ACTIVE SURVEILLANCE FOR AS MANY AS 40% OF PROSTATE CANCER PATIENTS

January 14, 2010 — For the first time, the National Comprehensive Cancer Network's (NCCN) practice guidelines for prostate cancer recommend the use of active surveillance as the sole initial treatment — not just an option — for many men with prostate cancer.

Specifically, active surveillance should be offered as the one and only initial treatment to 2 groups of patients: men with "low risk" and a life expectancy of less than 10 years, and men with "very low risk" and a life expectancy of less than 20 years.

"This could be as many as 40% of all men diagnosed with prostate cancer in the United States," James Mohler, MD, chair of the NCCN Guidelines Panel for Prostate Cancer, told Medscape Oncology.

Dr. Mohler, who is also chair of the Department of Urology at Roswell Park Cancer Institute in Buffalo, New York, said the increased emphasis on active surveillance, also known as watchful waiting, comes as evidence emerges about both the problem of overtreatment and the value of active surveillance.

"Growing evidence suggests that overtreatment of prostate cancer commits too many men to side effects that outweigh a very small risk of prostate cancer death," he summarized in a press statement.

However, another expert in active surveillance, Peter Carroll, MD, MPH, who applauded the NCCN's promotion of the strategy, thinks that its approach needs modification. He also said that there is a lot at stake for urologists, "who may have the whole issue of prostate cancer taken out of their hands."

The NCCN stipulations about life expectancy are impractical, suggested Dr. Carroll, who is chair of urology at the University of California, San Francisco.

"Clinicians do not consult life-expectancy tables or do calculations. They look the patient in the eye and make an estimation — and they tend to overestimate," he told Medscape Oncology.

Life expectancy should not be an issue anyway, Dr. Carroll suggested.

"All low-risk men should discuss active surveillance with their doctors, including young men who are likely to live another 40 years," he said.

Currently, only 8% to 12% of all prostate cancer is treated with active surveillance, said Dr. Carroll.

Dr. Carroll suggested that urologists and their patients need to be educated about active surveillance before issues related to the treatment of prostate cancer go the way of prostate-specific antigen (PSA) testing. "The controversy over PSA testing is now being played out in many mainstream venues, like the New York Times and the Wall Street Journal, and not necessarily urology publications," Dr. Carroll said.

"One of the top 10 news stories of 2009 on CNN is about how men may not need to get a PSA test," he said. "I find that very disturbing," he added.

Dr. Mohler and the NCCN seem to share some of Dr. Carroll's sense of urgency. "The committee felt strongly it was time to say something," Dr. Mohler added.

Other experts stressed that patient and clinician acceptance of active surveillance will grow in time, especially as data mature.

dam Kibel, MD, who is an investigator in the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance and treatment, said there are unknowns. "We don't know if active surveillance is more effective than treatment [with radiotherapy or prostatectomy] as an initial intervention in these patients."

"It is wholly possible that either radical prostatectomy or radiotherapy is more effective," added Dr. Kibel, who is chair of urology at the Washington University School of Medicine in St. Louis, Missouri.

Dr. Kibel said that the use of active surveillance hinges on a bet.

"The bet is that we can detect disease progression before it causes the patient harm," he explained.

Both Dr. Carroll and Dr. Kibel said the risk of patient harm is very small in the context of well-executed active surveillance. "Patients need to understand that there is some risk," said Dr. Carroll.

The NCCN endorsement of active surveillance should give the approach a shot in the arm, suggested Grace Lu-Yao, PhD, MPH, cancer epidemiologist at the Cancer Institute of New Jersey in New Brunswick, and author of a recent study of men on watchful waiting.

"It's likely to help some patients and clinicians consider the option more seriously," she told Medscape Oncology. She pointed out that watchful waiting has been option has in various treatment guidelines, including those of the National Cancer Institute since "at least the early 1990s."

The NCCN on Choosing Men for Active Surveillance

The NCCN defines active surveillance, in part, as "actively monitoring the course of disease with the expectation to intervene if the cancer progresses."

Patients with a low risk are defined as having a stage T1 to T2a tumor, having a Gleason score of 2 to 6, and having a PSA level below 10 ng/mL.

Patients with a very low risk, which is a new designation for the NCCN, are listed as:

• having a stage T1a tumor
• having a Gleason score of 6 or below
• having a PSA level below 10 ng/mL
• having fewer than 3 positive biopsy cores (with <50% cancer in each)
• having a PSA density below 0.15 ng/mL per gram.

For men with a low risk for recurrence and less than 10 years of life expectancy, the recommended monitoring for disease progression is the same as for very-low-risk men with less than 20 years of life expectancy.

In each case, the NCCN calls for PSA testing as often as every 6 months and a digital rectal exam as often as every 12 months. Following a required initial needle biopsy, subsequent biopsy is optional and can be repeated within 18 months, especially if there were 10 or more cores initially. The biopsy can be repeated within 6 months if there were fewer than 10 cores initially.

According to the NCCN, for low-risk men with more than 10 years of life expectancy, a repeat biopsy is required — it is not optional — as often as every 12 months.

This group of men should also be offered radiotherapy and radical prostatectomy as treatment options, says the NCCN.

Dr. Carroll said that the quality of the initial biopsy is key to choosing men for active surveillance. "It must be a well-performed extended-pattern biopsy," he said.

Dr. Mohler said that, in figuring out who is a candidate for active surveillance, estimating life expectancy is an important step.

"Life expectancy is typically less than 20 years for men by age 57," he said, referring to the Social Security Administration's current listing of average life expectancy for American males.

The NCCN also advises that if an individual is in their life's best quartile of health, 50% should be added to the estimation; if in the worst quartile, 50% should be subtracted; and if in the middle 2 quartiles, the estimation should not be altered.

Offering Active Surveillance to Men

The NCCN, in outlining its principles of active surveillance, said that active surveillance should be considered by the patient and "all of his physicians (urologist, radiation oncologist, medical oncologist, and primary care physician)."

In discussing active surveillance with patients who are good candidates, clinicians might want to emphasize the positive, suggested Dr. Mohler, referring to his own methods and not NCCN guidance.

Dr. Mohler said that previous research indicates that there is a period of observation during which low- and very-low-risk men can safely forgo treatment with radiotherapy or prostatectomy.

"No one is harmed in their curability by an 18-month period of observation," he said, citing research by active-surveillance pioneer Laurence Klotz, MD, from Sunnybrook and Women's College Health Sciences Centre in Toronto, Ontario, and others

"Active surveillance affords a man the opportunity to watch his cancer for a short time," he said.

Dr. Mohler explained that this time period allows for an assessment of PSA doubling time, which is one of the indicators of possible disease progression.

"Eighteen months is enough time for 3 more PSA values and a follow-up biopsy," Dr. Mohler noted.

Dr. Kibel, speaking of his experience with the START trial, which randomizes patients to either treatment (radical prostatectomy or radiotherapy) or active surveillance, suggested that education is a key to patient acceptance of active surveillance.

Once educated, some patients in START clearly prefer active surveillance, he said. "Many patients end up being concerned about possibly being randomized to treatment."

Data on Active Surveillance

Dr. Mohler said that the NCCN's confidence about recommending active surveillance stems in part from data from 3 centers — Sunnybrook; the University of California, San Francisco; and Johns Hopkins in Baltimore, Maryland.

"Experience at these centers makes it increasingly clear what happens to men who choose active surveillance," Dr. Mohler said.

In a recently published study by Dr. Klotz and colleagues at Sunnybrook (J Clin Oncol. 2010;28:126-131), the 10-year prostate cancer actuarial survival was 97.2% among low-risk men being treated with active surveillance. One third of the patients were reclassified as higher risk and offered treatment.

Dr. Carroll said that about 600 men are currently being treated with active surveillance at his center at the University of California, San Francisco.

With a median follow-up of "about 3.5 to 4 years," 24% of the patients have gone on to receive treatment, he said.

About one third of those men eventually chose treatment because of anxiety about surveillance" he explained. About two thirds were treated because of clinical changes or disease progression, he added.

There is also an important caveat about the patients in San Francisco: not all of them are "good candidates based on NCCN criteria," said Dr. Carroll.

Of the 600 patients, about one third have a higher Gleason score or some other clinical measure that places them outside the NCCN definition of very low or low risk.

Dr. Carroll explained that he and his colleagues are attempting to develop a "continuum of risk" rather than "rigid risk groups," to provide patients with a numerical value of risk instead placing them in a "box."

"Prostate cancer represents a spectrum of disease," he said, explaining that the risk categorizations of low, intermediate, and high are in need of a "more refined assessment."

Dr. Mohler said that he has 260 men under active surveillance in his personal practice. With a median follow-up of about 5 years, there have been 11 deaths, but none were from prostate cancer, he said. Also, 40% of the men are African Americans, which suggests that the approach works among these men as well, he said.

NEW PARADIGM NEEDED IN CANCER DRUG DEVELOPMENT

January 14, 2009 – A new paradigm for cancer-drug development is needed because the current focus on molecular-targeted compounds that act on key proteins is unlikely to have an impact on the most common cancers, according to Stephen Neidle, DSc, PhD, professor of chemical biology and director of the Center for Cancer Medicines at the School of Pharmacy, University of London, United Kingdom. A more "global" approach is needed, focusing on global differences in the biology, metabolism, or chemistry between normal and cancer cells, he believes.

"The current approach of molecular targeting is like shutting down 1 station in a railway network," he told Medscape Oncology. "This causes some disruption, but does not prevent the rest of the system from operating. What we need is something that can close down the whole system," he says.

Dr. Neidle was speaking last week at the 2010 School of Pharmacy lecture in London.

Molecular targeting has produced useful anticancer drugs, he said, citing as an example the "spectacular success" of imatinib (Gleevec, Novartis) in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). However, he suggested that this success is unlikely to be repeated for the more common cancers.

"We now know that a small number of mostly rarer cancers, such as CML and GIST, are driven by changes in a very few key proteins involved in cell growth," he said. "Targeting these proteins is effective," he conceded. However, most common cancers are genetically complex, he pointed out, and are often diagnosed when this complexity has already spun out of control.

There are also multiple pathways of signaling involved, and blocking one pathway can easily be compensated for elsewhere. "Hitting a single target is unlikely to halt tumor progression in these cancers," he said.

As evidence of this, Dr. Neidle cited the relatively small impact that new targeted therapies have had on the most common cancers, such as colorectal and breast cancer. The addition of these targeted agents has delayed progression or improved survival, but often by only a few weeks, and these new drugs are very expensive.

This has resulted in some of these news drugs not being accepted in the United Kingdom. A number of these drugs have been deemed not to be cost-effective by the National Institute of Clinical Excellent (NICE), and thus are not available on the National Health Service (NHS). These negative decisions have been widely covered in the lay media, he said, with emotive headlines such as "Life prolonging cancer drugs to be banned because they cost too much."

But, in fact, these negative decisions have been in the minority, he pointed out. NICE has appraised 79 cancer drugs, and 59 of these (75%) have been approved for use on the NHS.

Nevertheless, the fact remains that many of the new drugs have only a small impact on the disease. "We need new drugs capable of making a very significant difference to patients' survival," he said.

More "Global" Approach

Dr. Neidle advocated a more global approach to cancer-drug development, which would focus on global differences between normal cells and cancer cells. One approach would be to focus on telomerase, the universal driver of cellular immortality, which is activated in more than 85% of all cancers, he said. Another is the intriguing finding and "long neglected" Warburg effect, first noted 90 years ago, in which glucose levels are elevated in cancer patients. "This is now known to be involved in global cancer cell growth regulation, and has led to excitement and activity over this as a target," he added.

An example of this more global approach to cancer-drug development is abiraterone for the treatment of prostate cancer (which is currently in large phase 3 trials).

It has a novel mechanism of action; it is the first drug to inhibit the synthesis of testosterone, which drives the growth of most hormone-dependent cancers. Although other treatment approaches target testosterone (e.g., androgen-deprivation therapy), these block the hormone after it has been released and work outside the cell, Dr. Neidle pointed out. In contrast, the action of abiraterone is more fundamental — it works inside the cell to stop the hormone being produced.

This drug was originally synthesized in the United Kingdom in 1995, at the Institute for Cancer Research, as a result of a rational design for an inhibitor of the enzyme involved in the biosynthesis of testosterone, Dr. Neidle explained. But at that time, the steroid pathway was not a "fashionable" target, compared with signaling and kinase pathways, and prostate cancer was "until recently relatively ignored," he said. It was difficult to obtain funding in the early 1990s, and initial clinical trials with the drug were abandoned prematurely, he said.

"Abiraterone was rescued by the efforts of Dr. Johann de Bono with a phase 1/2 trial at the Royal Marsden Hospital in patients with advanced prostate cancer," he continued. The results showed a greater than 50% decline in prostate-specific antigen in 71% of patients and marked symptom improvement in a high proportion of patients.

On the basis of these clinical data, the small company, Cobra International, which had licensed the drug from the British Technology Group, was acquired for $1 billion last year by Johnson & Johnson, which is now investigating abiraterone in worldwide clinical trials, Dr. Neidle told the audience. The drug is expected to reach the market in 2011/12 and "will make a big difference to the treatment of prostate cancer," he predicted.

New Drugs Only "Part of the Picture"

New drugs have an important role to play in the 'war on cancer,' but they are only one part of the picture, said Sir Mike Richards, MD, national cancer director at the NHS, who also spoke at the event. Also vitally important is screening for cancer, because earlier diagnosis improves outcomes, and incorporating innovations in surgery and radiotherapy into clinical practice.

Some new drugs are having a very significant impact on cancer, Dr. Richards said, and he cited as examples imatinib in CML, rituximab in non-Hodgkin's lymphoma, and trastuzumab in HER2-positive breast cancer.

"But for many other drugs, the impact on survival or mortality is at best 'modest'," he said, "although individual patients can benefit significantly."

ASA404 A NOVEL VASCULAR DISRUPTING AGENT WITH A NEW MECHANSIM OF ACTION

January 14, 2010 (Coronado, California) — The addition of the experimental agent ASA404 to standard chemotherapy appears to improve outcomes in nonsmall-cell lung cancer (NSCLC). The drug, also known as vadimezan and DMXAA, was originally developed by Antisoma, but has since been acquired by Novartis.

According to the pooled results of a randomized phase 2 trial and a subsequent extension study, combining ASA404 with conventional treatment increased survival in patients with advanced squamous and with nonsquamous NSCLC.

The findings were presented here at the American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy.

Among patients with squamous NSCLC who received the combination therapy, survival was 10.2 months; among those who received only chemotherapy, survival was 5.5 months. In patients with nonsquamous NSCLC, overall survival was 14.9 months for those who received combination therapy and 11 months for those who received chemotherapy alone.

Adding ASA404 to standard therapy did not appear to increase toxicity, and there were no serious adverse events associated with bleeding, pulmonary hemorrhage, or hemoptysis.

"If the results of phase 3 trials confirm these findings, then we may have identified a better treatment option for patients with advanced lung cancer," lead author Mark McKeage, PhD, an associate professor in clinical pharmacology at the University of Auckland in New Zealand, said in an interview.

Different From Other Vascular Disrupters

ASA404 is a small-molecule tumor vascular-disrupting agent that destroys existing tumor vasculature and selectively inhibits tumor blood flow, causing extensive necrosis of the tumor core.

It differs from other vascular-targeting therapies that have been approved or are being investigated, in that it is applicable to both squamous and nonsquamous NSCLC, explained Dr. McKeage. "The efficacy and safety profiles are similar for both groups."

Although treatment options for patients with advanced-stage NSCLC are limited, this is particularly true for patients with squamous histology, because some agents demonstrate limited efficacy or serious toxicity. With agents such as bevacizumab (Avastin) and sorafenib (Nexavar), different safety profiles have been observed in squamous and nonsquamous patients, he pointed out.

As an example, in a phase 2 study that combined bevacizumab with carboplatin and paclitaxel (J Clin Oncol. 2004;22:2184-2191), a higher proportion of patients with squamous NSCLC than with nonsquamous histology experienced life-threatening pulmonary hemorrhage after receiving bevacizumab (31% vs 4%).

Pooled Analysis Shows Improved Survival

In this retrospective analysis, Dr. McKeage and colleagues compared the safety and activity of ASA404 in combination with standard paclitaxel and carboplatin treatment, using pooled results from phase 2 trials of ASA404.

A total of 108 treatment-naive patients with stage IIIb/IV NSCLC were enrolled in a phase 2 multicenter study, and were randomized to receive up to 6 cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 6 mg/mL per min) alone or with ASA404 (1200 mg/m²). Those enrolled in the extension study received the same chemotherapy regimen plus a higher dose of ASA404 (1800 mg/m²).

The data were pooled by histology and by treatment, and the 2 ASA404 doses were aggregated. The safety and activity study end points included response rate, time to tumor progression, and overall survival, and data from the histology subgroups and the treatment group were compared.

For all histologies combined, the median survival was 14.5 months for patients receiving the combination therapy and 8.8 months for chemotherapy alone. Safety data were available for 104 patients, and the most commonly reported grade 3/4 adverse events were blood and lymphatic disorders (n = 19; 18%). The rates of grade 3/4 blood and lymphatic events were not significantly different between the 2 histologic subgroups or between the 2 treatment groups.

"Lung cancer is the only cancer that kills over a million people a year," said Dr. McKeage. "Therapeutic advances have been gradual, incremental, and small in magnitude, but we are taking small steps forward."

These results support the phase 3 trials that are ongoing right now, which have just finished enrollment of 1200 patients, he added. ATTRACT-1 (Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment), will evaluate the addition of ASA404 to first-line treatment regimens in NSCLC, and ATTRACT-2 will evaluate it as part of second-line therapy. The trials have no restrictions on histology. Dr. McKeage predicted that the first results will be available approximately 1 year from now.

The most promising result from this study was that an improvement in survival was observed, said Paul A. Bunn Jr., MD, professor of medicine and James Dudley chair in cancer research at the University of Colorado, Denver.

"This doesn't mean that the phase 3 trials will be positive, but we have strong data going into it," said Dr. Bunn, who was not involved in the study. "The data are strong enough for the company to embark on an expensive phase 3 trial."

The study was funded by Antisoma. Dr. McKeage reports consulting for and receiving research funding from Antisoma and Novartis.

American Association for Cancer Research-International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy: Abstract A22. Presented January 14, 2010.

ALK INHIBITORS FOR A SUBSET OF LUNG ADENOCARCINOMA

January 15, 2010 (Coronado, California) —Targeted therapies, which include monoclonal antibodies and small-molecule inhibitors, are altering the treatment of cancer. A new therapy — ALK inhibitors — might soon be added to the list.

Oncogenic rearrangements of the anaplastic lymphoma kinase (ALK) gene have recently been described in nonsmall-cell lung cancer (NSCLC). Promising results from a phase 1 study, presented here at the American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.

PF02341066, an oral ALK inhibitor being developed by Pfizer, has demonstrated efficacy in ALK-positive patients. Thus far, 31 NSCLC patients with the ALK rearrangement have been enrolled in the study, and a response has been observed in 65% of this cohort.

"There are at least 12 easily identifiable oncogenes now for which there are new therapeutic agents," said Paul A. Bunn Jr., MD, professor of medicine and James Dudley chair in cancer research at the University of Colorado, Denver. "ALK is an oncogene and, in lung cancer, is activated not by mutation but by fusion with another gene."

The chromosomal rearrangements that interrupt the ALK gene and fuse it with another gene result in the creation of oncogenic ALK fusion genes. In turn, these enhance cell proliferation and survival.

"In my opinion, this drug should be approved for use worldwide, based on these data," said Dr. Bunn, who was not involved in the study. "But the [US Food and Drug Administration] has deemed that there are not enough data to approve it, so there is now a randomized trial — just starting in the United States — in which patients will be randomized to either the experimental agent or standard chemotherapy."

Dr. Bunn also noted that although PF02341066 appears to induce more responses than standard chemotherapy, it is not curative. Presumably, he surmised, patients will become resistant to it sooner or later.

Right Drug to the Right Patient

ALK is a receptor tyrosine kinase, which is normally expressed in discrete regions of the developing nervous system, and oncogenic rearrangements of ALK on the short arm of chromosome 2 were first described in anaplastic large-cell lymphomas more than 10 years ago, according to the study authors. Subsequently, they have been observed in other malignancies, including diffuse large B-cell lymphomas and malignant histiocytosis, and in several solid tumors, including inflammatory myofibroblastic tumors, squamous cell carcinomas of the esophagus, neuroblastoma and, most recently, in NSCLC.

ALK rearrangements in NSCLC are relatively rare, explained lead author D. Ross Camidge, MD, PhD, clinical director of the Thoracic Oncology Program at the University of Colorado, Denver. In an unselected NSCLC population, ALK gene rearrangements occur with a frequency of 3% to 5%.

Aside from the focus on a specific molecular target, Dr. Camidge explained, this study represents a paradigm shift in the way drugs are moved from the laboratory into human trials.

"When the right targeted agent is appropriately matched with the right target in the right patient, molecular efficacy hypotheses can now be tested effectively within first-in-human phase 1 studies," he told Medscape Oncology. "This can dramatically shorten the drug approval time by focusing on patients who may derive the most benefit from the drug."

ALK gene rearrangements occur almost exclusively in adenocarcinoma, and there doesn't seem to be any variation by ethnicity. But it is almost never seen in squamous cell or other types of lung cancer, said Dr. Camidge. In addition, light exsmokers or never-smokers appear to have significantly higher frequencies of ALK gene rearrangements.

Early Results Promising

Dr. Camidge and colleagues began the phase 1 trial in 2006, and the trial was originally focused on tumors with markers of cMET activation, one of the most common genetically altered tyrosine kinases in human cancers. However, during the dose-escalation phase, it was reported that ALK gene rearrangements also occur in NSCLC. At that time, lung cancer patients with proven ALK-gene-rearranged tumors were recruited into the study.

To date, 31 evaluable heavily pretreated NSCLC patients with ALK rearrangements have been recruited into the study, and they are continuing to enroll patients, explained Dr. Camidge. Within this cohort, there have been 19 partial responses and 1 complete response; patients remain on therapy for a median of 24 weeks.

"We have not yet reached progression-free survival," he said.

The effectiveness of PF02341066 validates oncogenic ALK rearrangements as a therapeutic target in this molecularly defined subset of NSCLC patients, and has allowed for the evaluation of PF02341066 in a randomized phase 3 setting without the need for a separate phase 2 study.

Other companies are working on ALK inhibitors, but they are further behind this one, said Dr. Bunn. "This particular drug inhibits both ALK and MET, and it was the first one developed."

Genetic Testing for Most Adenocarcinomas

Dr. Bunn pointed out that this study demonstrates that research can move quickly, given the right circumstances. "The fusion gene was first reported in lung cancer in 2007 and, in 2009, the benefit in patients was reported," he said. "Sometimes research in cancer is criticized for moving too slowly, but this is an example of something discovered in the laboratory that is benefiting patients 2 years later."

David Carbone, MD, PhD, Harold L. Moses chair in cancer research and director of the Specialized Program of Research Excellence in Lung Cancer at Vanderbilt-Ingram Cancer, in Nashville, Tennessee, emphasized the increasing importance of genetic testing. "From a wider perspective, with the knowledge of these inhibitors, we think that it is clear that most patients with adenocarcinomas of the lung should have genetic testing of their tumors done on a routine basis," he said.

"This is an extremely important point; none of these patients can be identified by clinical parameters — it is the mutations that identify these patients, and more and more of these drugs are going to become available," said Dr. Carbone, who was not involved with this study.

American Association for Cancer Research-International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy: Abstract A24. Presented January 13, 2009.

INDUCTION CHEMOTHERAPY FOR RECTAL CANCER

. J Clin Oncol. 2010 Jan 11. [Epub ahead of print]

Phase II, Randomized Study of Concomitant Chemoradiotherapy Followed by Surgery and Adjuvant Capecitabine Plus Oxaliplatin (CAPOX) Compared With Induction CAPOX Followed by Concomitant Chemoradiotherapy and Surgery in Magnetic Resonance Imaging-Defined, Locally Advanced Rectal Cancer: Grupo Cancer de Recto 3 Study.

Fernández-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, Vera R, Escudero P, Maurel J, Marcuello E, Luis Mengual J, Saigi E, Estevan R, Mira M, Polo S, Hernandez A, Gallen M, Arias F, Serra J, Alonso V.

Fundacion Instituto Valenciano de Oncología; Hospital General Univeristario; and Hospital Universitario La Fe, Valencia; Corporación Sanitaria Parc Taulí, Sabadell; Hospital Arnau de Vilanova, Lerida; Hospital General, Alicante; Hospital de Navarra, Pamplona; Hospital Clinico Lozano Blesa, Zaragoza; Hospital Clinic; Hospital del Mar Barcelona; and Hospital Santa Creu y Sant Pau, Barcelona; and Clinica Quiron; and Hospital Miguel Servet, Zaragoza, Spain.

PURPOSE: The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS: A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). RESULTS: On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION: Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

NEW TREATMENTS FOR PLATINUM SENSITIVE OVARIAN CANCER

. Int J Gynecol Cancer. 2009 Dec;19 Suppl 2:S63-7.

Changing the paradigm in the treatment of platinum-sensitive recurrent ovarian cancer: from platinum doublets to nonplatinum doublets and adding antiangiogenesis compounds.

Monk BJ, Coleman RL.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California-Irvine, 101 The City Drive, Orange, CA 92868, USA. bjmonk@uci.edu

OBJECTIVES: The optimal treatment for women with recurrent epithelial ovarian cancer is evolving. The objective of this review is to outline the transition away from platinum doublets toward nonplatinum combinations and review emerging data on antiangiogenesis therapy in this setting. MATERIALS AND METHODS: Recently published and presented data as well as ongoing clinical trials are discussed. RESULTS: Current clinical practice largely harmonizes with a paradigm that outlines a treatment algorithm for recurrent ovarian cancer based on the duration of platinum-free exposure. In this model, patients whose penultimate platinum compound exposure (platinum-free interval [PFI]) is longer than 6 months are generally offered a platinum agent or a platinum-containing doublet; those with a shorter interval are usually treated with a single nonplatinum agent. This is based on the simple contention that better clinical outcomes will be realized with platinum in those deemed platinum sensitive (PFI >6 months). However, it is becoming clear from various phase II and phase III clinical studies that the performance of many nonplatinum chemotherapeutic agents is also influenced by this parameter (PFI). Indeed, although definitive comparisons of nonplatinum drugs to novel cytotoxic agents are lacking, the clinical activity of these compounds might approach or exceed that of platinum agents. Although recognized by clinicians, the dichotomy that determines therapy based on PFI has not been formally accepted by the US Food and Drug Administration in all cases of drug labeling. For instance, whereas the combination of gemcitabine and carboplatin is now approved for patients with platinum-sensitive recurrent ovarian cancer, traditionally used platinum-resistant (PFI <6 style="border-bottom: 1px dashed rgb(0, 102, 204); cursor: pointer;" class="yshortcuts" id="lw_1263673965_8">liposomal doxorubicin are also approved by the US Food and Drug Administration as single agents in platinum-sensitive patients. Furthermore, the nonplatinum doublet pegylated liposomal doxorubicin and trabectedin has recently documented comparable activity to platinum combinations among patients with a PFI of longer than 6 months. To that end, the most prolific developmental therapeutics arena in ovarian cancer is biologically targeted therapy, particularly angiogenesis inhibitors. Although it is unknown if the clinical activity from these new agents will respect the chemotherapy-sensitive dichotomy, it is clear that they have the potential to augment efficacy, possibly in both traditionally chemosensitive and chemoresistant phenotypes. CONCLUSIONS: The term platinum sensitive should probably be replaced by chemotherapy sensitive, particularly as new nonplatinum agents and combinations are identified as active in this setting. Nonplatinum doublets are effective in treating platinum-sensitive recurrent disease, and adding antiangiogenesis agents to these combinations is a research priority.

PRIMARY CHEMOTHERAPY FOR INTRACRANIAL GERM CELL TUMORS

Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study.

da Silva NS, Cappellano AM, Diez B, Cavalheiro S, Gardner S, Wisoff J, Kellie S, Parker R, Garvin J, Finlay J.

Department of Pediatric Oncology, IOP-GRAACC/UNIFESP, São Paulo, SP, Brazil. nasjlasaba@terra.com.br

BACKGROUND: The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation. METHODS: Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4-6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4-6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGbeta) and/or CSF HCGbeta <50>50 mIU/ml. RESULTS: Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. CONCLUSION: These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT. Copyright 2009 Wiley-Liss, Inc.