Bone-Targeted Therapy in Breast Cancer

Expert Discusses State of Bone-Targeted Therapy in Breast Cancer
Danielle Bucco
Published Online: Monday, Mar 27, 2017
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Adam M. Brufsky, MD, PhD

Adam M. Brufsky, MD, PhD
Certain bone-targeted agents deserve more frequent use in oncology, although providers need to be mindful about patient conditions and the potential for osteonecrosis, said Adam M. Brufsky, MD, PhD, who provided an update on bone-targeted agents at the 2017 Miami Breast Cancer Conference.

Brufsky said denosumab (Xgeva) showed a disease-free survival benefit in postmenopausal women with early hormone receptor-positive breast cancer in the Austrian Breast and Colorectal Cancer Study Group-18 (ABCSG-18) trial. Denosumab was given to women who had received aromatase inhibitor (AI) therapy. From 2006 to 2013, the trial enrolled 3425 patients, of whom 3420 were randomly assigned to receive denosumab at 60 mg (n = 1711) or placebo (n = 1709) subcutaneously every 6 months. Denosumab reduced the rate of fracture in women by 50%, (HR, 0.50; P <.0001), compared with placebo.
Given the damage that adjuvant endocrine therapy can do to bone health in breast cancer patients, these findings may change clinical practice, said Brufsky, associate chief of the Division of Hematology/Oncology and co-director of the Comprehensive Breast Care Center, University of Pittsburgh.

The follow-up analysis of the benefits of adding denosumab to AI therapy showed that denosumab also reduces the risk of breast cancer recurrence and death in postmenopausal women.

In an interview with OncLive, Brufsky discussed considerations for using the bone-targeted agents denosumab and zoledronic acid (Zometa) in patients with breast cancer.

OncLive: What is new in bone-targeted therapies?

Brufsky: Based on meta-analysis studies, there are a number of bone-targeted agents in the postmenopausal setting that have demonstrated a 3% improvement in overall survival in patients with breast cancer at 10 years. The real question is, why do we not use them? There are clearly good data available and the questions revolve around which one do we use, how frequently we use it, and for how long. In my opinion, anywhere from 2 to 5 years in the meta-analysis seems to be the right amount.

There are some randomized trials that seem to provide a disease-free survival benefit such as with denosumab, which is a little bit different than the bisphosphonates. The ABCSG-18 trial gave us a very nice result that we need to talk about as a group of breast cancer physicians. Hopefully, we’ll come to some sort of consensus as to how these drugs should be used.

What is the current standard of care for patients with bone metastases?

When managing the patient with bone metastases, there are a number of therapies to consider. If the patient is ER-positive, consider using estrogen-receptor therapy. If the patient is triple-negative, oncologists will most likely treat with chemotherapy. If the patient is HER2-positive, consider using a combination of trastuzumab (Herceptin) plus pertuzamab (Perjeta). But more importantly, oncologists should be using a bone-targeted agent, either denosumab or zoledronic acid.

An interesting trial (NCT00869206) that has come up recently and was just published, was a randomized trial performed by the Cancer and Leukemia Group B cooperative trial group. It concluded that giving zoledronic acid every 3 months was equivalent to giving it monthly for the management of metastatic bone disease. In fact, the interesting thing is that, in this trial, the event rate that was observed—bone-related complications like a fracture, or a pain, or need for radiation of bone—was equivalent in the less-frequent dose compared with the monthly dose.

That is a big deal, because now patients only have to receive the medication every 3 months and not monthly. This is helpful for the patient; however, when a woman has metastatic breast cancer, there are a lot of things you find in a monthly visit that you may not see in the 3-month visit. I think the potential loss of that monthly screening is something we need to consider because there are things that a patient can develop that can be prevented before they get worse.

For example, a patient could develop the beginning of a spinal cord compression or start to have a little bit of weakness in her legs. The oncologist can pick that up on a monthly visit and may miss it on a visit every 3 months. I think we are going to be moving to visits every 3 months, and it will be positive in some instances that women only have to receive treatment every 3 months. It is less costly, and probably less toxic, but the concern the oncologist has is with patient management.

What are the adverse events for these bone-targeted agents?

There are not a lot of adverse events, but I think the biggest one is renal insufficiency, which can occur if you give the drug too fast. A certain proportion of women with zoledronic acid can get achiness and febrile syndromes that last up to 1 week or even 2 weeks. That is uncommon but it can happen.
The big one for both denosumab or zoledronic acid, is that a certain percentage of women, probably 1% or 1.5%, will develop osteonecrosis of the jaw. What this means is that they will develop an exposed bone that can erode, especially if the patient has had an implant or some sort of invasive dental procedure that does not heal, and this can be prevented by cognizance. Having a woman tell us that she is getting a dental procedure can help physicians adjust to whether they should give the drug or not.

My own bias is that this is somewhat of a peak effect. In other words, getting a dental procedure a day or 2 after getting the bisphosphonate is not going to be wise. Usually, it will delay the administration of a bisphosphonate 1 to 2 months due to the dental work.

What does the future hold for bone-targeted agents?

In my opinion, the big thing is the adjuvant therapy, especially if we are moving toward finding a group of patients who are not going to need chemotherapy, and we do not know that now. With all the new genomic testing that is coming out—whether it is the 70-gene assay, the 21-gene assay, or the PAM50—all of these tests are telling us that there is a subset of patients who do not need chemotherapy. The issue is that you have patients whom physicians are just going to treat with hormone therapy, but they could possibly still have a lot of nodes or have a high risk of recurrence, even if treated with endocrine therapy.

What should we do for those women? I suggest that, especially in the postmenopausal setting, bisphosphonates may give you a benefit if you are not going to give chemotherapy.
Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind placebo-controlled trial. Lancet. 2015;386(9992):433-443. doi: 10.1016/S0140- 6736(15)60995-3.

Nivolumab Recommended for EU Approval in Head and Neck Cancer

Nivolumab Recommended for EU Approval in Head and Neck Cancer
Jason M. Broderick @jasoncology
Published Online: Friday, Mar 24, 2017
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Emmanuel Blin

Emmanuel Blin
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of nivolumab (Opdivo) for the treatment of patients with squamous cell cancer of the head and neck (SCCHN) following progression on platinum-based therapy, according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.

The approval is based on the CheckMate-141 study, in which the median overall survival (OS) with nivolumab was 7.5 months compared with 5.1 months with investigator's choice (HR, 0.70; 95% CI, 0.52-0.92; P = .0101). The objective response rates (ORR) were 13.3% versus 5.8%, respectively.

The positive opinion will now be reviewed by the European Commission (EC) and a final approval decision for use in the European Union (EU) is expected in about 2 months. In the United States, nivolumab was previously approved by the FDA for SCCHN in November 2016.

“Nearly half of all patients with squamous cell cancer of the head and neck relapse within 2 years of treatment and limited advancements have been made in the last 10 years, underscoring the critical need for new treatment options for patients affected by this devastating illness,” Emmanuel Blin, senior vice president and chief strategy officer, BMS, said in a statement.

“We are very pleased that the CHMP has recommended the approval of Opdivo for adults with squamous cell cancer of the head and neck who have progressed on or after platinum-based therapy and look forward to working with the EC as they review this treatment as a potential option for patients in the EU,” added Blin.

In the trial, 361 patients with cancer of the oral cavity, pharynx, or larynx were randomized in a 2:1 ratio to receive nivolumab (n = 240) or investigator's choice of cetuximab (12.4%), methotrexate (44.6%), or docetaxel (43%; N = 121). Nivolumab was administered intravenously at 3 mg/kg every 2 weeks. Cetuximab was administered at 400 mg/m2 for the first dose followed by 250 mg/m2 weekly. Methotrexate was administered at 40 mg/m2 weekly. Docetaxel was administered at 30 mg/m2 weekly.

The median age of patients in the trial was 60 years, and 31.3% were ≥65 years of age. The majority of patients were male (83%), Caucasian (83%), and had an ECOG PS of 1 (78.4%). Most patients (54.8%) received ≥2 prior systemic therapies, and over 90% had received prior radiation therapy. HPV status was known for 49.3% of patients, using p16 status, and PD-L1 expression was available for 72% of enrolled patients.

The 1-year OS rates were 36% with nivolumab (95% CI, 28.5-43.4) compared with 16.6% for investigator’s choice (95% CI, 8.6-26.8). Similar improvements in survival were seen across demographic subgroups. The ORR in the nivolumab arm consisted of 6 complete responses (2.5%) and the stable disease (SD) rate was 22.9%. In the investigator's choice arm, 1 patient had a complete response and the SD rate was 35.5%.

The median progression-free survival (PFS) was 2 months with nivolumab versus 2.3 months with investigator's choice (HR, 0.89; 95% CI, 0.70-1.10; P = .3236). The 6-year PFS rates were 19.7% for nivolumab and 9.9% for investigator's choice of therapy.

Further analyses revealed distinct populations of patients who responded better to nivolumab monotherapy versus investigator's choice, specifically those with PD-L1–positive and HPV-positive SCCHN. Those with PD-L1 expression on ≥1% of cells experienced a median OS of 8.7 months with nivolumab compared with 4.6 months in the control arm (HR, 0.55; 95% CI, 0.36-0.83). In the HPV-positive group, the median OS was 9.1 months with nivolumab compared with 4.4 months with investigator’s choice (HR, 0.56; 95% CI, 0.32-0.99).

Those who tested negative for PD-L1 had a median OS of 5.7 months with nivolumab versus 5.8 months in the control arm (HR, 0.89; 95% CI, 0.54-1.45). In the HPV-negative arm, the median OS with nivolumab was 7.5 versus 5.8 months (HR, 0.73; 95% CI, 0.42-1.25).

Adverse events (AEs) were significantly less with nivolumab versus investigator's choice. There were 2 treatment-related deaths in the nivolumab arm related to pneumonitis and hypercalcemia. In the investigator's choice arm, there was 1 death related to lung infection.

Overall, grade 3/4 events were experienced by 13.1% of patients treated with nivolumab versus 35.1% for investigator’s choice. All-grade AEs were experienced by 58.9% of patients treated with nivolumab compared with 77.5% with investigator's choice. The most common grade 3/4 AEs with nivolumab were fatigue (2.1%), anemia (1.3%), and asthenia (0.4%). For investigator's choice, the most common grade 3/4 AEs were anemia (4.5%), alopecia (2.7%), fatigue (2.7%), diarrhea (1.8%), asthenia (1.8%), and mucosal inflammation (1.8%).
Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol. 2016;34 (suppl; abstr 6009).

Some Cancer Patients 'Hyperprogress' on Immunotherapy

Medscape Medical News > Conference News
Some Cancer Patients 'Hyperprogress' on Immunotherapy
Damian McNamara
March 09, 2017

LA JOLLA, California — When it comes to immunotherapy for cancer, "everyone likes to talk about the 'super-responders'," said an expert here at the 10th Future of Genomic Medicine Conference. But evidence is emerging that some patients become "hyperprogressors" and their cancer grows quickly soon after they start therapy.

"We've all heard that immunotherapy is great. And there is subset of patients who do really well with long-term remission, even in the metastatic setting," said Razelle Kurzrock, MD, from the University of California, San Diego School of Medicine. "But it's not all good."

"We began to notice that some patients were progressing rapidly on immunotherapy," she explained. To illustrate her point, she showed imaging from a 73-year-old patient with metastatic bladder cancer whose cancer "just exploded" in size after starting immunotherapy.

We need to figure out not only who to treat, but who not to treat.
"We need to figure out not only who to treat, but who not to treat. This will largely be done through genomics," Dr Kurzrock said.

For example, the MDM2 genes encode an oncoprotein that turns off p53 and other tumor-suppressor genes, boosting tumor formation in a number of cancer types when amplified. The amplification of MDM2 is also associated with hyperprogression after the initiation of immunotherapy.

The pace of progression is increased anywhere from five- to 40-fold.
"We've noticed now that all our patients with MDM2 amplification have responded this way," she reported, adding that progression is rapid. "The pace of progression is increased anywhere from five- to 40-fold."

One patient with MDM2 amplification assessed at the UC San Diego Center for Personalized Cancer Therapy was a 65-year-old woman whose endometrial stromal sarcoma progressed quickly on nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody immunotherapy. Another patient with MDM2 amplification, a 44-year-old woman with triple-negative breast cancer, underwent craniotomy and radiation therapy for brain metastases and then started pembrolizumab therapy, which also targets the PD-1 receptor. A few months later, her cancer progressed
"Late last year, a European group conducted a phase 1 trial and identified a small percentage of patients who were hyperprogressors, across all types of cancers," said Shubham Pant, MD, from the M.D. Anderson Cancer Center in Houston. Of the 131 evaluable patients, 9% were deemed to be hyperprogressors, he told Medscape Medical News (Clin Cancer Res. Published online November 8, 2016).

Those patients with hyperprogressive tumor growth did not have a significantly higher baseline tumor burden. However, hyperprogression was associated with older age (P < .05) and worse overall survival.
"It's a very interesting clinical question, but these are still early days," Dr Pant explained. It also raises questions: Which tumor types are most likely to progress? How do we identify the folks who are going to hyperprogress? And who responds well to immunotherapy?

Higher Mutational Burden, Better Response

It sounds counterintuitive, but sometimes people with more complex tumors and a higher tumor mutational burden respond better, Dr Kurzrock said.

"We did a study where tumor mutational burden — across tumor types — was linearly correlated to checkpoint inhibitors," she noted. "That makes sense. Once you reactivate the immune system, if there are a lot of neoantigens, the system has something to respond to."

Anti-PD1 and anti-programmed death ligand (PD-L1) checkpoint inhibitors might help "get the immune system out of check" in patients with a high mutational burden, she suggested.

Table. Responses to Immunotherapy

Tumor Mutational Burden Response Rates to Immunotherapy, %
Low 4
Intermediate 26
High 45
Very high 67


Not only does immunotherapy response correspond with tissue tumor burden, it also corresponds with the amount of circulating tumor (ct)DNA, said Dr Kurzrock, whose center has performed ctDNA analysis on more than 1500 patients to date.

One of these patients — a 49-year-old woman with high-grade neuroendocrine cervical cancer — presented with a very large abdominal tumor associated with a partial ureteral obstruction and impending bowel obstruction.

Liquid biopsy revealed "a whole lot of alterations. Most patients have two or three alterations in their ctDNA, but she was just packed," Dr Kurzrock explained.

Subsequent tissue-sample biopsy confirmed that the woman had 23 genetic mutations and a very high tumor burden but was a super-responder to nivolumab and radiation, she reported. "We believe at 15 months that she is in complete remission."

Dr Kurzrock reports receiving research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant; receiving consultant or advisory board fees from Actuate Therapeutics and XBiotech; and having ownership interest in Novena and Curematch. Dr Pant has disclosed no relevant financial relationships.

10th Future of Genomic Medicine (FOGM) Conference. Presented March 2, 2017.

Extended Breaks From Sunitinib Therapy ‘Feasible’ For Metastatic Clear Cell RCC

Extended Breaks From Sunitinib Therapy ‘Feasible’ For Metastatic Clear Cell RCC
Monitoring metastatic renal cell carcinoma patient tumour burden could allow periodic breaks in sunitinib therapy without adversely impacting efficacy

Date: 25 Jan 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Renal Cell Cancer

medwireNews: Preliminary results suggest that extended breaks from sunitinib therapy may be possible in patients with metastatic renal cell carcinoma (mRCC) without compromising treatment efficacy.

“Most patients demonstrated a stable sawtooth pattern with an increase in tumor burden while on a sunitinib treatment break and decreased tumor burden while receiving sunitinib”, the investigators report in the Journal of Clinical Oncology.

Seven of the 20 patients in the phase II study testing an intermittent dosing regimen guided by computed tomography imaging achieved “prolonged drug holidays” of between 3.2 and 43.6 months before experiencing a 10% or greater gain in tumour burden, they write.

Five patients had an overall increase in tumour burden over time and were switched to the standard 4 weeks on, 2 weeks off sunitinib schedule. One patient with bulky nodal disease who achieved a 17% decrease during the first four cycles, despite several dose reductions, began treatment 5 weeks into the initial 8-week break after showing clinical and radiographical progression.

At time of analysis, four patients were continuing with intermittent sunitinib, 12 had progressed and two patients had discontinued therapy because of side effects. One patient died from an unrelated brain haemorrhage and another patient withdrew from the trial.

“The [objective response rate] of 46% and [median progression-free survival] of 22.4 months observed in this trial are consistent with published data” and “support the hypothesis that an intermittent schedule does not compromise clinical outcome”, say Moshe Ornstein, from Cleveland Clinic Taussig Cancer Institute in Ohio, USA, and co-authors.

The current study used RECIST criteria to monitor 37 patients with treatment-naïve clear cell mRCC after four cycles of sunitinib 50 mg/day for 4 weeks followed by 2 weeks off treatment. Seventeen patients were excluded from beginning intermittent therapy because of progressive disease, toxicity or consent withdrawal at the end of cycle 4.

Treatment was paused for the remaining 20 patients who achieved a 10% or greater reduction in tumour burden – and a median decrease of 45% – and a restaging scan was performed at week 12.

Treatment continued when the patient experienced a 10% or higher increase in tumour burden. At this point, sunitinib was reinitiated for a further two cycles and tumour burden reassessed; patients who did not achieve a minimum 10% reduction continued with sunitinib cycles while those achieving this threshold of response had a further break from treatment.

In all, the 20 patients had 83 breaks, ranging from one to 11 breaks per patient, and a median of three per patient. The breaks lasted a median of 8.3 weeks and sunitinib retreatment lasted a median of 12.0 weeks. This translated to 1296.6 weeks off treatment, corresponding to 216 separate 6-week cycles and a median of nine cycles saved per patient, the researchers emphasize.

The median change in tumour burden was a gain of 1.6 cm during the treatment break and a decrease of 1.4 cm during retreatment, with a median relative increase during the treatment holiday of 44%.

Over the first four cycles of treatment, around half of the patients had a dose reduction to 37.5 mg/day (46%) or 25.0 mg/day (5%). In addition, 24% had their cycle switched to 2 weeks on, 1 week off with or without a dose reduction; these patients continued to intermittent therapy on this regimen.

The most common adverse events were fatigue (89%), mucositis (86%) and thrombocytopenia (84%), with the most common grade 3 events being hypertension (38%), neutropenia (24%) and fatigue (22%).

“The results of this trial suggested that implementation of this approach in select patients may result in reduced toxicities, improved quality of life, cost savings, and potentially improved clinical outcomes”, summarise Moshe Ornstein et al.

“A phase II/III clinical trial in Europe in which patients are randomly assigned to standard sunitinib dosing versus treatment on an intermittent schedule is ongoing”, they conclude.

Reference

Ornstein MC, Wood LS, Elson P, et al. A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol; Advance online publication 23 January 2017. DOI: 10.1200/JCO.2016.71.1184

Metastatic Pancreas Cancer tretament with Nab-Paclitaxel Leucovorin–Fluorouracil

Nab-Paclitaxel With Leucovorin–Fluorouracil Shows Metastatic Pancreas Cancer Promise
Leucovorin and fluorouracil could offer an alternative to gemcitabine for use with nab-paclitaxel in metastatic pancreatic adenocarcinoma

Date: 14 Mar 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Pancreatic Cancer

medwireNews: Phase II results point to nab-paclitaxel plus a simplified regimen of leucovorin and fluorouracil as a possible combination for the first-line treatment of patients with metastatic pancreatic adenocarcinoma.

The regimen MET the primary endpoint target of at least 50% of patients achieving 4 months of progression-free survival (PFS) and it had a “tolerable toxicity profile”, the authors report in The Lancet Gastroenterology and Hepatology.

“Our results are encouraging and suggest that the efficacy of this regimen should be investigated in a phase 3 randomised trial, comparing it with the nab-paclitaxel plus gemcitabine regimen with a patient-centred outcome (ie, overall survival)”, they believe.

Jean-Baptiste Bachet, from Groupe hospitalier Pitié Salpêtrière in Paris, France, and co-workers explain that while nab-paclitaxel plus gemcitabine is currently the standard treatment for metastatic pancreatic adenocarcinoma, gemcitabine is thought to be inefficient in 50–60% of cases.

They designed the open-label, non-comparative AFUGEM GERCOR trial to assess activity and safety of the two nab-paclitaxel-based regimens in patients with at least one measurable lesion and an ECOG performance status of 2 or lower.

The patients were followed-up for a median of 13.1 months. At 4 months, PFS was achieved by 56% of the 72 patients given nab-paclitaxel with leucovorin plus fluorouracil and by 54% of the 39 patients given nab-paclitaxel plus gemcitabine.

Serious treatment-related adverse events occurred in a comparable 38% and 37% of the leucovorin plus fluorouracil and the gemcitabine groups, respectively, and there was one death in each arm, neither of which was considered treatment related.

Grade 3 or 4 side effects were less common with leucovorin plus fluorouracil than with gemcitabine (77 vs 87%) and the two regimens had different toxicity profiles, the researchers say.

Leucovorin plus fluorouracil was most commonly associated with grade 3–4 neutropenia without fever (23%), fatigue (22%), paraesthesia (19%), diarrhoea (12%) and mucositis (10%), whereas the most frequent grade 3–4 events with gemcitabine were neutropenia without fever (32%), fatigue (21%), thrombocytopenia (18%), anaemia and liver Enzyme elevations (both 13%) and Paraesthesia (11%).

Updated analysis after a median of 24.3 months gave a median PFS of 5.9 months for the leucovorin plus fluorouracil group versus 4.9 months for the gemcitabine group, with an exploratory hazard ratio of 0.79. The corresponding overall survival values were 11.4 versus 9.2 months and a hazard ratio of 0.61.

The researchers write that 61% and 21% of the patients given leucovorin plus fluorouracil received second- and third-line chemotherapy, respectively, as did 56% and 15% of the patients given gemcitabine.

Median overall survival from the beginning of second-line therapy was 4.6 and 6.5 months in the two groups, respectively, whereas for leucovorin plus fluorouracil-treated and gemcitabine-treated patients who were not given a second-line treatment, median overall survival was 2.1 and 1.7 months, respectively.

“These results suggest that simplified leucovorin and fluorouracil could be a better backbone companion than gemcitabine to develop new regimens in combination with nab-paclitaxel for pancreatic adenocarcinoma, and that this regimen deserves to be investigated further in clinical trials”, the authors conclude.

Reference

Bachet J-B, Hammel P, Desramé J, et al. Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial. Lancet Gastroenterol Hepatol; Advance online publication 27 February 2017. DOI: http://dx.doi.org/10.1016/S2468-1253(17)30046-8

Metformin and Patients with Triple-Positive Primary Breast Cancer

Metformin May Extend Survival In Diabetes Patients with Triple-Positive Primary Breast Cancer
Diabetes patients with human epidermal growth factor receptor 2-positive, hormone receptor-positive primary breast cancer may benefit from metformin

Date: 16 Mar 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: AIDS-Associated Malignancies / Anal Cancer

medwireNews: A substudy of the ALTTO trial adds support to the hypothesis that metformin use may be protective in breast cancer patients with diabetes, finding improved survival outcomes in women with triple-positive primary disease who used the antidiabetes agent.

“Despite the lack of level one evidence, we believe that for patients with diabetes and [human Epidermal growth factor receptor] HER2-positive and hormone Receptor–positive disease, it is reasonable to recommend metformin treatment if patients have not already received treatment and to avoid as much as possible insulin use”, say Evandro de Azambuja, from Institut Jules Bordet in Brussels, Belgium, and co-investigators.

“From a prognostic point of view, patients with diabetes and HER2-positive and hormone receptor–positive disease who are treated with insulin should be considered at higher risk of recurrence”, they emphasize.

The current analysis includes data for 8381 patients who were randomly assigned to receive 1 year of trastuzumab or lapatinib therapy or the two agents in sequence or combination, including 2.2% of participants who had diabetes but no metformin treatment and 3.1% of patients who had used metformin for diabetes.

After a median of 4.5 years of follow-up, diabetes patients who were not treated with metformin had significantly poorer disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) than patients without diabetes. The hazard ratios (HRs) for these outcomes were 1.40, 1.56 and 1.87, respectively, after adjusting for timing of chemotherapy, hormone receptor status, lymph node status and other factors.

By contrast, patients with diabetes who had been prescribed metformin did not have significantly poorer DFS, DDFS or OS compared with the controls, the team reports in the Journal of Clinical Oncology.

Further analysis suggested that the increased risk of poor survival in diabetes patients who had not used metformin was only present in women who had hormone receptor-positive tumours. For example, the HR for DFS versus controls was a significant 2.05 for hormone receptor-positive patients versus a nonsignificant 0.99 in their hormone receptor-negative counterparts.

Moreover, when the researchers examined the impact of diabetes treatments, they found that metformin use was beneficial in diabetes patients with HER2-positive, hormone receptor-positive breast cancer, with a significant HR of 0.70 for DFS compared with diabetes patients not given metformin.

But insulin was associated with poorer outcomes in hormone receptor-positive diabetes patients with a significant HR for DFS of 2.29 compared with nonusers of insulin, whereas no association was found for hormone receptor-negative individuals.

“As ALLTO, like most clinical trials, tends to have a healthier population and likely a lower incidence of patients with diabetes than the general population, it would be important to address the hypotheses raised in this study with a larger group of patients who are more indicative of the real world”, the researchers caution.

“Another future direction would be to perform a large registry study that will observe prospectively patients with diabetes and HER2-positive breast cancer”, they recommend.

Nevertheless, the authors conclude that, while their analyses were unplanned, “our data provide evidence that the prognostic impact of diabetes and metformin treatment is also relevant in patients who were treated with the current standard adjuvant treatment.”

Reference

Sonnenblick A, Agbor-Tarh D, Bradbury I, et al. Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2–positive primary breast cancer: Analysis from the ALTTO phase III randomized trial. J Clin Oncol; Advance online publication 13 March 2017. DOI: 10.1200/JCO.2016.69.7722

Accelerated hypofractionated radiation therapy (AHRT) for non-small-cell lung cancer

Clinical and Translational Oncology

April 2017, Volume 19, Issue 4, pp 440–447
Accelerated hypofractionated radiation therapy (AHRT) for non-small-cell lung cancer: can we leave standard fractionation?

1.Department of Radiation OncologyHospital de la EsperanzaBarcelonaSpain
2.Hospital del Mar Medical Research Institute (IMIM)BarcelonaSpain
3.Pompeu Fabra UniversityBarcelonaSpain

First Online:
23 August 2016

DOI: 10.1007/s12094-016-1544-7

Cite this article as:
de Dios, N.R., Sanz, X., Foro, P. et al. Clin Transl Oncol (2017) 19: 440. doi:10.1007/s12094-016-1544-7



To report interim results from a single-institution study conducted to assess accelerated hypofractionated radiotherapy (AHRT) delivered with 3D conformal radiotherapy in two groups of patients with non-small cell lung cancer: (1) patients with early stage disease unable to tolerate surgery and ineligible for stereotactic body radiation therapy, and (2) patients with locally advanced disease unsuitable for concurrent chemoradiotherapy.
Methods/patients

A total of 83 patients (51 stage I–II, 32 stage III) were included. Radiotherapy targets included the primary tumor and positive mediastinal areas identified on the pre-treatment PET–CT. Mean age was 77.8 ± 7.8 years. ECOG performance status (PS) was ≥2 in 50.6 % of cases. Radiotherapy was delivered in daily fractions of 2.75 Gy to a total dose of 66 Gy (BED10 84 Gy). Acute and late toxicities were evaluated according to NCI CTC criteria.
Results

At a median follow-up of 42 months, median overall survival (OS) and cause-specific survival (CSS) were 23 and 36 months, respectively. On the multivariate analysis, PS [HR 4.14, p = 0.0001)], stage [HR 2.51, p = 0.005)], and maximum standardized uptake values (SUVmax) [HR 1.04, p = 0.04)] were independent risk factors for OS. PS [HR 5.2, p = 0.0001)] and stage [HR 6.3, p = 0.0001)] were also associated with CSS. No cases of severe acute or late treatment-related toxicities were observed.
Conclusions

OS and CSS rates in patients treated with AHRT for stage I–II and stage III NSCLC were good. Treatment was well tolerated with no grade three or higher treatment-related toxicity. PS, stage, and SUV max were predictive for OS and CSS.

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma

Original Article
Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma

James R. Perry, M.D., Normand Laperriere, M.D., Christopher J. O’Callaghan, D.V.M., Alba A. Brandes, M.D., Johan Menten, M.D., Claire Phillips, M.B., B.S., Michael Fay, M.B., Ch.B., Ryo Nishikawa, M.D., J. Gregory Cairncross, M.D., Wilson Roa, M.D., David Osoba, M.D., John P. Rossiter, M.B., B.Ch., Arjun Sahgal, M.D., Hal Hirte, M.D., Florence Laigle-Donadey, M.D., Enrico Franceschi, M.D., Olivier Chinot, M.D., Vassilis Golfinopoulos, M.D., Laura Fariselli, M.D., Antje Wick, M.D., Loic Feuvret, M.D., Michael Back, M.B., B.S., Michael Tills, M.B., B.S., Chad Winch, M.Sc., Brigitta G. Baumert, M.D., Wolfgang Wick, M.D., Keyue Ding, Ph.D., and Warren P. Mason, M.D., for the Trial Investigators*

N Engl J Med 2017; 376:1027-1037March 16, 2017DOI: 10.1056/NEJMoa1611977
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Background

Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown.
Methods

We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide.
Results

A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O6-methylguanine–DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups. Conclusions

In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677.)

Supported by grants (015469 and 021039) from the Canadian Cancer Society Research Institute, by an unrestricted grant from Schering-Plough (now Merck), and by the EORTC Cancer Research Fund from Belgium.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Perry and Laperriere contributed equally to this article.

We thank the patients and their families for their participation in this research.

Gastro-Oesophageal Cancer and MSI, MMRD Biomarkers

MSI, MMRD Biomarkers Might Guide Gastro-Oesophageal Cancer Periop Chemotherapy Use

Perioperative chemotherapy benefit in gastro-oesophageal cancer may vary with microsatellite instability and mismatch repair deficiency status

Date: 27 Feb 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Oesophageal Cancer / Gastric Cancer / Translational Research / Surgery and/or Radiotherapy of Cancer
medwireNews: Examining for Microsatellite instability (MSI) and Mismatch repair deficiency (MMRD) could help identify which gastro-oesophageal cancer patients will benefit from perioperative chemotherapy, research suggests.

“Because MSI or MMRD tumors comprise up to 10% to 20% of stomach cancers in some series, this finding has the potential to affect large numbers of patients”, the study authors believe.

The secondary post hoc analysis of the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial included MSI data for 303 participants who were treated for operable gastro-oesophageal cancer with surgery alone or alongside epirubicin, cisplatin and fluorouracil chemotherapy.

The original trial findings showed that 5-year overall survival (OS) was significantly longer in the patients given combined therapy, explain David Cunningham, from the Royal Marsden Hospital in London, UK, and co-authors in JAMA Oncology.

In all, 283 patients had tumours which showed microsatellite stability or low MSI, while 20 patients had high MSI, they report. And for the 254 patients with MMR results available for the proteins mutL homologue 1, mutS homologue 2, mutS homologue 6 and PMS1 homologue 2, concordance between high MSI and MMRD status was 97.6%.

Among the patients treated with surgery alone, median OS was not reached in the patients with high MSI or MMRD versus a median of 20.5 months for the patients who had neither Biomarker, giving a nonsignificant hazard ratio (HR) of 0.42.

For patients who had received perioperative chemotherapy, however, median OS was significantly shorter for those with high MSI or MMRD than those without, at 9.6 versus 19.5 months and a HR of 2.18.

“If validated, this finding has the potential to improve patient selection for perioperative chemotherapy and spare a significant proportion of patients with gastric cancer unnecessary treatment”, the MAGIC investigators say.

“We do not believe that these data justify a change in clinical practice; however, we recommend prospective trial validation to ascertain the optimal perioperative treatment for patients with [high MSI] gastric cancer.”

And they add: “In light of the remarkable success of anti–programmed cell death protein 1 therapies in MMRD colorectal cancer, alternative treatment strategies could be reasonably investigated for these patients.”

Reference

Symth EC, Wotherspoon A, Peckitt C, et al. Mismatch repair deficiency, microsatellite instability, and survival. An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol 2017; Advance online publication 23 February. doi:10.1001/jamaoncol.2016.6762

Cancer-Related Fatigue

Exercise, Psychological Interventions Beat Pharma Options For Cancer-Related Fatigue

Meta-analysis points to a strategy of exercise and psychological therapy rather than pharmaceutical treatment for patients with cancer-related fatigue

Date: 07 Mar 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Supportive Care
medwireNews: Clinicians should treat cancer-related fatigue (CRF) with exercise-based and/or psychological interventions, indicates a meta-analysis published in JAMA Oncology.

The data from 11,525 participants of 113 studies showed that these options had a stronger impact on CRF than did pharmaceutical agents, such as paroxetine hydrochloride or modafinil, say Karen Mustian, from the University of Rochester Medical Center in New York, USA, and co-authors.

The randomised controlled studies included in the meta-analysis were judged to be of good quality and to have sufficient data on fatigue to allow determination of a mean weighted effect size (WES) for CRF severity, the researchers explain.

Almost half (46.9%) of the studies were conducted in breast cancer patients and the remainder in those with other tumour types, with 44.2% including participants with nonmetastatic cancer, 9.7% only those with metastases and 29.2% with both populations.

Both exercise interventions and psychological interventions, and combined exercise and psychological interventions, impacted on CRF during and after cancer treatment, with significant moderate effects of 0.30, 0.27 and 0.26, respectively. By contrast, pharmacological interventions had a “significant but very small” WES of 0.09.

The authors believe their study is the first to indicate that the efficacy of CRF treatment is linked to eight different factors, with WES ranging from –0.91 to 0.99.

Specifically, CRF reductions were greatest in patients with early-stage cancer, those who had completed their primary treatment, and in participants given cognitive behavioural therapy types of psychological intervention. CRF interventions that were given to groups of patients and in person were also particularly effective, as were those measured using the Piper Fatigue Scale and where the control condition was standard care.

“However, exercise and psychological interventions produced significant improvements in CRF, even when a rigorous specific-component (behavioural placebo) control comparison was used”, the researchers say.

Likewise, the team suggests that their study has shown for the first time that CRF efficacy is not related to patient age, cancer type or whether the exercise recommended was aerobic, anaerobic resistance or a combination, but might be influenced by the timing of CRF intervention.

“For example, exercise may be the most effective treatment for patients receiving primary treatment, whereas psychological and exercise plus psychological interventions may be most effective for survivors who have completed primary treatment”, write Karen Mustian et al.

While recommending more phase III research into the use of exercise-based and psychological interventions, the researchers conclude: “Clinicians should prescribe exercise and psychological interventions as first-line therapy for patients experiencing CRF.”

Reference

Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceutical, psychological and exercise treatments for cancer-related fatigue. A meta-analysis. JAMA Oncol; Advance online publication 2 March 2017. doi:10.1001/jamaoncol.2016.6914

Utidelone Plus Capecitabine ‘Promising’ For Refractory Metastatic Breast Cancer

Utidelone Plus Capecitabine ‘Promising’ For Refractory Metastatic Breast Cancer
Combining an epothilone analogue with capecitabine may be effective against anthracycline- and taxane-refractory metastatic breast cancer

Date: 16 Feb 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Breast Cancer, Metastatic

medwireNews: Adding the epothilone analogue utidelone to capecitabine extends progression-free survival (PFS) in women with metastatic breast cancer refractory to both anthracycline- and taxane-based chemotherapy, suggest phase III trial results from China.

Reporting that the combination treatment has a “manageable safety profile”, the investigators believe their findings “support the favourable benefit–risk profile of this regimen and offer a new potential option for patients with heavily pretreated metastatic breast cancer.”

Median PFS was determined by independent radiology review to be 8.44 months for the 270 patients who were randomly assigned to receive 21-day cycles of chemotherapy consisting of utidelone 30 mg/m2 per day on days 1–15 plus capecitabine 1000 mg/m2 twice daily on days 1–14.

This compared with a median PFS of 4.27 months for the 135 patients using capecitabine only, giving a significant hazard ratio (HR) of 0.46.

“In our study, utidelone-related toxicities were generally mild to moderate and considered clinically manageable”, report Binghe Xhu, from National Cancer Venter/Cancer Hospital in Beijing, China, and co-workers.

Peripheral neuropathy was the most common grade 3 adverse effect in patients given utidelone plus capecitabine, affecting 22%. Noting that the patients had all previously used taxanes and other agents associated with peripheral neuropathy, the team hypothesizes that “[t]hese previous regimens could have sensitised patients to utidelone-induced peripheral neuropathy.”

Palmar–plantar erythrodysaesthesia was the most common grade 3 event common in patients given capecitabine alone (8%) and the third most common grade 3 event for those given combination treatment (7%), after neutropenia (12%).

There were sixteen serious adverse events in the combination treatment arm and 14 in the capecitabine only arm, with diarrhoea reported in three and two patients, respectively.

Further analysis indicated that patients given combination treatment were significantly more likely to have an objective response than those treated with capecitabine monotherapy (40.4 vs 21.5%) and to derive clinical benefit from treatment (53.9 vs 26.0%), defined as a complete or partial response or stable disease for at least 6 months.

The trial investigators explain in The Lancet Oncology that overall survival (OS) data are immature but that at cutoff utidelone plus capecitabine appeared to offer longer OS, at a median of 16.13 months versus 12.78 months with capecitabine monotherapy, and a significant HR of 0.63.

However, Xavier Pivot, from University Hospital J Minjoz in Besançon, France, cautions in an accompanying article that “[a]lthough encouraging, mature overall survival data are needed before making any decision for regulatory approval of utidelone.”

He also notes that a quarter of the patients in the trial had HER2-positive breast cancer and that subsequent targeted treatment may affect the final OS analysis.

“In the future, large randomised studies in metastatic breast cancer should include a statistical plan that is able to provide conclusions about overall survival and the population should be restricted to a group of patients that unquestionably require chemotherapy alone”, the commentator recommends.

References

Zhang P, Sun T, Zhang Q, et al. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracylines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol; Advance online publication 10 February 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30088-8

Piovot X. Classic cytotoxic drugs: a narrow path for regulatory approval. Lancet Oncol; Advance online publication 10 February 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30089-X