OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

		Associate Director Breast Oncology Research Texas Oncology US Oncology Breast Cancer Research Houston, TX

	Although much has changed in cancer therapeutics, chemotherapy-induced nausea and vomiting (CINV) remains a significant and much-feared adverse effect of treatment for many patients.

	Researchers are seeking to understand the molecular pathways through which CINV develops, and clinical practice guidelines have been updated to reflect the continuing complexity of treating CINV and personalizing therapy for individual patients.

	Physicians’ Education Resource (PER) offers a review of current and emerging agents, as well as guidelines on their use, in “Optimizing the Prevention of Chemotherapy-Induced Nausea and Vomiting: A 2011 Perspective,” an online continuing medical education course approved for 2.0 AMA PRA category 1 credits.

	There are three major classes of drugs that can be employed to treat CINV, according to the course paper:

		Neurokinin-1 (NK-1) antagonists—aprepitant, a capsule formulation of Emend (Merck) and fosaprepitant, an intravenous form of Emend

		Serotonin 5-HT3 receptor antagonists—dolasetron (Anzemet; Sanofi), granisetron, ondansetron, and palonosetron (Aloxi; Eisai)

	These drugs are available in different formulations, with some offered both intravenously and in tablet form. Granisetron is available in tablet, liquid, and injection forms, and as a transdermal patch (Sancuso; ProStrakan).

	For patients who fail to respond to these therapies, other medications such as antipsychotics and cannabinoids also may be options.

	In a question-and-answer perspective that is part of the PER course, Frankie Ann Holmes, MD, offers her views on evaluating patients with CINV and selecting therapies for them. Here is an excerpt from that discussion:

	What are the most significant challenges in the management of CINV?

	One of the most significant challenges in managing CINV awareness is that some clinicians do not regard a commonly used chemotherapy regimen, “AC” (doxorubicin with cyclophosphamide), as highly emetogenic. Highly emetogenic regimens are those that cause nausea and vomiting in unprotected patients more than 90% of the time. I have been to lectures where physicians have said, “Oh, that’s just AC.”

	So it is important to realize that our understanding of the potency of these regimens has changed, and that we need to be sure that we are maximally protecting patients for whom we prescribe AC.

	Another significant challenge is that we don’t have a good answer for the management of nausea. We don’t understand all the mechanisms driving it, the way we do the management of emesis. Emesis has now been understood as a series of molecular pathways, just like the targeted agents we use to bind or modulate the estrogen receptor or the anaplastic lymphoma kinase (ALK) inhibitors. We have agents that target these emetogenic pathways, but not so with nausea.

			Develops within a few minutes to several hours after treatment, usually peaks at 5 to 6 hours, and resolves within 24 hours

			Occurs more than 24 hours after chemotherapy and can last up to 5 days

			Occurs before the emetogenic agent is delivered in patients who previously have experienced CINV

			Refers to vomiting that occurs despite prophylaxis and requires "rescue" medication

			Occurs when patients have failed antiemetic prophylaxis and/or rescue medications in previous chemotherapy cycles and have emesis in succeeding cycles

		Source: Peck S. Optimizing the prevention of chemotherapy-induced nausea and vomiting (CINV): a 2011 perspective. Physicians' Education Resource website. 

. Published December 15, 2011. Accessed May 30, 2012.

	What steps do you take to personalize CINV treatment for each patient?

	Increasingly, we are tailoring or “personalizing” every aspect of our treatment. This also includes preemptive management of side effects by “profiling” patients who are more likely to experience nausea and vomiting. These include young patients, healthy women who consume little or no alcohol, and those who do not smoke. These are patients that we must target with maximum efforts. Obese patients may not be as high a risk of nausea and vomiting, but we need to inquire about their history. Did they have a lot of nausea and vomiting with their pregnancy? Do they have carsickness? Are they still very queasy? Obesity is not necessarily protective of emesis, especially if that obesity increases gastroesophageal reflux disease (GERD).

	GERD is another important condition that can contribute to low-grade, naggingly persistent nausea or vomiting. Many patients don’t think to mention this, but GERD can exacerbate CINV. So we need to ask patients, “Do you have any reflux ever, or do you have heartburn?” because we may wish to incorporate a proton pump inhibitor very early on in their treatment.

	What role do you see for newer agents in the management of CINV?

	The newer agents include the IV form of the neurokinin-1 (NK-1) inhibitor, which is fosaprepitant, and this has made it easier for our patients, because we do not have to ask them to bring their pills with them. They can receive this IV treatment at the same time as the other antiemetic agents, so that’s been very useful.

	Another new formulation of an older agent is the transdermal form of granisetron. This patch should be applied before chemotherapy, so it is a preparatory treatment and has a half-life of seven days. For those patients who are not good with pills, especially if they feel nauseated, and who are not keen on using suppositories, the transdermal form of granisetron is an attractive option.

Articles

Although much has changed in cancer therapeutics, chemotherapy-induced nausea and vomiting remains a significant and much-feared adverse effect of treatment for many patients.

CINV Therapies Detailed in Online PER Course

		University of Pittsburgh Cancer Institute, UMPC Cancer Center

	While ovarian cancer survival rates have improved slightly since the 1970s, the overall five-year survival for patients diagnosed with the tumor type stands at 43.7%, and thus lags behind the average rate of all cancers, which is 65.4% for the general population, according to federal statistics.

	Improving screening methods and other preventive measures in ovarian cancer is a top priority at institutions such as the University of Pittsburgh Cancer Institute (UPCI) in Pennsylvania. The center pooled its resources with Magee-Womens Research Institute to launch the Women’s Cancer Research Center in 2010.

	Research on ovarian cancer at the center is concentrated in promising new areas, according to Nancy E. Davidson, MD, director of UPCI. Delivering care also means incorporating the existing knowledge of oncologists, surgeons, and other members of the treatment team.

	“Ovarian cancer is a prime area to think about all of those approaches,” Davidson said. “I think all patients who are diagnosed with any form of ovarian cancer owe it to themselves to have consultation with representatives of all of these disciplines to try to make sure that they make the best possible decision about all the interventions that might be suitable for their own ovarian cancer.”

	Determining ways to prevent the spread of ovarian cancer by detecting it in early stages has proved challenging. Davidson said that the current screening methods for ovarian cancer are not providing enough useful information.

	“Large studies have gone on across the world, and at least so far in the setting of women with average risk for ovarian cancer, there does not appear to be a benefit to the use of something like CA 125 screening or transvaginal ultrasound,” said Davidson.

	“Women always want to do something that’s going to be good for them, but we always have to be weighing the benefits of the intervention with the harms of the intervention, and I think we always want to practice evidence-based medicine,” she said.

	Davidson noted that the center is placing an emphasis on research into vaccines and other immunotherapy strategies for ovarian cancer. One of the program’s directors, Robert P. Edwards, MD, was one of the researchers involved in a phase II study testing the efficacy of recombinant poxviruses that express tumor-associated antigens as potential vaccines for ovarian cancer.

Proceedings of the National Academy of Sciences

 online ahead of print in March, found that in 22 patients with advanced epithelial ovarian cancer at high risk of disease recurrence or progression, the median progressionfree survival was 21 months (95% CI, 16 months-29 months), and the median overall survival was 48 months, suggesting a meaningful clinical benefit.

					Localized (confined to primary site)

					Regional (spread to regional lymph nodes)

	Even amid promising new therapies, though, Davidson said the possibility of using traditional methods for treating ovarian cancer should not be ruled out, such as the surgical removal of the ovaries and fallopian tubes.

	“The key here is that a patient needs to undergo an adequate staging evaluation to understand the extent of her ovarian cancer,” Davidson said. “She needs to have a terrific pathology evaluation to understand the molecular and cellular type of ovarian cancer. She needs to consult with the experts to figure out what kind of therapy, what kind of tailored therapy is appropriate for her.”

			Howlader N, Noone AM, Krapcho M, eds, et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). National Cancer Institute website. 

. Published April 2012. Accessed June 7, 2012.

			Odunsi K, Matsuzaki J, Karbach J, et al. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients [published online ahead of print March 27, 2012].

While ovarian cancer survival rates have improved slightly since the 1970s, the overall five-year survival for patients diagnosed with the tumor type lags behind the average rate of all cancers.

Multidisciplinary Approaches Are Needed in Ovarian Cancer

		Vascular Biology/BioConjugate Group Pfizer Oncology Research Unit Pearl River, NY

	Hans-Peter Gerber has been leading the Vascular Biology/BioConjugate group at the Pfizer Oncology Research Unit in Pearl River, New York, since the acquisition of Wyeth in late 2009, building a program to develop novel biotherapeutics for oncology, including antibody-drug conjugates (ADCs). He has previously served as head of the Translational Biology Department at Seattle Genetics, where he contributed to the development of therapeutic antibodies and ADCs, including brentuximab vedotin (Adcetris, formerly called SGN-35) and SGN-75, and as a visiting scientist at Genentech, where he spent 11 years developing therapeutic antibodies that interfere with tumor angiogenesis. He is the author of more than 80 scientific publications and 10 book chapters, and co-inventor on 15 issued patents.

	The basic concept for ADCs is to combine the strengths of the two most successful classes of therapeutic compounds developed in oncology–the high selectivity of antibodies with the unrivaled potency of cytotoxic drugs–with the goal to increase the therapeutic index.

	What is their therapeutic role in cancer?

	Conventional monoclonal antibody therapeutics interfere with signaling functions of their target antigens but are frequently limited in their ability to induce significant antitumor responses when administered as single agents in patients with solid tumors. In support of this notion, most, if not all, current biologic compounds approved for the treatment of solid tumors are combined with standard-of-care treatment, which often include cytotoxic compounds. To overcome these limitations, several new technologies, including ADCs, are being developed to empower biotherapeutics and to improve their antitumor activities as single agents while maintaining their high tumor selectivity and good safety profiles.

	Currently, there is one approved ADC available, known as SGN-35 [brentuximab vedotin/Adcetris], an anti-CD30-auristatin conjugate that achieved >70% objective response rates in refractory Hodgkin lymphoma (HL) patients and >80% in anaplastic large cell lymphoma (ALCL) patients.

	Approximately 60 ADCs are being developed in oncology and more than 25 are undergoing clinical testing. The most common drugs or payloads used for conjugation to the targeting vehicles include tubulin inhibitors (such as auristatins, maytansines) or DNA double strand break-inducing compounds (such as calicheamicin) and DNA minor groove binder/ alkylators (such as duocarmycins). The majority of these payloads are derived from natural products. Among the more than 15 ADC programs undergoing clinical testing in solid tumors, 14 are based on tubulin inhibitors, including auristatins and maytansinoids, and one program incorporates a DNA minor groove binder/alkylator (duocarmycin).

	Auristatins are highly potent tubulin inhibitors, which interfere with tubulin polymerization and induce rapid cell death at low intracellular concentrations. Several auristatin-based drug conjugates are currently being developed as ADC payloads in preclinical and early-stage clinical studies. About half of the clinical programs use auristatin-based conjugates, consisting of a fully synthetic, pentapeptide tubulin inhibitor, which induces G2/M cell cycle arrest, leading to cell death.

	An anti-CD22 calicheamicin conjugate (CMC-544) is currently being tested in non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) patients in combination with rituximab, and objective response rates of >80% have been reported in refractory NHL patients.

	What is the most significant discovery related to ADCs in recent years?

	The key challenges in ADC research include improvements in potency and safety. The field is making rapid progress toward a better understanding of the physicochemical properties of ADCs, the biology of their targets, and how they impact the therapeutic index. Recent improvements in drug linker conjugations, in particular site-specific conjugation methods, resulted in a significant reduction in the off-target toxicity and potentially increased the therapeutic indexes of ADCs.

	The development of novel research concepts to study ADC targets, along with targeting vehicles, linkers, and payloads, have transformational potential for ADC development. One of the most promising areas of future ADC research is the identification of novel targets with optimal internalization kinetics and intracellular trafficking properties. The development of technologies enabling the screening of a large repertoire of targeting vehicles to select for compounds with optimal characteristics may represent an important future trend in ADC development.

Hans-Peter Gerber has been building a program to develop novel biotherapeutics for oncology, including antibody-drug conjugates, at the Pfizer Oncology Research Unit in Pearl River, New York.

Five Questions for Hans-Peter Gerber, PhD

		Elements of an Antibody-Drug Conjugate (ADC)

		References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169. 2. Senter PD. 

 2009;13(3):235-244. 3. Polson AG et al. Cancer Res. 2009;69(6):2358-2364.

		Reference: Carter PJ et al. Cancer J. 2008;14(3):154-169.

		Source: Antibody-drug conjugates (ADCs): empowering monoclonal antibodies to fight cancer. Seattle Genetics website. 

. Published June 2011. Accessed May 29, 2012. Reprinted with permission.

	Antibodies directed against tumor cell antigens or overexpressed proteins are currently the fastest-growing class of targeted cancer therapeutics. However, their success has been tempered by their limited efficacy as single agents. They are often combined with chemotherapeutic agents, which are much more effective at killing cells, but lack the selectivity of antibodies and, as a result, often have side effects as the drugs attack both normal and cancerous cells indiscriminately.

	The concept of combining the two approaches in the hope of achieving the best of both worlds is not novel, but has proved more difficult than expected to put into practice. The first generation of so-called antibody-drug conjugates (ADCs) met with disappointing results, and the first FDA-approved agent, Mylotarg (gemtuzumab ozogamicin; Pfizer) was withdrawn from the market in mid-2010.

	In recent years, we have come to appreciate the complexity of these molecules, and further research has led to the development of increasingly refined ADCs. These second- and even third-generation molecules are showing great promise. Last year, the FDA approved brentuximab vedotin (Adcetris; Seattle Genetics) for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Positive phase III trial results for trastuzumab emtansine (T-DM1; Genentech) for the treatment of HER2-positive metastatic breast cancer were recently announced, and many other new agents are entering clinical trials. (

	ADCs are therapeutic agents designed to target the delivery of chemotherapy to tumor cells. ADCs link cytotoxic agents to monoclonal antibodies that bind to tumor cell-specific antigens or to antigens that are overexpressed on the surface of tumor cells. The antibody acts as a sort of GPS system, and the theory is that this should increase delivery of potent cell-killing drugs to the tumor, while reducing the exposure of normal cells.

	ADCs are made up of three parts: a monoclonal antibody, a cytotoxic drug, and a linker that joins the two together. The antibody guides the ADC to target tumor cells, where it binds to cell surface antigens. The ADC is then taken into the cell and the cytotoxic drug is released to perform its cell-killing function.

	An important factor in the successful development of ADCs is the selection of wellcharacterized antigens to serve as the target for the antibody. The full expression pattern of the antigen throughout the body and on both healthy and tumor cells must be taken into consideration in order to avoid unwanted toxic side effects. Likewise, the expression of tumor-specific antigens within the tumor itself may be heterogeneous, with some cells displaying the antigen and others not, and this can affect the efficacy of the ADC.

	A number of tumor-associated antigens have been investigated as potential targets for the antibody component of ADCs. Blood cell cancers, including leukemia, lymphoma, and multiple myeloma are often chosen as cancer types in which to study ADCs, since malignant blood cells are more accessible to antibodies than solid tumors. As such, B- and T-cell surface proteins are frequently chosen as target antigens since they are widely expressed on the surface of malignant B and T cells in these types of cancer.

	Targets include B-cell surface proteins such as CD20, CD22, CD40, and CD79, and T-cell surface proteins such as CD25 and CD30, as well as proteins that are overexpressed on carcinoma cells, including the human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), prostate-specific membrane antigen (PSMA), and Cryptic family protein 1B (Cripto).

	Targeting the growth of new blood vessels (angiogenesis) and reducing the tumor blood supply is also a potentially promising option for ADCs, since angiogenesis is a rare process in healthy adults, but is a common hallmark of invasive cancers. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin; Genentech) is being investigated as a possible component of ADCs. Other targets include endothelial cell-linked antigens such as integrins or endoglin.

	Research is also being directed to developing a new class of vascular-targeting ADCs that release their cytotoxin into the extracellular space. The advantage of this approach is that it offers more comprehensive tumor coverage and doesn’t depend on the expression of a cell-surface antigen.

			Target Antigen Should Be Abundantly Expressed on Tumor Cells Compared to Healthy Cells

				Limited or no expression on normal or vital tissues

			Efficient internalization of target antigen increases drug delivery and enhances cell-killing

. 2008;14(3):154-169. 3. Polson AG et al. 

			Other Potential ADC Antitumor Activities

 retain mAb-mediated anticancer activities

				Apoptosis through direct intracellular signaling

				Tumor lysis through host immune effector cells

 2008;14(3):154-169. 2. Junttila TT et al [published online ahead of print August 21, 2010]. 

 doi:10.1007/s10549-010-1090-x. 3. Sharkey RM et al. 

	ï»¿Three main types of drugs are used as the cytotoxic component of ADCs: calicheamicin, maytansinoids, and auristatins. They fall into two classes, according to the mechanism via which they lead to cell death, with the two latter types causing the unraveling of structural fibers in the cell, and calicheamycin causing irreparable DNA damage.

	In order to maximize killing potential, the cytotoxic agent needs to be highly potent. The amount of ADC uptake has been found to be less than 0.1% of the total injected dose per gram of tumor. Therefore, using highly toxic drugs, such as maytansine derivatives, which are 100- to 10, 000-fold more potent than standard chemotherapy agents, ensures that what little gets into the cell has the maximum effect.

	The linker region is extremely important to ADC design, as a delicate balance must be struck between stability in the bloodstream (to ensure the toxin is not released prematurely) and efficient release of the payload once inside the cell.

	Cleavable or releasable linkers that are broken down inside the cell, allowing drug release, have been heavily investigated. Initially, hydrazone linkers (which are broken down only in the acidic environment of the cell) were used. However, these often suffer from poor stability in the blood, meaning that the antibody can fall off, and the errant ADC ”missile” either fails to detonate or strikes multiple targets around the body, rendering it ineffective or causing toxic side effects.

		Next-Generation ADCs: Designed to be Stable in Circulation and Release a Cytotoxic Agent in Target Cells

Newer ADC linker technology is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity

		References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1):5-13. 2. Alley SC et al. Curr Opin Chem Biol. 2010;14(4):529-537. 3. Teicher BA.Curr Cancer Drug Targets. 2009;9(8):982-1004.

		Antibody-drug conjugates (ADCs). Seattle Genetics website. Reprinted with permission.

	In recent years, many companies have begun to develop a range of linker chemistries that improve the stability of the ADC, while still allowing efficient drug release in the tumor cell. These include disulfide-based linkers (selectively broken down inside the tumor cell where the concentration of thiols is higher than in the blood) and peptide linkers (broken down by enzymes found inside the tumor cell).

	Some companies have even begun to use noncleavable linkers, including thioether linkers. It was initially thought that the linker had to be cleaved in order for the drug to become activated; however, it was discovered somewhat by accident that the linker can be degraded by the cellular protein degradation machinery, leading to drug activation. Another linker type that was recently described is the PEG4Mal linker, which is designed to target drug-resistant tumor cells as it cannot be pumped through multidrug resistance channels on the cell surface.

	No linker type is necessarily better than another; they may in fact be suited to different ADC designs and cancer types. However, cleavable linkers may be able to pass back out of the cell and attack surrounding cells, in a phenomenon dubbed “bystander killing.” This may be advantageous in certain situations but not in others.

	Mylotarg was the first ADC to be granted approval by the FDA, over a decade ago, for the treatment of relapsed CD33-positive acute myelogenous leukemia in older patients. However, it failed to demonstrate a clinical benefit in postmarketing studies and was withdrawn from the market in 2010.

	Interest in ADCs has been reignited in recent years, a fact that is reflected in the number of companies investing in ADC research and new agents reaching late-stage development, with brentuximab approved in August 2011. Researchers believe that further improvements can still be made to ADC design, and a third generation of agents is already emerging.

	ADC Therapeutics Sarl is developing ADCs based on a new type of cytotoxic agent, pyrrolobenzodiazepines, developed by Spirogen and researchers at University College, London. Mersana Therapeutics is focusing on developing ADCs using their Fleximer polymer backbone and customized linkers, designed to optimally link antibody and drug. Alternative targeting systems to antibodies are also in the early stages of evaluation. As companies pursue these and other efforts to combine optimized antibody, linker, and cytotoxin technology, the future looks extremely bright for these targeted agents.

					Approved by the FDA for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL) in August 2011, brentuximab is the first new drug for the treatment of HL in more than 30 years. It consists of an anti-CD30 antibody conjugated to the antimitotic agent monomethyl auristatin E (MMAE). CD30 is a cell membrane protein of the tumor necrosis factor receptor family.

					It was granted accelerated approval based on two single-arm multicenter clinical trials of patients with CD30-positive HL after failure of autologous stem cell transplant and patients with CD30-positive systemic ALCL who had previously received chemotherapy. The objective response rates (ORR) were 73% and 86%, respectively, while the complete remission (CR) rates were 32% and 57%, respectively, and the partial remission (PR) rates were 40% and 29%, respectively.

					T-DM1 combines the anti-HER2 antibody trastuzumab (Herceptin) with a derivative of the cytotoxin maytansine, called DM1. It is designed to selectively bind to HER2 receptors that are often overexpressed on tumor cells, particularly in patients with breast cancer.

					In the phase III EMILIA trial, T-DM1 extended median progression-free survival by 3.2 months in women with HER2-positive locally advanced or metastatic breast cancer compared with standard therapy of capecitabine plus lapatinib (9.6 months vs 6.4 months, respectively), according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting in June.

					Genentech has announced its intention to submit a biologics license application to the FDA, and its European counterpart, Roche, plans to submit a marketing authorization application to the European Medicines Agency.

Antibodies directed against tumor cell antigens or overexpressed proteins are currently the fastest-growing class of targeted cancer therapeutics.

Antibody-Drug Conjugates: Guided Missiles Deployed Against Cancerous Cells

		Harald zur Hausen, MD, who won a Nobel Prize in 2008 for elucidating the human papilloma viruses that cause cervical cancer, calls for vaccinating young males and females in a speech at the Society of Gynecologic Oncology conference.

	Without question, the most important study discussed at the SGO meeting was the long and eagerly awaited results of the phase III randomized Gynecologic Oncology Group (GOG) trial that compared the GOG standard of paclitaxel, doxorubicin, and cisplatin (TAP) with the widely recognized clinical community standard of carboplatin plus paclitaxel as primary chemotherapeutic management of metastatic or recurrent endometrial cancer.

	A total of 1381 patients were treated on this trial from 2003 to 2009. The study revealed the equivalence (or in statistical terminology, the noninferiority) in outcome for the carboplatin/paclitaxel regimen compared with the three-drug combination. The median progression-free survival in this study was 14 months in both trial arms, with median overall survival found to be 32 months for carboplatin/ paclitaxel versus 38 months for TAP, respectively (hazard ratio, 1.01). As anticipated, the two- drug combination was associated with a more favorable toxicity profile (less thrombocytopenia, vomiting, diarrhea, metabolic side effects) compared with the TAP program.

	While the intent of this commentary is to highlight study results presented at the annual SGO meeting, it is appropriate to acknowledge the controversy surrounding the conduct of this trial, specifically the complex decision-making process that led the GOG to consider this three-drug combination to be its standard treatment regimen in this clinical setting. Hopefully, the study outcome will result in the discontinuation of the use of this more toxic strategy in the routine management of metastatic or recurrent endometrial cancer.

	ï»¿ï»¿Here are several other studies with noteworthy findings:

	A GOG phase III trial compared the standard-of-care program of weekly cisplatin plus external beam radiation (chemoradiation) with cisplatin plus tirapazamine and external beam radiation as primary therapy for stages IB2, IIA, IIIB, and IVA cervical carcinoma.

 It had been hypothesized that tirapazamine might sensitize hypoxic cells to the effects of the cisplatin and radiation. While the study was discontinued slightly early (after 402 patients were randomized) due to an issue with drug supply, the trial failed to reveal any impact of the experimental regimen on either progression-free or overall survival, compared with the control arm. Of relevance, this study failed to support the concept that sensitization of the hypoxic cell population can favorably impact outcome in cervical cancer.

		Illustration courtesy of Alan Hoofring/Don Bliss/National Cancer Instituteï»¿

	A provocative phase II trial from the Brazilian National Cancer Institute examined the combination of erlotinib plus cisplatin and radiation in the treatment of previously untreated locally advanced cervical cancer.

 Previous preclinical work had revealed that the epidermal growth factor receptor (EGFR) is commonly expressed in cervical cancer, and frequently overexpressed. In this noncomparative study, 34 of the 36 evaluable patients (94%) achieved a clinical complete response. This regimen appears worthy of future investigation in a phase III randomized trial compared with the gold standard of concurrent cisplatin plus radiation in this clinical setting.

	In a phase II trial examining the novel combination of bevacizumab plus temsirolimus as therapy for recurrent or persistent endometrial cancer, investigators in the GOG treated a total of 53 patients, of whom 12 experienced a response, including one complete response.

 The median progression-free survival of the population was 5.6 months, with a median overall survival of 17 months. This study was based on preclinical data revealing that the PTEN tumor suppressor gene is commonly inactivated in endometrial cancer. Further, prior studies had demonstrated clinical activity for bevacizumab in this clinical setting. The objective response rate observed in this population of fairly heavily pretreated patients suggests this regimen is worthy of further investigation in endometrial cancer.

	A GOG study examined the activity of single-agent bevacizumab as a treatment strategy for recurrent sex cord or stromal ovarian tumors.

 The antiangiogenic agent was delivered at the standard dose as employed in other clinical settings (15 mg/kg every 21 days). Of 36 patients entered into the trial, six achieved a partial response (17%). The median progression-free survival in the entire group was 8.6 months. Of note, several patients have remained on study for quite extended periods of time ( >1 year). These data provide support for the conclusion that bevacizumab is a clinically active drug in recurrent sex cord and stromal ovarian tumors and should be considered an acceptable management strategy in this setting.

	Finally, in an interesting retrospective analysis of the question of whether maintaining dose intensity in patients receiving primary chemotherapy for advanced ovarian cancer improves survival, investigators in the GOG study failed to demonstrate a favorable impact of such a strategy on outcome.

 In a population of 591 individuals treated in a previously reported phase III trial (GOG 182) who completed the eight scheduled cycles, 263 required a dose modification. There was no difference in the hazard ratio for time to disease progression or overall survival (median 49.4 months vs 50 months for patients requiring or not requiring a dose modification, respectively). Further, the use of a granulocyte colony-stimulating factor to maintain dose intensity did not appear to impact outcome. These data provide strong support for the conclusion that dose modifications, if required due to the development of excessive toxicity, do not negatively impact survival in ovarian cancer.

is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania.

			Miller D, Filiaci V, Fleming G, et al. Late-breaking abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study [published online ahead of print May 17, 2012]. 

. 2012;125(3):771. doi: 10.1016/j.ygyno.2012.03.034.

			DiSilvestro D, Ali S, Peter C, et al. A Gynecologic Oncology Gr oup phase III randomized trial of weekly cisplatin and radiation versus cisplatin and tirapazamine and radiation in stage IB2, IIA, IIIB and IVA cervical carcinoma limited to the pelvis [published online ahead of print March 6, 2012]. 

. 2012; 125(suppl 1):S3-S4. doi:10.1016/j.ygyno.2011.12.003.

			Rodrigues A, Alves F, Carmo C, et al. INCA-GYN001: erlotinib added to cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell cervical carcinoma—a phase II trial and correlative tumor molecular profiling [published online ahead of print March 6, 2012]. 

 2012;125(suppl 1):S3. doi:10.1016/j. ygyno.2011.12.002.

			Alvarez E, Brady W, Walker J, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study [published online ahead of print March 6, 2012]. 

. 2012;125(suppl 1):S17. doi:10.1016/j.ygyno.2011.12.041.

			Brown J, Brady W, Schink J, et al. Late-breaking abstract 2: bevacizumab shows activity in treating recurrent sex cord-stromal ovarian tumors: results of a phase II trial of the Gynecologic Oncology Group [published online ahead of print May 17, 2012]. 

 2012;125(3):771- 772. doi:10.1016/j.ygyno.2012.03.03.

			Olawaiye A, Java J, Krivak T, et al. Does maintaining adjuvant chemotherapy dose intensity have an impact on the outcome of treatment in ovarian cancer patients?: a Gynecologic Oncology Group study [published online ahead of print March 6, 2012]. 

. 2012;125(suppl 1):S25. doi:10.1016/j.ygyno.2011.12.058.

A summary of findings from the 43rd Annual Meeting on Women's Cancer with the potential to impact routine management of women with pelvic malignancies.

Regimen in Recurrent Endometrial Cancer Challenged: TAP Not Superior to Less-Toxic, Two-Drug Therapy

	Three medical societies have joined in endorsing low-dose computed tomography (LDCT) screening for patients at high risk of developing lung cancer, but with cautionary comments about unanswered questions over the potential harms of the scans and the difficulty of implementing the guidelines in clinical practice.

	In May, the American Society of Clinical Oncology and the American College of Chest Physicians issued joint guidelines focusing on older patients with a history of heavy smoking after a systematic review of available research. The American Thoracic Society also endorsed the findings.

	The recommendations call for annual LDCT screening of people aged 55 to 74 who have smoked for ≥30 pack-years and either continue to smoke or have quit within the past 15 years. Screening is not recommended for smokers who have smoked <30 packyears, are younger than 55 or older than 74, have quit smoking >15 years ago, or have severe comorbidities.

	In addition, the guidelines recommend that screenings be conducted in locations that can offer the same comprehensive care and expertise with LDCT as sites that participated in the National Lung Screening Trial (NLST), which involved 53,454 current or former smokers from 33 sites across the country.

	The trial found that screening with LDCT reduced the number of lung cancer-related deaths (

					Number of events per screening method (%)

					Rate of events per 100,000 person-years

					Number needed to screen to prevent 1 event

LDCT indicates low-dose computed tomography;

	Heather Wakelee, MD, who specializes in thoracic malignancy research, believes the NLST results are noteworthy but shares concerns over implementing screening programs.

	“Before the results of this study were made available, we didn’t have solid data,” said Wakelee. “This study was really the first to show a clear mortality benefit.”

	An estimated 8 million Americans would fall under the recommended screening criteria and as many as 4000 lives could be saved annually, leading researchers have said. However, Wakelee said that while the benefits are clear for this particular population, there are a number of concerns that remain.

	For example, Wakelee said that the risk of developing secondary malignancies as a result of the radiation is unknown because there has not been enough follow-up of patients in the NLST to determine that risk. Patients were followed for five years. Without knowing that risk, Wakelee said it could be difficult making similar recommendations to at-risk patients in a younger age range.

	Additionally, the rate of false-positives found with LDCT lung cancer screening is significantly higher than with chest x-rays. Wakelee said that studies have shown that the rate of false-positives with LDCT is approximately 25%, while the rate of false-positives found with chest x-rays is closer to 7%.

	“We have to determine what algorithm is needed with these different nodules,” Wakelee said. “It might mean following up with another scan in three months instead of a year.”

	Wakelee also said that the low-dose form of LDCT used in the NLST is not typically what pulmonologists and oncologists use for screening. Additionally, there is no standardized measure of what a pulmonologist would use to determine how large a mass needed to be in order to suggest it was potentially cancerous.

	Wakelee suggested that clinics approach screening with a team-based mentality by keeping open communication between pulmonologists and oncologists to better interpret any information acquired through LDCT screening.

			Statement from the American Society of Clinical Oncology and the American College of Chest Physicians on the joint systematic review and clinical practice guideline on the role of CT screening for lung cancer (endorsed by the American Thoracic Society). American Society of Clinical Oncology website. 

. Published May 20, 2012. Accessed June 7, 2012.

			Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for lung cancer: a systematic review [published online ahead of print May 20,2012]. JAMA. doi:10.1001/jama.2012.5521

Three medical societies have joined in endorsing low-dose computed tomography screening for patients at high risk of developing lung cancer.

LDCT Scans Gain Support Amid Lingering Concerns

		Illustration depicts T lymphocytes attacking a migrating cancer cell. Novel ways to improve the ability of T lymphocytes to enhance immune response are under study.

	At this time last year, immunotherapy was in the limelight. Within a span of less than 12 months, the FDA had approved the first anticancer therapeutic vaccine and an antibody with a unique mechanism of action. Advocates of cancer-fighting immune strategies felt vindicated after facing skepticism and disappointment.

	Today, immunotherapy is maintaining its momentum in clinical development programs, with explorations under way in many tumor types, including breast and lung cancers previously considered poor candidates for such modalities.

	More than a dozen active immunotherapies are in late-stage development (

). And, an early-phase study into an immunotherapy agent targeting the programmed death-1 (PD-1) pathway in three different tumor types emerged as one of the most noteworthy abstracts at the American Society of Clinical Oncology (ASCO) annual meeting in June.

	At the same time, significant challenges remain in translating research discoveries into clinical use and in the marketplace, where immunotherapy has sometimes struggled to establish solid financial footing.

 interviewed several experts on the front lines of the immunotherapy field. Here are their thoughts:

Professor, Medicine and Oncology, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA

	Mary L. Disis, MD, is a chief co-investigator of the Cancer Immunotherapy Trials Network (CITN), which links researchers at 27 institutions with the intention of creating a pipeline of agents that can move into advanced trials. The National Cancer Institute launched the network in April 2011, designating the Fred Hutchinson Cancer Research Center as its headquarters.

	Disis said the rationale for establishing the CITN was “the explosion of new agents that are being developed for the immune system,” particularly after the FDA approved sipuleucel-T (Provenge) for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer in April 2010 and ipilimumab (Yervoy) for unresectable and metastatic melanoma in March 2011.

	“Seeing the approval of immune therapy treatments really working in patients with very advanced-stage disease, where you would expect the immune system wouldn’t be so effective, has spurred a desire to rapidly test and bring forward novel reagents across different tumors, not just melanoma or prostate cancer, that will really make a difference in the lives of patients with both advanced-stage disease and earlier-stage disease,” said Disis.

	The CITN members plan to work as a unit to design trials and investigate biomarkers.

		Table 1. Novel Active Immunotherapies in Late-Stage Development

					Newly diagnosed, metastatic renal cell carcinoma

					Autologous dendritic cells loaded with patient's messenger RNA

					Phase III ADAPT trial to start mid-2012; FDA Fast Track designation

					Stage I/II pancreatic adenocarcinoma after surgical resection

					2 separate allogenic pancreatic cancer cell lines engineered to express a-Ga

					Phase III under way; FDA Fast Track designation

					First-line treatment for stage III/IV melanoma

					Plasmid/lipid-based, encoding DNA sequences for 

 microglobulin to form an MHC class I complex

					Phase III trial in final stages of patient follow-up; FDA Fast Track designation

					Indolent follicular non-Hodgkin lymphoma

					Hybridoma-derived idiotype vaccine made from patient's tumor cells

					Biovest International/ National Cancer Institute

					Phase III trial completed; FDA filing planned

					Advanced/metastatic renal cell carcinoma

					Combination of multiple tumor-associated peptides

					Stage IIIB/IV NSCLC after 0-5 prior chemotherapy treatments

					Four NSCLC cell lines gene-modified to block the secretion of TGF-β

					Phase III trial under way; FDA Fast Track designation

					Recombinant antigen-specific cancer immunotherapeutic

					Advanced primary squamous cell carcinoma of the oral cavity/soft palate

					Mixture of cytokines, including interleukins, interferons, chemokines, and colony-stimulating factors

					CEL-SCI Corporation/Teva Pharmaceuticals Industries/ Orient Europharma

Immunotherapy is maintaining its momentum in clinical development programs, with explorations under way in many tumor types, including breast and lung cancers previously considered poor candidates for such modalities.

June 2012 | Oncology Live®

CINV Therapies Detailed in Online PER Course

Multidisciplinary Approaches Are Needed in Ovarian Cancer

Five Questions for Hans-Peter Gerber, PhD

Antibody-Drug Conjugates: Guided Missiles Deployed Against Cancerous Cells

Regimen in Recurrent Endometrial Cancer Challenged: TAP Not Superior to Less-Toxic, Two-Drug Therapy

LDCT Scans Gain Support Amid Lingering Concerns

High Points and Hurdles: Immunotherapy Moves Forward

Mutations Pass From Primary to Recurrent Endometrial Cancer

Targeting Non-Mutant EGFR: Genetic and Clinical Biomarkers May Help Validate Use of Inhibitors