	The March issues of our oncology publications mark an exciting new era in the growth and maturity of our Oncology Specialty Group. Our partnership with the John Theurer Cancer Center gives us two renowned physician editors to lead our flagship publications, 

. More importantly, however, this partnership opens up a dialog with an entire facility of oncologists and allows our readers to have an open exchange with a team of experts—physicians, nurses, pharmacists, social workers, nutritionists, etc&mdash;whose collective goal is to provide extraordinary care to oncology patients.

	This new relationship brings us the breadth of expertise and professional exposure that will allow us to expand our coverage of the market and provide our readers with a comprehensive family of oncology publications that keep you engaged and informed.

	Thank you for reading…and stay tuned to see the positive effects of this exciting new partnership.

Articles

The March issues of our oncology publications mark an exciting new era in the growth and maturity of our Oncology Specialty Group. 

Partnership for Progress

 Visiting policies, especially those pertaining to children, differ from hospital to hospital and from unit to unit. To avoid disappointment, be sure to ask about these policies before promising a visit to your child. Also keep in mind that, depending on the type of treatment they are receiving, cancer patients may have compromised immune systems that make them especially vulnerable to contagious illnesses such as the common cold or flu. For this reason, children (and adults) should visit only when they are healthy.

Whenever possible, schedule your visit for a time when you can devote your full attention to your child. Hospitals are always busy places but some times are busier than others, such as during shift changes, physician rounds, and scheduled tests or treatments. Children often enjoy visiting a parent during mealtime. This gives them a sense of normalcy in that they can do the same thing they are used to doing at home: eat with mom or dad. Ask the hospital’s dietary department if you can order an extra meal for your child.

Young children have short attention spans, even when visiting a beloved family member. While an adult might be happy to sit at a patient’s bedside for hours, toddlers, preschoolers, and younger school-age children are usually ready to move on to a new activity after 15 or 20 minutes. The adult who accompanies your child to the hospital should be prepared to provide appropriate distractions (such as toys or coloring books) or to take him or her for breaks outside the patient area (such as a trip to the cafeteria). Ideally, more than 1 adult would accompany multiple children on a visit, allowing 1 adult to stay behind with the patient while another gives a child a break or leaves early, should the need arise.

For many children, a visit with a hospitalized parent is their very first exposure to hospitals and all things medical. Hospitals are full of new and sometimes frightening sights, sounds, and smells. Children also may be upset by the sight of an ill parent whose appearance is different from what they are used to seeing. Children who are prepared for what they might experience while visiting are less likely to be upset or fearful during and after the visit. For older children, simple age-appropriate explanations of what they might see and hear are usually sufficient. For younger children, supplementing such explanations with a book that includes pictures of wheel chairs, IV poles, monitors, and so on can be especially helpful.

Watch your children and try to see what they see. A child may, for example, be frightened or confused by a piece of equipment or by another patient, but may be too young or too afraid to verbalize those feelings. Whether during or after the visit, a conversation that starts with, “I noticed that you saw your mom’s roommate and all of those machines she is using. Do you want to ask me any questions?” is a great way to encourage healthy discussion. It is also important to differentiate the sights and sounds that pertain to a child’s parent from those that do not. For example, telling a child, “That lady has an illness that is different from what your mom has, and that machine is for her, not for your mom” can be extremely reassuring.

Nearly every large hospital employs 1 or more child life specialists. These experts in child development are specially trained to help children deal with medical issues. They can help answer questions and give age-appropriate explanations about your diagnosis, your treatment, and what the child will experience when he or she comes to the hospital. If your hospitalization is planned (eg, an upcoming surgery), a child life specialist may be able to arrange a tour ahead of time. This way, your child will know what to expect before the first visit.

Children can sometimes be fearful about visiting a hospitalized parent. The reasons for such feelings vary widely, and depend upon factors such as age, maturity level, previous experience with hospitals, and ability to cope with the parent’s illness. A child should never be forced to visit an ill parent or made to feel guilty about not wanting to do so. Instead, children should be encouraged to communicate in ways that make them feel most comfortable, such as by phone, e-mail, letters, or video chat.

Many hospitals and cancer support organizations offer programs, such as support groups, not only for patients but for their family members as well. Ask your oncology nurse or social worker about age-appropriate programs designed to help your children cope with issues related to your diagnosis, treatment, and hospitalization.

Today’s computer and communication technologies can allow you to have face-to-face visits with your children even when they are unable to physically come to the hospital. Video tools, such as Skype or Yahoo Messenger, are great ways to supplement actual visits or to replace them when they are not possible. If family members or friends are unable to provide you with the necessary equipment, ask your oncology nurse or social worker if the hospital can supply you with what you need.

Before your children come for a visit, make sure an adult talks with them about the type of behavior that is expected while in patient areas. Respect your roommate’s privacy and need for rest by keeping voices down and curtains drawn, or consider moving your visit to a common area, such as a lounge. Laura Bruck is a Cleveland, Ohio-based freelance writer and editor who has specialized in healthcare reporting since 1987.

Although most hospitals encourage visits from children, you should keep in mind the following tips to help ensure that those visits are happy ones for you and your kids.

10 Tips for Making the Most Out of a Child's Visit With a Hospitalized Parent

It was 2 days after her very first mammogram when Lisa Vance got a call from her physician’s office requesting that she come in to discuss the results. Even so, it never occurred to her to be worried. Instead, the 40-year-old mother of 2 was reassured by her physician’s assertion that he’d be “very surprised if it turned out to be anything at all.”

	Lisa had undergone an initial lumpectomy and then another to obtain clear margins. Still relatively confident, she went alone to discuss the pathology results with her surgeon rather than having her husband, Chris, take a day off from the steel mill. But she soon questioned that decision. “I heard the word cancer, and that was it,” she recalled. “The rest was basically, ‘Blah, blah, blah.’”

	What Lisa heard only vaguely in the din of her panic were the words “ductal carcinoma in situ” and “mastectomy.” Her relative calm now a distant memory, she recalled feeling like “a nervous wreck” and immediately started thinking the worst.

	Lisa’s thoughts turned to her husband and 2 young children, 3-year-old Christopher and 1-year-old Kayla. She knew that Christopher was old enough to at least understand that his mommy was sick and needed to go to the hospital to get better. But Kayla was just a baby and Lisa wondered how she could help her grasp what was about to happen.

	Powered by what she now believes was a healthy dose of denial, Lisa picked up a journal and began to write to her children.

	I just found out that I have to have a mastectomy. I’m really scared and don’t want to do this but I want to be here for you to see you grow up. I’m going to fight this. I’m strong and I can do this! I have support from my wonderful husband and my great family and friends. This is just another bump in the road. 

	While Lisa certainly is not the first mother to document a fight with cancer for her children, her reasons for doing so were somewhat unique. “I don’t think I started writing in anticipation of not being there for my kids,” she said. “Instead, I wanted them, especially Kayla, to understand at a later time what they couldn’t possibly understand at such a young age.”

	Still trying to catch her breath, Lisa, this time with her husband, Chris, arrived at the surgeon’s office to discuss her upcoming mastectomy and undergo preoperative testing. She said, “I was just starting to wrap my brain around what was about to happen in 2 weeks, but there’s no way I could have prepared myself for the next 2 minutes.”

	Just as the nurse began to take Lisa’s vital signs, Chris, in what Lisa describes as an almost apologetic voice, began to complain of chest pains. Within hours, Chris was undergoing triple stent placement as Lisa sat in disbelief in the hospital’s surgical lounge. (A fourth stent was inserted just 4 weeks after Lisa’s mastectomy.)

	Daddy was admitted to the hospital. The doctor said he had a heart attack and needs four stents in his heart! Kids, I’m so sorry you have to see Mommy and Daddy sick like this! 

	"In a strange way, Chris’ heart attack gave me something to focus on other than my own issues,” said Lisa, who immediately switched gears to resume her usual role as caregiver and nurturer. “I had 2 weeks to prepare for my mastectomy, but I also had a sick husband and a son who was absolutely devastated that his daddy couldn’t come home.”

	You’re taking this very hard. Your daddy is your best buddy and you don’t like to see him sick! It breaks my heart to see you cry but we’re going to make sure mommy and daddy get the best care and get better! 

	To Kayla, the days that followed were much like any other, with the exception that many more family members were nearby to make a fuss over her. With 4 siblings each, Lisa and her husband had no shortage of family support. But Christopher was having a hard time dealing with the reality of his father’s hospitalization and his mother’s upcoming surgery. “He was a question machine,” said Lisa, who recalled a constant barrage of queries, such as, “Will mommy be OK?” and “Why is daddy sick?”

	Lisa and her husband tried their best to answer each question honestly, and they took their cues from their son’s questions rather than sitting him down for a formal talk. Even so, Christopher seemed better able to comprehend his father’s situation than his mother’s. “Christopher could see that his daddy was sick,” said Lisa. “But Mommy just looked like Mommy to him, and it was hard for him to grasp some abstract concept about something that had yet to happen.”

	With Chris now home from the hospital, the couple found it somewhat easier to reassure their son. In the end, Christopher seemed comforted to know that “Daddy’s heart was sick but is better now” and “Mommy has a boo-boo but the doctors are going to make her better.”

	On March 25, 2009, Lisa underwent a total mastectomy of the right breast with immediate reconstruction at Parma Community Hospital in Cleveland, Ohio. Her cancer was designated as stage I, but lymph node metastasis necessitated 4 rounds of chemotherapy. The estrogen-sensitive malignancy also required treatment with tamoxifen and goserelin, and Lisa now deals with the onset of medically induced menopause.

	With “no time to fall apart,” she saved her “breakdowns” for her sisters and mother. “I know it sounds like a cliché, but I wanted to be strong for the kids,” she said. “At some point, the journal will show them that their mom really did cry and that crying is OK.”

	It’s very hard on all of us. It’s breaking my heart that you kids have to go through this. We just have to remember that this medicine will make mommy get better. 

	But like so many women who share the diagnosis of breast cancer, Lisa glossed over the description of her recovery from surgery, and even the chemotherapy, and cited her hair loss as “the worst thing of all.” I knew I was going to lose my hair but it didn’t hit home until it started to fall out in clumps,” said Lisa, who had always taken pride in her short, spiky cut. It was then that she, with her family in tow, embarked on her extreme hair makeover—with Christopher taking the first turn with the clippers. “I wanted to involve him and let Kayla watch what was happening,” said Lisa. “It was a bad day, but it gave us all a little sense of control.”

	Today, you were mommy’s hero and protector. We were at a basketball game and a little boy asked you why your mommy has no hair. You told him that your mommy had a bad booby. That was so cute and such a good way for one child to tell another that his mommy has cancer. 

	At first, Lisa wore scarves and baseball caps. But when she finally invested in a wig, it was her son who made the ultimate decision. Dear Christopher, Today I went to get my wig cut. Kayla just looked at mommy and giggled. But you looked at me and started to cry!

	Christopher’s sobbing continued as he ran into his room and slammed the door. Between sobs he pleaded with his mom to go back to wearing baseball caps.

	I hope my hair grows back fast, buddy! But for now, I’m taking my wig off because I think it’s scaring you. You told me you just wanted me to wear a baseball cap all the time. I’m going to do what you and your sister wish! 

	On July 9, 2010, Lisa went for her last round of chemotherapy. She will follow up with semiannual and then annual blood work, and she continues her regimen of goserelin injections and tamoxifen. Her second, and most recent, mammogram revealed no sign of disease, and Lisa’s oncologist has declared her cancer-free.

	Well, kids, this is my last treatment. Yes! I can’t wait until this is over. I’ve been feeling very emotional and crabby. You kids and Daddy have been great! I’m sorry Mommy has to be this way. I’m going to be strong for all of you! 

	“In one way, I still don’t believe I ever had cancer,” she said. “But on the other hand, there’s a part of me that’s convinced the cancer still isn’t really gone.” Despite her oncologist’s pronouncement that a recurrence is unlikely, Lisa said she has yet to experience a day when she is not fearful of the cancer returning.

	Even so, she does not want her cancer, or even her survivor’s status, to become her identity. She said, “It’s part of my makeup but it’s not who I am.” And this, says Lisa, is what she has tried to impart in her journal. “I want my kids to understand that something bad happened to us all, but that we were able to make it through and come out even stronger.”

	Sure enough, Lisa and her husband, who had been married only 7 years when their world came crashing down, feel closer than ever. “We know this kind of thing can make you or break you as a couple,” she said.

	As she did for 8 years before her diagnosis, Lisa continues to walk in annual Susan G. Komen “For the Cure” events with her sisters and friends by her side. Chris, who walked in the first event after his wife’s diagnosis, decided his first walk would be his last. “It was just too emotional for him,” said Lisa, who plans to one day take her children, if they express a desire to join her.

	When asked if he remembered his mom and dad being sick, Christopher, now age 6, remarked, “When you get to the end of the story, it’s good.” As for Kayla, her mom plans to show her the journal when she turns 16. “I want her to know how much we love each other and how hard we fought to stay together,” said Lisa. “I guess, in its truest form, the journal is simply a love letter to my family.”

	__________________________________________________________________________

Laura Bruck is a Cleveland, Ohio-based freelance writer and editor who has specialized in healthcare reporting since 1987.

It was 2 days after her very first mammogram when Lisa Vance got a call from her physician's office requesting that she come in to discuss the results. Even so, it never occurred to her to be worried. 

Dear Kayla and Christopher: A Mom With Breast Cancer Documents Her Battle for Her 2 Young Children

	While the beginnings of endocrine therapy for breast cancer can be traced to the 19th century, 

 the exact mechanisms of tumor response and resistance to endocrine manipulation still remain to be elucidated. The first truly successful targeted therapy against the estrogen receptor (ER) came with the resurrection of the compound ICI 46474, as tamoxifen, after it was initially abandoned in 1972.

 Although several endocrine therapies, including selective ER modulators, aromatase inhibitors (AIs), progestins, androgens, and luteinizing hormone-releasing hormone (LHRH) agonists, are available today, the quest for a better tamoxifen still continues. Many promising agents in the preclinical setting have not proven nearly as effective as tamoxifen in the clinical setting.

	In the early 1990s, a new compound, ICI 182780, a 7 alpha-alkylamide analogue of estradiol with promising preclinical activity, was selected for additional clinical studies under the name of fulvestrant.

 A pure novel antiestrogen, fulvestrant competitively binds to ER and blocks receptor dimerisation. The unstable fulvestrant- ER complex then undergoes accelerated degradation, resulting in downregulation of the ER with subsequent inhibition of ER-DNA binding and abrogation of the expression of genes associated with tumor progression, metastasis, and angiogenesis

 Fulvestrant produces dosedependent reductions in the cellular levels of ERs and progesterone receptors (PGRs), resulting in more profound effects in tumors that express both hormonal receptors.

 Fulvestrant’s distinct mechanism of action ensures a lack of cross-resistance with other hormonal agents and no known estrogen agonist effects.

 Following a pivotal phase III clinical trial,

 fulvestrant 250 mg by monthly intramuscular injection was approved by the FDA in April 2002 for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

	Prior to the fulvestrant era, data on the endocrine treatment of breast cancer favored the use of third-generation AIs over progesterone, tamoxifen, and older AIs.

 Preclinical research and early clinical studies of fulvestrant suggested that it would outperform existing endocrine therapies for hormone receptor-positive breast cancer. So far, however, several randomized clinical trials have shown only comparable efficacy but no obvious superiority of fulvestrant to tamoxifen, anastrazole, or exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer.

	There are 3 possible explanations for fulvestrant’s lack of superiority compared to other endocrine therapies: 1) a delay in obtaining steady-state levels, 2) the competitive effect from circulating estrogens, and 3) the inability to reach the maximally effective and tolerated dose.

	In most early clinical trials of fulvestrant, the drug was administered as a monthly, slow intramuscular injection of 5 ml of 50 mg/ml solution containing 250 mg of fulvestrant, plus excipients (ethanol 96%, benzyl alcohol, benzyl benzoate, and castor oil). With this so-called approved dose (AD) regimen it can take 3 to 6 months to reach steady-state levels. Early progression of patients on the AD regimen led to the concept of a loading dose (LD) regimen, which consisted of a 500 mg injection on day 1, then 250 mg injections on days 14 and 28, and monthly 250 mg injections of fulvestrant thereafter. The LD regimen produced steady-state plasma fulvestrant concentrations in 28 days as opposed to 3 months with the AD regimen.

 The use of the LD fulvestrant regimen, however, not only failed to prove superior to exemestane in patients who failed prior nonsteroidal AIs, but also was not better than anastrozole monotherapy alone, even when combined with anastrozole.

Competitive Effect from Circulating Estrogens 

	Fulvestrant competes with estradiol for binding at the ER. Preclinical data show that complete estrogen blockade, by downregulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone.

 Since the major source of estradiol in postmenopausal women is by aromatization of androgens, the combination of AIs with fulvestrant may enhance the efficacy of fulvestrant by reducing plasma estrogen levels.

	Several small-size studies of AI and fulvestrant have been reported. Massarweh and colleagues

 conducted a phase II trial to evaluate the efficacy of anastrozole/ fulvestrant/gefitinib as initial therapy in postmenopausal women with locally advanced or metastatic breast cancer. While the planned sample size was 60 patients, the trial was closed after 15 patients due to poor accrual. Of the 15 patients entered into the trial, 3 patients withdrew. Of the remaining 12 patients, 2 had a compete response, 5 had a partial response, 5 had stable disease, and 2 had progressive disease. Mrozek and colleagues

 reported preliminary results of an ongoing phase II trial evaluating the combination of fulvestrant and exemestane in postmenopausal women with hormone receptorpositive advanced breast cancer previously treated with chemotherapy, tamoxifen, or nonsteroidal AIs in the adjuvant or advanced disease setting. Patients received exemestane 25 mg starting on day 1, with fulvestrant 250 mg monthly added on day 8. At the time of the report, 19 women had been enrolled. Nine patients had a progression-free survival (PFS) of more than 6 months (range: 6-20 months), with 8 of these patients still receiving treatment. An additional 8 patients had progression prior to 6 months. Accrual to this trial is ongoing.

	At the Saint Francis Cancer Treatment Center in Grand Island, Nebraska, we evaluated the combination of letrozole and fulvestrant in 32 postmenopausal patients with hormone receptor-positive metastatic breast cancer who had prior chemotherapy and/or non-AI endocrine therapy. Letrozole was given 2.5 mg daily along with monthly fulvestrant 250 mg given via intramuscular injection. Overall clinical benefit rate was 71%, with a mean clinical benefit duration of 15 months. Eight patients progressed under therapy. Older age, less than 4 prior lines of therapy, and expression of both ER and PGR were predictive of clinical benefit.

	In the large open-label randomized FACT (Fulvestrant and Anastrozole in Combination Trial) study, the combination of the fulvestrant LD regimen plus anastrozole versus anastrozole alone at first relapse in patients with hormone receptor-positive metastatic breast cancer showed similar time to progression and overall survival rates.

 Two other large phase III trials, Southwest Oncology Group (SWOG) SO226 and SOFAE (Study of Faslodex vs Exemestane with/without Arimidex), in postmenopausal women with metastatic breast cancer following progression on nonsteroidal AIs are currently ongoing and their results are eagerly awaited. Both studies are utilizing the fulvestrant LD regimen.

Inability to Reach Maximally Effective and Tolerated Doses 

	The short-term biological and dose-response effects of fulvestrant was first evaluated by Robertson and colleagues.

 Fourteen to 21 days prior to surgery, a single-dose intramuscular administration of fulvestrant at 50 mg, 125 mg, or 250 mg produced a dose-dependent reduction in both ER and PGR expression in resected hormone receptor-positive breast cancer specimens from postmenopausal women. There was no plateau in the decrease of ER in response to administered fulvestrant doses. In another study, the administration of fulvestrant doses up to 750 mg in premenopausal women were shown to be biologically active and well tolerated, other than injection-site reactions.

 There has been increasing interest in administering fulvestrant at doses in excess of the currently labeled amounts, up to and including as much as 1 gram per month. To do so with current formulations would require considerably larger volumes than could be injected intramuscularly at any 1 time, or would require administration at multiple sites or at multiple times throughout the month. Thus, the search continues for injectable formulations of fulvestrant that can deliver more than 250 mg in less than 5 ml or that can be administered by transdermal or topical route.

 Finding the maximally effective and tolerated dose and route of administration remains an elusive pharmacological and clinical challenge.

	The most recent important contribution to the field of endocrine therapy of breast cancer comes from the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial. Di Leo and colleagues

 compared the clinical benefit of the fulvestrant HD regimen versus the AD regimen in postmenopausal women with ER-positive tumors who were previously exposed to at least 1 endocrine therapy. The fulvestrant HD regimen consisted of a 500 mg injection on day 1, day 14, and day 28, followed by monthly 500 mg injections thereafter. Compared to the fulvestrant AD regimen, the fulvestrant HD regimen was associated with a statistically significant and clinically relevant increase in PFS corresponding to a 20% reduction in the risk of progression. Two similar prior studies—1 in a Japanese patient population (FINDER1) and the other in a white patient population (FINDER2)&mdash;of postmenopausal women with ER-positive, locally advanced/ metastatic breast cancer have also been reported.

 In these 2 studies, the pharmacokinetics, efficacy, and tolerability of fulvestrant in 3 different dose regimens—HD, LD, and AD&mdash;were compared as opposed to 2 dose regimens in the CONFIRM study (ie, HD vs AD). The fulvestrant HD regimen produced steady-state concentrations within 1 month that were approximately double of those seen with the fulvestrant LD or AD regimens.

	With its larger patient population than the FINDER1 and FINDER2 studies, the CONFIRM trial may have provided valuable pharmacokinetic data if it were available. In the FINDER1 and FINDER2 trials, while there appeared to be a trend toward improved efficacy, no statistically significant differences could be shown in terms of efficacy between the HD and LD regimens compared to the AD fulvestrant regimen, as was shown in the CONFIRM trial. Although the results of the CONFIRM trial suggest that the fulvestrant HD regimen should replace the AD regimen, the following important questions remain unanswered:

		If there was a loading-dose arm in the CONFIRM trial, would the results be different?

		Considering that the data from the FACT study indicates that combining the fulvestrant LD regimen plus an AI is not superior to AI alone, should the dose of fulvestrant be changed from LD to HD in the 2 ongoing, large combination trials (ie, SOFEA and SWOG SO226) of fulvestrant with AIs?

		Knowing that higher doses of fulvestrant (750 mg) can be safely delivered and effective even in premenopausal women,24 should we pursue a maximally effective and tolerable dose concept and focus our research efforts on finding the optimum delivery systems for fulvestrant?

		Should the patients who have failed a prior AD or LD fulvestrant regimen be rechallenged with an HD fulvestrant regimen in clinical practice?

		Should we be more selective in choosing patients for fulvestrant therapy (ie, both ER- and PGR-positive patients as opposed to ER- and/or PGR—positive or unknown)?

		Finally, has the time come for exploring the combination of fulvestrant with biologics and signal transduction inhibitors along with AIs?

	While endocrine therapy of breast cancer remains a highly important and effective strategy for the treatment of hormone receptor-positive disease, the longstanding quest for a perfect endocrine therapy remains out of reach. Questions concerning the optimal endocrine agent with its optimal setting, sequence, and combination with other agents still remain unanswered. If a maximally effective and tolerated dose and delivery system could be established for fulvestrant, there seems to be a great potential for the use of this novel and versatile drug. Fulvestrant’s possibilities might include first-line and subsequent use in the premenopausal/ postmenopausal metastatic hormone receptor-positive breast cancer setting; adjuvant endocrine treatment of premenopausal/postmenopausal hormone receptor-positive breast cancer; and in combination regimens with other existing endocrine therapies or biologics and with signal transduction inhibitors to overcome endocrine resistance in the metastatic, adjuvant premenopausal/postmenopausal settings. Results of several ongoing clinical trials addressing some of these possibilities are eagerly awaited, as are the new clinical trials of fulvestrant.

Angela Mae Obermiller, PharmD, is the pharmacy supervisor, and Mehmet Sitki Copur, MD, is the medical director of oncology and at Saint Francis Cancer Treatment Center in Grand Island, Nebraska.

The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Mehmet Sitki Copur, MD, Department of Medical Oncology, Saint Francis Cancer Treatment Center, 2116 W Faidley Ave, Grand Island, NE 68802-9804, or e-mail 

Love RR, Philips J. Oophorectomy for breast cancer: history revisited. J Natl Cancer Inst. 2002;94:1433-1434.

Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discovery. 2003;2:205-213.

Silverman SL. New selective estrogen receptor modulators (SERMs) in development. Curr Osteoporos Rep. 2010;8:151-153.

Lee JW, Lee YS, Yoo KH, et al. LY-6K gene: A novel molecular marker for human breast cancer. Oncol Rep. 2006;16:1211-1214.

Johnston SJ, Cheung KL. Fulvestrant—a novel endocrine therapy for breast cancer. Curr Med Chem. 2010; 17:902-914.

Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873.

Dodwell D, Wardley A, Johnston S. Postmenopausal advanced breast cancer: options for therapy after tamoxifen and aromatase inhibitors. Breast. 2006;15:584-594.

Dowsett M. Preoperative models to evaluate endocrine strategies for breast cancer. Clin Cancer Res. 2003;9:502S-510S.

Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short term biological effects of 7alpha-(9-(4,4,5,5,5- pentafluoropentylsulfinyl)-nonyl-estra-1,3,5(10)triene-3, 17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with breast cancer. Cancer Res. 2001;61:6739-6746.

McKeage K, Curran MP, Plosker GL. Fulvestrant: a review of its use in hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Drugs. 2004;64:633-648.

Robertson JFR, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women; a prospective combined analysis of 2 multicentre trials. Cancer. 2003;98:229-238.

Bross PF, Cohen MH, Williams GA, et al. FDA drug approval summaries: fulvestrant. Oncologist. 2002;7:477-480.

Mauri D, Pavlidis N, Polyzos NP, et al. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis. J Natl Cancer Inst. 2006;98:1285-1291.

Howell A, Robertson JF, Abram P, et al Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: A multinational double blind randomized trial. J Clin Oncol. 2004;22:1605-1613.

Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-3403.

Osborne CK, Pippen J, Jones SE, et al. Double-blind randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy: Results of a North American trial. J Clin Oncol. 2002;20:3386-3395.

Chia S, Gradishar W, Mauriac L, et al. Double-blind randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor positive advanced breast cancer; results from EFFECT. J Clin Oncol. 2008;26:1664-1670.

Bergh J, Jonsson PE, Lidbrink E, et al. First results from FACT— An open-label randomized phase III study investigating loading dose of fulvestrant combined with anastrozole versus anastrozole at first relapse in hormone receptor positive breast cancer [abstract 23a]. Presented at: San Antonio Breast Cancer Symposium; December 2009; San Antonio, TX.

Macedo LF, Sabnis GJ, Goloubeva OG, Brodie A. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res. 2008;68:3516-3522.

Jelovac D, Macedo L, Goloubeva OG, et al. Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res. 2005;65:5439-5444.

Massarweh SA, Tham YL, Weis H, et al. A phase II study of anastrozole and fulvestrant in combination with gefitinib in patients with newly diagnosed ER-positive breast cancer [abstract 1050]. Presented at: American Society of Clinical Oncology Meeting; June 1-5, 2007; Chicago, IL.

Mrozek E, Schaaf LJ, Ramaswamy B, et al. Phase II trial of exemestane in combination with fulvestrant in postmenopausal women with hormone responsive advanced breast cancer: no evidence of a pharmacokinetic interaction between exemestane and fulvestrant [abstract 6131]. Presented at: San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX.

Obermiller AM, Copur MS, Bolton M, et al. Letrozole(L)/ Fulvestrant(F) combination in second line or more for estrogen receptor (ER) positive ( ) metastatic breast cancer (MBC): efficacy and predictive factors of response. Submitted to be presented at American Society of Clinical Oncology Meeting; June 2011; Chicago, IL.

Young OE, Renshaw L, Macaskill S, et al. Effects of fulvestrant 750 mg in premenopausal women with estrogen-receptor-positive primary breast cancer. Eur J Cancer. 2008;44:391-399.

Intellectual Property Library. Fulvestrant formulations. US 2009/0227549 A1. September 10, 2009;1-11.

Shravani P, Vinod KR, Teja BB, et al. Designing and characterization of reservoir type transdermal formulation of fulvestrant. Int J Pharm Sci Rev Res. 2010;5:59-63.

Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;Oct 20(28):4594-4600.

Ohno S, Rai Y, Iwata H, et al. Three dose regimens of fulvestrant in postmenopausal Japanese women with advanced breast cancer: results from a double-blind phase II comparative study (FINDER1). Ann Oncol (Epub ahead of print; April 21, 2010).

Pritchard KI, Rolski J, Papai Z, et al. Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2). Breast Cancer Res Treat. 123:453-461.2010.

Although several endocrine therapies are available today, the authors of this commentary contend that the quest for a better tamoxifen is ongoing.

The Longstanding Quest for a Better Endocrine Therapy Continues High-Dose Fulvestrant: Have We Found Its Effective Dose, Combination, Setting, or Sequence?

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with an annual incidence of 12 to 14 per million persons.

 The tumors are found in the stomach (52%), small intestine (25%), colon (11%), esophagus (5%), and rectum (2%), as well as in the omentum, mesentery, and peritoneum.

 The cellular origin of GISTs is thought to be the interstitial cells of Cajal (ICC), the intestinal pacemaker.

 GISTs appear histologically similar to leiomyosarcomas of the GI tract but are positive for the immunohistochemical marker for the KIT protein (CD117).

 The tumors occur in three histologic variants: spindle cell type (70%), epithelial type (20%), and combined spindle cell-epithelial type (10%).

	The characteristic pathologic feature of GISTs is the activating mutations of KIT, which occur in roughly 85% of cases.

 Approximately 5% to 8% of GISTs have mutations of the platelet-derived growth factor receptor alfa (PDGFRα) gene

 and wild-type GIST accounts for the remainder of GIST mutations. The most common KIT mutation is on exon 11 (64%), followed by exon 9 (15%), exon 13 (<2%), and exon 17 (1%).

 The most common PDGFRα mutation is the D842V substitution on exon 18.

 The majority of exon 9 mutations occur in the small bowel and most PDGFRα mutations occur in the stomach. The exon 11 mutations are distributed throughout the GI tract.

	The presenting signs and symptoms of GIST vary from abdominal pain, bloating, or bleeding, to incidental findings on imaging or at the time of surgery. Surgery is the mainstay of treatment for localized GIST. Clinical prognostic variables used to predict recurrence include tumor size, mitotic activity, and location of the tumor within the GI tract; high-risk factors include size >5 cm, >5 mitoses per 50 high-power fields, and location in the small bowel.

 The use of exon mutational analyses as an independent risk factor is under investigation.

	Patients with metastatic or surgically nonresectable disease do not respond to the standard cytotoxic therapy used for sarcomas, and have poor outcomes. With the introduction of imatinib (Gleevec), an oral tyrosine kinase inhibitor (TKI) that selectively targets KIT, ABL, BCR-ABL, and PDGFR, up to 80% of patients experience clinical benefit, with stable or responding disease lasting a median of approximately 20 months.

 Common side effects of imatinib include fluid retention, rash, arthralgias, myalgias, nausea, and fatigue.

	Two large phase III trials compared once-daily imatinib 400 mg to a twice-daily 400 mg regimen in patients with metastatic GIST. These two studies—conducted in the United States and Canada by the Southwest Oncology Group (SWOG)

 and in Europe and Australia (EU-AUS) by the European Organization for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group

—used the same selection criteria for study entry, treatment, and follow-up, the purpose being to later combine data. A total of 743 patients were enrolled in the SWOG trial and were followed for a median of 54 months. The median progression-free survival (PFS) was 18 months on once-daily imatinib and 20 months on the twice-daily imatinib, with median overall survival (OS) of 55 months and 51 months, respectively. There was no statistically significant difference in response rates, PFS, or OS between the two dosages. The EU-AUS enrolled 946 patients and their initial report, with a median follow up of slightly over 25 months, demonstrated a PFS advantage for the twice-daily dosing but no OS advantage. Subsequently, with longer follow up of 40 months, the EU-AUS investigators reported that once-daily and twice-daily dosing resulted in similar PFS and OS.

	Combining the SWOG and EU-AUS data with those from a median follow-up of 45 months, a meta-analysis of 1640 patients showed a small but significant PFS-related difference in patients on the twice-daily regimen as compared to those treated with the standard single dose (estimated hazard ratio [HR], 0.89; 95% CI, 0.79-1.00 but significant [

 = .04, Wald test]). The benefit of the higher dose of imatinib was seen mainly in patients with the KIT exon 9 mutation.

	What then should be the initial dose of imatinib for patients with metastatic GIST? Should patients with the exon 9 mutation be started at a higher dose? Because overall survival is similar with both dosages and because higher doses of imatinib are associated with increased toxicity, it is reasonable to start all patients with metastatic GIST on 400 mg per day. If a tumor has an established exon 9 mutation, and response to therapy is important, an initial higher dose of imatinib should be used.

	Specific treatment options show promise for the rare exon 18 mutation in PDGFRα, D842V, and wildtype GIST, which are more resistant to imatinib.

 Masitinib, for example, is a new TKI with greater in vitro activity and selectivity for the wild-type c-KIT receptor than imatinib. When masitinib was studied in 30 patients with newly diagnosed metastatic GIST, investigators reported a median PFS of 41.3 months and a 3-year OS of 89.9%.

 Side effects included asthenia, diarrhea, edema, nausea, vomiting, and rash. While the study was small, these findings compare favorably to those seen with imatinib. Further study is warranted to evaluate the effects of masitinib for the wild-type subset. In advanced disease, patients with wild-type GIST might benefit from the combination of TKI and cytotoxic chemotherapy.

	For patients whose disease progresses on the standard once-daily 400 mg dose of imatinib, dosing can be increased to 600 mg or 800 mg per day. The median PFS in the SWOG study on crossover to an 800 mg/day dose was 5 months (95% CI, 2-10 months), with a response rate of 3% (95% CI, 1%-7%).

 In the EU-AUS, the response rate was 2%, with a median PFS of 81 days when switching to the 800 mg/day dose.

	After disease progression or intolerance to imatinib at any dose, the next-line FDA-approved agent is sunitinib (Sutent), an oral multi-targeted receptor TKI of KIT, PDGFR, VEGFR-1, VEGFR-2, VEGFR- 3, FLT3, and RET. In the initial study confirming activity of sunitinib, patients with GIST whose disease progressed or who were unable to tolerate imatinib were randomized to sunitinib 50 mg/day (4 weeks on followed by 2 weeks off) or placebo; 312 patients were randomized in a 2:1 ratio.

 The trial was unblinded at the first interim analysis because of the significantly longer time to tumor progression (TTP) in the sunitinib arm (median TTP, 27.3 weeks [95% CI, 16-32] in the sunitinib group vs 6.4 weeks [95% CI, 4.4-10] in those receiving placebo), at which point patients on placebo could cross over to sunitinib. Attempts to modify the 50 mg/day (4 weeks on, 2 weeks off) regimen to a continuous 37.5 mg/day schedule has been shown to be well tolerated and to have similar efficacy.

 The main adverse effects of sunitinib include fatigue, diarrhea, skin darkening, and nausea.

	Other TKIs used in cases of imatinib and sunitinib failure include nilotinib (Tasigna) and sorafenib (Nexavar). Nilotinib is a second-generation TKI with activity against KIT, PDGFR, and BCR-ABL. Despite having similar targets to those of imatinib, nilotinib’s intracellular concentration is 7 to 10 times higher than that of imatinib.

 Nilotinib has clinical activity in patients whose disease has progressed on imatinib or sunitinib, demonstrating a PFS of 12 weeks and a median OS of 34 week.

 Clinically important adverse effects are mild, with grade I to II rash, headache, pruritus, fatigue, diarrhea, nausea, and cytopenias.

	Sorafenib is a multitargeted inhibitor of RAF/MEK/ERK, KIT, VEGFR, and PDGFR, with clinical activity in third- and fourth-line therapy. Sorafenib has demonstrated in vitro potency against GIST tumors with imatinib-resistant secondary mutations involving the KIT activation loop.

 Adverse effects included skin tenderness, hypertension, hypophosphatemia, headache, and fatigue.

	There is scientific rationale to combine TKIs as they have different pathways of resistance; indeed, combining TKIs may render it possible to overcome resistance. In an open-label, phase I dose-escalation study, patients with imatinib-resistant GIST were treated with nilotinib in combination with imatinb with promising results.

 An ongoing, randomized phase II study of nilotinib alone versus nilotinib combined with imatinib in patients whose disease has progressed on a high dose of imatinib should help delineate the role of combination therapy.

	Although standard chemotherapy is not effective against GIST, the combination of imatinib and low-dose doxorubicin has shown activity in imatinib-resistant GIST, especially in wild-type GIST.

 In a phase I/II study, 26 patients with imatinib-resistant GIST were treated with imatinib 400 mg/day and doxorubicin 15-20 mg/m2/weekly x 4 cycles.

 The median overall PFS was 3.3 months (95% CI, 2.1-4.6), but subsequent analysis based on wild-type status revealed a median PFS of 7 months (95% CI, 1.7-12.3) for patients with wild-type GIST and 2.7 months (95% CI, 1.7-3.7; 

= .134) for those without (10 mutant, 6 not assessed).

	Pointing to other potential targets, a preclinical study demonstrated a 58% reduction in tumor volume with the HSP90 inhibitor IPI-504 combined with imatinib.

 A clinical trial of IPI-504 was terminated early due to severe toxicity. A phase III trial (S0502) comparing imatinib alone to imatinib with bevacizumab was closed early due to poor patient accrual. More recently, insulin-like growth factor receptor inhibitors have been shown to be overexpressed in pediatric GIST and in wild-type GIST, and might be a target in that subset of GIST.

 Moreover, the downstream pathways of KIT/PDGFRα, including PI3K, AKT, mTOR, and BRAF, could be targeted in conjunction with imatinib.

	Following tumor response in GIST patients treated with imatinib has provided oncologists who specialize in sarcomas with opportunities to explore new endpoints for response. The use of positron emission tomography (PET) [18F] fluorodeoxyglucose (FDG) has been studied extensively in patients with GIST. Patients with advanced GIST who are treated with imatinib and followed by PETFDG will show decreased PET-FDG uptake (decreased SUVmax) within 24 to 48 hours.

 Studies have suggested that patients with early responses to imatinib demonstrated by PET-FDG have a significantly better PFS, and that this type of imaging will predict those who will respond to imatinib.

 The optimal cut-off of SUVmax and time to obtain PET-FDG is unknown, but a decrease in SUVmax at 2 months is reasonable. It should be noted that Medicare does not cover PET imaging for GIST.

	When computed tomography (CT) is used to follow imatinib-treated GISTs, responding tumors will demonstrate decreased density as measured by CT attenuation coefficient (Hounsfield unit [HU]). Paradoxically, such tumors might also show an increase in size, which is thought to reflect central necrosis and swelling of the tumor. Following GIST tumors by size alone is, therefore, inadequate. Choi and colleagues, from the MD Anderson Cancer Center, proposed a new CT criteria for assessing tumor response of GIST that includes not only size, but also incorporates tumor density changes by HU. To this end, a partial response (PR) would be defined as a decrease in size of >10% or a decrease in tumor density of HU >15% with no new lesions and progression would be defined as an increase in tumor size of >10% with failure to meet PR criteria by tumor density (HU) on CT. The remaining findings would be classified as new lesions, new intratumoral nodules, or increase in the size of the existing intratumoral nodules.

 Confirmation and validation of the Choi criteria is now underway by other research groups. The use of Choi criteria for non-GIST tumors has not been validated and RECIST is still used for non-GIST disease.

	Patients with advanced GIST are generally continued on imatinib therapy indefinitely as long as they are tolerating therapy and their disease is controlled. There are, however, some patients who have been on imatinib for some period of time and want to discontinue and then resume the treatment when their tumor begins to grow. This is analogous to intermittent androgen blockade for men with metastatic hormone-sensitive prostate cancer. A clinical study by the French sarcoma group tested the hypothesis of interruption of imatinib therapy in responding patients in the BFR14 study.

 Patients on imatinib with responding GISTs were randomized to discontinue treatment at 1 and 3 years or to continue on therapy. Those who discontinued therapy had a median PFS of 6 months and the investigators reported no OS difference between the continuous and the interrupted arms. The concern is that interrupted imatinib therapy might decrease the time to imatinib resistance. The time to imatinib resistance was similar in both arms of the study, but it was under-powered to identify a statistically significant difference.

 The recommendations are to continue imatinib long-term until disease progression or the development of untoward adverse effects,

 but periodic interruptions in imatinib therapy could be considered for selected patients who have toxicities from therapy and understand the risks and benefits of interruption of therapy.

	Surgery for metastatic GIST is a valid option at initial presentation and for selected patients whose disease progresses on imatinib. Typically, patients with widespread progressive disease while on imatinib or other agents do not benefit from palliative surgery

; however, if a patient on imatinib has isolated disease progression of one or two lesions or within a lesion (intratumoral progression), surgical resection can be beneficial.

 The theory is that the other sites of metastatic disease are being controlled with imatinib, but isolated tumor resistance can occur in 1 or 2 of the lesions, and removing the resistant clone can allow patients to continue on imatinib while their other sites of GIST remain under control. The use of ablative options should also be considered. Ablative techniques such as cryoablation and radiofrequency ablation in selected tumor progressions can be performed safely and repeatedly.

	Despite surgical resection of primary disease, some patients will develop recurrent disease. With the efficacy of imatinib in advanced disease, it is postulated that adjuvant therapy with imatinib would improve recurrence-free survival (RFS) and overall survival. Beginning in 2002, a randomized, phase III, double-blind, placebo-controlled trial of imatinib in resected GIST was performed in the United States and Canada (American College of Surgeons Oncology Group [ACOSOG] Z9001).

 Patients with tumors that were both >3 cm in size and KIT-positive were randomly assigned to 1 year of once-daily imatinib (400 mg) or placebo. The primary endpoint of the published study was RFS. The study was terminated early because the pre-determined RFS efficacy boundary was crossed. Of the 718 patients randomized at early termination (median follow-up, 19.7 months), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had tumor recurrence, with the use of imatinib significantly improving RFS, as compared to placebo (98% [95% CI, 96-100] vs 83% [78-88]) at 1 year. There was no difference in OS between the groups. Subset analysis post hoc showed recurrencefree benefits in the imatinib group in all tumors based on size >3 cm and <6 cm, >6 cm and <10 cm, and >10 cm, but the major benefit was seen in the >10 cm group.

 Reviewing the recurrence-free curves, it appears that the recurrence-free benefit lasts an additional 6 months after discontinuing imatinib; hence, after 18 months from randomization, the rate of recurrence increases. This 6-month PFS is consistent with the French BFR14 metastatic GIST study, showing a 6-month PFS after discontinuation of imatinib in patients with responsive disease.

	Optimal duration of adjuvant imatinib therapy is being evaluated in 2 studies in Europe. The EORTC is comparing 0 versus 2 years of imatinib and the Scandanavian Sarcoma group (SSG) trial XVIII is comparing 1 versus 3 years of imatinib. The endpoint of both studies is RFS and results will not be available for several years.

	The dose of imatinib for these adjuvant trials is 400 mg/day. Increasing the dose to 400 mg twice daily for exon 9 mutations makes theoretical sense and could be considered, but it is unknown if the higher dose of imatinib in this group is beneficial. In addition, none of the reported studies or trials in progress will be able to confirm if adjuvant imatinib will improve OS in high-risk disease. The most we will be able to confirm is the RFS achieved with imatinib.

	The ACOSOG Z9001 study did not stratify based on exon mutational analysis nor mitotic activity, but subsequent analysis of Z9001 findings incorporating exon mutational analysis and mitotic activity has been reported.

Tumor mitotic rate, size, location, and mutation status were available in 513 of 718 patients. On multivariate analysis of the placebo arm, RFS was worse with high mitotic rate, tumor size, small bowel location, and KIT exon 11 mutation. On multivariate analysis in the imatinib arm, RFS was worse with high mitotic rate, tumor size, and small bowel or rectal location. Patients with the KIT exon 9 mutation had similar RFS. There was no statistical difference in RFS between study arms in patients with wild-type KIT and those with PDGFRα.

	Are there high-risk groups for which prolonged adjuvant imatinib is justified? Based on the available data, patients with large tumors, especially those >10 cm, and tumors with high mitotic rates of >5 mitoses per 50 high power fields [HPF] are at exceptionally high risk of relapse after discontinuation of imatinib, and could be offered prolonged imatinib therapy (for >1 year). The optimal duration of prolonged therapy is unknown and will need to be reviewed in the context of available data and tolerance to therapy, as the use of adjuvant imatinib may only delay recurrence and might have no impact on OS.

Active Phase III Trials for First-Line Therapy

	Currently, there are two major trials in the United States that are open and accruing patients with metastatic GIST for first-line therapy. The first of these trials is sponsored by AB Science (AB1010) and is comparing mastinib to imatinib at 400 mg or 600 mg/day. The other major trial, sponsored by Novartis, is comparing nilotinib to imiatinib. Details on these studies are available at 

	The treatment of GIST has changed dramatically in the past decade. Prior to the use of imatinib, which has prolonged survival, patients with advanced/metastatic disease had a dismal prognosis. After progression on standard dose of imatinib, additional benefit can be anticipated with increased doses. Although higher doses of imatinib, sunitinib, nilotinib, sorafenib, and other agents have clinical benefit, these benefits are short-lived and newer agents are desperately needed. The use of imatinib after curative surgery can prolong RFS and there is hope that a longer duration of adjuvant therapy might improve outcomes. A greater understanding of exon mutations will be useful in helping to direct and tailor therapies in patients with GIST.

Scott H. Okuno, MD, is an associate professor of oncology in the Department of Oncology, Mayo Clinic, in Rochester, Minnesota.

The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Scott H. Okuno, MD, Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN 55905, or e-mail 

Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103(4):821-829.

Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813-3825.

Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastro-intestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Path. 1998;152(5):1259-1269.

Fletcher CDM, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Path. 2002;33(5):459-465.

Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.

Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710.

Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42(8):1093-1103.

In this review article, the author discusses the use of tyrosine kinase inhibitors in the management of patients with gastrointestinal stromal tumors.

Spring 2011 | Special Issues

Partnership for Progress

10 Tips for Making the Most Out of a Child's Visit With a Hospitalized Parent

Dear Kayla and Christopher: A Mom With Breast Cancer Documents Her Battle for Her 2 Young Children

The Longstanding Quest for a Better Endocrine Therapy Continues High-Dose Fulvestrant: Have We Found Its Effective Dose, Combination, Setting, or Sequence?

The Use of Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumors (GIST)

The Clinical and Economic Value of Rituximab for the Treatment of Hematologic Malignancies

From the Editor: A Word of Welcome