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• Supportive Care
• Esophageal Carcinoma – Survival Advantage with Cetuximab
• Highlights from the 2008 ASTRO Meeting
• Highlights from the 2008 Breast Cancer Symposium
• Ontario Clinical Oncology Group Trial of Accelerated Hypofractionated Whole Breast Irradiation
• Quick Poll

Supportive Care

There are 2 new opportunities coming on the market for the prevention of chemotherapy-induced nausea and vomiting (N & V). Neither is a new drug, but instead, both are new formulations of available drugs that will expand the availability to physicians and patients.

Palonosetron (Aloxi) currently has US Food and Drug Administration (FDA) approval in an injectable form for the prevention of acute and delayed N & V associated with initial and repeat courses of both moderately and highly emetogenic chemotherapy. It is also approved for the prevention of postoperative N & V for up to 24 hours following surgery. On August 24, 2008, the FDA gave approval for an oral capsule formulation for the prevention of chemotherapy-induced nausea and vomiting (CINV). The new approval is a single 0.5 mg capsule given to patients about 1 hour prior to the start of chemotherapy. In phase II trials, toxicities from treatment with palonosetron included 3.7% of patients reporting headache, and 0.6% of patients with constipation.

There has also been recent approval from the FDA to market the granisetron transdermal system (Sancuso) that is a transdermal patch for the prevention of CINV. The granisetron transdermal system delivers granisetron, a 5-HT3 receptor antagonist, steadily into the bloodstream for up to 7 days. Each patch contains 34.3 mg of granisetron delivering 3.1 mg/24 hours. The granisetron transdermal system has been shown to be as efficacious as oral granisetron in preventing nausea and vomiting in patients undergoing chemotherapy. The granisetron transdermal system offers this protection through a single transdermal patch application.

The FDA approved the granisetron transdermal system for the prevention of CINV based on the results of a multicenter, phase III, randomized, double-blind, double-dummy, controlled study comparing the efficacy, tolerability, and safety of the granisetron transdermal system with once-daily oral granisetron (2 mg). The trial enrolled 641 patients who received moderately or highly emetic multiday chemotherapy, and met its primary endpoint of noninferiority for complete control of CINV compared to oral granisetron. The most common adverse event was constipation. Headache was less common with the patch than the oral formulation. It is anticipated that the patch will be available by the end of 2008.

Esophageal Carcinoma ? Survival Advantage with Cetuximab

Platinum-based chemotherapy with or without fluorouracil has been a mainstay of therapy for multiple years for patients receiving front-line systemic therapy for inoperable, recurrent or metastatic squamous cell carcinoma of the head and neck. Cetuximab (Erbitux) is a monoclonal antibody that inhibits ligand binding to the epidermal growth factor receptor (EGFR) and stimulated antibody-dependent cell-mediated cytotoxicity. Between December 2004 and 2005, 442 patients were randomly assigned to receive platinum-fluorouracil +/- cetuximab. The chemotherapy was delivered on an every 3-week schedule and patients were allowed a maximum of 6 cycles of therapy. The results showed that adding cetuximab to platinum-based chemotherapy with fluorouracil prolonged the median overall survival from 7.4 months to 10.1 months in the group who received the cetuximab (P = .04). In addition, median progression-free survival (PFS) was prolonged from 3.3 to 5.6 months and response rate increased from 20% - 36%. Toxicities were similar with the exceptions of more cases of sepsis (9 vs 1) in the cetuximab arm as well as skin reactions or infusion-related reactions in that arm compared to chemotherapy alone. The authors suggested that prior to the availability of cetuximab, there has not been a significant advancement in the improvement of survival for patients with advanced head and neck cancer for over 30 years. Thus, this survival difference is all that much more remarkable.

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116-1127.

Highlights from the 2008 ASTRO Meeting

Prostate Cancer

Ten-Year Results of Long Term Adjuvant Androgen Deprivation with Goserelin in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy: A Phase III EORTC Study

The purpose of the trial was to compare the PFS, overall survival (OS), and prostate cancer mortality among men with locally advanced prostate cancer who were randomly assigned to external radiation therapy (RT) with or without long-term androgen deprivation (LTAD). In addition, long-term cardiovascular and bone toxicity were assessed as well. Between 1987 and 1995, 415 men (< age 81) with locally advanced prostate cancer were randomly allocated to radiation delivered up to 50 Gy over 5 weeks, followed by a boost of 20 Gy in 10 fractions to the prostate and seminal vesicles with or without LTAD, given by a monthly injection of goserelin (Zoladex) 3.6 mg for 3 years. Results: At a median follow-up of 9.1 years, 192 of 415 men have died (112 on RT and 80 on RT + LTAD). The addition of LTAD increased the 10-year overall survival from 39.8% to 58.1% (P = .0004), clinical PFS from 22.7% to 47.7% (P<.0001), and distant PFS from 30.2% - 51% (P<.0001). The 10-year cumulative incidence of prostate cancer mortality was 31% on RT and 11.1% on RT+LTAD (P<.001). The 10-year cumulative incidence of cardiovascular mortality was 11.1% and 8.2%, respectively. Two pathologic fractures were reported in the combined treatment arm at years 7.2 and 9.9 after study entry. This robust study supports the use of LTAD in addition to RT in men with locally advanced prostate cancer by meeting all of its PFS and OS endpoints without additional significant long-term morbidity.

Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: A Phase III EORTC Study. Int J Radiat Oncol Biol Phys. 2008;72(1)S30-31. Abstract 65.

Highlights from the 2008 Breast Cancer Symposium

Neoadjuvant Trastuzumab and Chemotherapy

143 women with HER2-positive breast cancer entered onto a neoadjuvant clinical trial at the M. D. Anderson Cancer Center. Patients received 12 weekly cycles of paclitaxel with concurrent weekly trastuzumab, followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC 75) every 3 weeks x 4 cycles with concurrent trastuzumab. At the conclusion of chemotherapy, patients went on to receive local therapy, and then continued with trastuzumab for an additional 6 months. The purpose of the presentation was to determine the pathologic complete response (pCR) rate and to determine the HER2 status on the residual cancer for those patients achieving less than a pCR. Results: 72 of 143 women achieved a pCR (50.3%); 61 (42.7%) achieved a partial response (PR); 7 (4.9%) stable disease (SD); and 3 (2.1%) had progressive disease (PD). Of the 61 women with a PR, 23 had adequate specimen for HER2 testing in their residual disease. The remainder of the data is based on these 23 women. Of these 23 women, HER2 by fluorescence in situ hybridization (FISH) was verified on the original tumor biopsy. On the post-chemotherapy residual disease, 16 (69.6%) had tumors that were HER2 amplified by FISH, but 7 (30.4%) were HER2-negative. With a median follow-up of 10.2 months, 2 (2.8%) of patients achieving a pCR had recurred compared to 8 (11.3%) of patients with <pCR had recurred. Three of 7 patients who converted from HER2-positive to HER2-negative had recurred as well. The authors concluded that the above listed chemotherapy regimen results in a high pCR rate when given in the neoadjuvant setting for women with HER2-positive breast cancer, but approximately 1/3 of women with a less than pCR will convert their breast cancer to HER2-negative. Recommendations are to repeat markers on the final surgical specimen in patients with residual disease after neoadjuvant chemotherapy, and to consider testing all areas of metastases as well for similar reasons.

Mittendorf EA, Esteva FJ, Wu Y, et al. Determination of HER2 status in patients achieving less than a pathologic complete response following neoadjuvant therapy with combination chemotherapy plus trastuzumab. Presented at: Breast Cancer Symposium; Washington, District of Columbia; September 5 - 7, 2008. Abstract 150.

HER 2 Concordance Between IHC and RT-PCR and FISH and RT-PCR

HER2 is 1 of 16 cancer related genes in the Oncotype Dx Breast Cancer Assay. The messenger ribonucleic acid (mRNA) level of HER2 is determined by the reverse transcription polymerase chain reaction (RT-PCR) assay in all Recurrence Score (RS) determinations. Two abstracts were presented that evaluated the concordance of HER2 as measured by RT-PCR with HER2 measured by immunohistochemistry (IHC) and by FISH.

Baehner, et al presented concordance findings from 776 women who had participated in the phase III randomized trial comparing 4 cycles of doxorubicin-cyclophosphamide (AC) with doxorubicin-docetaxel (AT) in women with 0 - 3 positive lymph nodes. That trial has shown no difference in disease-free survival (DFS) or OS after 76 months of follow-up. The cohort sample for this study included 179 specimens in women who have developed a recurrence, and 597 specimens from women without a recurrence. In the study, 755 samples had evaluable HER2 by central IHC and by central RT-PCR using Oncotype Dx. Of the 121 specimens that were HER-2 IHC-positive, 94 (78%) were positive by RT-PCR and 27 (22%) were RT-PCR–negative. Of the 443 specimens that were negative by IHC, only 4 (1%) were positive by RT-PCR. This resulted in a concordance rate of 95%. Baehner subsequently presented data from a separate database by comparing FISH and RT-PCR in a large Kaiser Permanente case control study. The study population included women < 75 years of age diagnosed with node-negative breast cancer between1985-1994, and who had received no chemotherapy. These cases were matched with controls that were randomly selected, matched on age, race, diagnosis year, and the use of tamoxifen. The report is based on 568 women with sufficient tumor tissue for FISH. Of the 56 women with FISH-positive cancer, only 1 was negative by RT-PCR. Of the 419 specimens that tested negative by FISH, 11 (3%) were positive by RT-PCR and 408 (97%) were negative by RT-PCR. These data resulted in a concordance rate of 97%.

The authors concluded that for HER2 status, there is a high degree of overall concordance between central IHC and FISH for gene amplification and central RT-PCR for quantitative gene expression. They suggested that quantitative RT-PCR by Oncotype Dx for HER-2 status is an alternative to IHC and FISH.

Sparano JA, Baehner FL, Goldenstein LJ, et al. Concordance between HER2 RNA and protein expression and relationship between topoisomerase 2A RNA expression and recurrence after adjuvant doxorubicin-containing chemotherapy for operable breast cancer. Presented at: Breast Cancer Symposium; Washington, District of Columbia; September 5 - 7, 2008. Abstract 13.

Baehner FL JR, Achacoso NS, Maddala T, et al. HER2 assessment in a large Kaiser Permanente case-control study: Comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories. Presented at: Breast Cancer Symposium; Washington, District of Columbia; September 5 - 7, 2008. Abstract 41.

E-Learning: E-mail case: Multiple Myeloma Presenting with Renal Failure This activity presents a case and discussion highlighting therapy alternatives for the patient who presents with multiple myeloma with renal insufficiency. Visit elc.imedex.com for accredited activities on your own time.

Ontario Clinical Oncology Group Trial of Accelerated Hypofractionated Whole Breast Irradiation

During an educational session at the 2008 Breast Cancer Symposium, and subsequently at the 2008 ASTRO meeting in September 2008, Dr Timothy Whelan presented data from a large randomized trial that accrued 1234 women with T1-2, N0, M0 breast cancer who had undergone breast conserving surgery. Patients, who had been accrued between 1993 and 1996, were randomly assigned to 1 of 2 radiation treatment arms. Patients in arm A (accelerated hypofractionated whole breast irradiation [AHWBI]) received whole breast irradiation of 42.5 Gy in 16 fractions over 22 days Patients in arm B (standard whole breast irradiation [SWBI]) received 50 Gy in 25 fractions over 35 days. A boost was not given in either arm. Patients were stratified by age, size of the primary tumor, and systemic therapy. Results: At 10 years, the local recurrence rate in arm A was 6.2% and arm B was 6.7%. Local recurrence rates per stratified group were as follows:

There were no significant differences in the incidence of moderate or severe late radiation morbidity in the skin or subcutaneous tissues. The authors concluded that AHWBI is associated with excellent local control and limited long-term morbidity, and that it is more convenient and less costly than SWBI. Dr Whelan subsequently estimated that 60% - 70% of women with early-stage breast cancers in Canada were receiving AHWBI.

Whelan TJ, Pignol J, Julian J. Long-term Results of a Randomized Trial of Accelerated Hypofractionated Whole Breast Irradiation Following Breast Conserving Surgery in Women with Node-Negative Breast Cancer. Int J Radiat Oncol Biol Phys. 2008;72(1)S28. Abstract 60.

What's Next?

To enhance the few abstracts presented here from the 2008 Breast Cancer Symposium, there are 6 “Best of the Day” interviews from leading national and international breast cancer surgical, radiation, and medical oncologists that are available in the Imedex E-Learning Center

The next issue of OncoFacts™ will be in November 2008 and then monthly throughout the year.

OncoFacts™ Editor:

Christy Russell, MD

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