Doctors need to be careful when prescribing macrolide antibiotics to patients on calcium-channel blockers (CCBs) because of an underappreciated drug-drug interaction that can lead to hypotension and shock, new research shows [1]. The findings are important because millions of people take CCBs and many are prescribed antibiotics every year, say Dr Alissa J Wright (University of Toronto, ON) and colleagues in a study published online January 17, 2011 in CMAJ.Although the interaction "is perfectly predictable based upon the pharmacology of the drugs, it has been previously documented in only about five case reports," senior author Dr David Juurlink(University of Toronto, ON) explained to heartwire . He says that this study is the first rigorous attempt to describe the clinical consequences of this interaction: "In a sense, this paper attaches a risk estimate to how dangerous this drug combination is."
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin orclarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
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SURVIVAL BENEFIT WITH MITOXANTRONE IN RELAPSED ALL
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The survival rate for children with acute lymphoblastic leukemia (ALL) has dramatically increased over the past few decades, from about 50% to more than 80%. Despite these advances, patients who relapse often do poorly, and ALL remains a leading cause of death in children.
However, a new study has found that in patients in first relapse, mitoxantrone confers a significant benefit in progression-free and overall survival, compared with idarubicin. In fact, randomization was halted early by the Data and Safety Monitoring Committee because of differences in progression-free and overall survival between the 2 treatment groups.
The study was presented here at the American Society of Hematology 52nd Annual Meeting, and was published in the December 11 issue of the Lancet.
Vaskar Saha, MBBS, PhD, professor of pediatric oncology at the University of Manchester, United Kingdom, and colleagues found that the estimated 3-year progression-free survival was 35.9% (95% confidence interval [CI], 25.9 - 45.9) in children who received idarubicin, compared with 64.6% (95% CI, 54.2 - 73.2) in those who received mitoxantrone (P = .0004).
Similarly, 3-year overall survival was 45.2% (95% CI, 34.5 - 55.3) for idarubicin and 69.0% (95% CI, 58.5 - 77.3; P = .004) for mitoxantrone. "Mitoxantrone almost halved the hazard of an event at any given timepoint for both progression-free and overall survival," the authors note.
Suitable End Points for Drug Assessment
In an accompanying editorial, Martin Schrappe, MD, PhD, from the University Medical Center Schleswig-Holstein, Kiel, Germany, points out that the difference between the 2 regimens "translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment."
Dr. Schrappe notes that another finding of this study concerns end points for drug assessment. The quantitative detection of minimal residual disease has major prognostic importance in both adult and pediatric leukemia, he explains. In the current study, however, minimal residual disease was measured in intermediate-risk patients at the completion of treatment, but no difference could be detected between the 2 study groups.
"On the basis of minimal residual disease as a surrogate end point, this highly efficacious combination of drugs would not have been considered for further assessment," he writes. This finding is relevant "for ongoing discussions on suitable end points for drug assessment."
Lower Toxicity With Mitoxantrone
In the trial, Dr. Saha and colleagues randomized 216 patients from 1 to 18 years of age with first relapse of ALL to receive either idarubicin or mitoxantrone during induction. The trial was undertaken in 22 centers in the United Kingdom and Ireland and 9 in Australia and New Zealand; neither the patients nor the healthcare workers were masked.
All high-risk patients and intermediate-risk patients with postinduction high minimal residual disease underwent allogenic stem cell transplantation after 3 blocks of therapy. Standard-risk patients and the remaining intermediate-risk patients continued with chemotherapy.
Median follow-up was 41 months in both groups, and the estimated 3-year progression-free survival of the entire cohort was 50.3% (95% CI, 42.9 - 57.3); overall survival was 57.1% (49.5 - 63.9). The adjusted hazard ratio for progression-free survival was 0.54 (95% CI, 0.36 - 0.82; P = .003), and for overall survival was 0.56 (95% CI, 0.36 - 0.87, P = .01).
Of 212 evaluable patients, 108 (51%) remain in second complete remission (45 of 109 [41%] in the idarubicin group and 63 of 103 [61%] in the mitoxantrone group).
A third complete remission was achieved in 6 of 38 patients in the idarubicin group and in 3 of 18 in the mitoxantrone group. A total of 49 patients underwent transplantation in each study group, after which 16 (33%) in the idarubicin group and 2 (4%) in the mitoxantrone group relapsed.
The authors note that throughout the trial, grade 3 or higher toxic effects were significantly lower with mitoxantrone than with idarubicin (incidence rate ratio mitoxantrone/idarubicin, 0.86; 95% CI, 0.75 - 0.98; P = .02). The toxic effects during the first 2 phases of the study were significantly higher with idarubicin than with mitoxantrone. These events were primarily hepatic and gastrointestinal.
Cytotoxics Still Have Role
Mitoxantrone has only been infrequently used in therapeutic trials in pediatric ALL, the researchers write. "A perception that optimization has been reached with available drugs has shifted focus towards newer drugs and targeted therapy."
They note that these newer agents will be prohibitively expensive for many patients (whereas mitoxantrone is a cheap and readily available), and clearly need further clinical assessment in this population.
"Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukemia," they conclude.
The study was funded by Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation. Dr. Saha reports participating in speaker bureaus and advisory boards for EUSA Pharma, Genzyme, Medac, Kyowa-Hakko, and Novartis. Coauthor Philip Ancliff, MA, MRCP, MRCPath, from Great Ormond Street Hospital, London, United Kingdom, reports receiving travel support from Genzyme and Gilead. Coauthor Nicholas Goulden, MB, ChB, MRCP, FRCPath, PhD, also from Great Ormond Street Hospital, reports participating in advisory boards for Enzon. Dr. Schrappe has disclosed no relevant financial relationships
However, a new study has found that in patients in first relapse, mitoxantrone confers a significant benefit in progression-free and overall survival, compared with idarubicin. In fact, randomization was halted early by the Data and Safety Monitoring Committee because of differences in progression-free and overall survival between the 2 treatment groups.
The study was presented here at the American Society of Hematology 52nd Annual Meeting, and was published in the December 11 issue of the Lancet.
Vaskar Saha, MBBS, PhD, professor of pediatric oncology at the University of Manchester, United Kingdom, and colleagues found that the estimated 3-year progression-free survival was 35.9% (95% confidence interval [CI], 25.9 - 45.9) in children who received idarubicin, compared with 64.6% (95% CI, 54.2 - 73.2) in those who received mitoxantrone (P = .0004).
Similarly, 3-year overall survival was 45.2% (95% CI, 34.5 - 55.3) for idarubicin and 69.0% (95% CI, 58.5 - 77.3; P = .004) for mitoxantrone. "Mitoxantrone almost halved the hazard of an event at any given timepoint for both progression-free and overall survival," the authors note.
Suitable End Points for Drug Assessment
In an accompanying editorial, Martin Schrappe, MD, PhD, from the University Medical Center Schleswig-Holstein, Kiel, Germany, points out that the difference between the 2 regimens "translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment."
Dr. Schrappe notes that another finding of this study concerns end points for drug assessment. The quantitative detection of minimal residual disease has major prognostic importance in both adult and pediatric leukemia, he explains. In the current study, however, minimal residual disease was measured in intermediate-risk patients at the completion of treatment, but no difference could be detected between the 2 study groups.
"On the basis of minimal residual disease as a surrogate end point, this highly efficacious combination of drugs would not have been considered for further assessment," he writes. This finding is relevant "for ongoing discussions on suitable end points for drug assessment."
Lower Toxicity With Mitoxantrone
In the trial, Dr. Saha and colleagues randomized 216 patients from 1 to 18 years of age with first relapse of ALL to receive either idarubicin or mitoxantrone during induction. The trial was undertaken in 22 centers in the United Kingdom and Ireland and 9 in Australia and New Zealand; neither the patients nor the healthcare workers were masked.
All high-risk patients and intermediate-risk patients with postinduction high minimal residual disease underwent allogenic stem cell transplantation after 3 blocks of therapy. Standard-risk patients and the remaining intermediate-risk patients continued with chemotherapy.
Median follow-up was 41 months in both groups, and the estimated 3-year progression-free survival of the entire cohort was 50.3% (95% CI, 42.9 - 57.3); overall survival was 57.1% (49.5 - 63.9). The adjusted hazard ratio for progression-free survival was 0.54 (95% CI, 0.36 - 0.82; P = .003), and for overall survival was 0.56 (95% CI, 0.36 - 0.87, P = .01).
Of 212 evaluable patients, 108 (51%) remain in second complete remission (45 of 109 [41%] in the idarubicin group and 63 of 103 [61%] in the mitoxantrone group).
A third complete remission was achieved in 6 of 38 patients in the idarubicin group and in 3 of 18 in the mitoxantrone group. A total of 49 patients underwent transplantation in each study group, after which 16 (33%) in the idarubicin group and 2 (4%) in the mitoxantrone group relapsed.
The authors note that throughout the trial, grade 3 or higher toxic effects were significantly lower with mitoxantrone than with idarubicin (incidence rate ratio mitoxantrone/idarubicin, 0.86; 95% CI, 0.75 - 0.98; P = .02). The toxic effects during the first 2 phases of the study were significantly higher with idarubicin than with mitoxantrone. These events were primarily hepatic and gastrointestinal.
Cytotoxics Still Have Role
Mitoxantrone has only been infrequently used in therapeutic trials in pediatric ALL, the researchers write. "A perception that optimization has been reached with available drugs has shifted focus towards newer drugs and targeted therapy."
They note that these newer agents will be prohibitively expensive for many patients (whereas mitoxantrone is a cheap and readily available), and clearly need further clinical assessment in this population.
"Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukemia," they conclude.
The study was funded by Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation. Dr. Saha reports participating in speaker bureaus and advisory boards for EUSA Pharma, Genzyme, Medac, Kyowa-Hakko, and Novartis. Coauthor Philip Ancliff, MA, MRCP, MRCPath, from Great Ormond Street Hospital, London, United Kingdom, reports receiving travel support from Genzyme and Gilead. Coauthor Nicholas Goulden, MB, ChB, MRCP, FRCPath, PhD, also from Great Ormond Street Hospital, reports participating in advisory boards for Enzon. Dr. Schrappe has disclosed no relevant financial relationships
8 HPV TYPES CAUSE 90% OF CERVICAL CANCER
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A massive multinational cervical cancer study described as "the benchmark for all time" has confirmed that 8 human papillomavirus (HPV) types cause more than 90% of all cervical cancers worldwide, and that HPV 16, 18, and 45 cause 94% of cervical adenocarcinomas.
The study was published online October 15 in the Lancet Oncology.
The research team, led by Silvia de Sanjose, MD, from Institut Català d'Oncologia-Catalan Institute of Oncology in Barcelona, Spain, concludes that "HPV types 16, 18, 31, 33, 34, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines."
Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America, in Philadelphia, Pennsylvania, told Medscape Medical News: " I suspect the next generation of cervix cancer vaccines will specifically include each of the 8 HPV types noted in this paper, since this will cover 90% of the cases of cervix cancer."
Currently, the 2 HPV vaccines on the market — Gardasil (Merck & Co) and Cervarix (GlaxoSmithKline) — protect against subtypes 16 and 18; together, these cause 70% of cervical cancer. In addition, Gardasil offers protection against 2 other subtypes (HPV 6 and 11) that cause genital warts.
However, there has been some evidence that the current vacciness might offer at least some cross-protection against other cervical cancer subtypes. A Merck research team, led by Janine Bryan, PhD, reported that Gardasil immunization induces antibodies capable of neutralizing HPV 45 in vitro (Hum Vaccin. 2007;3:109-115). The cross-reactive, cross-neutralizing antibodies were generated at reduced titers, compared with vaccine-specific types, and the researchers emphasized that antibody titers required for cross-protection against nonvaccine types were not known at that time.
The mechanism behind the cross-neutralization is that a single HPV species can contain several types. The HPV A9 species that contains type 18 also contains type 45. The HPV A7 species that contains type 16 also contains type 58, which was linked to cervical cancer in the de Sanjose multinational study.
There are also conclusions from the latest study on HPV screening. The researchers note that "our results also suggest that type-specific, high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45."
HPV 16, 18, and 45 are the most common types, and occur at a much younger age than other high-risk HPV genotypes. As such, these 3 HPV types should be the focus of future type-specific HPV screening, say the authors.
Massive Multinational Study
The researchers in this retrospective cross-sectional study collected samples from 10,575 cases of invasive cervical cancer diagnosed between 1949 and 2009 from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Polymerase chain reaction and DNA testing were used to identify the HPV genotype present in these tissue samples. They found that 8977 (85%) were positive for HPV DNA.
Over the 60-year study period, the 8 most common HPV types identified were (in descending order of frequency) 16, 18, 45, 33, 31, 52, 58, and 35. Together, they account for 91% of all cases of cervical cancer. HPV 16, 18, and 45 were found in 75% of the most common type of cervical cancer (squamous cell) and in 94% of adenocarcinomas (the second most common form).
Across 5 continents and despite a wide variety of screening programs, women infected with HPV types 16, 18, and 45 were diagnosed with cervical cancers an average of 4 years earlier than women with other high-risk HPV types. The researchers also found that HPV 16, 18, and 45 were more likely to be integrated into the human genome than other HPV types.
The authors recommend that, in light of the early presentation of cases of invasive cervical cancer that were positive for HPV 45, this genotype should be considered in type-specific screening protocols, and women who are positive should be offered closer surveillance.
Future Directions
The authors conclude that "this international effort . . . reinforces the rationale for prevention of cervical cancer through use of existing vaccines."
In an editorial comment that accompanied the study, Cosette Wheeler, MD, from the University of New Mexico Health Sciences Center, in Albuquerque, suggests that the HPV-negative cases were likely due to artifacts such as tissue inadequacy, nucleic-acid degradation in formalin-fixed tissues, low viral loads, and potential misdiagnosis, in part due to the absence of staging data and of stains to exclude samples of endometrial origin.
"Although a minor fraction of invasive cervical cancer might still arise, independent of HPV, studies of fresh-frozen cancer tissues suggest that this is only a small percentage of all invasive cancers," Dr. Wheeler writes.
Dr. Wheeler concludes that "the overall HPV prevalence data confirm the inclusion of specific pools of high-risk HPV in routine cervical screening and in the next generation of HPV vaccines."
Dr. de Sanjose reports receiving consultancy fees from Qiagen, Sanofi, and GlaxoSmithKline. Dr. Wheeler reports receiving research funding from Roche Molecular Systems, Merck & Co., and GlaxoSmithKline, and travel support from GlaxoSmithKline.
The study was published online October 15 in the Lancet Oncology.
The research team, led by Silvia de Sanjose, MD, from Institut Català d'Oncologia-Catalan Institute of Oncology in Barcelona, Spain, concludes that "HPV types 16, 18, 31, 33, 34, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines."
Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America, in Philadelphia, Pennsylvania, told Medscape Medical News: " I suspect the next generation of cervix cancer vaccines will specifically include each of the 8 HPV types noted in this paper, since this will cover 90% of the cases of cervix cancer."
Currently, the 2 HPV vaccines on the market — Gardasil (Merck & Co) and Cervarix (GlaxoSmithKline) — protect against subtypes 16 and 18; together, these cause 70% of cervical cancer. In addition, Gardasil offers protection against 2 other subtypes (HPV 6 and 11) that cause genital warts.
However, there has been some evidence that the current vacciness might offer at least some cross-protection against other cervical cancer subtypes. A Merck research team, led by Janine Bryan, PhD, reported that Gardasil immunization induces antibodies capable of neutralizing HPV 45 in vitro (Hum Vaccin. 2007;3:109-115). The cross-reactive, cross-neutralizing antibodies were generated at reduced titers, compared with vaccine-specific types, and the researchers emphasized that antibody titers required for cross-protection against nonvaccine types were not known at that time.
The mechanism behind the cross-neutralization is that a single HPV species can contain several types. The HPV A9 species that contains type 18 also contains type 45. The HPV A7 species that contains type 16 also contains type 58, which was linked to cervical cancer in the de Sanjose multinational study.
There are also conclusions from the latest study on HPV screening. The researchers note that "our results also suggest that type-specific, high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45."
HPV 16, 18, and 45 are the most common types, and occur at a much younger age than other high-risk HPV genotypes. As such, these 3 HPV types should be the focus of future type-specific HPV screening, say the authors.
Massive Multinational Study
The researchers in this retrospective cross-sectional study collected samples from 10,575 cases of invasive cervical cancer diagnosed between 1949 and 2009 from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Polymerase chain reaction and DNA testing were used to identify the HPV genotype present in these tissue samples. They found that 8977 (85%) were positive for HPV DNA.
Over the 60-year study period, the 8 most common HPV types identified were (in descending order of frequency) 16, 18, 45, 33, 31, 52, 58, and 35. Together, they account for 91% of all cases of cervical cancer. HPV 16, 18, and 45 were found in 75% of the most common type of cervical cancer (squamous cell) and in 94% of adenocarcinomas (the second most common form).
Across 5 continents and despite a wide variety of screening programs, women infected with HPV types 16, 18, and 45 were diagnosed with cervical cancers an average of 4 years earlier than women with other high-risk HPV types. The researchers also found that HPV 16, 18, and 45 were more likely to be integrated into the human genome than other HPV types.
The authors recommend that, in light of the early presentation of cases of invasive cervical cancer that were positive for HPV 45, this genotype should be considered in type-specific screening protocols, and women who are positive should be offered closer surveillance.
Future Directions
The authors conclude that "this international effort . . . reinforces the rationale for prevention of cervical cancer through use of existing vaccines."
In an editorial comment that accompanied the study, Cosette Wheeler, MD, from the University of New Mexico Health Sciences Center, in Albuquerque, suggests that the HPV-negative cases were likely due to artifacts such as tissue inadequacy, nucleic-acid degradation in formalin-fixed tissues, low viral loads, and potential misdiagnosis, in part due to the absence of staging data and of stains to exclude samples of endometrial origin.
"Although a minor fraction of invasive cervical cancer might still arise, independent of HPV, studies of fresh-frozen cancer tissues suggest that this is only a small percentage of all invasive cancers," Dr. Wheeler writes.
Dr. Wheeler concludes that "the overall HPV prevalence data confirm the inclusion of specific pools of high-risk HPV in routine cervical screening and in the next generation of HPV vaccines."
Dr. de Sanjose reports receiving consultancy fees from Qiagen, Sanofi, and GlaxoSmithKline. Dr. Wheeler reports receiving research funding from Roche Molecular Systems, Merck & Co., and GlaxoSmithKline, and travel support from GlaxoSmithKline.
3 DRUG INDUCTION CHEMOTHERAPY BEST FOR LOCALLY ADVANCED HEAD AND NECK CANCER?
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The addition of docetaxel to standard induction chemotherapy with cisplatin and fluorouracil (PF) significantly improves the long-term survival of patients with locally advanced squamous cell head and neck cancer, reducing their likelihood of dying by 26% over 6 years.
These long-term results from the TAX 324 trial, published online January 12 in the Lancet Oncology, confirm that the 3-drug regimen — docetaxel, cisplatin, and fluorouracil (TPF) — should become the standard of care for all patients with locally advanced squamous cell cancer of the head and neck who are candidates for induction chemotherapy, say the authors.
"This is the longest follow-up with this regimen, and it is the longest follow-up of any regimen in head and neck cancer," said lead author Jochen Lorch, MD, from Harvard Medical School in Boston, Massachusetts. "The results from our study will definitely lay the concerns as to whether TPF is truly superior to PF to rest."
This study with 6-year results confirms earlier data showing the superiority of the 3-drug regimen; the 2-year results were published in 2007 (N Engl J Med. 2007; 357:1705-1715).
Comparing 3- and 2-Drug Regimens
The TAX 324 trial involved 501 patients with stage 3 or 4 disease randomized to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy for 5 days per week for 7 weeks.
The TPF regimen consisted of docetaxel 75 mg/m2, followed by intravenous cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 per day, administered as a continuous 24-hour infusion for 4 days. The PF regimen consisted of intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days.
Most patients (69%) had 3 or more years of follow-up. Significantly more patients survived in the TPF group than in the PF group (hazard ratio, 0.70; P = .006). Median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006).
The study also found that patients treated with TPF had better locoregional control (P = .04), but the incidence of distant metastases did not differ significantly.
Benefits Endure With Time
To see whether these benefits endured with time, Dr. Lorch and his colleagues performed an analysis of data gathered retrospectively from the TAX 324 patients' medical records as of December 1, 2008.
With a median follow-up of 72.2 months (95% confidence interval [CI], 68.8 to 75.5), they found that the original survival advantage was sustained.
The median overall survival in the TPF group was 70.6 months (95% CI, 49.0 to 89.0); in the PF group, it was 34.8 months (95% CI, 22.6 to 48.0; P = .014).
The estimated survival at 5 years was 52% in the TPF group and 42% in the PF group. Progression-free survival was significantly longer for patients receiving TPF than for those receiving PF (median, 38.1 vs 13.2 months).
In a subgroup analysis, patients with hypopharyngeal and laryngeal tumors had significantly longer progression-free survival with TPF than with PF (median, 20.9 vs 10.1 months). They also had a significantly lower risk for disease progression than PF-treated patients.
Patients with larynx and hypopharynx disease also fared better if they received TPF. Their median overall survival was 51.9 months, compared with 23.5 months for those treated with PF.
Surrogates for Toxicity
In addition, the researchers looked at tracheostomy and dependence on a gastric feeding tube as surrogates for treatment-related long-term toxicity. They report that no significant differences in these measures were detected between the treatment groups.
In the TPF group, 3 of 91 patients (3%) remained feeding-tube dependent, compared with 8 of 71 patients (11%) in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, compared with 8 of 71 patients (11%) in the PF group.
"The data suggest that TPF is at least not any worse, and if anything may be a little better in terms of the long-term toxicities of feeding tubes and tracheostomies, but those data were somewhat limited," Dr. Lorch said.
"It was a little difficult to get reliable data because often there was no mention of whether they had tracheostomies or feeding tubes. When patients are being followed for years, it may not always be mentioned in physicians' notes, so this was one limitation of our study," he told Medscape Medical News.
Nevertheless, Dr. Lorch said that the take-home message for oncologists is that TPF should be considered the regimen of choice in squamous cell head and neck cancer patients with large primary tumors or extensive lymphadenopathy.
In an accompanying editorial, June Corry, MD, and Danny Rischin, MD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, agree that the continued superior results with TPF over PF definitively answer the question of which regimen is better.
But Role of Induction Is Unclear
However, the editorialists point out that the role of induction chemotherapy in the overall treatment of locally advanced head and neck cancer is still unclear.
"Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation," they write. "Weekly low-dose carboplatin (as used in TAX 324) is not a recognized standard concomitant regimen, and no data are available showing it to be better than radiation alone."
The lack of comparative data raises concerns that subjecting patients to a protracted course of treatment "might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival in locally advanced head and neck cancer," they write.
Some trials comparing sequential regimens with induction TPF and concomitant chemoradiation have closed early. "Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy," they write.
Drs. Corry and Rischin also note that oropharyngeal cancers that are associated with human papillomavirus (HPV) have better outcomes than HPV-negative cancers. They warn that not stratifying patients according to their HPV status might confound the interpretation of such trials.
The study was supported by Sanofi-Aventis. Dr. Lorch, Dr. Corry, and Dr. Rischin have have disclosed no relevant financial relationships.
These long-term results from the TAX 324 trial, published online January 12 in the Lancet Oncology, confirm that the 3-drug regimen — docetaxel, cisplatin, and fluorouracil (TPF) — should become the standard of care for all patients with locally advanced squamous cell cancer of the head and neck who are candidates for induction chemotherapy, say the authors.
"This is the longest follow-up with this regimen, and it is the longest follow-up of any regimen in head and neck cancer," said lead author Jochen Lorch, MD, from Harvard Medical School in Boston, Massachusetts. "The results from our study will definitely lay the concerns as to whether TPF is truly superior to PF to rest."
This study with 6-year results confirms earlier data showing the superiority of the 3-drug regimen; the 2-year results were published in 2007 (N Engl J Med. 2007; 357:1705-1715).
Comparing 3- and 2-Drug Regimens
The TAX 324 trial involved 501 patients with stage 3 or 4 disease randomized to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy for 5 days per week for 7 weeks.
The TPF regimen consisted of docetaxel 75 mg/m2, followed by intravenous cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 per day, administered as a continuous 24-hour infusion for 4 days. The PF regimen consisted of intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days.
Most patients (69%) had 3 or more years of follow-up. Significantly more patients survived in the TPF group than in the PF group (hazard ratio, 0.70; P = .006). Median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006).
The study also found that patients treated with TPF had better locoregional control (P = .04), but the incidence of distant metastases did not differ significantly.
Benefits Endure With Time
To see whether these benefits endured with time, Dr. Lorch and his colleagues performed an analysis of data gathered retrospectively from the TAX 324 patients' medical records as of December 1, 2008.
With a median follow-up of 72.2 months (95% confidence interval [CI], 68.8 to 75.5), they found that the original survival advantage was sustained.
The median overall survival in the TPF group was 70.6 months (95% CI, 49.0 to 89.0); in the PF group, it was 34.8 months (95% CI, 22.6 to 48.0; P = .014).
The estimated survival at 5 years was 52% in the TPF group and 42% in the PF group. Progression-free survival was significantly longer for patients receiving TPF than for those receiving PF (median, 38.1 vs 13.2 months).
In a subgroup analysis, patients with hypopharyngeal and laryngeal tumors had significantly longer progression-free survival with TPF than with PF (median, 20.9 vs 10.1 months). They also had a significantly lower risk for disease progression than PF-treated patients.
Patients with larynx and hypopharynx disease also fared better if they received TPF. Their median overall survival was 51.9 months, compared with 23.5 months for those treated with PF.
Surrogates for Toxicity
In addition, the researchers looked at tracheostomy and dependence on a gastric feeding tube as surrogates for treatment-related long-term toxicity. They report that no significant differences in these measures were detected between the treatment groups.
In the TPF group, 3 of 91 patients (3%) remained feeding-tube dependent, compared with 8 of 71 patients (11%) in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, compared with 8 of 71 patients (11%) in the PF group.
"The data suggest that TPF is at least not any worse, and if anything may be a little better in terms of the long-term toxicities of feeding tubes and tracheostomies, but those data were somewhat limited," Dr. Lorch said.
"It was a little difficult to get reliable data because often there was no mention of whether they had tracheostomies or feeding tubes. When patients are being followed for years, it may not always be mentioned in physicians' notes, so this was one limitation of our study," he told Medscape Medical News.
Nevertheless, Dr. Lorch said that the take-home message for oncologists is that TPF should be considered the regimen of choice in squamous cell head and neck cancer patients with large primary tumors or extensive lymphadenopathy.
In an accompanying editorial, June Corry, MD, and Danny Rischin, MD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, agree that the continued superior results with TPF over PF definitively answer the question of which regimen is better.
But Role of Induction Is Unclear
However, the editorialists point out that the role of induction chemotherapy in the overall treatment of locally advanced head and neck cancer is still unclear.
"Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation," they write. "Weekly low-dose carboplatin (as used in TAX 324) is not a recognized standard concomitant regimen, and no data are available showing it to be better than radiation alone."
The lack of comparative data raises concerns that subjecting patients to a protracted course of treatment "might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival in locally advanced head and neck cancer," they write.
Some trials comparing sequential regimens with induction TPF and concomitant chemoradiation have closed early. "Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy," they write.
Drs. Corry and Rischin also note that oropharyngeal cancers that are associated with human papillomavirus (HPV) have better outcomes than HPV-negative cancers. They warn that not stratifying patients according to their HPV status might confound the interpretation of such trials.
The study was supported by Sanofi-Aventis. Dr. Lorch, Dr. Corry, and Dr. Rischin have have disclosed no relevant financial relationships.
FALLOPIAN TUBE CANCER STAGING
|
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis:Carcinoma in situ (limited to tubal mucosa)
T1: Tumor limited to the fallopian tube(s)
T1A: Tumor limited to one tube, without penetrating the serosal surface; no ascites
T1B: Tumor limited to both tubes, without penetrating the serosal surface; no ascites
T1C: Tumor limited to one or both tubes with extension onto or through the tubal
serosa, or with malignant cells in ascites or peritoneal washings
T2: Tumor involves one or both fallopian tubes with pelvic extension
T2A: Extension and/or metastasis to the uterus and/or ovaries
T2B: Extension to other pelvic structures
T2C: Pelvic extension with malignant cells in ascites or peritoneal washings
T3: Tumor involves one or both fallopian tubes, with peritoneal implants outside the
pelvis
T3A: Microscopic peritoneal metastasis outside the pelvis
T3B: Macroscopic peritoneal metastasis outside the pelvis 2 cm or less in greatest
dimension
T3C: Peritoneal metastasis outside the pelvis and more than 2 cm in diameter
* FIGO no longer includes Stage 0 (Tis)
Note: Liver capsule metastasis is T3/Stage III; liver parenchymal metastasis
M1/Stage IV. Pleural effusion must have positive cytology for M1/Stage IV.
REGIONAL LYMPH NODES (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
DISTANT METASTASIS (M)
M0: No distant metastasis (no pathologic M0; use clinical M to complete stage group)
M1: Distant metastasis (excludes metastasis within the peritoneal cavity)
PATHOLOGIC STAGE GROUPING
GROUP T N M
0* Tis N0 M0
I T1 N0 M0
IA T1a N0 M0
IB T1b N0 M0
IC T1c N0 M0
II T2 N0 M0
IIA T2a N0 M0
IIB T2b N0 M0
IIC T2c N0 M0
III T3 N0 M0
IIIA T3a N0 M0
IIIB T3b N0 M0
IIIC T3c N0 M0-Any T N1 M0
IV Any T Any N M1
*FIGO no longer includes Stage 0 (Tis)
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