85% of patients with FL have a t(14;18) translocation that can be used as a molecular marker for the disease. The translocation results in bcl-2 oncogene rearrangement and bcl-2/igh mrna overexpression. Cells containing this translocation are detectable by PCR assay. Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) is an immunoconjugate composed of an anti-cd20 monoclonal antibody linked to the chelator tiuxetan to the pure beta-emitting radioisotope 90Y. This phase 3 trial was conducted to evaluate the safety and efficacy of 90Y ibritumomab tiuxetan when used as consolidation of first CR or PR remission in patients with previously untreated, advanced-stage FL. Methods: Patients were eligible if they were 18 years old, had stage III or IV histologically confirmed CD20(+) FL, a WHO performance status of 0 to 2, were in CR (including unconfirmed CR) or PR, and had < 25% bone marrow involvement with lymphoma following first-line therapy. Patients were randomly assigned to stop treatment (control) or consolidation with the radioimmunotherapy (RIT). Patients randomized to RIT received rituximab 250 mg/ m 2 IV on day -7 and day 0, followed on day 0 by a single infusion of 90Y ibritumomab tiuxetan 14.8 MBq/kg (0.4 mci/kg). Blood samples were collected from 414 patients: 206 assigned to the control group and 208 assigned to the RIT group. Bcl-2 rearrangement was detected in only 186 of the patients. The remaining patients were excluded from the PCR analysis. The primary endpoint of the study was progression-free survival (PFS) and was reported in an earlier study. Results: Ninety percent (61 of 68) of the treated patients converted from bcl-2 PCR-detectable to undetectable disease status compared to only 38% (21 of 59) of the control group. The median PFS was significantly prolonged in patients converting to bcl-2 PCR-undetectable status; 40.8 months in the treated group vs. 24 months in the control group (p < 0.01; HR, 0.339). In patients who had bcl-2 detectable disease at randomization, treatment with RIT significantly prolonged median PFS: 38.4 vs. 8.2 months in the control group (p < 0.01; HR, 0.293). Conclusion: Eradication of PCRdetectable disease occurred more frequently after treatment with 90Y ibritumomab tiuxetan and was associated with a prolonged PFS. Managed Care Implications: Patients with FL responding to initial therapy 42 managedcareoncology Quarter

6 should be considered for consolidation therapy with RIT. Title: Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from the Proton Radiation Oncology Group/ American College of Radiology Authors: Zietman AL, Bae K, Slater JD, et al. Reference: J Clin Oncol. 2010;28: Purpose: Most prostate cancer cases diagnosed in the U.S. are detected at an early stage, with external-beam radiation being one of the principal treatment options. Concern exists that conventional-dose radiation therapy does not eradicate the disease in a significant number of patients who subsequently relapse with an increase in PSA and the need for secondary therapy. Simply increasing the dose delivered to the local tumor may lead to improved survival but carries the risk for greater side effects unless the volume of normal tissue exposed to radiation therapy can be reduced. This randomized trial used the technology of proton beam to conformally increase the radiation dose to the prostate while sparing normal tissue, thus testing the hypothesis that increasing radiation dose improves clinical outcomes. Methods: This randomized, controlled trial was designed to compare two different radiation doses delivered by conformal techniques. Patients were stratified to ensure balance between the groups in respect to serum PSA (< 4 ng/ml vs ng/ml) and for nodal status (Nx vs. N0). All patients received conformal photon beam therapy to a fixed dose of 50.4 Gy. The difference between the two arms was in the boost dose that was delivered using proton beam. The boost dose was either 19.8 Gy or 28.8 Gy for a total dose of either 70.2 Gy (standard dose) or 79.2 Gy (high dose). Patients were eligible if they had early-stage prostate cancer (stage T1b-T2b), a PSA level 15 ng/ml, and no evidence of metastatic disease by both bone scan and abdominopelvic CT scan. The primary objective was to determine whether local failure (LF) at five years in the high-dose arm was reduced compared to the standarddose arm. Secondary objectives were biochemical failure (BF), increasing PSA, OS, and toxicity. Results: A total of 393 men were randomly assigned to receive either standard-dose (n = 197) or highdose (n = 196) therapy. The median follow-up was 8.9 years. Patients receiving high-dose therapy were less likely to have LF with a hazard ratio of The 10-year BF rates were 32.4% for conventional-dose therapy and 16.7% for high-dose therapy (p < ). This difference held only for those patients with low-risk disease (n = 227, or 58% of patients): 28.2% vs. 7.1% (p < ) favoring high-dose therapy. There was a strong trend in the same direction for those patients in the intermediate-risk group (n = 144, or 37% of patients): 42.1% vs. 30.4% (p = 0.06). There is no difference in OS between the two treatment arms (78.4% vs. 83.4%; p = 0.41). Two percent of patients in both arms experienced late grade genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade 3 gastrointestinal (GI) toxicity. managedcareoncology.com 43

7 Conclusion: High-dose radiation therapy shows superior long-term cancer control for men with localized prostate cancer. This was achieved without an increase in late grade 3 urinary or rectal morbidity. Managed Care Implications: Improvement in the method of radiation therapy delivery conformal, proton beam boost, and IMRT will allow for higher doses of radiation to be administered safely and lead to improved outcomes in men with early-stage prostate disease. Title: Vaginal brachytherapy vs. pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, noninferiority, randomized trial. Authors: Nout RA, Smit V, Putter H, et al. Reference: Lancet. 2010;375: Purpose: Endometrial cancer is the most common gynecological malignancy in postmenopausal women in developed countries. The majority of patients (80%) present with stage I disease and have a favorable prognosis. Treatment consists of a total abdominal hysterectomy and bilateral salpingooophorectomy. Studies by both PORTEC-1 and the Gynecology Oncology Group (GOG) have shown the addition of EBRT can significantly reduce the rate of locoregional recurrence vs. those patients who are observed following surgery, particularly patients with high-intermediate-risk disease. The majority of relapses are noted in the vagina. Retrospective studies reported vaginal brachytherapy (VBT) to be very effective in preventing vaginal recurrences. This study was established to compare whether VBT is as effective as EBRT in preventing vaginal recurrence. Methods: Patients with endometrial adenocarcinoma were eligible based on features of having highintermediate-risk disease age > 60 years and stage IC grade, grade 1 or 2 disease or stage IB grade 3 disease and stage IIA disease, any age (apart from grade 3 with > 50% myometrial invasion). All patients had a WHO performance status of 0 to 2. Patients were stratified based upon FIGO (International Federation of Gynecologists and Obstetricians) stage, radiotherapy center, and age. Patients were randomly assigned to pelvic EBRT (46 Gy in 23 fractions; n = 214) or VBT (21 Gy high-dose rate in three fractions or 30 Gy low-dose rate; n = 213). Brachytherapy was delivered with a vaginal cylinder covering the proximal half of the vagina. High-dose therapy consisted of 21 Gy in three fractions of 7 Gy, each administered one week apart. Low dose consisted of 30 Gy at cgy/h in one session. The primary endpoint of the study was vaginal recurrence with a secondary endpoint comparing the toxicity of the regimens. Results: At a median follow-up of 45 months (range 18-78), three vaginal recurrences have been diagnosed after VBT and four after EBRT. Estimated five-year recurrence rates were 1.8% with VBT and 1.6% with EBRT (p = 0.74). Five-year locoregional relapse rates were 5.1% with VBT and 2.1% with EBRT (p = 0.17). There was no difference in OS (84.8% vs. 79.6%; p = 0.57) or disease-free survival (82.7% vs. 78.1%; p = 0.74). Grade 1 and 2 GI toxicity (EORTC-RTOG scale) increased significantly at the completion of EBRT (53.8%) vs. VBT (12.6%). The incidence decreased with further follow-up and lost statistical significance after 24 months. Conclusion: VBT is effective in ensuring vaginal control with fewer GI toxic effects than EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial cancer of high-intermediate risk. 44 managedcareoncology Quarter

8 Managed Care Implications: As newer forms of radiation therapy become available, randomized studies such as this will play a critical role in determining the appropriate form of radiation therapy for a given disease. Title: Three-year outcomes of breast intensity-modulated radiation therapy with simultaneous integrated boost. Authors: McDonald MW, Godette KD, Whitaker DJ, et al. Reference: Int J Rad Onco Biol Phys [published online ahead of print as doi: /j.ijrobp ]. Purpose: Breast radiation for invasive breast cancer and ductal carcinoma in situ has become an integral part of breast-conserving therapy. It controls local tumor spread and benefits the patients in terms of OS. Conventional breast radiation therapy (RT) is delivered to the whole breast over a course of five weeks with five daily fractions per week. An additional radiation boost to the resection cavity may extend total treatment time to six or seven weeks. Despite proven benefit, a minority of patients do not receive postoperative RT due to the fact that their physician feels the risk of breast RT outweighs the benefit in individual cases. Improvements have been made in radiation techniques to minimize toxicity. Compared with conventional tangential breast RT, IMRT is a treatment approach that reduces acute skin toxicity. Early randomized studies showed improved late cosmesis with breast IMRT. The introduction of multibeam inverse planned IMRT technique using a simultaneous integrated boost (SIB-IMRT) to the resection cavity provides a greater dose per fraction to the resection cavity than to the remainder of the breast and allows the traditional sequential boost to be eliminated. This shortens the course of therapy. The purpose of this paper was to report clinical experiences using SIB-IMRT. Methods: Records were reviewed to identify patients with stage 0 to III breast cancer who had received SIB-IMRT following conservative surgery between January 2003 and December Patients underwent conservative surgery. Those at sufficient risk for distant metastases were offered adjuvant chemotherapy. Patients with hormone receptor (+) disease generally received adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor. Radiation therapy was usually initiated within four weeks of completing all surgery and chemotherapy. The most common SIB-IMRT delivered 1.8 Gy to the ipsilateral breast tissue and 2.14 Gy to the resection cavity. This yielded a breast dose of 45 Gy in 25 fractions and a cavity dose of Gy in 28 fractions. During treatment, acute toxicity was assessed at least weekly and graded according to the Common Terminology Criteria for Adverse Events version 3. Endpoints of the study included incidence of acute skin toxicity, OS, and locoregional recurrence (LRR). Results: A total of 354 patients were treated, 282 with invasive breast cancer and 74 with ductal carcinoma in situ (DCIS). Median follow-up was 33 months with a range from four to 73 months. Acute skin toxicity was grade 1 in 57% of cases, grade 2 in 43%, and grade 3 in <1% of all patients treated. Assessment of global breast cosmesis at a minimum of three years was available in 142 cases and was judged as good or excellent in 96.5% and fair in 3.5%. For invasive breast cancer, the threeyear OS was 97.6% and the LRR was 2.8%. For patients with DCIS, the three-year OS was 98% and the LRR was 1.4%. Conclusion: Breast SIB-IMRT reduced treatment duration by five fractions with a favorable acute toxicity profile and low cardiac dose for left breast treatment. At three years, LRR was excellent and initial assessment suggested good or excellent cosmesis in a vast majority of evaluable patients. Managed Care Implications: Newer radiation techniques such as SIB- IMRT offer a means of delivering higher doses of radiation in shorter fractions to the tumor while sparing normal tissue. It should be considered the standard of care for most patients with early-stage breast cancer requiring radiation therapy. managedcareoncology.com 45