MOST ONCOLOGISTS are familiar with the findings of the plenary sessions featured at the 2017 ASCO Annual Meeting, with topics ranging from the duration of adjuvant oxaliplatin-based therapy in stage III colon cancer to patient-reported outcomes for symptom monitoring during routine cancer treatment. However, among the wealth of important research presented at the ASCO Meeting are the possibly overlooked studies summarized briefly here. They focus on novel treatments of sarcoma, brain metastases in breast cancer, and several types of lymphoma as well as updates on both childhood cancer survivors and testicular cancer survivors.
New Sarcoma Treatments
ALDOXORUBICIN prolonged progression-free survival in patients with relapsed/refractory liposarcoma and leiomyosarcoma compared with standard treatments in a phase III trial.1 Further, aldoxorubicin compared favorably with standard treatment of soft-tissue sarcoma.
“The response to aldoxorubicin and its impressive lack of cumulative cardiotoxicity may make it a superior anthracycline for treating advanced soft-tissue sarcoma.”— Sant P. Chawla, MD
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Aldoxorubicin, as given in this trial, had minimal cardiotoxicity compared with doxorubicin. “The response to aldoxorubicin and its impressive lack of cumulative cardiotoxicity may make it a superior anthracycline for treating advanced soft-tissue sarcoma,” said lead author Sant P. Chawla, MD, of the Sarcoma Oncology Center, Santa Monica, California.
Aldoxorubicin is a novel anthracycline that binds to albumin in the circulation and is carried to the tumor by the albumin. The phase III study randomized 433 patients: 218 to receive aldoxorubicin at 350 mg/m2 (equivalent to 250 mg/m2 of doxorubicin) every 3 weeks and 215 to receive investigator’s choice of chemotherapy, including pazopanib (Votrient), gemcitabine/docetaxel, dacarbazine, doxorubicin, and ifosfamide.
Two-thirds of patients in each treatment arm had received doxorubicin previously. Median progression-free survival was 4.11 months for aldoxorubicin vs 2.96 months for investigator’s choice. In the patients with liposarcoma and leiomyosarcoma, who comprised 57% of the sarcoma population, median progression-free survival was 5.32 months vs 2.96 months, respectively (P = .0080). Overall survival was similar between the aldoxorubicin-treated group and investigator’s choice—about 12 months.
In another phase II trial, sponsored by the Sarcoma Alliance for Research Through Collaboration (SARC), the checkpoint inhibitor pembrolizumab (Keytruda) demonstrated activity in two types of soft-tissue sarcoma: undifferentiated pleomorphic sarcoma and dedifferentiated or pleomorphic liposarcoma, according to the final results of the SARC028 trial presented by Melissa A. Burgess, MD, of the University of Pittsburgh.2 A biomarker analysis embedded in the design of the single-agent trial showed that response correlated with programmed cell death 1 ligand (PD-L1) status and baseline infiltrating cytotoxic T cells.
Melissa A. Burgess, MD
“Pembrolizumab has clinical activity in undifferentiated pleomorphic sarcoma and dedifferentiated and pleomorphic liposarcoma, and expansion cohorts in these two subtypes are planned. Ongoing biomarker analysis may guide combination strategies,” Dr. Burgess reported.
SARC028 included 2 groups of patients: those with soft-tissue sarcomas (10 patients in each of 4 different cohorts of undifferentiated pleomorphic sarcoma, dedifferentiated or pleomorphic liposarcoma, synovial sarcoma, and leiomyosarcoma) and those with bone sarcoma (40 patients, including 22 with osteosarcoma, 13 with Ewing sarcoma, and 5 with chondrosarcoma). Most patients received at least two previous treatments.
At a median follow-up of 19 months, the projected overall response rate was 18%. In the soft-tissue sarcoma arm, there was one complete response and six partial responses. When the investigators broke down the responses by soft-tissue sarcoma type, they found one complete response and three partial responses in those with undifferentiated pleomorphic sarcoma as well as a partial response in two patients with dedifferentiated or pleomorphic liposarcoma and in one with synovial sarcoma. The median response duration in the soft-tissue sarcoma arm was 33 weeks; median progression-free survival was 18 weeks; and median overall survival was 49 weeks.
In the bone sarcoma arm, there were two partial responses, and nine patients had stable disease. The median duration of response was 43 weeks; median progression-free survival was 8 weeks, and median overall survival was 52 weeks.
Grade 3 and 4 adverse events were reported in 7% of the soft-tissue sarcoma group and 12% of the bone sarcoma group. Further biomarker analysis is planned.
Neratinib/Capecitabine for Brain Metastases
IN PATIENTS with advanced HER2-positive breast cancer and central nervous system (CNS) metastases, neratinib (Nerlynx) plus capecitabine appear to be an active combination. In a study of 37 pretreated patients, the CNS response rate was 49% by composite criteria (CNS volumetric response) and 24% by RANO-BM (Response Assessment in Neuro-Oncology-Brain Metastases) criteria (a secondary endpoint). The median time to CNS progression was 5.5 months, reported Rachel Freedman, MD, of the Dana-Farber Cancer Institute, Boston.3
Rachel Freedman, MD
In TBCRC 022, a study of the Translational Breast Cancer Research Consortium, neratinib was dosed at 240 mg once daily, and capecitabine was dosed at 750 mg/m2 twice daily for 14 days, followed by a 7-day rest period. Patients received diarrhea prophylaxis.
“Prolonged disease control was seen in many patients. At least 6 cycles of therapy were initiated by 51%, and 19% initiated 10 or more cycles,” Dr. Freedman reported.
Grade 3 toxicity possibly related to treatment was reported by 51%, including diarrhea in 32%. Dose reductions or holds due to toxicity were necessary for 57% of patients, and 19% discontinued due to toxicity.
Median overall survival was 13.5 months, and estimated 12-month survival was 57%. “Although our observed median overall survival is similar to that reported in past studies,” she noted, “49% of our study patients were alive as of April 1, 2017.”
Sara Tolaney, MD, MPH
Study discussant Sara Tolaney, MD, MPH, also of Dana-Farber, said neratinib/capecitabine was an “active combination for progressive CNS metastases,” but she expressed concern that diarrhea occurred despite loperamide and resulted in dose holds, reductions and discontinuations. Dr. Tolaney also noted that at least 10 other drugs and combinations are being evaluated to address this unmet need.
Non-Hodgkin and Mantle Cell Lymphomas
BENDAMUSTINE/RITUXIMAB (Rituxan) achieved similar survival compared with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) as front-line therapy for patients with two types of lymphoma, according to long-term follow-up of two separate studies. Both studies suggest that bendamustine/rituximab offers benefits over R-CHOP/R-CVP but does not significantly improve survival.
The BRIGHT study found bendamustine/rituximab was noninferior in terms of response rates but also found that bendamustine/rituximab was superior in terms of progression-free survival, HR = 0.61 (0.45–0.85; P = .0025) to R-CHOP and R-CVP in patients with treatment-naive indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma.4 Five-year progression-free survival was 65.5% for bendamustine/rituximab and 55.8% for R-CHOP/R-CVP.
For indolent NHL, 5-year progression-free survival was 70.3% for bendamustine/rituximab vs 62% for R-CHOP/R-CVP. Among the patients with mantle cell lymphoma, 5-year progression-free survival was 39.7% and 14.2%, respectively.
Five-year overall survival was 81.6% in the bendamustine/rituximab arm compared with 85% in the R-CHOP/R-CVP arm, which was not significantly different. Overall survival was comparable for lymphoma types. More secondary malignancies developed in the bendamustine/rituximab arm (19% vs. 11%).
“There is a significantly greater benefit in bendamustine/rituximab vs R-CHOP/R-CVP and a greater benefit for bendamustine/ rituximab vs R-CVP. The strongest benefit was in the mantle cell lymphoma subgroup,” said Ian Flinn, MD, of the Sarah Cannon Research Institute, Nashville.
Ian Flinn, MD
Ten-year follow-up of the StilL NHL1 study showed bendamustine/rituximab had a time-to-next-treatment benefit (used as a surrogate for progression-free survival) compared with R-CHOP in treatment-naive indolent NHL or mantle cell lymphoma.5 The 10-year results are similar to those of the original study, which showed significantly better median progression-free survival for the bendamustine/rituximab group: not yet reached for bendamustine/rituximab vs 69.5 months for R-CHOP (P < .0001). Bendamustine/rituximab had better tolerability, and at the time, the authors concluded it should be a preferred first-line treatment.
Mathias J. Rummel, MD, PhD
At 10 years of follow-up, the time to next treatment was not yet reached in the bendamustine/rituximab arm and 56 months in the R-CHOP arm (P < .0001). More patients treated with R-CHOP underwent autologous stem cell transplantation: 11 vs 3 in the bendamustine/rituximab arm.
No difference was observed between the two treatment arms in the number of secondary malignancies. Overall survival was not statistically different, but it was numerically higher in the bendamustine/rituximab arm: 70.3% vs 66.3%, reported Mathias J. Rummel, MD, PhD, of Justus-Leibig University, Giessen, Germany.
The formal discussant of these trials, Brad S. Kahl, MD, of Washington University School of Medicine, St. Louis, indicated both bendamustine/rituximab and R-CHOP are acceptable regimens. He said the role of maintenance rituximab therapy is still unproven after bendamustine/rituximab.
Brad S. Kahl, MD
Childhood Cancer Survivors
MORE RECENTLY diagnosed surviviors of many childhood cancers have a lower incidence of serious chronic diseases later in life, compared with survivors diagnosed in prior decades. Temporal changes in treatment (ie, reduced intensity) were correlated with observed reductions in serious morbidity, according to the Childhood Cancer Survivor Study.6
Investigators examined data from a cohort of childhood cancer patients diagnosed between 1970 and 1999, from 31 North American cancer centers, who were under age 21 at diagnosis and were alive 5 years from diagnosis. Patients had been treated for leukemia, lymphoma, CNS malignancies, Wilms tumor, neuroblastoma, soft-tissue sarcoma, and bone sarcoma. Detailed treatment exposure data were available from medical records.
“Not only are more children being cured, but they also have a lower risk for developing serious health problems due to cancer treatment later in life.”— Todd M. Gibson, PhD
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The cohort included 23,601 survivors whose median time since diagnosis was 21 years and whose median age at last follow-up was 28 years. The 15-year cumulative incidence for severe, disabling, life-threatening, or fatal chronic conditions, as analyzed by treatment decade, follow: 1970 to 1979 (12.7%); 1980 to 1989 (10.1%); and 1990 to 1999 (8.9%). The largest decreases over the 3 decades occurred among survivors of Wilms tumor and Hodgkin lymphoma, for whom there were reductions of 43% and 25%, respectively.
Specifically, by cancer type, the following were the cumulative incidences of serious morbidity at 15 years after diagnosis for survivors diagnosed and treated in the 1970s vs the 1990s:
- Wilms tumor: 13% vs 5%
- Hodgkin lymphoma: 18% vs 11%
- Astrocytoma: 15% vs 9%
- NHL: 10% vs 6%
- Acute lymphoblastic leukemia: 9% vs 7%.
“The greatest reductions were found in the incidence of endocrine conditions and new cancers, followed by gastrointestinal disorders and neurologic conditions, but, surprisingly, the incidence of cardiovascular disease did not drop,” said Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital, Memphis.
“Our analysis marks the first comprehensive assessment of changes in the rates of chronic health complications over time in a large group of cancer survivors,” Dr. Gibson revealed. “From our findings, it is clear that, in general, survivors diagnosed and treated in more modern treatment eras are doing better. Not only are more children being cured, but they also have a lower risk for developing serious health problems due to cancer treatment later in life.”
Timothy Gilligan, MD, MSc
“We have an increase in cure rates and a reduction in the probability of adverse health consequences, and this represents huge progress,” commented ASCO expert Timothy Gilligan, MD, MSc, of the Cleveland Clinic in Ohio.
Hypogonadism After Testicular Cancer Treatment
MORE THAN ONE-THIRD of testicular cancer survivors have low testosterone levels later in life, placing them at risk for a variety of chronic health conditions, a large multicenter study has shown.7 The study evaluated the first 491 participants of the Platinum Study, which aims to be the largest analysis of survivors of testicular cancer worldwide. All patients received chemotherapy and were younger than age 55 when diagnosed. The median age at clinical evaluation for chronic effects was 38 years.
“Testicular cancer occurs at a young age and is highly curable, and patients can expect to live for 40 years after diagnosis, but there is a long-term risk for late complications from treatment,” said Mohammad Issam Abu Zaid, MBBS, of Indiana University School of Medicine, Indianapolis.
Mohammad Issam Abu Zaid, MBBS
Among survivors, 38% had a low testosterone level or were on testosterone replacement therapy. Patients were most likely to have low testosterone levels if they were overweight or obese, whereas patients were less likely to have low testosterone levels if they were physically active. The type of chemotherapy regimen did not have an impact. Polymorphisms in the SHBG gene appeared to be related as well, but the study was underpowered to confirm an association.
Compared with survivors who had normal testosterone levels, testicular cancer survivors with low testosterone levels were more likely to be on medication for hypertension (19% vs 11%), high cholesterol (20% vs 6%), erectile dysfunction (20% vs 12%), diabetes (6% vs 3%), and anxiety and depression (15% vs 10%). Some of these health problems have been previously linked to low testosterone among men in the general population and testicular cancer survivors, Dr. Abu Zaid noted.
“Clinical and genetic factors can increase the risk for hypogonadism, and providers should screen testicular cancer survivors for hypogonadism and treat those with symptoms,” he concluded.
Dr. Gilligan commented on this study at a press briefing: “This is an important study and sends a loud message to those of us who take care of these patients. We need to watch for this and ask our patients about symptoms…. I don’t think many doctors are as aware of this as they might be.”
Dr. Gilligan did not, however, endorse measuring testosterone levels in all patients, since there is much debate about what levels are problematic. “Instead, looking for symptoms is the key,” he suggested.
DISCLOSURE: For full disclosures of the quoted speakers, please see the online version of this article at www.ascopost.com.
REFERENCES
1. Chawla SP, et al: 2017 ASCO Annual Meeting. Abstract 11000. Presented June 2, 2017.
2. Burgess MA, et al: 2017 ASCO Annual Meeting. Abstract 11008. Presented June 2, 2017.
3. Freedman RA, et al: 2017 ASCO Annual Meeting. Abstract 1005. Presented June 3, 2017.
4. Flinn I, et al: 2017 ASCO Annual Meeting. Abstract 7500. Presented June 3, 2017.
5. Rummel MJ, et al: 2017 ASCO Annual Meeting. Abstract 7501. Presented June 3, 2017.
6. Gibson TM, et al: 2017 ASCO Annual Meeting. Abstract LBA10500. Presented June 3, 2017.
7. Zaid MIA, et al: 2017 ASCO Annual Meeting. Abstract LBA10012. Presented June 3, 2017.
