The addition of albumin-bound paclitaxel (nab-paclitaxel) to the treatment standard gemcitabine significantly lengthened survival in patients with metastatic pancreatic cancer, researchers report (

The results are from the phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), which found that nab-paclitaxel added to gemcitabine significantly improved overall survival (OS), the primary efficacy endpoint, as well as the secondary endpoints of progression-free survival (PFS) and response rate.

“This large, randomized, international phase III study showed that nab-paclitaxel plus gemcitabine led to a significant improvement in survival at all time points,” Daniel D. Von Hoff, MD, distinguished professor and physician-in-chief at the Virginia G. Piper Cancer Center at Scottsdale Healthcare/Translational Genomics Research Institute, and colleagues write.

The team randomized 861 patients to receive nab-paclitaxel 125 mg/m

 days 1, 8, and 15 every 4 weeks or gemcitabine alone 1000 mg/m

 weekly for 7 weeks, and afterwards on days 1, 8, and 15 every 4 weeks in the first-line setting. Study participants had a Karnofsky performance-status score ≥70 and had not previously received chemotherapy for metastatic disease.

On the basis of the trial’s results, the FDA recently approved the nab-paclitaxel/gemcitabine combination for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas. Pancreatic cancer is the fourth leading cause of cancer-related mortality in Europe and the United States, the authors pointed out. Gemcitabine has long been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer. The 5-year survival rate in patients with metastatic disease is 2%. Patients receiving gemcitabine have been found to have 1-year survival rates of 17% to 23%. The present study was prompted by findings from a phase I-II trial of nab-paclitaxel combined with gemcitabine that demonstrated promising efficacy and a manageable safety profile in previously untreated patients with metastatic pancreatic adenocarcinoma.

In the present study, the median OS was 8.5 months for the nab-paclitaxel-gemcitabine group and 6.7 months for the gemcitabine monotherapy. The 1-year survival rates were 35% and 22% in the two groups, respectively, whereas the 2-year survival rates were 9% and 4%.

The nab-paclitaxel-gemcitabine cohort had a median PFS of 5.5 months versus 3.7 months for the gemcitabine monotherapy cohort. The response rate determined by independent review was significantly higher with nab-paclitaxel plus gemcitabine than with solo gemcitabine. Combination therapy was superior for most prespecified subgroups.

The median duration of treatment was 3.9 months for combination therapy and 2.8 months for treatment with gemcitabine alone.

The overall safety profile for the two treatment regimens was in line with that cited in earlier reports. The rate of serious life-threatening events was similar with the two regimens, and adverse events were usually grade 3 or lower and resolved without specific treatment.

Peripheral neuropathy, however, occurred more often in patients who received combination therapy but generally rapidly resolved when nab-paclitaxel was withdrawn temporarily after which the dosage was decreased and treatment resumed.

The investigators point out that the study was conducted at academic and community centers in North America, Europe, and Australia. Additional strengths included the use of randomization and the large sample, which produced similar treatment groups.

They added that a shortcoming of their study was that they did not measure quality of life.

	The results of the MPACT study are very exciting to any oncology nurse. Those of us of a certain age remember when essentially all we had to offer was fluorouracil (5FU) or palliative care.

	Gemcitabine was approved in 1996 as first-line treatment for patients with locally advanced or metastatic adenocarcinoma of the pancreas for patients previously treated with 5FU. Gemcitabine not only increased overall survival (OS) but improved quality of life, and became the gold standard for treating adenocarcinoma of the pancreas. Over the years it was used in various combinations, ie, GTX (gemcitabine/docetaxel/ capecitabine).

	In 2004, a retrospective study looked at GTX and determined it demonstrated excellent response rates and superior survival; however, no phase III studies were done comparing it with gemcitabine alone. Gemcitabine was also used in combination with oxaliplatin (gem/ox); however, this never became a standard of care.

	In 2010 the PRODIGE 4/ACCORD 11 trial found the FOLFIRINOX (fluorouracil/leucovorin/irinotecan/ oxaliplatin) regimen doubled median progression-free survival and improved median overall survival from 6.8 months to 11.1 months when compared to gemcitabine in patients with metastatic adenocarcinoma of the pancreas. This essentially revolutionized the treatment of metastatic pancreatic cancer. The downside is that this is a very difficult regimen for patients to tolerate. It requires growth factor support, aggressive antiemetics, and, frequently, visits to our center for intravenous fluids due to dehydration either from inadequate intake or diarrhea. In addition, those patients who are elderly and/or with many comorbidities might not be good candidates for such an aggressive therapy.

	Now in 2013 comes MPACT which showed that the addition of nab-paclitaxel to gemcitabine significantly improved OS, as well as progression-free survival (PFS) and response rate compared with gemcitabine alone. This led to its approval for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas. Unbelievably, we now have another weapon in our arsenal. This regimen would certainly be appropriate for many of the patients who either are not be able to tolerate FOLFIRINOX, or even for those patients who progress on FOLFIRINOX, and would certainly offer a better outcome than gemcitabine alone. While outcomes are still not what we would like to see, we certainly are able to offer patients better outcomes than we could even 5 years ago. Hopefully, this trend will continue.

Articles

The addition of albumin-bound paclitaxel (nab-paclitaxel) to the treatment standard gemcitabine significantly lengthened survival in patients with metastatic pancreatic cancer

Nab-Paclitaxel Boosts Survival in Pancreatic Cancer

		Robert Morreale/Visual explanations, LLC

	Older patients with advanced hematologic malignancies who receive a minimally toxic nonmyeloablative regimen before allogeneic hematopoietic cell transplantation (HCT) have favorable overall survival (OS) and progression-free survival (PFS) rates, according to the results of a recent study.

	Mohammed L. Sorror, MD, with Fred Hutchinson Cancer Research Center, and colleagues examined outcomes in 372 patients who underwent conditioning with a low dose of total body irradiation either alone or combined with 90 mg/m2 of fludarabine prior to HCT. Postgrafting immunosuppression included mycophenolate mofetil plus a calcineurin inhibitor (cyclosporine or tacrolimus) in different schedules.

	Subjects were aged 60 to 75 years with advanced hematologic malignancies who underwent HCT in multicenter prospective clinical trials from 1998 to 2008. The patients were divided into 3 groups according to age: 218 patients were aged 60 to 64 years, 121 patients were aged 65 to 69 years, and 33 patients were aged 70 to 75 years.

		Adult Blood & Marrow Stem Cell Transplantation Program

		While the prevalence of most hematologic malignancies increases with age, advanced age has historically been a limiting factor to proceed with HCT. With the advent of nonmyeloablative conditioning regimens, patients who may have been previously excluded from HCT due to older age may now be eligible for transplant.

		Sorror et al, report a 5-year survival rate of 35% with minimal organ toxicity. These results are encouraging, and may offer a potentially curable treatment to older adults who are ineligible for myeloablative conditioning regimens.

		Older patients undergoing allogeneic HCT have different issues compared to younger patients. These include the number of comorbidities and its effects in terms of medication interactions; prescription coverage, as many of these patients have Medicare; and increased organ toxicity.

		Utilization of a nonmyeloablative conditioning regimen addresses each of these issues, making it reasonable to consider HCT in patients otherwise ineligible. Evaluating patients and utilizing risk assessment strategies to determine functional age (compared to chronological age) may help predict which type of conditioning regimen is best suited for each individual.

		The projected incidence of newly diagnosed hematologic malignancies is climbing; therefore, incorporating curative treatment options to a larger subset of this population is undoubtedly appealing. By broadening the eligibility criteria for HCT, future direction and possible changes made to healthcare policy may be necessary.

	Irrespective of age, the 5-year OS and PFS rates were 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. The 5-year survival rates ranged from 23% (95% CI, 11%-35%) in patients who had high comorbidity burden, and high relapse risk to 69% (95% CI, 44%-95%) in patients with low comorbidity burden and low relapse risk. Also, half of these patients were never hospitalized, and two-thirds of survivors had eventual resolution of their chronic graft versus host disease with restoration of normal or near-normal physical function as demonstrated by their Karnofsky Performance Status scores.

	Sorror and associates said that their findings are “encouraging,” especially with respect to relapse, considering the poor outcomes seen with nontransplantation treatments. They did note, however, that a major drawback of their study was the lack of a control group receiving standard therapy or supportive care.

	Increasing age has long been blamed for the higher mortality after high-dose allogeneic HCT for patients with hematologic malignancies. The intense, cytotoxic conditioning regimens that precede transplantation are intended to decrease tumor burden but may cause organ toxicity. As a result, only younger, healthy patients have been deemed eligible for high-dose HCT.

	A longstanding cutoff age of 55 to 60 years has meant that most patients with hematologic malignancies have been denied allogeneic HCT, given that hematologic malignancies are primarily diseases of the elderly, with the median age at diagnosis of most hematologic malignancies ranging from 65 to 70 years.

	Also, the availability of good treatment options for older patients with advanced hematologic malignancies is becoming increasingly important. With current demographic trends, it is projected that 20% of the population will be aged 65 years or older within the next 2 decades, and also that the number of newly diagnosed hematologic malignancies in older populations will increase by 77%.

	Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. 

Older patients with advanced hematologic malignancies who receive a minimally toxic nonmyeloablative regimen before allogeneic HCT have favorable OS and PFS rates.

Nonmyeloablative Conditioning Before Cell Transplantation Shows Potential in Older Patients With Hematologic Malignancies

New findings demonstrate a recent increase in the annual completion rates of vaccination against human papillomavirus (HPV) infection, which is a necessary cause of cervical cancer. However, the data, from a large and nationally representative sample of female adolescents, also show that significant gaps persist in vaccination completion according to race/ethnicity and poverty.

	Linda M. Niccolai, PhD, with the Yale School of Public Health in New Haven, Connecticut, and associates used data obtained in the 2008 and 2009 National Immunization Survey on teenage girls (NIS-Teen) who received at least 1 dose of HPV vaccine.

	Two HPV vaccines are approved by the FDA to protect against HPV-16 and HPV-18, which are responsible for 70% of cervical cancer cases. The Advisory Committee on Immunization Practices (ACIP) recommends the routine use of either vaccine in a 3-dose series for girls aged 11 or 12 years. The second and third doses should be given at 2 and 6 months, respectively. A catch-up vaccination is also recommended up to age 26 for girls and women who did not previously receive all 3 doses.

	Several studies have documented suboptimal HPV vaccination completion rates ranging from 13% to 16%. White adolescents have been found to be more likely to complete the series than Hispanics and blacks, and teens with private insurance were more likely to complete the series than teens with public insurance.

	However, prior studies showing disparities in HPV vaccination completion have been plagued by limitations. For example, the earlier investigations did not directly examine completion rates using multivariate modeling to assess independent correlates of completion. They have also been limited by small "and possibly nonrepresentative samples."

	The primary outcome measure in the present study was completion of the 3-dose series defined as having received at least 3 doses of either vaccine as documented in healthcare provider reports.

	Overall, 55% of girls who had initiated HPV vaccination completed the 3-dose series, 21% received 1 dose, and 24% received 2 doses.

	The percentage that completed the series was significantly higher in 2009 than 2008 (60% vs 48%; 

	After adjusting for covariates, including access to care, adolescents who were black (adjusted odds ratio [AOR] = 0.48; 95% confidence interval [CI] = 0.40-0.57) or Hispanic (AOR = 0.75; 95% CI = 0.64- 0.88) were significantly less likely to complete the vaccination series than whites. Adolescents living below the federal poverty level were significantly less likely to complete vaccination than adolescents with household incomes > $75,000 (AOR = 0.76; 95% CI = 0.63-0.92).

	The interaction between race/ethnicity and year was not significant (

	Niccolai et al described the hike in HPV vaccination completion rates from 2008 to 2009 as "far from optimal" but "encouraging." Completion of the vaccination series may be problematic because the first dose may be administered at a routine yearly preventive appointment, but the second and third doses require follow-up visits. These subsequent appointments, in turn, call for "knowledge, motivation, positive attitudes toward vaccination, and additional financial resources such as the ability to pay for vaccine or, if the cost of vaccine is covered by health insurance or a government program, the ability to take time off work for parents, transportation visits, or office visit copayments."

	The authors caution that the precise extent to which the study cohort is representative of all adolescents living in the United States is not known despite a "strong survey design and use of weights." A major reason is that the study lacked potentially important information on doses of HPV vaccine given by providers other than those who responded to the provider survey. In addition, the study was not able to determine whether adolescents who had not completed the vaccination series had not done so because they had only begun the series within the prior 6 months.

	Also, the NIS-Teen survey did not include other factors that might be relevant, including the employment status of the parents and family structure.

		Niccolai LM, Mehta NR, Hadler JL. Racial/Ethnic and poverty disparities in human papillomavirus vaccination completion. 

New findings demonstrate a recent increase in the annual completion rates of vaccination against human papillomavirus (HPV) infection.

Jill Stein

Articles

Nab-Paclitaxel Boosts Survival in Pancreatic Cancer

Nonmyeloablative Conditioning Before Cell Transplantation Shows Potential in Older Patients With Hematologic Malignancies

HPV Vaccination Completion Rates Increase, but Gaps Remain