TUMOR INIATING CELLS

Tumour-initiating cells

16.10.09

Category: Scientific News

Challenges and opportunities for anticancer drug discovery

The conventional approach for anticancer drug discovery is to target cell proliferation rather than self renewal and/or differentiation, and so is often biased to select targets with homogeneous expression patterns and potent compounds that kill the bulk tumour cells. In addition, some traditional preclinical models may not reflect clinical complexities such as tumour hierarchy. Tumour-initiating cells (popularly known as cancer stem cells) that depend on a niche and developmental pathways involving paracrine or juxtacrine signalling may demand more sophisticated drug discovery platforms than the two-dimensional tissue culture or subcutaneous xenograft models that have traditionally been used to characterize autonomous tumour cells and autocrine signalling in cancer. The large body of evidence in support of the cancer stem cell hypothesis and the related therapeutic strategies require adjustments to anticancer drug discovery platforms to make them more clinically relevant wrote Bin-Bing S Zhou of the Oncology Discovery, Wyeth Research and collaborators in the Abbott Laboratories and The Hospital for Sick Children, Toronto, Canada in an article published in the October 2009 issue of Nature Reviews Drug Discovery.

Many aspects of the aberrant differentiation that is associated with poor prognosis in cancer can be best explained by the cancer stem cell hypothesis. This is underscored by the fact that, in clinical trials for advanced cancers, tumour regression often does not translate into clinically significant increases in patient survival. Efficacy against minimal residual disease, metastasis, delayed relapse and tumour-free survival are expected to correlate with the mechanism-based activity of agents that target tumour-initiating cells.

Given that tumour regression might not be the most relevant early end point, biomarkers for tumour-initiating cells in patients who are receiving cancer therapy need to be developed. However, translating the markers that are used to enrich for tumour-initiating cells into clinical biomarkers is not necessarily straightforward. Circulating tumour cells, although extremely rare, are a potential alternative to invasive biopsies as a source of tumour tissue for the detection, characterization and monitoring of tumour-initiating cells from solid tumours. A microchip technology that is based on microfluidics was shown to be sensitive and able to detect circulating tumour cells in almost all of the examined patients with recurrent carcinomas.
It is also important to study the relevance to tumour-initiating cells of current biomarkers: both PSA and CA125 are expressed in differentiated tumour cells; it is still unclear whether they are surrogate only to a bulk tumour cell population or to a tumour-initiating cell population as well. If genetic (for example, gene amplification) or epigenetic (for example, promoter methylation) changes or multiple changes of related pathways could be used to predict the dependence of a tumour-initiating cell on certain oncogenic pathways, some of the self-renewal signalling molecules could represent an Achilles' Heel of cancer. Inhibitors of these pathways would have considerable antitumour activity alone. In this regard, a diagnostic procedure to prescreen patients with such genetic or epigenetic changes might be essential for drug development.

Among various agents that target self-renewal pathways, small molecules that target the Hedgehog pathway are in early clinical studies, and have shown promising results. The SMO antagonist cyclopamine was shown to lead to rapid regression of basal cell carcinoma in all four patients in which it was tested. In addition, an orally-administered small-molecule antagonist of SMO, GDC-0449, has shown limited toxicity and partial responses in advanced basal cell carcinoma tumours in a phase I clinical trial. It is advancing to phase II trials for metastatic colorectal cancer and other advanced epithelial tumours. The majority of patients with basal cell carcinoma have genetic mutations in Hedgehog pathway mediators; it is unclear whether GDC-0449 will be as effective in other tumour types that do not have such mutations or whether it must be combined with other agents to show clinical activity. This combination approach could be further complicated by the emerging role of Hedgehog signalling in tumour stromal cells. GDC-0449 and other SMO antagonists will therefore provide an interesting test of clinical strategies in targeting renewal signalling.

There are several antibodies against cell surface markers of tumour-initiating cells in clinical studies. EPCAM is highly expressed in numerous solid tumours, and was recently shown to be expressed on tumour-initiating cells from breast, prostate, colon and pancreatic cancer. EPCAM-specific mAbs have shown a limited efficacy in clinical trials, suggesting that immune tolerance or ADCC stimulated by these mAbs by itself might not be effective in killing EPCAM-overexpressing tumour cells in clinical settings. To overcome the limitations of the naked antibodies, catumaxomab was designed to bind to both human EPCAM (the target on the tumour) and human CD3 (the target on T cells), bringing cancer cells into proximity with the immune-system cells that can destroy them. In addition, catumaxomab induces ADCC and is undergoing advanced study in patients with malignant ascites. Conversely, mAbs against CD44 can differentiate tumour-initiating cells and have single-agent activity in certain preclinical models. It remains to be seen whether these mAbs will show single-agent activity in clinical settings or whether they will also need to be coupled with cytotoxic approaches.

Tumours with populations of proliferating progenitor-like cells may take a long time to regress, even if tumour-initiating cells are destroyed. For some cancers, continued although limited proliferation of bulk tumour cells might be sufficient to cause irreversible pathological damage. It is necessary to kill all cancer cells that have the potential to contribute to disease, particularly for cancers with little evidence of hierarchical organizations. Genetic and epigenetic instability could also confound the effectiveness of agents that otherwise efficiently target tumour-initiating cells. It may be important to combine agents that target tumour-initiating cells with conventional agents that reduce the bulk of the tumour, and the optimal manner of combination could depend on the therapeutic window of the agents, the life span of the bulk tumour cells, and the nature and stability of the tumour hierarchy in that particular tumour type.

More work is required to understand how current, partially effective, chemotherapeutic and tumour-targeted agents affect different levels of the tumour hierarchy. Some combination treatment strategies have already emerged from preclinical studies. In the future, combination therapy, including cytotoxic, tumour-targeted drugs and agents that target tumour-initiating cells, may be aimed at tumour-initiating cells, rapidly proliferating tumour cells and their niches — simultaneously or sequentially. It is hoped that this new strategy will result in the rapid removal of all tumour cell subpopulations and avoid the possible repopulation of the tumour mass by tumour-initiating cells or by originally differentiated tumour cells that have regained renewal activity. Although the paths for developing agents that target tumour-initiating cells are not straightforward, the cancer stem cell hypothesis provides an important framework for drug discovery and cancer treatment, with the potential to find novel antitumour activities, to have an impact on cancers with undifferentiated phenotypes and to yield long-term benefits for many patients with cancer.

ANOTHER DOUBLET FAILURE FOR PANCREATIC CANCER

Phase III randomized trial comparing gemcitabine plus cisplatin vs. single-agent gemcitabine in chemotherapy-naive patients with advanced pancreatic cancer

21.10.09

Category: Scientific News

The GIP-1 (Gruppo Italiano Pancreas – GOIM/GISCAD/GOIRC) study

Single-agent gemcitabine remains standard first-line treatment for patients with advanced pancreatic cancer (APC). The Gruppo Italiano Pancreas (GIP)-1 phase III trial compared the combination of gemcitabine and cisplatin vs. gemcitabine alone. Results were presented at the Annual Meeting of American Society of Clinical Oncology held this year in Orlando, USA and during Plenary session of the AIOM 11th National Congress of Medical Oncology, Milan, Italy (10-13 October, 2009) by lead author, Dr Giuseppe Colucci of the Istituto Tumori “Giovanni Paolo II”, Ospedale Oncologico di Bari.

Patients with locally advanced and/or metastatic pancreatic cancer, age 18-75, Karnofsky Performance Status (KPS) ≥50, were randomized to receive gemcitabine (arm A) or gemcitabine + cisplatin (arm B). No maximum number of cycles was planned. Primary endpoint was overall survival (OS). To have 80% power of detecting a 0.74 Hazard Ratio (HR) of death (corresponding to increase in median OS from 4.8 to 6.5 months), with bilateral alpha=0.05, 400 patients were planned and 355 deaths were required. Clinical benefit, objective response rate (ORR), progression-free survival (PFS), toxicity and quality of life were secondary endpoints.

From April 2002 to April 2007, 400 patients were enrolled (A:199, B; 201) in 46 Italian institutions. Median age was 63 years (range 35-75), 59% males, 84% stage IV, 83% KPS ≥80. Median OS was 8.3 vs. 7.2 months in arm A and B, respectively; median PFS 3.9 vs. 3.8 months in arm A and B; and ORR 10.1% in arm A and 12.9% in arm B (none significantly important). Clinical benefit was experienced by 23.0% in arm A and 15.1% in arm B (p=0.057). Combination chemotherapy produced more anaemia (50% vs 39%, G3: 5% vs 1%), more neutropenia (44% vs 36%, G3&4: 25% vs 14%) and more thrombocytopenia (57% vs 29%, G3&4: 16% vs 5%). No relevant differences were seen in non-haematological toxicity.

The authors concluded that weekly combination of gemcitabine and cisplatin as first-line treatment of APC failed to demonstrate any improvement compared to single-agent gemcitabine.

EVEROLIMUS FOR NSCLC

Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors

22.10.09

Category: Scientific News

Researchers found only phospho AKT as a significant independent predictor of worse PFS

Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. Of 14 NSCLC patients treated with either 30 or 70 mg weekly RAD001 in two phase I studies, disease stabilization and partial response (PR) were observed in four patients and one patient, respectively. The most commonly observed adverse events associated with RAD001 are stomatitis, rash, anemia, fatigue, and anorexia. In addition, pneumonitis is also a known side-effect of mTOR inhibitors. Based on these considerations, the phase II study of RAD001 was conducted by multi-institutional group of researchers led by Dr Vassiliki A Papadimitrakopoulou of the Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, USA. They assessed the efficacy of RAD001 monotherapy in advanced NSCLC patients heavily pretreated with systemic therapy.

Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing.

Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum 2. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common ≥ grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS.

The authors published results in the October issue of Annals of Oncology and concluded that RAD001 administered orally at a continuous daily dose of 10 mg was well tolerated and showed modest clinical activity in heavily pretreated patients with advanced-stage NSCLC. Preclinical evidence suggests additive or synergistic interactions of combinations of EFGR and mTOR inhibitors in NSCLC and sensitization of cells to DNA-damaging agents via mTOR inhibition. Based on the activity seen with monotherapy and preclinical results, further clinical evaluations of RAD001 in combination with erlotinib and chemotherapeutic agents for advanced NSCLC have been initiated.

TGF-B AMBIGUOUS ROLE IN CANCER PROGRESSION

LONDON (Reuters) Oct 20 - Scientists who watched tumor cells spread in living mice said on Sunday they had found a gene signal controlling how cancer cells move, which could help companies design new drugs to fight the disease.

Scientists working for Cancer Research UK used hi-tech imaging techniques to watch how breast cancer cells spread in mice. They found that signaling from transforming growth factor (TGF)-beta was crucial to whether cells moved as single entities or in clumps.

TGF-beta signaling is only active in singly moving cells, not in collectively moving cells. And in singly moving cells, the signal is on when they move and off when they stop in a new place to grow, the researchers reported in the journal Nature Cell Biology.

"The results helped us to find the set of genes that are behind the spread of breast cancer -- and that the genes need to be first turned on and then off in order for single cancer cells to be able to relocate," said Dr. Erik Sahai, head of the tumor cell biology lab at Cancer Research UK's London institute.

He said several pharmaceutical firms were investigating how to stop TGF-beta from functioning, but stressed they were "very much in the development phase."

"As yet there is no new drug in the pipeline," Dr. Sahai said, "But because we now know what these cancer cells are actually doing, it gives us lots of new ideas about how to stop them."

A May 2007 paper in the Journal of Clinical Investigation reported that surgery, chemotherapy or radiation raises levels of TGF-beta and could actually cause tumors to spread.

But as yet, relatively little has been known about how cancer cells spread because it is very difficult to track them when they are moving.

"In a medium-sized tumor there could be a billion cells -- and only a small proportion might break away and spread. So it is like trying to find, and understand, a moving needle in a very big haystack," said Dr. Sahai.

He and his colleagues used multiphoton confocal microscopy to track fluorescently labeled breast cancer cells in mice.

When the TGF-beta signal was blocked, the tumor spread via clumps of cells in the lymphatic system -- limiting how far it could go, the researchers said.

But when cells could receive the TGF-beta signal, they moved as single entities. When the TGF-beta signal was first turned on, the cells could spread through the blood. When it was turned off, they could grow again in a new location.

"It seems they can't multitask," said Dr. Sahai. "They can't move and grow at the same time, they can only do one or the other."

Nature Cell Biology 2009.

NOBEL-NOBEL

Between 20% and 40% of lung cancer patients will have bone metastases, Dr. Nikos K. Karamanos, from the University of Patras, and colleagues note. Recent experimental evidence suggests that third generation bisphosphonates can block proliferation and induce apoptosis in a wide range of cancer cells, including those from both small and non-small-cell lung cancers.

The current study, reported in the International Journal of Cancer for October 1, featured 144 patients with stage IV lung cancer and evidence of metastases on bone scan. Of these patients, 87 had bone pain and received zoledronic acid, 4 mg IV every 21 days, while the remaining 57 did not receive the drug. All of the subjects were treated with docetaxel and carboplatin.

The median survival period for zoledronic acid users was 578 days, significantly longer than the 384 days achieved in the comparison group (p <>

The researchers also found that as the number of zoledronic acid treatment cycles increased, so did the survival period and the time to disease progression (p <>

By contrast, zoledronic acid use appeared to have no significant effect on bone pain, the report indicates.

Zoledronic acid use was also associated with a drop in urine levels of N-telo-peptide of type I collagen (NTx), an indicator of bone breakdown. However, this was only seen in patients who had levels no greater than 29 nM BCE/mM creatinine at baseline.

"The addition of bisphosphonates seems to increase overall survival in lung cancer patients with bone metastases, and the prolongation of (bisphosphonate) administration is correlated with longer survival and time to progression," the authors conclude.

"Furthermore, initial NTx to creatinine ratios seem to have a negative correlation with time to progression and patient survival, whereas response to chemotherapy and survival is correlated with lower NTx to creatinine ratio levels."

Int J Cancer 2009;125:1705-1709.

CA-125 LEVEL AFTER ADJUVANT CHEMOTHERAPY AND RISK OF RELAPSE

Gynecol Oncol. 2009 Oct 8. [Epub ahead of print]

Related Articles, LinkOut

Value of serum CA125 levels in patients with high-risk, early stage epithelial ovarian cancer.

Kang WD, Choi HS, Kim SM.

Department of Obstetrics and Gynecology, Chonnam National University Medical School, 8 Hakdong, Dong-gu, Gwangju, Republic of Korea.

OBJECTIVES: The aim of this study was to ascertain whether serum CA125 level is predictive of disease progression in patients with high-risk, early stage (stage IA/B grade 3, stage IC any grade, stage I clear cell, or stage II) epithelial ovarian cancer who have achieved a complete response to chemotherapy. METHODS: Between January 1998 and April 2004, we reviewed the records of 95 patients with high-risk, early stage epithelial ovarian cancer who had elevated CA125 levels at the time of diagnosis and were complete responders after 6 cycles of adjuvant paclitaxel/carboplatin chemotherapy. A receiver operating characteristic curve was used to determine the most useful CA125 level in predicting disease progression and Cox proportional hazards models adjusted for covariates were used for analyses. RESULTS: The 5-year progression-free survival (PFS) was 70.5%. The optimal cutoff point of CA125 after completing adjuvant chemotherapy to predict disease progression was 12 U/mL (sensitivity, 71.4%; specificity, 82.1%). On multivariate analysis, CA125 level>12 U/mL after completing adjuvant chemotherapy was an independent prognostic factor predictive for disease progression. The risk of recurrence was higher for CA125 level>12 U/mL (hazards ratio=10.567; P<0.001).>12 U/mL (P<0.001). CONCLUSIONS: CA125 level after 6 cycles of adjuvant chemotherapy is a strong independent prognostic factor for high-risk, early stage epithelial ovarian cancer after achieving a complete response.

EMPIRICAL ANTIVIRAL TERATMENT FOR PERSON WITH SUSPECTED INFLUENZA

October 20, 2009 — On October 16, the US Centers for Disease Control and Prevention (CDC) issued interim guidelines for chemoprophylaxis and early empiric antiviral treatment in persons with suspected influenza, including 2009 H1N1 influenza infection and seasonal influenza.

The new interim recommendations, which update those from September 22, 2009, aim to assist clinicians during the 2009-2010 influenza season in prioritizing use of antiviral medications for hospitalized patients and those at higher risk for complications from influenza. The CDC notes that the recommendations can be modified as indicated by local epidemiologic data, patterns of antiviral susceptibility, antiviral supply considerations, or observed changes in the clinical presentation or antiviral susceptibility of 2009 H1N1 influenza. These guidelines should be considered interim recommendations and will be updated as needed.

"As of October 3, 2009, 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza (previously referred to as novel influenza A [H1N1])," the guidelines authors write. "Among people who become infected with 2009 H1N1, certain groups appear to be at increased risk of complications and may benefit most from early treatment with antiviral medications. Based on currently available data, approximately 70% of persons hospitalized with 2009 H1N1 influenza have had a recognized high risk condition."

High-risk groups include children younger than 2 years, adults 65 years or older, and pregnant women and those up to 2 weeks after delivery or miscarriage. In addition, persons at high-risk include those with immunosuppression; disorders compromising respiratory tract function or handling of respiratory secretions or increasing risk for aspiration; or chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease), or metabolic diseases (including diabetes mellitus).

Updated Guidelines

Updates since the September 22, 2009, guidelines include the following:

• The guidelines authors elucidate considerations for treatment and chemoprophylaxis in persons vaccinated with the 2009 H1N1 and seasonal influenza vaccines.
• In addition to pregnant women, those up to 2 weeks postpartum or after a miscarriage are now included as being at increased risk for complications from 2009 H1N1 influenza.
• For children younger than 1 year, additional oseltamivir dosing instructions are given.
• Adverse events and contraindications associated with use of oseltamivir and zanamivir are reviewed.

The guidelines note that antiviral medications can decrease the severity and duration of influenza illness and can lower the risk for severe illness, mortality, and other complications. Treatment or prophylaxis with antiviral medications is not necessary for most healthy individuals with an illness consistent with uncomplicated influenza or for those who appear to be recovering from influenza. Severe symptoms, including evidence of lower respiratory tract infection or clinical deterioration, in persons of any age or previous health status presenting with suspected influenza should mandate prompt empiric antiviral therapy.

All persons hospitalized for suspected or confirmed influenza should be treated with oseltamivir or zanamivir. Persons with suspected or confirmed influenza who are at higher risk for complications, described in the fourth paragraph, should be considered for early empiric treatment with oseltamivir or zanamivir.

Compared with older children and adults, children aged 2 to 4 years are more likely to need hospitalization or urgent medical evaluation for influenza. However, the risk is still much lower vs children younger than 2 years, and antiviral treatment is not necessarily needed for children aged 2 to 4 years with mild illness and without high-risk conditions.

When antiviral treatment is indicated, it should be started as soon as possible because maximal benefits ensue when patients begin treatment within the first 2 days of illness, although some studies of patients hospitalized for seasonal and 2009 H1N1 influenza have shown possible benefit of antiviral therapy started later than 48 hours after symptom onset.

Measures to minimize delays in starting treatment may include educating individuals who are at higher risk for influenza complications of the signs and symptoms of influenza and the need for early treatment as soon as possible after onset of influenza symptoms such as fever or respiratory tract symptoms. In addition, these patients and those who report severe illness should have rapid access to telephone consultation and clinical evaluation. Empiric treatment based on telephone contact may be considered for patients at higher risk for influenza complications, if hospitalization is not needed, and if this will result in markedly less delay before treatment is started.

Because a negative rapid test result for influenza does not rule out influenza, treatment should not be delayed pending laboratory confirmation of influenza. Sensitivity of rapid tests ranges from 10% to 70% for detection of 2009 H1N1.

In accordance with guidelines from local and state health departments, real-time reverse transcriptase-polymerase chain reaction testing for 2009 H1N1 influenza infection should be prioritized for individuals with suspected or confirmed influenza requiring hospitalization.

Consideration for antiviral chemoprophylaxis should usually be limited to individuals at greater risk for influenza-related complications who have been exposed to someone likely to have been infected with influenza. After a suspected exposure, however, early treatment may be an option preferred vs chemoprophylaxis.

Those persons at high risk who are household or close contacts of confirmed or suspected influenza cases can be educated regarding the early signs and symptoms, and if these develop, they can be instructed to contact their healthcare provider immediately for evaluation and possible early treatment. When vaccinated persons have a suspected exposure, early recognition of illness and treatment when indicated are preferred vs chemoprophylaxis.

Circulating Viruses

In the 2009-2010 influenza season, the most common influenza viruses among those circulating are likely to be 2009 H1N1 influenza viruses, especially in younger age groups, but circulation of seasonal influenza viruses is also anticipated. These predictions are based on global experience to date, but the timing and intensity of seasonal influenza virus vs 2009 H1N1 circulation may not be accurately predicted in advance.

The 2009 H1N1 viruses now circulating are susceptible to oseltamivir and zanamivir but are resistant to amantadine and rimantadine. Based on new antiviral resistance or viral surveillance data, however, recommended antiviral treatment regimens may change accordingly. The updated guidelines contain information on the dose and dosing schedule for oseltamivir and zanamivir. The emergency use of oseltamivir in children younger than 1 year is reviewed in an April 2009 Emergency Authorization.

PREFER LOW DOSE DEXAMETHASONE FOR MYELOMA

October 22, 2009 — The trial showing that low-dose dexamethasone is superior to high-dose dexamethasone when added to lenalinomide (Revlimid, Celgene) for initial therapy of myeloma was published online October 22 in the Lancet Oncology.

This trial was stopped early when overall survival at 1 year was shown to be significantly better with the low-dose dexamethasone regimen; not surprisingly, the lower dose of this steroid was also associated with less toxicity.

When these results were first presented in 2007, principal investigator Vincent Rajkumar, MD, from the Mayo Clinic in Rochester, Minnesota, called for clinical practice to be changed and for low-dose dexamethasone to replace the use of the high-dose dexamethasone, which had been the standard.

This trial shows clearly that more is not better, Dr. Rajkumar noted. The use of the high dose is not supported by trial data; "it was really something that was picked out of a hat and has been used ever since," he explained.

Other experts in the field concurred, as reported by Medscape Oncology at the time. "This is a landmark trial," said Jean-Luc Harousseau, MD, founding member of the Intergroupe Francophone du Myeloma, who was not involved in the study. "We are seeing long-term results with fewer side effects in patients of all ages. These are the best survival data we have seen in newly diagnosed multiple myeloma."

Now, in the paper detailing the results, Dr. Rajkumar and colleagues state that "the results of this trial show that the use of high-dose dexamethasone is not needed for the most part in the context of new active agents for myeloma and, as a result, almost all current phase 3 trials have adopted low-dose dexamethasone as the standard in combination regimens."

In an accompanying editorial, Antonio Palumbo, MD, and Francesca Gay, MD, from the University of Turin in Italy, write that low-dose dexamethasone plus lenalidomide has "thus been established" as initial therapy for myeloma.

"A prolonged gentle treatment approach with low-dose dexamethasone seems an effective and well tolerated front-line regimen, particularly in elderly patients with myeloma," they write.

However, they add that more randomized phase 3 trials are needed to verify whether low-dose dexamethasone plus lenalinomide can become a new standard of care for patients with myeloma. It needs to be establish whether the optimal therapeutic strategy should be long-term treatment with lenalidomide and steroids or short-term treatment followed by consolidation with autologous transplantation.

Better Short-Term Survival, Less Toxicity

The trial involved 445 patients with untreated symptomatic myeloma, all of whom received lenalidomide 25 mg for 21 days. They also received dexamethasone, but were randomized to either a low dose (40 mg on days 1, 8, 15, and 22 of a 28-day cycle) or high dose (40 mg on days 1–4, 9–12, and 17–20 of a 28-day cycle). Treatment continued for 4 cycles, after which patients could continue or choose to pursue stem-cell transplantation.

The primary end point of the trial was response at 4 months, and this was significantly better in the high-dose group — 79% had a complete or partial response, compared with 68.3% of the low-dose group (P = .008).

However, an interim analysis after 1 year showed significantly better overall survival in the low-dose group, with 96% still alive, compared with 87% in the high-dose group (P = .0002).

As a result of this survival difference, the trial was stopped, and patients on the high-dose regimen were crossed over to the low-dose regimen. The data monitoring committee recommended that the data be made public, and Dr. Rajkumar reported the findings in 2007 at the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology.

"The lack of correlation between response and overall survival has been previously reported in myeloma," the researchers note.

Not surprisingly, lower doses of the steroid had less toxicity. During the first 4 months, 1 of the 220 patients in the low-dose group died, compared with 12 of the 222 patients in the high-dose group (P = .003).

Grade 3 or worse toxic effects were reported by 35% of patients in the low-dose group and by 52% of those in the high-dose group (P = .0001). The most common of these were deep vein thrombosis (26% in the low-dose group vs 12% in the high-dose group; P = .0003), infections, including pneumonia (16% vs 9%; P = .04), and fatigue (15% vs 9%; P = .08).

What Happens Next?

The editorial points out that at 3 years, there was no difference in survival between the 2 groups.

However, when patients completed 4 months of the trial, they could opt for 1 of several different treatment options, and each of these was associated with a different survival rate. When the researchers conducted a landmark analysis at 4 months on the 431 patients who were still alive, they found that:

• Patients who stopped treatment at 4 months and underwent stem cell transplantation, as recommended by the trial protocol (n = 90), had a 3-year overall survival rate of 92%;
• Patients who continued on primary therapy beyond 4 months (n = 248) had a 3-year survival rate of 79%;
• Patients who discontinued treatment at 4 months and did not pursue transplantation (n = 93) had a 3-year survival rate of 55%.

"Results of the landmark analysis suggest that short-term treatment cannot be considered an optimal option unless followed by autologous transplantation," the editorialists write. These results emphasize "the importance of transplantation as a therapeutic strategy, even in the era of new agents," they add.

The funding for this study came from the US National Cancer Institute. Dr. Rajkumar has disclosed no relevant financial relationships, but some of his coauthors reported links with Celgene (the manufacturer of lenalidomide) and other companies; full details can be found in the paper. Dr. Palumbo reports receiving honoraria from Celgene, Jansen-Cilag, and Pharmion. Dr. Gay has disclosed no relevant financial relationships.

Lancet Oncol. Published online October 22, 2009.

RENAL COLIC AND DIETARY RECOMMENDATIONS

Patients with renal colic account for nearly 1 million visits to emergency departments (EDs) in the United States annually.^[1-3] According to 1 study, the estimated lifetime risk of developing a kidney stone is approximately 12% for white men.^[2,3] Approximately 50% of patients with previous urinary calculi have a recurrence within 10 years.^[4]

Calcium oxalate stones are the most common stone encountered by practicing emergency physicians.^[5] Discharge instructions for patients who are stable for outpatient treatment often include discussion of hydration and pain control, along with medications to potentially facilitate passage of the stone.

The optimal diet for patients able to be safely discharged from the ED may not be commonly discussed with patients, but it has the potential to affect recurrence of renal calculi and return visits to the ED.

Because calcium oxalate is the most common component of kidney stones, an increase in urinary oxalate increases the risk for calcium oxalate concentration and subsequent stone formation to a greater degree than urinary calcium. Urinary oxalate is derived from 2 separate sources: endogenous synthesis and diet. The foods highest in oxalate content are spinach, rhubarb, beets, chocolate, nuts, concentrated brans, legumes, soy, tea, sesame seeds, parsley, and berries. Avoidance of these foods with promotion of adequate hydration may help to reduce recurrent stone formation.^[6]

Additional research also suggests that reducing dietary sodium intake may have a role in preventing incident kidney stones.^[7] High amounts of salt intake combined with inadequate hydration increase risk for stone formation.

Consumption of calcium-rich foods (ie, dairy products) in moderate amounts helps to bind oxalic acid, further reducing oxalate absorption, a known factor in calcium oxalate stone formation.^[7] This recommendation, however, does not apply to individuals who absorb excess dietary calcium from the intestine. In those cases, restricting calcium intake is useful.

Recommendations to consume generous amounts of water (2.5- 3 L daily) as a preventative measure have been advocated for patients in whom kidney stones form. Multiple studies recommend patients to maintain urine output > 1 L/day to reduce the recurrence of renal colic.^[8]

Interestingly, and contrary to popular belief, multiple observational studies have found that consumption of coffee, tea, beer, and wine in moderation are associated with a reduced risk for stone formation.^[9,10]

Although previous data and observational studies have suggested an increased risk for stone formation associated with soda consumption, after adjusting for other diet-related issues, soda consumption (caffeine-free soda, diet soda, and regular soda) was not associated with an increased risk for stone formation as described in 2 studies.^[9,10]

Additional studies have also demonstrated that consumption of orange juice as well as lemonade can increase urinary citrate concentrations and pH, thereby reducing risk for stone formation.^[11]

Based on a recent study, orange juice is preferred over lemonade and cranberry juice due to greater alkalinizing potential and ability to increase urinary citrate excretion, resulting in greater stone solubility.^[11]

An alternative intervention for patients who suffer from recurrent calcium stones is the addition of potassium citrate as a dietary supplement. Potassium citrate prevents recurrent calcium kidney stones by increasing urinary pH, which enhances urinary citrate excretion; high urinary citrate concentrations increase the solubility of stone-forming salts.^[12]

Conclusions

Dietary oxalate contributes up to 50% of urinary oxalate for typical diets. Dietary restriction of oxalates is effective in reducing urinary oxalate and consequently stone recurrence in most patients in whom kidney stones form.

Simultaneous consumption of calcium-rich foods in moderate amounts further reduces oxalate absorption from oxalate-containing foods.

Reduction in dietary salt intake and careful attention to adequate hydration to ensure urine output > 1 L/day are also critical to reduce recurrence of calcium stones.

The addition of 1 serving of daily citrus juice (orange juice preferred over lemonade), or the use of potassium citrate as a supplement, may also help to reduce stone recurrence in patients who have recurrent kidney stones.

IT BECOMES BORING

October 21, 2009 — The US Food and Drug Administration (FDA) has approved pazopanib tablets (Votrient, GlaxoSmithKline) for the treatment of patients with advanced renal cell carcinoma.

Pazopanib is the sixth drug to be approved for the treatment of kidney cancer since 2005. This year, about 49,000 people have been diagnosed with the disease, and 11,000 have died, FDA officials said in a news release.

"The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness," noted Richard Pazdur, MD, director, Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. Newly approved drugs include sorafenib, sunitinib, temsirolimus, everolimus, and bevacizumab.

FDA approval of pazopanib was based on data from a randomized, double-blind multicenter phase 3 study (n = 435), showing that its use significantly increased progression-free survival relative to placebo (9.2 months vs 4.2 months; P < .001).

The recommended dose of pazopanib is 800 mg taken once daily at least 1 hour before or 2 hours after a meal. Dose reductions to 400 mg are indicated for patients requiring concomitant treatment with strong cytochrome P 450 isoenzyme 3A4 (CYP 3A4) inhibitors; coadministration of strong CYP 3A4 inducers should be avoided.

Adverse events reported in 20% or more of patients receiving pazopanib include diarrhea, hypertension, hair depigmentation, nausea, anorexia, and vomiting.

Increases in serum transaminase and bilirubin levels were also observed, in some cases leading to severe and fatal hepatotoxicity. Liver chemistries should be measured at baseline and regularly during treatment with pazopanib. Dosing reductions are indicated for patients with moderate hepatic impairment; pazopanib is not recommended for patients with severe liver dysfunction.

Caution is advised when treating patients at increased risk for QT interval prolongation; monitoring electrocardiograms and electrolytes should be considered.

Because of the risk for potentially fatal hemorrhagic events, pazopanib should not be used in patients with a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months.

Blood pressure should be well-controlled before initiating treatment with pazopanib, and patients should be monitored for hypertension and treated as needed.

Pazopanib can cause fetal harm and should not be used in pregnancy, the FDA said.

LETROZOLE AND BEVACIZUMAB FOR BREAST CANCER

: J Clin Oncol. 2009 Oct 19. [Epub ahead of print]

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Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer.

Traina TA, Rugo HS, Caravelli JF, Patil S, Yeh B, Melisko ME, Park JW, Geneus S, Paulson M, Grothusen J, Seidman AD, Fornier M, Lake D, Dang C, Robson M, Theodoulou M, Flombaum CD, Norton L, Hudis CA, Dickler MN.

Breast Cancer Medicine Service and the Departments of Radiology, Biostatistics, and Renal Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and University of California San Francisco Comprehensive Cancer Center, San Francisco, CA.

PURPOSE: Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor-positive metastatic breast cancer (MBC). METHODS: Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. RESULTS: Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease >/= 24 weeks was noted in 67%. Median PFS was 17.1 months. CONCLUSION: Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

TRASTUZUMAB FOR ENDOMETRIAL CANCER

Gynecol Oncol. 2009 Oct 17. [Epub ahead of print]

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Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: A Gynecologic Oncology Group study.

Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, Berek JS, Chapman JA, Disilvestro PA, Horowitz IR, Fiorica JV.

University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA.

PURPOSE: This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification. PATIENTS AND METHODS: Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response. RESULTS: Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). class="yshortcuts" id="lw_1256334090_16">Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

NEW STANDARD PROTOCOL FOR CHOROID PLEXUS TUMORS

October 22, 2009 — A new standard protocol appears to improve survival in children with rare choroid plexus tumors, according to research presented at the 41st Annual Meeting of the International Society of Pediatric Oncology (SIOP).

The interim findings suggest that the protocol, which consists of combination chemotherapy and in some cases radiation, improves survival nearly 2-fold.

The Choroid Plexus Tumor (CPT)-SIOP-2000 study began 10 years ago. It has grown to include over 100 institutions from more than 20 countries, and is the largest collaborative study to date that addresses treatment of choroid plexus tumors. "The whole international community has come together to help these children," said lead author Johannes Wolff, MD, head of pediatric neuro-oncology at the Children's Cancer Hospital, University of Texas MD Anderson Cancer Center in Houston.

No Standard Treatment, Algorithm Developed

Because of the rarity of this tumor, there is no standard treatment protocol other than surgical resection. Choroid plexus tumors originate in the choroid plexus epithelium and are typically located in the ventricles. Although they account for only 1% to 4% of all pediatric brain tumors, they represent 13% of tumors that occur in the first year of life, the authors note. Choroid plexus tumors are the most frequent brain tumor diagnosed at birth, and the majority of children are younger than 3 years at the time of diagnosis.

According to the World Health Organization classification, there are 3 histological tumor grades: choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP), and choroid plexus carcinoma (CPC). As far as prognostic features and clinical outcomes, APPs are in an intermediate position between CPP and CPC. However, Dr. Wolff explained, the grades can be misleading because tumors can progress to higher grades and metastases can occur in all histological grades.

The protocol was drawn from an algorithm that was developed by Dr. Wolff and colleagues and from clinical research. A total of 155 patients were registered between January 2000 and January 2009, and the interim analysis presented at the meeting reported on data for 101 children.

All of the patients had undergone a surgical resection, and the study design divided participants into an observation group and a treatment group who received further therapy. "We used the algorithm to decide who needed immediate treatment and who didn't," Dr. Wolff told Medscape Oncology. "Patients in the observation group were at lower risk and they were closely followed for disease progression."

Study Groups

Observation Group	Treatment Group
CPP without metastases APP without residual tumor and without metastases	CPP with metastases APP with residual tumor or metastases All cases of CPC

All patients in the treatment group received etoposide and vincristine, which was combined with either carboplatin or cyclophosphamide. Risk-adapted radiotherapy was only administered to patients older than 3 years. A total of 44 patients were treated and, of those, 41% received radiotherapy.

"The overall response rate was more than 50% after 2 cycles of chemotherapy and more than 80% after 6 cycles," said Dr. Wolff. "That is the main message from our study — chemotherapy is effective in shrinking these tumors."

As of January 2009, 16 of 101 patients experienced a relapse; 75% had a local relapse (6 patients with local and 6 patients with local and distant), and 58% had a distant relapse (4 patients).

Interim Survival Data

Survival	Observation Group (n = 57)	Treatment Group (n = 44)
Overall	57 censored	35 censored
Event-Free	53 censored	31 censored

Patients who received radiation therapy also did better, Dr. Wolff explained. When evaluating the impact of histology on survival, patients with CPC had the poorest overall and event-free survival.

As for the 2 different chemotherapy regimens, there are no data on which is more effective. "We don't have the final answer for that, but the preliminary result looks like there will be no difference," said Dr. Wolff.

Toxicity was fairly mild, he added. There was some grade 3 and 4 leukopenia after the second chemotherapy cycle, but the incidence of serious infections and mucositis was low.

Dr. Wolff pointed out that "we know that chemotherapy works and radiation helps," but there are still unresolved challenges, such as what to do with young children with metastatic tumors. Another challenge is that although radiation improves the prognosis, most patients with this type of tumor are too young.

Moving Into the Future

The next phase of the trial, CPT-SIOP-2009, will develop a new study structure to evaluate the whole field of possible chemotherapy. Although the current study established that these tumors are sensitive to combinations of etoposide, vincristine, carboplatin, and cyclophosphamide, information about other protocols is lacking, he explained.

Patients will receive 1 of 4 chemotherapy combination regimens, using drugs that are already approved, that have demonstrated success in treating other types of pediatric tumors, and for which toxicity in infants is known. In addition, said Dr. Wolff, intrathecal chemotherapy with etoposide will be given to certain subgroups.

"This will be a randomized, 4-armed, open-label, multicenter study, with a safety review component, designed to find the best treatment protocol for patients of any age with newly diagnosed choroid plexus tumors," he said.

In the international community, there has been great interest in CPT-SIOP-2009, which will require 190 patients to be enrolled for 5 years. "We have received letters of intent from 35 nations, and the estimated number of patients will be more than enough," he said.

Looking further ahead to CPT-SIOP-2014, Dr. Wolff explained that, by then, the final results of CPT-SIOP-2000 will be available, although they are expected to be similar the interim results that were presented at the meeting. Preliminary results of CPT-SIOP-2009 are also expected at that time.

The study was funded through the German Children's Cancer Foundation.

41st Annual Meeting of the International Society of Pediatric Oncology: Abstract O.156. Presented October 9, 2009

JAK KINASE INHIBITORS FOR RHEUMATOID ARTHRITIS

October 22, 2009 (Philadelphia, Pennsylvania) — An investigational oral Janus kinase (JAK) inhibitor achieved significant responses in patients with active rheumatoid arthritis (RA) when used alone or in combination with methotrexate, according to preliminary clinical trials reported here at American College of Rheumatology (ACR) 2009.

Based on these positive results, the drug will be moved forward to phase 3 trials, researchers announced. Both studies were sponsored by Pfizer.

Molecule CP 690,550 "is truly unique as a biologic agent targeted to a specific molecule — the JAK — which activates the cell nucleus to produce multiple cytokines and proinflammatory factors implicated in inflammation and in RA. It is also an oral targeted agent," said Joel M. Kremer, MD, Pfaff Family Professor of Medicine at Albany Medical College in New York, and lead author of 1 of 2 phase 2b trials presented at the meeting. The anti-tumor necrosis factor drugs currently on the market for the treatment of RA are injectable.

The first study, a 24-week double-blind placebo-controlled trial, was an evaluation of 384 patients with active RA who failed on background methotrexate and had longstanding disease. Results were reported by R.M. Fleischmann, MD, from the Metroplex Clinical Research Center in Dallas, Texas.

Patients were randomized to 1 of 5 different doses of CP 690,550 (1 mg, 3 mg, 5 mg, 10 mg, or 15 mg twice daily) or placebo. Methotrexate therapy was discontinued during this 24-week study.

Patients who received a 5, 10, or 15 mg twice-daily dose of the JAK inhibitor without background methotrexate experienced significant improvements in ACR response rates and Disease Activity Score (DAS) 28 remission rates at week 24, compared with the placebo group.

At 24 weeks, the percentage of patients who achieved at least a 20% improvement according to the ACR definition (ACR20) with JAK inhibitor monotherapy were 51% (P ≤ .05), 65.6% (P ≤ .0001), and 66.7% (P ≤ .0001) for a 5, 10, or 15 mg twice-daily dose, respectively, compared with 25.4% for the placebo group.

The percentage of patients with at least a 50% improvement (ACR50) was 34.7% (P ≤ .05), 44.3% (P ≤ .0001), and 54.4% (P ≤ .0001), respectively, compared with 10.2% for the placebo group.

The percentage of those who achieved at least a 70% improvement ( ACR70) was 20.4% (P ≤ .05), 37.7% (P ≤ .0001), and 33.3% (P ≤ .01) for a 5, 10, or 15 mg twice-daily dose, respectively, compared with 6.8% for the placebo group.

Remission, as measured by DAS28, was observed in 14.6% of those receiving the 5 mg twice-daily dose (P ≤ .05), 21.3% of those receiving the 10 mg twice-daily dose (P ≤ .01), and 21.1% of those receiving the 15 mg twice-daily dose (P ≤ .01), compared with 1.8% for the placebo group.

A second 24-week double-blind placebo-controlled study of CP 690,550 involved 507 patients with active RA despite ongoing treatment with methotrexate. In this study, patients remained on stable background methotrexate therapy, and the JAK inhibitor was added in 1 of 6 doses (1, 3, 5, 10, or 20 mg once daily; or 15 mg twice a day) or placebo.

Clinical responses occurred for all 6 doses of the JAK inhibitor, but the 5, 10, and 20 mg once-daily doses and the 15 mg twice-daily dose achieved significant ACR response rates and DAS28 remission rates compared with placebo; results were consistent with those in the monotherapy study.

"This is a promising treatment for patients with RA. Like all new agents in development, we will need to determine the longer-term safety and efficacy, as well as the dose that might eventually be used in the clinic," Dr. Kremer said. Pfizer plans to go forward with 5 and 10 mg twice-daily doses in its phase 3 investigation.

In both studies, the most common treatment-emergent adverse events were urinary tract infection, headache, and diarrhea. Most adverse events were mild or moderate in severity. Serious adverse events leading to discontinuation were infrequent. Adverse effects for CP 690,550 were consistent with those reported in other studies of RA patients, and included dose-dependent decreases in mean neutrophil counts and increases in serum cholesterol levels. For patients receiving background methotrexate, increased transaminase levels were consistent with those in previous RA studies.

Based on these studies, Dr. Kremer thinks that the 5 and 10 mg twice-daily doses will be moving forward in the phase 3 development program. He said that the 15 mg twice-daily dose is associated with elevated transaminase levels and the 20 mg once-daily dose is not as effective as the 5 or 10 mg twice-daily doses.

Exciting Approach

"This new JAK inhibitor should be considered a major advance in the treatment of RA," said Eric Matteson, MD, chair of rheumatology at the Mayo Clinic in Rochester, Minnesota.

"JAK is 1 piece of the puzzle of this polygenic and polymorphic disease process," he explained,

Dr. Matteson said that having an oral targeted agent for the treatment of RA would be a practical advantage for patients and physicians, but he cautioned that a drug targeted to a specific disease mechanism can result in unwanted effects on the immune response. Further study is needed to characterize the dosing and the safety of this new drug.

"This is a potentially exciting approach. We hope it will provide additional efficacy along with convenience of administration. It will probably be used in combination with other drugs," he said.

The studies were sponsored by Pfizer. Dr. Fleischmann reports financial ties with Abbott, Amgen, Wyeth, Celgene, Centocor, Roche, Genentech, Pfizer, Lilly, UCB, Regeneron, Array, Lexicon, and GlaxoSmithKline. Dr. Kremer reports financial ties with Abbott, Amgen, BMS, Centocor, Genentech, Pfizer, and UCB. Dr. Matteson reports financial ties with Amgen, Wyeth, Centocor, UCB, Genentech, and Pfizer, but reports no JAK-specific disclosures.

American College of Rheumatology (ACR) 2009: Abstracts 1924 and 1925. Presented October 20, 2009.

HOW TO MAKE A SOUP

Acta Oncol. 2009 Oct 20. [Epub ahead of print]

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A dose escalation study of docetaxel plus capecitabine in combination with oxaliplatin in patients with advanced solid tumors.

Amarantidis K, Xenidis N, Chelis L, Chiotis A, Tentes A, Chatzaki E, Kortsaris A, Polychronidis A, Karakitsos P, Kakolyris S.

Department of Medical Oncology, University General Hospital of Alexandroupolis, Greece.

Abstract Objectives. Capecitabine (CAP), Oxaliplatin (OX) and Docetaxel (DOC) have shown considerable activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of their combination in patients with advanced solid tumors. Patients and methods. Twenty-one patients were enrolled. The patient's median age was 68 years, 15 were male, and 12 were chemo-naïve. DOC was administered on day 1 as an 1-hour (iv) infusion at a standard dose of 50 mg/m(2). OX was administered on day 1 as a 2-hour (iv) infusion at escalating doses ranging from 70-80 mg/m(2). CAP was administered orally on days 1 to 7 at escalating doses ranging from 2 000-2 750 mg/m(2) given as two daily divided doses. Treatment was repeated every two weeks. Results. Six different dose-levels were examined. At dose-level VI, two of three enrolled patients presented DLTs (one patient diarrhea and asthenia grade 3 and another grade 3 diarrhea), and thus, the recommended MTD for future phase II studies is CAP 2 750 mg/m(2) , DOC 50 mg/m(2) and OX 75 mg/m(2). A total of 121 treatment cycles were administered. Grade 3 neutropenia was observed in six (5%) treatment cycles and grade 3 thrombocytopenia in one (1%). There was no febrile episode. Grade 3 asthenia was observed in three (14%) patients, grade 3 diarrhea in four (19%), grade 3 neuropathy in one (5%), and grade 1/2 hand-foot syndrome in three (14%). Other toxicities were uncommon. There was no treatment related death. Four (29%) PRs and seven (50%) SD were observed among 14 evaluable patients. Responses were seen in patients with renal (n = 1), gastric (n = 2) and pancreatic (n = 1) cancer. Conclusions. These results demonstrate that CAP, DOC and OX can be safely combined at clinically relevant doses and this regimen merits further evaluation.

GEMCITABINE BETTAR TAHN MITOMYCIN FOR BLADDER CANCER

J Clin Oncol. 2009 Oct 19. [Epub ahead of print]

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Randomized Phase III Trial on Gemcitabine Versus Mytomicin in Recurrent Superficial Bladder Cancer: Evaluation of Efficacy and Tolerance.

Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S.

Oncologica Operative Unit "S. Giovanni di Dio" Hospital, ASL Napoli3 Frattaminore; Department of Biochemistry and Biophysics, Second University of Naples, Via Costantinopoli; Unit of Urology, "Santa Maria La Pietà" Hospital, Casoria, Naples; and the Campus Biomedico University, Section of Oncology, Rome, Italy.

PURPOSE: Approximately 30% to 40% patients with a superficial bladder cancer treated with Bacille Calmette-Guerin (BCG) or epirubicin do not respond; of the initial responders, 35% have a relapse within 5 years. We compare the therapeutic efficacy and toxicity of intravescical infusions of gemcitabine (GEM) with mitomycin (MMC) in patients with a recurrent superficial bladder cancer. PATIENTS AND METHODS: Patients with a history of a previously treated, recurrent Ta-T1, G1-G3 bladder transitional cell carcinoma were enrolled in the study. The patients received a 6-week course of GEM infusions or 4-week course of MMC. In both arms, for the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during the first year. RESULTS: A total of 120 patients were enrolled and randomly assigned to either the MMC or GEM treatment arm. At the end of the study, 109 patients (55 in MMC and 54 in GEM) were assessable. The median duration of follow-up was 36 months for either arm. In the GEM arm, 39 (72%) of 54 patients remained free of recurrence versus 33 (61%) of 55 in MMC arm. Among patients with recurrences, 10 in the MMC arm and six in the GEM arm also had a progressive disease by stage. The incidence of chemical cystitis in the MMC arm was statistically higher than in the GEM arm (P = .012). CONCLUSION: This study demonstrates that GEM has better efficacy and lower toxicity than MMC; therefore, GEM appears as a logical candidate for intrabladder therapy in patients with refractory transitional cancer.

CISPLATIN MONOTHERAPY FOR HEPATOBLASTOMA

October 21, 2009 — In the treatment of the rare childhood disease of hepatoblastoma, a simple monotherapy with cisplatin is not inferior to a combination of cisplatin and doxorubicin in patients with "standard-risk" disease, according to the results of a new randomized trial of 255 children published in the October 22 issue of the New England Journal of Medicine.

The children receiving cisplatin had rates of complete resection and survival similar to those in children receiving the combination adjuvant therapy, according to the international group of authors, led by Giorgio Perilongo, MD, from the University Hospital of Padua in Italy.

"We recommend the use of cisplatin alone for all standard-risk hepatoblastoma," Dr. Perilongo told Medscape Oncology.

The rate of complete resection, which was the trial's primary end point, was 95% in the cisplatin-monotherapy group and 93% in the cisplatin–doxorubicin group.

Three-year event-free survival and overall survival were, respectively, 83% and 95% in the monotherapy group and 85% and 93% in the cisplatin–doxorubicin group. The children were followed for a median of 46 months.

The similar event-free and overall survival rates "bode well for the definitive cure of children with standard-risk hepatoblastoma," write the investigators of the trial, known as International Childhood Liver Tumour Strategy Group 3 (SIOPEL 3).

Predictably, the monotherapy was also less toxic. Acute grade 3 or 4 events, including febrile neutropenia, were much more frequent in the cisplatin–doxorubicin group than in the monotherapy group (74.4% vs 20.6%).

However, Dr. Perilongo and his colleagues noted that strategies consisting of primary surgery and adjuvant multiagent cisplatin-based chemotherapy have resulted in "excellent outcomes" in children with limited extension hepatoblastoma. Differences in risk stratification between these various studies did not allow the investigators from making direct comparisons, they explain.

The current study did not include any children with high-risk disease. These patients are more difficult to treat and are part of the future challenges in hepatoblastoma, said Dr. Perilongo.

"The next steps in hepatoblastoma research are to refine our risk stratification in order to further reduce therapy, improve the cure of children with high-risk hepatoblastoma, and develop a biological drive therapeutic approach based on new agents," he said.

Building on Past Studies

SIOPEL 3 is an outgrowth of the findings of the group's 2 earlier trials. In SIOPEL 1, the investigators administered cisplatin–doxorubicin and identified 2 pretreatment prognostic factors: intrahepatic tumor extension and lung metastases. Based on these findings, they established pretreatment risk groups: standard risk (tumor confined to the liver and not more than 3 hepatic sectors) and high risk (tumors involving the entire liver and beyond).

In SIOPEL 2, which was a pilot study for the current trial, the researchers tried cisplatin monotherapy for the first time, using insight from another trial (J Clin Oncol. 2000;18:2665-2675) that showed a multiagent antracycline-free regimen was just as effective as cisplatin–doxorubicin but with no cardiotoxicity.

In the new study, tumor extension was graded using the pretreatment tumor extension system (PRETEXT). Only standard-risk patients (those with PRETEXT grades I–III) were eligible, and all children had to be younger than 16 years.

Between 1998 and 2006, 126 children were assigned to cisplatin monotherapy (every 14 days) and 129 to cisplatin–doxorubicin (every 21 days). The median number of cycles of preoperative chemotherapy was 4 in both groups. The children were resected on the basis of tumor response and then administered postoperative chemotherapy (both groups had a median of 2 cycles).

The rate of complete resection was chosen as the primary end point for a number of reasons, including the fact that it is the "single most important prognostic factor for long-term survival and event free-survival" in these patients, say the authors.

Not Quite Enough Patients

The authors noted that, in this noninferiority design, they could not statistically prove their conclusion that the 2 regimens were comparable. The reason was the limited number of patients; still, the similar rates of event-free survival and overall survival "provide support" for the noninferiority of cisplatin monotherapy, they argue.

In terms of negative outcomes, 19 patients in the monotherapy group (15%) and 15 in the cisplatin–doxorubicin group (12%) had disease progression or relapse. Seven children in the monotherapy group and 8 in the cisplatin–doxorubicin group died.

Some hearing loss was documented in about a third of all patients tested (53 of 168); however, there was no difference between the 2 groups.

With regard to cardiotoxicity, the investigators said that the small number of affected patients required "longer follow-up" to accurately assess any impairments.

Importantly, during the trial, the protocol was amended and children with alpha-fetoprotein levels of less than 100 ng/mL were excluded because of "mounting evidence of a poor outcome in these patients," write the authors.

The researchers have disclosed no relevant financial relationships.

New Engl J Med. 2009;361:1662-1670.

IDARUBICIN MAYBE BETTER FOR AML

J Clin Oncol. 2009 Oct 13. [Epub ahead of print]

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Daunorubicin Versus Mitoxantrone Versus Idarubicin as Induction and Consolidation Chemotherapy for Adults With Acute Myeloid Leukemia: The EORTC and GIMEMA Groups Study AML-10.

Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, Muus P, Marmont F, Marie JP, Labar B, Thomas X, Di Raimondo F, Willemze R, Liso V, Ferrara F, Baila L, Fazi P, Zittoun R, Amadori S, de Witte T.

Department of Cellular Biotechnologies and Hematology, "Sapienza" University; Department of Hematology, National Cancer Institute "Regina Elena"; Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, GIMEMA Foundation; Department of Hematology, "Tor Vergata" University Hospital, Rome; Department of Medical Sciences, "Regina Apostolorum" Hospital, Albano Laziale; Department of Hematology "Le Molinette", "S.G. Battista" Hospital, Turin; Department of Hematology, "Ferrarotto" Hospital, Catania; Department of Hematology, University Hospital, Bari; Department of Hematology, "A. Cardarelli" Hospital, Napoli, Italy; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Department of Hematology, Radboud University Medical Center, Nijmegen; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands; Department of Hematology, Hotel-Dieu, Paris; Department of Hematology, "Edouard Herriot" Hospital, Lyon, France; and Institute of Hematology, University Hospital Centre Rebro, Zagreb, Croatia.

PURPOSE: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. RESULTS: The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well: the 5-year overall survival rates were 34%, 34%, and 31%, respectively. CONCLUSION: In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.