EUROPEAN GUIDELINES FOR MIGRAINE ACUTE TREATMENT

October 1, 2009 — Oral non-steroidal anti-inflammatory drugs and triptans, preceded by antiemetics such as metoclopramide or domperidone, are now advised for the acute treatment of migraine under updated treatment guidelines just published by a task force of the European Federation of Neurological Societies.

Dr. Stefan Evers of the University of Munster, Germany, and colleagues reported the guidelines in the September issue of the European Journal of Neurology.

Evers told Reuters Health by e-mail that in addition to the recommendation noted above, the guidelines, last revised in 2006, include only relatively minor changes:

--Zolmitriptan tablet and nasal spray and rizatriptan tablets were determined to be effective in children and adolescents.

--Topiramate is recommended for prophylactic treatment of chronic migraine.

--Botulinum toxin A is not considered effective in episodic migraine.

He noted that in contrast to common practice in the United States, in Europe, typically "antidepressants are not recommended as first choice in the prophylaxis of migraine."

Dr. Stephen D. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, Philadelphia, defended the use of antidepressants for migraine, telling Reuters Health by phone that "Evidence for the tricyclic antidepressants is quite good."

He also said that this difference in the European and U.S. approaches to treatment rests partly on differing definitions of what constitutes migraine. Silberstein said that he hopes to one day see a unified, worldwide set of guidelines for drug treatment of migraine.

The new guidelines were developed through a review of the relevant literature in English, French or German as of the end of 2008. Task force members had to agree unanimously on all recommendations.

Although doctors often give antiemetics before analgesics, to prevent vomiting and increase resorption, the report noted that no prospective, randomized, placebo-controlled studies have yet proved that this practice accomplishes its goal. The authors added that there is no evidence that combining an antiemetic with an analgesic increases the analgesic's effectiveness.

For very severe migraine attacks, the guidelines recommend intravenous acetylsalicylic acid or subcutaneous sumatriptan as the drugs of first choice. Status migrainosus, in which migraine lasts almost without interruption for more than 72 hours, "can be treated by corticosteroids, although this is not universally held to be helpful, or dihydroergotamine," according to the recommendations.

For migraine prophylaxis, beta-blockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are the drugs of first choice.

The guidelines also include recommendations for specific situations, such as emergencies, menstrual migraines, migraine in pregnancy, and migraine in children and adolescents.

Eur J Neurol. 2009;16:968-981.

HERPES ZOSTER AND STROKE RISK

October 8, 2009 — A new epidemiological study suggests that the risk for stroke, both ischemic and hemorrhagic, is increased by 30% after a herpes zoster attack. The risk is even higher, about 4-fold, if the attack involves the eye (herpes zoster ophthalmicus).

Herpes zoster infection, also known as shingles, has been shown in other studies to be associated with an increased risk for stroke, the researchers, with lead author Jiunn-Horng Kang, MD, from the Department of Physical Medicine and Rehabilitation and chair of the Sleep Physiological Lab at Taipei Medical University Hospital in Taiwan, point out. Their study is the first attempt to their knowledge to look at the exact risk and frequency of stroke after herpes zoster attacks.

There is still no established therapy to prevent herpes zoster vasculopathy and associated stroke, Dr. Kang told Medscape Neurology. Early antiviral medication could have an important role, he noted, but this role still needs to be studied.

"From the practical view, physicians should be aware of the potential elevated risk of stroke when they care [for] patients with acute herpes zoster attack," he said. "Furthermore, [careful] monitoring and management of the preexisting risk factors for stroke such as hypertension, hyperlipidemia, and diabetic mellitus could be helpful to reduce the risk for stroke."

The report was published online October 8 and will appear in the November issue of Stroke.

Large- and Small-Vessel VZV Vasculopathy

Primary varicella zoster virus (VZV) infection usually affects children and causes varicella or chicken pox, the researchers note. Although some children can have serious complications, varicella is usually benign and transient. The VZV then becomes inactive, sequestered in the sensory and autonomic ganglia. By mechanisms that are not entirely clear, the researchers note, spontaneous reactivation of VZV causes lesions with painful vesicles known as herpes zoster or shingles.

There have been numerous reports linking VZV vasculopathy and stroke syndrome after zoster attacks since the 1970s, the authors write, and VZV is the only recognized human virus able to replicate in cerebral arteries. "It is hypothesized to spread along the nerve fibers to the blood vessels, where it induces further inflammatory and thrombotic responses," Dr. Kang and colleagues note.

VZV vasculopathy can affect both the large and small vessels. In large-vessel VZV vasculopathy, vessels are damaged by inflammation induced by the virus, which can result in stroke. Small-vessel VZV vasculopathy, in contrast, can manifest as nonspecific symptoms including fever, headache, seizures, weakness, consciousness disturbances, and cognitive impairments, known as small-vessel encephalitis.

"To our knowledge, despite many case reports of conditions associated with VZV vasculopathy, large sample data regarding the exact frequency and risk of stroke occurring postherpes zoster attack are still lacking," the authors write.

In this study, the researchers used a data set released by the Taiwan National Health Research Institute in 2006, a representative sample of enrolees in Taiwan's National Health Insurance program. For this analysis, they identified a total of 7760 patients who received treatment for herpes zoster between 1997 and 2001 and matched them with 23,280 randomly selected subjects. The researchers then calculated the 1-year stroke-free survival for patients who received treatment for herpes zoster and for control subjects.

During the 1-year follow up, a total of 439 strokes occurred, 133 among those treated for herpes zoster (1.71%) and 306 from the control group (1.31%). The log rank test showed that those treated for herpes zoster had a significantly lower stroke-free survival rate (P < .001).

The risk for stroke after herpes zoster was increased by 31% compared with that for control patients and increased more than 4-fold for herpes zoster ophthalmicus.

Risk for Stroke After Herpes Zoster Attack vs Control During 1-Year Follow-up

Group	Adjusted Hazard Ratio	95% Confidence Interval	P
Herpes zoster	1.31	1.06 – 1.60	<.05
Herpes zoster ophthalmicus	4.28	2.01 – 9.03	<.001

The risk was increased for both ischemic and hemorrhagic stroke, and in both men and women, but only for those subjects who were 45 years of age or older, not for younger subjects.

Risk for Stroke After Herpes Zoster Attack vs Control by Stroke Type, Sex, and Age

Group	Adjusted Hazard Ratio	95% Confidence Interval	P
Ischemic stroke	1.31	1.07 – 1.65	.009
Intracerebral or subarachnoid hemorrhage	2.79	1.69 – 4.61	<.001
Men	1.32	1.01 – 1.75	<.05
Women	1.30	1.01 – 1.75	<.05
Age ≥ 45 years	1.31	1.06 – 1.63	<.05

"Although varicella zoster virus vasculopathy is a well-documented complication that may induce a stroke postherpes zoster attack, it does not fully account for the unexpectedly high risk of stroke in these patients," the authors conclude.

Asked to speculate on the potential mechanisms involved, Dr. Kang told Medscape Neurology that they think the most likely explanation is direct invasion of the cerebral vessels by the herpes zoster virus.

"Previous studies have shown that VZV can replicate and damage the vessel and induce an inflammatory process," he noted. "The vasculopathy results in further occlusion or rupture of involved vessels, manifested as ischemic or hemorrhagic stroke."

In addition, factors including postherpetic neuralgia, systemic diseases, general health status, or preexisting atherosclerosis could also contribute to the occurrence of stroke.

The authors have disclosed no relevant financial relationships.

Stroke. Published online October 8, 2009.

SATRAPLATIN FOR PROSTATE CANCER

J Clin Oncol. 2009 Oct 5. [Epub ahead of print]

Related Articles, LinkOut

Multinational, Double-Blind, Phase III Study of Prednisone and Either Satraplatin or Placebo in Patients With Castrate-Refractory Prostate Cancer Progressing After Prior Chemotherapy: The SPARC Trial.

Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabrò F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M.

San Camillo and Forlanini Hospitals, Rome, Italy; Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Klinika Nowotworow Ukladu Moczowego, Centrum Onkologii-Instytut, Warsaw, Poland; Centre Antoine Lacassagne, Nice; Institut Jean Godinot, Reims, France; Hospital E. Rebagliati-EsSalud, Lima, Peru; Cancer Research UK Institute for Cancer Studies, Birmingham; Guy's Hospital, London, United Kingdom; National Institute of Oncology, Budapest, Hungary; Universitätsklinikum der Carl-Gustav-Carus Universität, Dresden, Germany; Columbia University, New York, NY; Tulane Medical School, New Orleans, LA; Raleigh Hematology Oncology Clinic, Raleigh, NC; and GPC Biotech, Princeton, NJ.

PURPOSE: This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen. PATIENTS AND METHODS: Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP). RESULTS: A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin. CONCLUSION: Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

IMATINIB FOR PH+ ALL

J Clin Oncol. 2009 Oct 5. [Epub ahead of print]

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Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group Study.

Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Wang C, Davies SM, Gaynon PS, Trigg M, Rutledge R, Burden L, Jorstad D, Carroll A, Heerema NA, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B.

Children's Oncology Group; Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplant, British Columbia's Children's Hospital, University of British Columbia, Vancouver, BC; Cook Children's Medical Center, Hematology and Oncology, Fort Worth; Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX; Phyllis and David Komansky Center for Children's Health, Weill Cornell Medical Center, New York; Department of Pediatrics, New York University Medical Center, New York, NY; Department of Pediatrics and University of Florida Shands Cancer Center, University of Florida College of Medicine; Children's Oncology Group Statistics and Data Center, and the Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, FL; Department of Preventive Medicine, University of Southern California; Hematology and Oncology Children's Hospital Los Angeles, Los Angeles; Children's Oncology Group Coordinating Center, Arcadia, CA; Pediatric Hematology and Oncology, The Children's Hospital and University of Colorado Cancer Center, Aurora, CO; Stem Cell Transplantation, Children's Hospital Medical Center Cincinnati, Cincinnati; Department of Pathology, The Ohio State University, Columbus, OH; Thomas Jefferson University, Philadelphia, PA; Department of Radiation Oncology, Nova Scotia Cancer Centre and Dalhousie University, Halifax, NS; Midwest Children's Cancer Center, Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; University of Alabama at Birmingham, Birmingham AL; and Department of Pathology, Johns Hopkins Hospital, Baltimore, MD.

PURPOSE: Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. PATIENTS AND METHODS: We evaluated whether imatinib (340 mg/m(2)/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph- ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. RESULTS: Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% +/- 11% (95% CI, 64% to 90%), more than twice historical controls (35% +/- 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% +/- 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% +/- 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. CONCLUSION: Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

ANTI-EGFR AGENTS HARMFUL FOR COLORECTAL CANCER PATIENTS WITH KRAS MUTATION

October 9, 2009 (Philadelphia, Pennsylvania) — For the second time in a major clinical study, patients with colorectal cancer whose tumors contain the mutant form of the KRAS gene have shown negative outcomes when treated with an antiepidermal growth factor receptor (EGFR).

It is already well established that only patients with wild-type KRAS tumors benefit from treatment with an anti-EGFR agent and that patients with KRAS mutations do not.

In both Europe and the United States, labeling for the anti-EGFR agents now calls for use only in patients with wild-type tumors, as reported by Medscape Oncology.

However, the finding that these drugs produce a negative outcome in patients with mutated KRAS is relatively novel. This finding has now been reported with both of the anti-EGRF inhibitors, panitumumab (Vectibix) and cetuximab (Erbitux).

The negative finding with panitumumab comes from the PRIME study, and has just been reported — initially at the recent European Society of Medical Oncology (ESMO) meeting in Berlin, Germany, and last week here at the annual meeting of the International Society of Gastrointestinal Oncology (ISGIO).

In the PRIME study, panitumumab was used with the FOLFOX regimen as first-line treatment for colorectal cancer; results showed worse outcomes in patients with KRAS mutations receiving panitumumab plus FOLFOX than in those receiving FOLFOX alone.

The negative finding with cetuximab was reported in 2008, and comes from the Dutch CAIRO2 study. In that study, when cetuximab was added to a regimen of chemotherapy and bevacizumab for the first-line treatment of colorectal cancer, outcomes in patients with KRAS mutations were worse.

At the ISGIO meeting, PRIME investigator Salvatore Siena, MD, said that the reason for the detrimental effect of panitimumab in patients with mutated KRAS "remains unknown." Dr. Siena is from Ospedale Niguarda Ca'Granda, in Milan, Italy.

These varied treatment outcomes in colorectal cancer patients serve as a reminder of the importance in determining the molecular biology of their tumors, said a member of a panel discussion on metastatic colorectal cancer at ISGIO. "Going forward, the right thing to do is to get the information on all patients," said Howard Hochster, MD, from the New York University Cancer Institute in New York City.

Currently in the United States, only stage IV patients are all profiled for their tumor status, noted panel member Leonard Saltz, MD, from Memorial Sloan-Kettering Cancer Center in New York City.

"Whether we can justify profiling all colorectal cancer patients from an insurance point of view is another question," he added

Coke and Pepsi

Both panitumumab and cetuximab are anti-EGFR monoclonal antibodies. Both panitumumab and cetuximab are approved in the United States for metastatic colorectal cancer, but as second-line agents. Panitumumab is approved as a monotherapy, whereas cetuximab is approved both as a monotherapy and in combination with irinotecan.

"Cetuximab and panitumumab are like Coke and Pepsi," said Dr. Saltz told Medscape Oncology at ISGIO. "They are 2 brands of a very similar drug."

Two new trials with panitumumab were presented at both ESMO and ISGIO. In both studies, the agent was used in combination with chemotherapy for metastatic colorectal cancer — with FOLFOX as a first-line treatment (the PRIME study) and with FOLFIRI as a second-line treatment.

"These are marketing studies," said Dr. Saltz. "Panitumumab is not a meaningful new treatment."

However, Dr. Saltz highlighted a number of ways in which panitumumab has value for clinicians and patients.

"Panitumumab is about 20% cheaper than cetuximab. And in the Southern United States, allergic reactions to cetuximab are much higher than in other regions for some reason. Panitumumab can be a treatment option," he said.

However, another attendee at ISGIO approached by Medscape Oncology was enthusiastic about panitumumab and its possible use in combination with chemotherapy for metastatic colorectal cancer.

"Current practice is to use bevacizumab as the targeted therapy in metastatic colorectal cancer," said Bert O'Neil, MD, from the University of North Carolina in Chapel Hill.

The new studies with panitumumab are valuable, said Dr. O'Neil. "These are 2 very important trials because potentially they will give [American] clinicians an earlier opportunity to use an anti-EGFR agent in combination with chemotherapy," he said.

Results With Panitumumab in Combination with Chemotherapy: 2 Studies

In the PRIME trial, a phase 3 multicenter European study, patients were randomized to receive either panitumumab plus FOLFOX or FOLFOX alone as first-line therapy for metastatic adenocarcinoma of the colon or rectum. The patients had received no previous chemotherapy for metastatic disease and no previous oxaliplatin therapy. The primary end point was progression-free survival.

In patients with wild-type KRAS tumors, panitumumab statistically significantly improved progression-free survival when added to FOLFOX (n = 325), compared with FOLFOX alone (n = 331) (median, 9.6 vs 8.0 months; hazard ratio [HR], 0.80; P = .02).

In patients with mutant KRAS tumors, panitumumab statistically significantly decreased progression-free survival when added to FOLFOX (n = 219), compared with FOLFOX alone (n = 221) (median, 7.3 vs 8.8 months; HR, 1.29; P = .02).

The adverse event profile was "as expected" with an anti-EGFR antibody, said investigator Dr. Siena.

In the other phase 3 study, also conducted in Europe, patients were randomized to receive either panitumumab plus FOLFIRI or FOLFIRI alone as a second-line treatment. Patients had metastatic adenocarcinoma of the colon or rectum and only 1 previous chemotherapy regimen for their metastatic disease. The coprimary end points were progression-free survival and overall survival.

In patients with wild-type KRAS tumors, panitumumab statistically significantly improved progression-free survival when added to FOLFIRI (n = 303), compared with FOLFOX alone (n = 294) (median, 5.9 vs 3.9 months; HR, 0.73; P = .004).

Overall survival was also better in patients with wild-type tumors receiving panitumumab plus FOLFIRI, compared with FOLFIRI alone, but not significantly (median, 14.5 vs 12.5 months; HR, 0.85; P = .12).

There was no evidence of benefit in patients with mutated KRAS tumors, said lead investigator Michel Ducreux, MD, from Institut Gustave Roussy in Villejuif, France. However, notably, in this study, these patients did not do worse on panitumumab, as they did in the PRIME trial.

Combination Therapy Approach: Modest Benefit

In a recent essay published in the March/April 2009 issue of the official publication of ISGIO, Gastrointestinal Cancer Research, Dr. Saltz described the current strategy in colorectal cancer of combining, with standard chemotherapy, various new drugs, such as an anti-EGFR agent or the anti-vascular endothelial growth factor bevacizumab, as a case of "if you can't beat 'em, join 'em."

He explained that none of a variety of new agents have met the hope that they would replace standard chemotherapy as the new first-line standard, and described the overall benefit of combination therapy as "modest."

Dr. Saltz has also been an outspoken critic of the cost of targeted therapies, as reported by Medscape Oncology.

Given the performance of various would-be alternatives to chemotherapy for colorectal cancer, it is likely that new agents will be accompanied by specific diagnostic criteria, such as KRAS status, for the selection of appropriate patients for treatment, he writes. The approach will protect patients with "little or no likelihood of success from the expense and toxicity of treatment."

GRADE PREDICTS RISK OF LOCAL RELAPSE AFTER BREAST CONSERVING THERAPY

NEW YORK (Reuters Health) Oct 02 - High-grade pathology, but not margin status, is associated with an increased risk of local relapse after breast-conserving therapy for stage I and II invasive breast cancer, according to a report published online ahead of print in the Journal of Clinical Oncology.

"In contrast with the opinion of several clinicians, margin involvement with limited microscopic tumor spread is not a relevant predictive factor for a local breast recurrence," Dr. Harry Bartelink from The Netherlands Cancer Institute, Amsterdam, told Reuters Health by email. "Other factors like age and high grade invasive tumors are much more relevant prognostic factors."

Dr. Bartelink and colleagues in the EORTC Boost Versus No Boost Trial investigated the long-term impact of pathological characteristics on local relapse in 1616 women whose stage I or II invasive breast cancer had been treated with breast-conserving therapy and whole breast irradiation, with or without an extra boost dose of 16 Gy (with negative margins) or 10 to 26 Gy (with positive margins).

On multivariate analysis, the presence of high-grade invasive ductal carcinoma and age younger than 50 years were associated with a significantly increased risk of local relapse, the authors report, whereas the additional boost dose to the tumor bed significantly reduced the local relapse rate.

In patients with high grade invasive ductal carcinoma, the boost reduced the cumulative 10-year local relapse rate from 18.9% to 8.6%. In addition, in women younger than 50, the extra irradiation reduced the 10-year cumulative local relapse rate from 19.4% to 11.4%.

Margin involvement and differentiation in grade of ductal carcinoma in situ did not have a significant impact on the local relapse rate.

"(In) the last 10 years, too much focus was given to margin involvement by surgeons and pathologists," Dr. Bartelink said. "The consequence of this finding is that (fewer) re-excisions or even mastectomies are required when focal involvement of the margins is found by the pathologists."

"We are at present involved in the development of a nomogram (based upon the classical criteria coming from tumor size, pathological features and planned systemic treatment) to predict the chance of a local breast recurrence in an individual patient," Dr. Bartelink added.

In a linked editorial, Drs. Shannon MacDonald and Alphonse G. Taghian at Harvard Medical School, Boston, suggest that the lack of association between positive margins and relapse could be explained by the small number of patients with a positive margin or the way the patients were grouped.

"Although this subgroup analysis did not find margins to be a prognostic factor for local recurrence, numerous studies have found it to be one of the strongest prognostic factors," the editorialists write. "Surgical re-excision for positive margins should continue to be routinely performed."

J Clin Oncol 2009;27.

DCIS RECCURENCE HIGHER IN YOUNGER WOMEN

NEW YORK (Reuters Health) Oct 06 - Younger women who undergo breast-conserving surgery and radiotherapy for ductal carcinoma in situ (DCIS) are more likely to experience recurrence than are older women, according to the results of a large population-based study.

Among women who are no older than 50 years at diagnosis, those who are 44 years and younger have a recurrence rate of around 22% compared with a rate of 14% in older women (p = 0.01). The corresponding 10-year actuarial local-recurrence free survival (LRFS) rates are 75% and 85% (p = 0.005).

The study findings were presented Tuesday at a press briefing for the 2009 Breast Cancer Symposium, to be held later this week in San Francisco.

Prior research has shown that treatment of DCIS with breast-conserving surgery followed by radiotherapy can achieve low recurrence rates. "What is unclear is the significance of young age in DCIS," lead author Dr. Iwa Kong, from Odette Cancer Center, Toronto, told attendees. "Some studies have suggested that young women have higher recurrence rates."

The present study examined the outcomes of 583 Canadian women who were no more than 50 years of age when diagnosed with DCIS between 1994 and 2003 and who were treated with breast-conserving surgery and radiotherapy. The subjects were followed for a median of 8.5 years.

Most of the women received 50 Gy in 25 fractions, and 121 (21%) received a boost, the researchers note.

Overall, 99 women (17%) experienced a local recurrence. Five- and 10-year actuarial local recurrence-free survival (LRFS) rates were 88% and 81%, respectively. Invasive local recurrence developed in 38 women (6.5%), resulting in 5- and 10-year actuarial invasive LRFS rates of 95% and 93%, respectively.

The recurrence rates for women aged 40 years or less, and women ages 40 to 44 years, were 23% and 21%, respectively, while the rate for women ages 45 to 50 years was 14%.

"DCIS is a highly curable illness with good outcomes," Dr. Kong said. "However, our preliminary data suggest that young women have a higher risk of recurrence following lumpectomy and radiation." Further research is needed to understand the reason for this finding and to determine the optimal treatment for young women with DCIS, she added.

BREAST TUMOR "EVOLUTION"

The findings suggest looking at primary tumor tissue may be a more precise way to spot tumor-initiating mutations than looking at metastatic cell lines, note Dr. Samuel Aparicio of the BC Cancer Agency in Vancouver and his colleagues.

Dr. Aparicio and his team examined genetic material from an estrogen-receptor-alpha-positive lobular breast tumor and from a metastasis of that tumor that occurred nine years later. They report their findings in the October 8th issue of Nature.

The researchers sequenced the genome and transcriptome of the metastasis, ultimately identifying 32 non-synonymous coding somatic point mutations. Five of the 32 mutations were found in the primary tumor, six were identified at lower frequencies, 19 were not found at all, and two were undetermined. The researchers also identified two new RNA editing events from their analysis of the genome and transcriptome of the metastasis.

It is not clear, Dr. Aparicio and his colleagues indicate, whether the 19 new mutations were a result of radiation therapy or "innate tumor progression."

Most analysis of coding mutations in breast cancer has been done in estrogen-receptor-positive disease, and has looked at metastatic cell lines or samples, the researchers note. These studies have "suggested the presence of large numbers of passenger events as well as drivers," they write.

"Our results show the importance of sequencing samples of tumor cell populations early as well as late in the evolution of tumors, and of estimating allele frequency in tumor genomes," they add. "Our observations suggest that the sequencing of primary breast cancers and pre-invasive malignancy may reveal significantly fewer candidates for tumor initiating mutations."

Nature 2009;461:809-813.

MORE DATA SUPPORT GENETIC TEST TO PREDICT RESPONSE TO TAMOXIFEN

October 7, 2009 — More data are available to support the use of a genetic test to predict a woman's response to tamoxifen, so that those who will not respond can be offered alternative therapies.

The test identifies women with an inherited deficiency in the CYP2D6 gene, which codes for an enzyme that breaks tamoxifen into its active metabolites. Women with this deficiency — about 8% to 10% of the Caucasian population — do not metabolize tamoxifen, and so do not release its active metabolites. This means that they do not benefit from the protection it offers against breast cancer recurrence.

Using the test to identify this small group would allow these patients to be offered alternative therapies that would work, such as aromatase inhibitors.

The new data, collected from 1325 women with early breast cancer and were receiving tamoxifen as adjuvant therapy, are published in the October 7 issue of the Journal of the American Medical Association.

"This large study validates our previous findings in a sufficiently powered manner," said second author Matthew Goetz, MD, from the Mayo Clinic in Rochester, Minnesota. Not only were there more patients, there was more comprehensive genotyping and an extended follow-up, he said in an interview with Medscape Oncology.

The majority of the data (n = 1100 women) come from clinical practices in Germany; the remainder (n = 225 women) come from a clinical trial in the United States, Dr. Goetz explained. Most of the women (95%) were postmenopausal, he added.

The study showed that women lacking the CYP2D6 enzyme function (poor metabolizers) had an almost 2-fold increased risk of developing breast cancer, compared with women who had full CYP2D6 function (good metabolizers).

There was also an intermediate group — women in whom only 1 of the 2 alleles on the CYP2D6 gene is functional (intermediate metabolizers). This group accounts for about 20% to 25% of the Caucasian population, and they "do slightly worse" on tamoxifen than the women who are good metabolizers, Dr. Goetz explained. What should be done about these intermediate metabolizers is currently unclear, he said, adding that more data are needed.

Testing in the Clinic

Dr. Goetz and colleagues first reported the association between CYP2D6 and tamoxifen in 2005/06, and the Mayo Clinic changed its practice then, he said. For 3 years now, they have been testing all postmenopausal women with estrogen-receptor-positive breast cancer who are being considered for tamoxifen adjuvant therapy. Women who are found to be deficient in CYP2D6 are then counseled and offered alternative therapies, he explained.

Several tests for CYP2D6 are commercially available, Dr. Goetz noted.

When asked whether he would advise all physicians to test for CYP2D6 before prescribing tamoxifen, Dr. Goetz replied: "If you have alternative therapies that are effective, why would you give a drug such as tamoxifen that has been identified as having a much higher risk of recurrence in a small subset of patients. I think that is really the crux of the issue . . . that a predictive factor is helpful when there is an alternative therapy."

He added that the aromatase inhibitors are "very effective in postmenopausal women with breast cancer; in fact, they have been shown to be more effective than tamoxifen."

The issue of tamoxifen and CYP2D6 was discussed at a US Food and Drug Administration Advisory Committee meeting in October 2006. At that meeting, the committee agreed to recommend a label change for tamoxifen to highlight the fact that poor metabolizers are at increased risk for breast cancer recurrence. However, Dr. Goetz pointed out, "it hasn't happened yet."

At that same meeting, the committee did not reach a consensus on whether to recommend that women be tested. "Some members believed that the genetic test should be recommended, whereas others believed that it should be mentioned in the label as an option for discussion between the healthcare provider and patient. However, the majority indicated that it should be included in an appropriate section of the package insert," Dr. Goetz wrote in a report (Clin Pharmacol Ther. 2008;83:160-166).

Approached for outside comment, Hyman Muss, MD, from the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill School of Medicine, said there is some controversy in this field because not all of the studies have confirmed the finding. Dr. Muss spoke to Medscape Oncology at the San Antonio Breast Cancer Symposium, where a different set of data — but the same conclusions — were reported by Dr. Goetz and colleagues.

Despite the uncertainty, Dr. Muss told Medscape Oncology that he is in favor of using the test after discussing it with the patient, if the patient agrees.

Dr. Muss explained that using the test would identify women who would not respond to tamoxifen, and would allow the physician to offer an alternative but appropriate treatment. "For example, in a postmenopausal woman, you could use an aromatase inhibitor or another drug like tamoxifen, such as toremifene," he explained. "In a premenopausal woman, you could consider ovarian suppression or possibly another selective estrogen-receptor modulator, although nothing has been tested as extensively as tamoxifen," he added.

"Even it turns out that this is all wrong, you have done no harm," Dr. Muss said. "But if it turns out that this is important, then you have done some good, because otherwise 5% to 10% of women would not have been treated appropriately." Those women would have been taking tamoxifen without benefiting from it. Also, the "women who are poor metabolizers are less likely to suffer from side effects of the treatment, so they will be telling their doctor how well they are doing on tamoxifen," he said. They tolerate the drug well, and so they continue on it, but they are not getting any benefit from it, he pointed out.

"That is why I would argue in favor of using this test — if it turns out not to be important, I haven't lost anything by changing my patients to alternative effective options, but if it turns out to be true and I haven't used the test, then I will have been treating 10% of my patients with a drug that doesn't work," Dr. Muss said.

Developing Active Metabolite

Dr. Goetz noted that his group is now working with the National Cancer Institute to develop the active metabolite of tamoxifen, endoxifen, into a drug for clinical use. The team hopes to start clinical trials within the next 6 to 12 months.

Using endoxifen in place of tamoxifen would remove the need for CYP2D6 testing, Dr. Goetz said. But what began as a potential new drug for poor metabolizers might turn out to be a "better drug for all patients," he said. Preclinical tests suggest that endoxifen is about 100-fold more potent than tamoxifen; it has a higher affinity for the estrogen receptor and is better at suppressing the proliferation of breast cancer cells in vitro, he said.

NOVARTIS WINS PHARMACEUTICAL PRIZE

October 7, 2008 — Novartis Oncology has been awarded the 2009 Prix Galien USA for Best Pharmaceutical Product for its innovative drug imatinib mesylate (Gleevec, Glivec). The award, considered to be the industry's highest accolade for pharmaceutical research and development, is often considered to be the Nobel Prize of the pharmaceutical industry.

"It is a great honor for Gleevec to be the winner of such a significant award," said David Epstein, CEO and president of Novartis Oncology, in a statement. "Before Gleevec, oncologists dreamed of targeted, precise therapies but few believed them possible. Now, nearly a decade since its first approval, Gleevec has more than fulfilled its promise — triggering an intensive search for targets in other serious diseases and stimulating the development of new targeted therapies."

Imatinib won the International Prix Galien in 2002.

The award was created in France in 1970 by French pharmacist Roland Mehl as a means of recognizing and promoting significant advances in pharmaceutical research. Since that time, it has expanded to other countries, and was introduced in the United States in 2007. This year's Prix Galien USA winners were selected from 21 candidates.

Imatinib has been marketed since 2001, when it received accelerated regulatory approval in the United States for Philadelphia chromosome-positive chronic myeloid leukemia. It has since been approved for 8 other indications, including KIT (CD117)-positive gastrointestinal stromal tumors.

This is not the first time that imatinib has been honored. Earlier this year, as reported by Medscape Oncology, researchers Brian Druker, MD, Nicholas Lydon, PhD, and Charles Sawyers, MD, shared the prestigious Lasker-DeBakey Clinical Medical Research Award for their work in developing this new class of drug.

In addition, a number of prizes have been awarded for research related to the discovery and preclinical work on imatinib. These include the Bruce F. Cain Award from the American Association for Cancer Research and the Warren Alpert Foundation Scientific Prize, awarded by Harvard Medical School.

In 2007, Novartis Pharmaceuticals Canada Inc, received the Belleau-Nickerson Award for imatinib, which recognizes the therapeutic, social, and economic contribution of a drug product marketed in the past 10 years. Novartis Pharmaceutics Canada Inc also won the Prix Galien Canada Most Innovative Product Award in 2002.

Another Oncology Winner

The Prix Galien USA is now awarded in 3 categories that offer broad implications for future biomedical research: best pharmaceutical agent, best biotechnology product, and best medical device. The award committee, with its 11 members, is comprised of 7 Nobel Laureates, founders of major biotech companies, and editors of world-renowned biology journals.

In addition to imatinib, another oncology product took home an award. The CellSearch Circulating Tumor Cell (CTC) Test from Veridex took home the award for Best Medical Technology. The CellSearch System is the first diagnostic test to automate the capture and detection of CTCs, as well as using CTCs to determine the prognosis and overall survival of patients with metastatic breast, colorectal, or prostate cancer at any time during the course of treatment.

"Nominees for the Prix Galien USA stand apart from other drugs and technologies in the marketplace for the amount of research and level of skill that was invested in the development of these products that improve lives," said Gerald Weissmann, MD, Prix Galien USA committee chair, NYU School of Medicine research professor of medicine, director of the Biotechnology Study Center, and editor-in-chief of The FASEB Journal, in a release.

BETTER TO AVOID WBRT AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES?

October 7, 2009 — Patients with brain metastases who were treated with whole-brain radiation therapy in addition to stereotactic radiosurgery were found to be at greater risk for cognitive decline, but did not show improved survival over surgery alone, according to a study published online October 2 in the Lancet Oncology.

"In our study, patients who received radiosurgery plus whole-brain radiation were at twice the risk of developing learning and memory problems at 4 months [than] patients getting radiosurgery alone," said lead study author Eric Chang, MD, associate professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston.

In fact, the trial was stopped early by the data monitoring committee because there was a high probability (96%) that patients who were randomized to receive stereotactic radiosurgery plus whole-brain radiation therapy were significantly more likely to show a cognitive decline.

"Giving whole-brain radiation therapy in conjunction with stereotactic radiosurgery is highly controversial in the United States right now," said Dr. Chang. "Some might argue it is the standard treatment, but there is no consensus on this point. I would say there is a fair proportion of centers that do it, but there are many centers that do not."

Dr. Chang added that this study provides the strongest evidence to date that supports giving radiosurgery alone with close clinical monitoring as the preferred treatment strategy for patients newly diagnosed with a limited number of brain metastases. "We advocate the judicious and appropriate use of surgery, radiosurgery, or whole-brain irradiation only if needed for any recurrences that may develop later on in the brain," he told Medscape Oncology.

"I would advocate that physicians and their patients who are interested in preserving cognitive function and memory strongly consider using stereotactic surgery alone with close clinical monitoring in the initial management of their brain metastases," Dr. Chang said.

"Our strategy is consistent with the trend toward personalized medicine — tailoring therapies to the patient and their disease rather than applying a 'one size fits all' approach of giving whole-brain radiation therapy to all patients with brain metastases," he added.

Worse Neurocognitive Function With Combined Therapy

The trial was designed to enroll 90 patients and had about 80% power to detect a 30% difference in the neurocognitive end point of total recall, but the study was halted early by the data monitoring committee after the accrual of 58 patients. Patients with 1 to 3 newly diagnosed brain metastases were randomly assigned to receive stereotactic radiosurgery plus whole-brain radiation (n = 30) or stereotactic radiosurgery alone (n = 28) from January 2001 to September 2007.

The primary end point was neurocognitive function, objectively measured as a significant deterioration (5-point drop from baseline) in Hopkins Verbal Learning Test–Revised (HVLT-R) total recall at 4 months.

At 4 months, there was 96% confidence that total recall at 4 months for patients receiving the combination strategy (7 of 11 patients assessed [64%] deteriorated) was inferior to total recall for those who underwent stereotactic radiosurgery alone.

The researchers noted that a difference in total recall persisted at 6 months, with a mean posterior probability of decline of 28% for patients receiving the combination strategy and of 8% for those who underwent radiosurgery alone, with 90% confidence.

The HVLT–R delayed recall (22% in the combination group vs 6% in the radiosurgery-alone group; 86% confidence) and HVLT–R delayed recognition (11% vs 0%, respectively; 86% confidence) tests at 4 months indicated that it was highly probable that patients who underwent whole-brain radiation therapy had worse neurocognitive function than those who underwent surgery only.

Tumor Control Better, But Does Not Improve Survival

At 4 months, 4 patients (13%) in the radiosurgery-alone group had died, compared with 8 (29%) in the combination group. The researchers also observed that the median and 1-year overall survival was higher for patients in the radiosurgery-alone group than for those in the combination group (median survival, 15.2 vs 5.7 months; overall survival, 63% vs 21%; P = .003).

However, local tumor control at 1 year was higher for those in the combination group (100% vs 67%; P = .012), as was the distant brain tumor control rate (73% vs 45%; P = .02) and 1-year freedom from central nervous system recurrence (73% vs 27%; P = .0003).

Even though whole-brain radiation therapy reduced the risk for brain tumor recurrence, it did not increase overall survival. The authors note that the association between an increased risk for systemic deaths and whole-brain radiation therapy has been reported previously, and systemic deaths might be related to mechanisms involving central nervous system injury. That is a possibility that should be explored in future preclinical and clinical studies, they write.

There was 1 case of grade 3 toxicity in the combination group (seizures, motor neuropathy, depressed level of consciousness) that was attributed to radiation treatment. In the radiosurgery-alone group, there was 1 case of grade 3 toxicity (aphasia), which was attributed to radiation treatment, and 2 cases of grade 4 toxicity diagnosed as radiation necrosis.

PEGINTRON FOR ADJUVANT TREATMENT OF MELANOMA

October 7, 2009 — A longer-acting formulation of interferon was narrowly recommended for approval for use in malignant melanoma at a US Food and Drug Administration (FDA) advisory committee meeting.

The product, pegylated interferon alfa-2b (Pegintron, Schering-Plough), is administered subcutaneously once weekly by self-injection. The application for use in malignant melanoma suggested it could be used for 5 years.

The company said that this offers a more convenient administration schedule than the unpegylated formulation of the same product, Intron A, which is already approved for use in malignant melanoma. Intron A is administered by intravenous infusion for 5 days a week during the initial 4-week treatment period — which necessitates daily visits to a physician's office — followed by subcutaneous injections 3 times weekly for 48 weeks.

Pegintron is already marketed for use in the treatment of chronic hepatitis C in combination with ribavirin (Rebetol, Schering-Plough). However, the dose used for malignant melanoma is 2 times higher than that used for hepatitis.

Offers an Alternative

The FDA asked its Oncologic Drugs Advisory Committee to consider whether the new product offered sufficient benefit to warrant approval. The agency pointed out that the clinical trial of the product that was submitted with the application (EORTC 18991) showed a significant prolongation of relapse-free survival. "However, there was no effect on overall survival observed and substantial toxicity occurred with the treatment regimen administered in this study," it added.

At the dose used in this study, the product "can be toxic, likely decreasing the quality of life during drug administration," the agency pointed out.

"Potential benefits associated with delaying a relapse without a survival benefit would be to avoid the morbidity of surgical procedures for resection of recurrent disease and the possible psychological benefit of being tumor-free," according to the FDA.

"The primary question raised by this application is whether there is a favorable risk:benefit profile" for this product, the agency stated in its briefing documents.

The committee voted 6 to 4 in favor of recommending approval.

"This will provide an alternative that is at least more convenient for patients," said Michael Link, MD, head of oncology at Stanford University School of Medicine in California, according to a Reuters report of the meeting. Other experts suggested that having this formulation available would mean that patients who could not manage the daily visits for intravenous infusions for logistic reasons would have a chance to receive adjuvant interferon treatment.

Schering-Plough noted in documents filed for the meeting that the benefit for relapse-free survival with the standard product, Intron A, is well established, but added that individual trials have not consistently demonstrated a survival benefit. However, a meta-analysis, using individual patient data, of adjuvant interferon therapy trials in more than 6000 patients demonstrated a survival benefit that was statistically significant, with an absolute increase in 5-year survival of 2.8% (from 47.1% to 49.9%; P = .008).

Clinical Data From EORTC Trial

The clinical data to support the application comes from a trial conducted by the European Organization for the Research and Treatment of Cancer (EORTC), which has already been published and commented upon in medical journals.

The trial, known as EORTC 18991, was conducted in 1256 advanced malignant melanoma patients, and showed that Pegintron had a significant impact on relapse-free survival, increasing it to 34.8 months, compared with 25.5 months in the observational group (P = .01).

When the study was published in the Lancet (2008;372:117-126), an accompanying editorial (2008;372:89-90) noted that the median follow-up of 3.8 years was "too short for final conclusions," as reported by Medscape Oncology at the time. The significant improvement seen in recurrent-free survival could disappear after therapy ends, but then again, longer follow-up might show a significant overall survival advantage for those patients, which "would represent the real advance we've been awaiting for," the Lancet editorialists wrote.

More data from that trial, with details about the adverse effects and impact on quality of life, were reported earlier this year in the Journal of Clinical Oncology (2009;27:2916-2923), and an accompanying editorial (2009;27:2896-2897) questioned whether the toxicities are worth it, as reported by Medscape Oncology. That study showed that the toxicities encountered with the pegylated product were similar to those seen in other studies using standard interferon alpha in melanoma, and included fatigue, hepatotoxicity, and depression.

"These data are important and disappointing and do not support a conclusion that using pegylated interferon alfa-2b, at least with the schedule used in EORTC 18991, will either greatly improve the tolerability or significantly increase the feasible duration of treatment for adjuvant interferon in high-risk melanoma," the editorialists comment in the Journal of Clinical Oncology. However, they too remarked that the follow-up of this trial is still early, and that longer-term data may yet show improved outcomes, including an impact on overall survival.

CLINICAL ACTIVITY OF A C-MET ALK INHIBITOR

Clinical activity observed in a phase I dose escalation trial of an oral cMET and ALK inhibitor

05.10.09

Category: Scientific News

Treatment with PF-02341066 demonstrates marked clinical activity against tumors harboring activated ALK gene rearrangements

The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). Patients who harbor this mutation do not benefit from epidermal growth factor receptor (EGFR) tyrosine kinases (TKIs) and should be directed to trials of ALK-targeted agents. First described in 2007, the fusion results from a small inversion within chromosome 2p, which leads to expression of a chimeric tyrosine kinase, in which the N terminal half of echinoderm microtubule-associated protein-like 4 (EML4) is fused to the intracellular kinase domain of anaplastic lymphoma kinase (ALK).

Prof. José Baselga discussed results presented first at the ASCO Annual Meeting in Orlando, US, this year and during the Best of 2009 session at the ECCO 15 – ESMO 34 Congress in Berlin by Dr Eunice Kwak of the Massachusetts General Hospital Cancer Center, Boston, US. Prof. Baselga said that translocations for decades have been the hallmark of hematologic malignancies and that this represents a new finding in solid tumors. EML4-ALK possesses potent oncogenic activity both in vitro and in vivo. Small molecule inhibitors that target ALK can effectively block this activity. Mesenchymal-epithelial transition (MET) factor is a proto-oncogene that encodes a protein MET, also known as cMET or hepatocyte growth factor receptor (HGFR). Abnormal MET activation in cancer correlates with poor prognosis – aberrantly active MET triggers tumor growth, formation of new blood vessels, and metastasis. Prof. Baselga went on to say that 2009 will be remembered for the development of PF 02341066, a selective, ATP-competitive, small molecule oral inhibitor of the cMET/HGFR and ALK receptor tyrosine kinases.

Dr Kwak and colleagues conducted first in humans a phase I dose-escalation trial evaluating PF-02341066 as an oral single agent to investigate safety, pharmacokinetics (PK), and pharmacodynamics in patients with advanced cancer (excluding leukemias). PF-02341066 was administered under fasting conditions QD or BID on a continuous schedule to patients in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID.

Thirty-seven patients were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL, and NSCLC. The maximum tolerated dose (MTD) was 250 mg BID. Three dose-limited toxicities (DLTs) were observed: grade 3 increase in ALT (one patient at 200 mg QD) and grade 3 fatigue (two patients at 300 mg BID). The most common adverse events (AEs) were nausea, emesis, fatigue, and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A two- to four-fold increase in the oral midazolam (MDZ) AUC was observed following 28 days of PF-02341066 dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF-02341066 to be an inhibitor of CYP3A. Ten patients have entered an enriched RP2D cohort of patients with tumors harboring cMET amplification/gene mutation or ALK fusion genes. There has been one confirmed partial response (PR) in a sarcoma patient with ALK rearrangement (inflammatory myofibroblastic tumor). Among 10 NSCLC patients whose tumors harbor EML4-ALK rearrangement, one patient has had a PR, two patients have achieved unconfirmed PR and four patients have had stable disease (SD). (Three patients experienced reduction in tumor burden by 20% in measurable lesions and one has been treated for 28 weeks.)

The authors concluded that the MTD of PF-02341066 is 250 mg BID. All AEs were manageable and reversible. There was no evidence of non-linear PK at PF 02341066 doses > 100 QD. Future directions in PF-02341066 research for the current phase I clinical trial are to continue to enroll ALK patients in an enriched cohort, to access mature progression-free and overall survival data, to conduct genetic characterization of ALK fusion partners and ALK variants in responders and non-responders, and to continue efforts to identify patients with MET amplifications or mutations. A clinical development has allowed enrollment to begin for a randomized phase III registration trial of PF-02341066 vs. chemotherapy (pemetrexed or docetaxel) in NSCLC patients with ALK rearrangement after failure of first line therapy. This study highlights the importance and feasibility of incorporating prospective molecular genotyping into early-phase clinical trials of novel targeted therapies.

HOW TO MAKE A SOUP

Lung Cancer. 2009 Sep 22. [Epub ahead of print]

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Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer: A multicenter phase II study.

Xenidis N, Kotsakis A, Kalykaki A, Christophyllakis C, Giassas S, Kentepozidis N, Polyzos A, Chelis L, Vardakis N, Vamvakas L, Georgoulias V, Kakolyris S.

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

PURPOSE: The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer. PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100mg/m(2) on days 1-3 and cisplatin 80mg/m(2) on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20mg/m(2) on day 1 and etoposide 50mg/m(2) on day 4 within 5-6 weeks, followed by three courses of irinotecan 60mg/m(2) on days 1, 8, and 15 and cisplatin 60mg/m(2) on day 1 of a 4-week cycle. RESULTS: There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3-4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6-41.2 months), the median survival time was 19 months (95% CI: 14.5-23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively. CONCLUSIONS: Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC.

SUNITINIB AND PROSTATE CANCER

Jpn J Clin Oncol. 2009 Sep 22. [Epub ahead of print]

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Biochemical and Pathological Response of Prostate Cancer in a Patient with Metastatic Renal Cell Carcinoma on Sunitinib Treatment.

Song IC, Lim JS, Yun HJ, Kim S, Kang DY, Lee HJ.

1Department of Internal Medicine, Daejeon Regional Cancer Center, Chungnam National University Hospital.

Sunitinib is a small molecular inhibitor of tyrosine kinases and is used to treat advanced renal cell carcinoma and gastrointestinal stromal tumour after disease progression or intolerance to imatinib therapy. Here, we describe biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma during sunitinib treatment. A 62-year-old man was referred to our hospital because of a mass in the scalp. He was diagnosed with left renal cell carcinoma with right renal and scalp metastases. In addition, synchronous prostate cancer involving less than one-half of the right lobe was found with a prostate-specific antigen (PSA) value of 23.4 ng/ml. Treatment was begun with sunitinib (50 mg daily, 4 weeks on and 2 weeks off). Regarding the prostate cancer, active monitoring was planned considering the far advanced renal cell carcinoma. Surprisingly, the PSA level was 3.4 ng/ml at week 6 and 0.2 ng/ml at week 12, and it subsequently remained normal. At the time of writing (cycle 6 of sunitinib therapy), the prostate nodule significantly decreased in size. Furthermore, a 12-core re-biopsy revealed pathological evidence of regression with sunitinib treatment, with control of his renal cell carcinoma.

CHEMOTHERAPY AND ARRHYTHMIA

Europace. 2009 Oct 3. [Epub ahead of print]

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Introducing a new entity: chemotherapy-induced arrhythmia.

Guglin M, Aljayeh M, Saiyad S, Ali R, Curtis AB.

Department of Cardiology, University of South Florida, 2A Columbia Drive, Suite 5074, Tampa, FL 33618, USA.

The relationship between chemotherapy and arrhythmias has not been well established. We reviewed the existing literature to better understand this connection. We reviewed published reports on chemotherapy-induced arrhythmias in English using the PubMed/Medline and OVID databases from 1950 onwards as well as lateral references. Arrhythmias were reported as a side effect of many chemotherapeutic drugs. Anthracyclines are associated with atrial fibrillation (AF) at a rate of 2-10%, but rarely with ventricular tachycardia (VT)/fibrillation. Taxol and other antimicrotubular drugs are safe in terms of pro-arrhythmic side effects and do not cause any consistent rhythm abnormalities. Arrhythmias induced by 5-fluorouracil, including VT, are mostly ischaemic in origin and usually occur in the context of coronary spasm produced by this drug. Cisplatin-particularly with intrapericardial use-is associated with a very high rate of AF (12-32%). Melphalan is associated with AF in 7-12% of cases, but it does not appear to cause VT. Interleukin-2 is linked to frequent arrhythmia, mostly AF. We summarized the available data on chemotherapy-induced arrhythmia, particularly AF and VT. Studies with prospective data collection and thorough analyses are needed to establish a causal relationship between certain anticancer drugs and arrhythmia.