| EXPLORE PRIMELINES | December 2009 Issue |
| Pharma News | From the Literature: |
Additional Publications Worth Reading | Other prIME Activities |
prIME Oncology wishes you a very happy and prosperous 2010.
Ofatumumab Approved for Chronic Lymphocytic Leukemia
On October 26, 2009, the US Food and Drug Administration approved GlaxoSmithKline and Genmab’s novel anti-CD20 antibody, ofatumumab (Arzerra™), for the treatment of patients with chronic lymphocytic leukemia that is resistant to standard therapy with fludarabine and alemtuzumab.
From the Business World: Merck, A New Pharma Giant
The merger completed on November 4, 2009, between Merck & Company and its long-time joint venture partner, Schering-Plough Corporation, catapulted Merck from the world’s eighth-largest to second-largest pharmaceutical company behind Pfizer Inc. The resulting company will retain Merck’s name and will have a more diverse portfolio across important therapeutic areas including cardiology, respiratory diseases, oncology, neuroscience, infectious diseases, immunology, and women’s health. In terms of oncology, Schering-Plough’s current oncology products will enable Merck to expand its presence in the oncology arena and provide the necessary foundation to take advantage of the combined company’s promising pipeline, which includes an mTOR inhibitor (MK-8669, ridaforolimus) in phase III trials, and several products in phase II trials such as a cyclin-dependent kinase inhibitor (dinaciclib, SCH 727965) and two antibodies against the insulin-like growth factor receptor (MK-0646 and robatumumab).
Can a Change in Hormone Receptor Status Influence the Outcome of Breast Cancer?
Neoadjuvant chemotherapy is routinely used for breast cancer to improve the potential for breast conserving surgery, and this can result in a period of 2 to 3 months between the initial core needle biopsy (CNB) and surgical resection, after which patients with hormone receptor (HR)–positive tumors typically receive adjuvant endocrine therapy for up to 5 years. Moreover, the decision to administer endocrine therapy is often based on the HR status determined from the CNB. However, it is well documented that the HR status of the primary tumor can change from the time CNB is performed—prior to neoadjuvant chemotherapy—to the time the tumor is surgically resected. This occurs in approximately 15% of cases, but it is not known what affect this may have on long-term outcomes.
This question was addressed in a retrospective study of 368 patients who received neoadjuvant chemotherapy and were subsequently treated with either standard adjuvant chemotherapy or endocrine therapy. Patients were divided into 4 groups on the basis of the HR status of their tumor before and after neoadjuvant chemotherapy, and whether they did or did not receive adjuvant endocrine therapy. Patients assigned to group A (n = 184) were HR positive both before and after neoadjuvant chemotherapy and received adjuvant endocrine therapy; group B (n = 47) exhibited HR status conversion (29 positive to negative and 18 negative to positive) and received adjuvant endocrine therapy; group C (n = 12) exhibited HR status conversion (11 negative to positive) and did not receive adjuvant endocrine therapy; group D (n = 125) were HR negative both before and after neoadjuvant chemotherapy and did not receive endocrine therapy. The 3-year disease-free survival (DFS) rates in groups A, B, C, and D were 80%, 78%, 36%, and 72%, respectively. After controlling for other prognostic factors that could influence DFS by Cox multivariate regression analysis, patients in group C had significantly worse DFS compared to groups A and B (HR = 6.88; P<.001), whereas DFS was similar in groups A and B (HR = 1.16; P = .652). Overall survival (OS) was also significantly worse in group C. Although this was a retrospective study with small numbers of patients, it suggests that conversion of HR status does not affect outcome, a priori, but failure to administer adjuvant endocrine therapy to patients who convert from HR negative to HR positive can adversely affect DFS and OS. The authors concluded that the HR status of the tumor should be evaluated not only in CNB specimens obtained before the initiation of neoadjuvant chemotherapy, but also in specimens obtained during surgery.
Br J Cancer. 2009;101(9):1529-1536.
The Role of Radiotherapy in Ductal Carcinoma In Situ: A Clinical Dilemma
The benefit of postsurgical radiotherapy (RT) to maintain local tumor control in patients with ductal carcinoma in situ (DCIS) of the breast is somewhat controversial. This controversy began with the favorable outcomes reported from retrospective studies in highly selected patients treated with excision alone who experienced low rates of local recurrence. These studies raised important questions regarding the need for RT in the conservative management of DCIS. Subsequently, however, 4 prospective randomized trials demonstrated that RT after surgical excision reduced the risk of local recurrence by approximately 50%, and subset analyses suggested that all subgroups, even those with favorable clinical or pathologic features, derived some benefit from RT. Unfortunately, these trials were not uniform with respect to defining the completeness of surgical excision. Although they demonstrated that RT reduces local recurrence in the context of routine tissue processing and minimal negative margins, they did not answer the question of whether a complete excision, determined by a thorough pathologic and radiologic evaluation to ensure negative margins, could eliminate the need for RT. Indeed, a retrospective analysis by Silverstein and colleagues showed that, regardless of the size or grade of DCIS, complete excision with a 1-cm margin of normal breast tissue could eliminate the need for RT.
The study by Hughes et al reported in the November 10 issue of the Journal of Clinical Oncology prospectively tested the hypothesis that, in selected patients with DCIS, detailed pathologic assessment involving sequential sectioning of the complete surgical specimen could determine truly negative margins and identify a group of patients who may not require postsurgical RT. This study restricted enrollment to patients with either low-grade or intermediate-grade DCIS ≤2.5 cm or high-grade DCIS (defined as nuclear grade 3 with necrosis) ≤1 cm. Margins of at least 3 mm were required, and postexcision mammography was performed to ensure no residual calcification. At a median follow-up of more than 6 years, the 5-year rate of local recurrence (ipsilateral breast cancer) was 6% among 565 patients with low/intermediate-grade DCIS and 15% among 105 patients with high-grade DCIS. Based on these results, the authors concluded that rigorously evaluated and selected patients with low/intermediate-grade DCIS and negative margins ≥3 mm have an acceptably low rate of local recurrence without RT, but excision alone is inadequate treatment for patients with high-grade DCIS.
In the accompanying editorial, Jay Harris and Monica Morrow commented that these results will not change current treatment recommendations for high-grade DCIS and longer follow-up is needed in the low/intermediate-grade group before the results should be considered practice-changing. Moreover, the population of patients with low/intermediate-grade DCIS enrolled in this study had a median age of 60 years, and the majority had lesions ≤1 cm with margins >5 cm. Therefore, the patient population was not representative of the majority of patients with low/intermediate-grade DCIS. Finally, these are heterogeneous tumors, and neither tumor size nor completeness of excision appears to determine the long-term risk of recurrence. The challenge for the future is to identify markers that reliably predict the clinical behavior of these tumors and allow informed treatment decisions.
J Clin Oncol. 2009;27(2):5319-5324. (editorial 5303-5305)
Optimizing Trastuzumab Therapy for HER2-Positive Breast Cancer
In their editorial, which discusses the results of studies regarding HER2-positive breast cancer published in the December 1 issue of the Journal of Clinical Oncology, Harold Burstein and Eric Winer discuss data that help to define the optimal use of trastuzumab in the adjuvant setting. Although the clinical benefit of adjuvant trastuzumab in patients with HER2-positive breast cancer has been clearly demonstrated in a number of large trials, clinicians continue to encounter practical questions regarding which patients should receive trastuzumab, whether it should be combined concurrently or sequentially with chemotherapy, and the optimal duration of trastuzumab therapy. For example, the benefits of adjuvant trastuzumab have not been prospectively defined in patients with small primary tumors (≤1 cm) and negative lymph nodes (ie, T1abN0). However, patients with T1abN0 HER2-positive disease are clearly at increased risk of recurrence compared to their HER2-negative counterparts, and Burstein and Winer suggest that trastuzumab should be considered in this cohort provided the risk of short-term toxicity can be minimized. With regard to the optimal combination of trastuzumab with chemotherapy, the available data suggest that concomitant administration is more effective than sequential administration. Finally, with respect to the optimal duration of therapy, the majority of adjuvant trials administered trastuzumab for at least 1 year. However, that paradigm is challenged by the FinHer trial in which trastuzumab was administered for only 9 weeks concomitant with either docetaxel or vinorelbine in the subset of patients with HER2-positive tumors. The final results of the FinHer trial suggest that adjuvant trastuzumab, administered even for a short time concomitant with docetaxel, reduces the risk of recurrence and improves distant DFS compared with docetaxel alone, and this regimen was associated with minimal clinical toxicity (J Clin Oncol. 2009;27(34):5685-5692 ). Given the favorable safety profile of this regimen, Burstein and Winer commented that a short course of trastuzumab plus chemotherapy may be a good option in the T1abN0 population. To address this question, they are currently conducting a study to prospectively evaluate paclitaxel plus trastuzumab for 12 weeks followed by maintenance trastuzumab in women with stage I breast cancer (NCT00542451).
J Clin Oncol. 2009;27(34):5671-5673.
Is Gemcitabine plus Capecitabine a New Standard for Advanced Pancreatic Cancer?
Since 1997, gemcitabine has been considered the standard of care for the treatment of advanced pancreatic cancer based on evidence that it significantly improves OS compared to 5-fluorouracil, yielding a median OS of approximately 6 months in most studies. Since then, numerous studies have investigated whether gemcitabine-based combination regimens can further improve OS compared to gemcitabine alone, but none have succeeded. Perhaps the greatest interest has been in combining gemcitabine with capecitabine, because both are known to be active agents in this disease. In the November 20 issue of the Journal of Clinical Oncology, Cunningham et al published the results of a large (n = 533) phase III randomized study comparing gemcitabine with gemcitabine plus capecitabine in patients with advanced pancreatic cancer. The combination of gemcitabine plus capecitabine significantly improved response rate (19% versus 12%; P = .034) and PFS (HR = 0.78; P = .004), but there was only a trend toward improvement in OS (HR = 0.85; P = .08) compared with single-agent gemcitabine. In addition, the authors performed a meta-analysis that included two previously published smaller studies evaluating the combination of gemcitabine plus capecitabine. The results of this meta-analysis involving 935 patients demonstrated a statistically significant OS benefit associated with combination therapy (HR = 0.86; P = .02) compared with gemcitabine alone. On the basis of these results the authors concluded that the combination of gemcitabine and capecitabine can be considered a new treatment option for patients with advanced pancreatic cancer. However, in their editorial, Josep Tabernero and Teresa Macarulla commented that this conclusion should be viewed with caution because the chemotherapy schedules and dose intensities of gemcitabine and capecitabine used in the 3 studies were completely different, and none of these studies individually demonstrated a significant OS advantage for the combination regimen. Therefore, one has to conclude that the there is no definitive conclusion yet as to whether this combination is better than gemcitabine alone.
J Clin Oncol. 2009;27(33):5513-5518. (editorial 5487-5491)
Human Papillomavirus Defines a New Prognostic Subgroup in Oropharyngeal Squamous Cell Carcinoma
Chemoradiotherapy has long been the standard of care for squamous cell carcinoma (SCC) of the oropharynx, larynx, and hypopharynx in an effort to preserve organ function. While this approach is generally effective, new therapeutic strategies have been explored over the past 5 years with the goal of reducing the risk of distant metastasis. Novel strategies include taxane-based induction chemotherapy and combinations of cetuximab with radiotherapy, which have been shown to reduce distant metastasis and improve locoregional tumor control. Kies et al reported the results of a small phase II study combining cetuximab with a weekly regimen of carboplatin and paclitaxel induction chemotherapy in 47 patients with oropharyngeal SCC. This regimen produced a high objective response rate (19% complete response and 77% partial response), and clinical outcomes were excellent following local, risk-adjusted radiotherapy, chemoradiotherapy, or surgery. Even more noteworthy is the fact that 12 of 26 (46%) tumor specimens available for human papillomavirus (HPV)–16 testing were positive for HPV-16, and this subset of patients had significantly better PFS and OS compared to patients with HPV-negative tumors. In his editorial, Danny Rischin discusses the implications of these data and the growing evidence that HPV-positive SCC of the head and neck represents a distinct prognostic subgroup. The study reported by Kies et al provides further confirmation that the subset of patients with HPV-positive SCC has improved outcomes when treated with chemoradiotherapy. Unfortunately, given that this study contained a mix of HPV-positive and HPV-negative tumors, interpretation of the results is difficult, and it is not possible to discern whether the experimental regimen is an improvement over standard chemoradiotherapy.
The proportion of HPV-associated oropharyngeal SCC appears to be steadily increasing and now represents the majority of new oropharyngeal cancers in some countries. Moreover, HPV-positive oropharyngeal SCC is distinct with regard to risk factors, clinical features, sensitivity to treatment, and prognosis. Compared to patients with HPV-negative tumors, patients with HPV-positive oropharyngeal SCC have markedly improved survival after chemoradiotherapy. Therefore, Rischin argues that HPV-positive oropharyngeal SCC should be studied separately or, at a minimum, be included as a stratification factor in randomized trials. Studying these 2 subgroups separately would also allow for more attention to be focused on strategies to improve treatment outcomes in patients with HPV-negative SCC who have a poor prognosis.
J Clin Oncol. 2009 Nov 16. [Epub ahead of print] (editorial 2009 Nov 16 [Epub ahead of print])
ABVD Remains Standard for Advanced-Stage Hodgkin Lymphoma
For nearly two decades, the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD regimen) has been the standard treatment for advanced-stage Hodgkin lymphoma. More recently, several novel, short-duration regimens have been developed to reduce cumulative doses of chemotherapy agents associated with long-term toxicity and to increase the dose-intensity by reducing the treatment intervals and total duration of therapy. One such regimen, known as Stanford V (SV), is a weekly alternating regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide and prednisone, administered for 12 weeks. The SV regimen with consolidation radiotherapy to sites of initial bulky disease and splenic deposits appeared promising in single-institution and multicenter phase II studies. At 5-years, 85% to 89% of patients were progression-free, and the 5-year OS rate was 96% in both studies.
Based on these results, the United Kingdom National Cancer Research Institute Lymphoma Group conducted a prospective randomized phase III trial to test the hypothesis that SV is superior to the ABVD regimen. Five hundred patients received protocol treatment and radiotherapy was administered to 73% of patients receiving SV and 53% of those receiving ABVD chemotherapy. However, the results showed no difference in response rate (91% vs 92%),
5-year PFS (74% vs 76%), or 5-year OS (92% vs 90%) between the SV and ABVD regimens, respectively. The authors reiterated that only 73% of patients in the SV arm received radiotherapy, which may explain the worse outcomes compared with the previous trials where approximately 90% of patients received radiotherapy. Nevertheless, this prospectively randomized trial showed that these 2 regimens have equivalent efficacy and safety profiles. Although the ABVD regimen was associated with more grade 4 pulmonary toxicity, it offers the potential to avoid radiotherapy (and associated toxicity) in patients who achieve a complete response, and it is likely to remain standard therapy. However, for some patients, the SV regimen may be preferred because of the brief duration of treatment and reduced risk of acute pulmonary toxicity.
J Clin Oncol. 2009;27(32):5390-5396.
ADDITIONAL PUBLICATIONS WORTH READING
- Yerushalmi R, Hayes MM, Gelmon KA, et al. Breast Carcinoma—Rare Types: Review of the Literature. Ann Oncol. 2009;20(11):1763-1770. A comprehensive review of 16 rare subtypes of breast cancer provides a better understanding of each subtype and the optimal approach to therapy.
- Branford S, Melo JV, Hughes TP. Selecting Optimal Second-Line Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia Patients After Imatinib Failure—Does the BCR-ABL Mutation Status Really Matter? Blood. 2009 Oct 30 [Epub ahead of print].This article investigates whether or not BCR-ABL mutations matter when selecting an optimal second-line tyrosine kinase inhibitor for CML after imatinib failure, and comes to the conclusion that the mutations do, in fact, matter.
- Golfinopoulos V, Pentheroudakis G, Salanti G, Nearchou AD, Ioannidis JP, Pavlidis N. Comparative Survival with Diverse Chemotherapy Regimens for Cancer of Unknown Primary Site: Multiple-Treatments Meta-Analysis. Clin Cancer Res. 2009;35(7):570-573. Meta-analysis of 10 randomized controlled trials finds that no chemotherapy regimen has been shown to prolong survival in patients with cancer of unknown primary site. Regimens using either platinum, taxanes, or both need further testing.
- Balch CM, Gershenwald JE, Soong S-J, et al. Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol. 2009 Nov 16. [Epub ahead of print]. Charles Balch and colleagues release the final version of the 2009 AJCC melanoma staging and classification recommendations, which is based on a multivariate analysis of nearly 40,000 patients.
- Joensuu H, Kellokumpu-Lehtinen PL, Huovinen A, et al. Adjuvant Capecitabine in Combination with Docetaxel and Cyclophosphamide plus Epirubicin for Breast Cancer: An Open-Label, Randomized Controlled Trial. J Clin Oncol. 2009;10(12):1145-1151. Adjuvant capecitabine-based chemotherapy in the FinXX trial reduced breast cancer recurrence compared with a standard chemotherapy regimen, but a high percentage of patients discontinued treatment due to adverse events.
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