PET–CT Head & Neck Cancer Patients and Neck Dissection

PET–CT Reveals Need For Neck Dissection In Head & Neck Cancer Patients
Positron emission tomography–computed tomography may reduce the need for neck dissection in patients undergoing adjuvant treatment for head and neck cancer

Date: 29 Mar 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Head and Neck Cancers / Imaging, Diagnosis and Staging / Surgery and/or Radiotherapy of Cancer

medwireNews: Imaging can guide the need for neck dissection in patients with Squamous cell carcinoma of the head and neck, say researchers who report the use of surveillance to be equally effective in patients with and without human papillomavirus (HPV)-associated malignancy.

As reported in The New England Journal of Medicine, the team used positron emission tomography–computed tomography (PET–CT)-guided surveillance to identify patients who had an incomplete or equivocal response 12 weeks after completing chemoradiotherapy and thus required neck dissection.

The 282 patients randomly assigned to the surveillance group had noninferior overall survival at 2 years compared with the 282 patients assigned to undergo planned neck dissection before or after chemoradiotherapy, despite neck dissection occurring in just 54 versus 221 patients.

Indeed, the 2-year overall survival rate slightly favoured surveillance, at 84.9% versus 81.5% for planned neck dissection. And the hazard ratio of 0.92 MET the prespecified definition of noninferiority for surveillance, with the 95% confidence interval ruling out an unfavourable difference of more than 4 percentage points, the authors report.

Hisham Mehanna, from the University of Birmingham in the UK, and fellow PET–NECK Trial Management Group investigators say that this remained true after considering gender, age, tumour characteristics and treatment schedules, and after adjusting for HPV p16 expression status.

“[O]ur trial may actually underestimate the benefit of PET-CT–guided surveillance in patients with head and neck cancer”, the authors suggest, noting that their protocol recommended neck dissection in patients with an equivocal response, defined as imaging-negative residual mass or mild tracer uptake in normal-sized nodes.

“However, a recent study suggests that nodal disease may take longer to involute in patients with HPV-positive disease”, they explain. “It is therefore conceivable that patients in our trial who had HPV-positive tumors and equivocal PET-CT findings (especially with enlarged nodes) at the 3-month assessment might have achieved a cure without neck dissection if they had undergone PET-CT at a later time."

Locoregional control at 2 years was reached by 91.9% of the surveillance group and 91.4% of the planned neck dissection group, although the researchers note that the 2-year rate was better in the neck dissection patients who underwent surgery after chemoradiotherapy than beforehand, at 94.8% versus 90.4%.

Nodal recurrence was reported in three surveillance patients and one planned dissection patient, while distant metastases were recorded in 21 and 23 patients, respectively.

Among patients who underwent surgery, the surveillance and planned neck dissection groups had comparable rates of surgical complications (42 vs 38%). Global health status scores showed a small difference between the groups at the 6-month check-up, in favour of surveillance, but this was lost after 2 years.

Most (84%) patients had oropharyngeal cancer and 75% tested positive for the HPV infection-associated protein p16. The majority of patients had nodal stage N2a (17%) or N2b (61%) disease, while the remainder had N2c or N3 tumours.

“Although 5 of the 9 patients with stage N3 disease in the PET-CT surveillance group had complete responses, extrapolation of a PET-CT–guided surveillance policy to this higher-risk group of patients cannot currently be justified because of the small number of such patients in the trial”, the researchers caution.

Reference

Mehanna H, Wong W-L, McConkey CC, et al. PET–CT surveillance versus neck dissection in advance head and neck cancer. New Engl J Med 2016; Advance online publication 23 March.DOI: 10.1056/NEJMoa1514493

Molecular Screening of Advanced Refractory Cancer Patients

Routine Molecular Screening of Advanced Refractory Cancer Patients
An analysis of the ProfilER-01 study presented at ASCO 2017

Date: 09 Jun 2017
Topic: Personalised medicine

During Clinical Science Symposium entitled “Translating Tumor Sequencing Into Clinical Decision-Making: The Record to Date” held on 3 June at ASCO 2017 Annual Meeting in Chicago, US, the investigators from the Centre Léon Bérard in Lyon, France presented the results of a molecular analysis of the patients included in the ProfilER-01 study, one of the largest trial assessing high-throughput genomic analyses for large varieties of cancer. The findings show that routine genomic testing is feasible in a local and regional setting. They found that screening of heavily pretreated advanced cancer patients limits the number of patients who can actually receive molecular targeted therapy, but patients who could receive recommended molecular targeted agent have a better overall survival than those who did not.

ProfilER (NCT01774409) is a prospective molecular profiling clinical trial exploring cancer cell genomic alterations in patients with advanced disease to guide targeted treatment. Patients with confirmed diagnosis of advanced cancers are eligible. DNA extracted from either archival or fresh collected tumour samples was analyzed by targeted exon sequencing of cancer related genes and whole genome array comparative genomic hybridization (CGH). A multidisciplinary molecular board, consisting from a panel of clinicians and scientists, analyzed genomic data and recommended molecular targeted therapies when actionable alterations are found.

In total 2676 patients were enrolled (of whom 316 ongoing); 1944 with tumour genomic profiles; 1004 (52%) with at least one actionable mutation. Sex ratio was 45%:55% (male:female). Median age range was 59 years.

Among patients with actionable alterations affected tumour types were breast cancer, gynaecological cancers, head and neck cancer, lung cancer, sarcoma, CNS malignancies, colorectal cancer, liver, pancreatic and biliary tract cancers.

Mutations (including substitutions and small indels), amplifications and homozygous deletions were observed in tumour samples.

The most common actionable mutations were on KRAS, PIK3CA, CDKN2A homozygous deletions, PTEN homozygous deletions, CCND1, FGFR1, MDM2, HER2 and HER1.

Molecular targeted therapies were recommended in 676 patients. Among them, 143 (7%) initiated a recommended molecular targeted therapy. Molecular targeted therapies received were mTOR inhibitors, anti-angiogenic tyrosine kinase inhibitors (TKI), EGFR TKI, inhibitors of cell cycle.

In patients with initiated molecular targeted agent therapy, median overall survival was 3.3 years and 5-year survival rate 34.8%. In patient in whom molecular targeted therapy was not initiated, the 5-year survival rate was 28.1%.

The authors concluded that in this series of cancer patients, CGH and NGS identified actionable alterations in more than half patients that led to treatment recommendation in 35%. Most patients treated derived benefit from the recommended molecular targeted therapy, but these represent a minority of the whole population screened.

ProfilER-2 is planned to compare the academic gene-panel with a commercial, 315 gene test from Foundation Medicine. This trial will assess whether screening a larger number of genes leads to more molecular targeted agent recommendations. The WES and WGS in routine screening are currently in preparation under France Medicine Genomics 2025 plan. The authors also questioned if there is a value of exploring patients in an earlier setting.

Reference

Tredan O, Corset V, Wang Q, et al. Routine molecular screening of advanced refractory cancer patients: An analysis of the first 2490 patients of the ProfilER Study. J Clin Oncol 35, 2017 (suppl; abstr LBA100)

Urinary RNA Test Points To Aggressive Prostate Cancer

Urinary RNA Test Points To Aggressive Prostate Cancer
Measuring RNA expression of two prostate cancer markers identifies which prostate cancer patients have Gleason score 7 or above disease

Date: 22 May 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Translational Research

medwireNews: Urinary RNA testing could help identify which patients diagnosed with early-stage prostate cancer have aggressive disease, suggest study findings published in JAMA Oncology.

“The multiplex urinary RNA algorithm was developed and validated in cohorts of men presenting for initial prostate biopsy owing to elevated PSA [prostate-specific Antigen] or abnormal DRE [digital rectal examination] findings and therefore represents a strategy to refine biopsy decisions after PSA screening rather than replacing PSA testing”, explain the researchers.

The team measured the expression of two RNA markers of aggressive prostate cancer – PCA3 and TMPRSS2:ERG –in the urine after DRE to determine if this would improve the specificity of detection of tumours with a Gleason score of 7 or above compared with a PSA test alone.

For the initial developmental cohort of 516 men, aged 33–85 years, the team used a threshold of urinary PCA3 and TMPRSS2:ERG that preserved sensitivity for detection of aggressive prostate cancer at 95%. This improved the specificity for detection from 18% with PSA alone to 39% with the test.

Analysis of the second, validation cohort of 561 men, aged 27–86 years, confirmed that using the RNA test increased specificity significantly, from 17% to 33%, while maintaining sensitivity at 93%.

“Use of these tests to select men for initial biopsy after elevated PSA or abnormal DRE findings showed that 42% of men would have been safely excluded from undergoing unnecessary prostate biopsy, while high sensitivity for aggressive cancer was retained”, say Martin Sanda, from Emory University School of Medicine in Atlanta, Georgia, USA, and co-authors.

“These findings suggest that urinary RNA testing can mitigate harms of prostate screening while retaining the benefits of identifying aggressive cancers suitable for treatment.”

And cost analysis indicated that using the test to restrict biopsy use and target biopsy to high-risk men, rather than all patients with an abnormal PSA, would reduce the cost of both cancer detection and care, with the greatest potential savings among men aged 55–64 years.

But the researchers add: “Relative to [US Protective Services Task Force] recommendations (where men would undergo neither PSA testing nor consequent biopsy), urine RNA testing to select men for biopsy would reduce treatment costs for advanced disease, but these were offset by costs of biopsies and care for early-stage prostate cancer.”

Reference

Sanda MG, Feng Z, Howard DH, et al. Association between combined TMPRSS2:ERG and PCA3 RNA urinary testing and detection of aggressive prostate cancer. JAMA Oncol; Advance online publication 18 May 2017. doi:10.1001/jamaoncol.2017.0177

Dacomitinib For Advanced EGFR-Mutated NSCLC

ARCHER Supports First-Line Dacomitinib For Advanced EGFR-Mutated NSCLC
Progression-free survival in patients with newly diagnosed advanced non-small-lung cancer with an epidermal growth factor receptor mutation is higher with dacomitinib than gefitinib

Date: 09 Jun 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Non-Small-Cell Lung Cancer, Metastatic

medwireNews: Results from the ARCHER 1050 trial of patients with newly diagnosed advanced EGFR-positive non-small-cell lung cancer (NSCLC) suggest that first-line dacomitinib is superior to gefitinib for both progression-free survival (PFS) and duration of response (DOR).

“Dacomitinib should be considered as one of the new treatments for first-line management of patients with the EGFR mutation and in addition to the three existing drugs, we now have a fourth one,” presenting author Tony Mok, from the Chinese University of Hong Kong, told delegates at the 2017 annual meeting of the American Society of Oncology, held in Chicago, Illinois, USA.

The phase III trial compared the second-generation irreversible EGFR Tyrosine kinase inhibitor (EGFR–TKI) with the first-generation EGFR–TKI gefitinib as a first-line treatment for patients with advanced NSCLC with an activating EGFR mutation but no central nervous system metastases or prior TKI therapy.

After a median of 22.1 months, the primary endpoint of PFS by blinded independent review was 14.7 months for the 227 patients randomly assigned to receive dacomitinib 45 mg/day versus 9.2 months for the 225 patients who received gefitinib 250 mg/day, giving a significant hazard ratio (HR) of 0.59 in favour of dacomitinib.

“The median PFS with dacomitinib of 14.7 months is actually among the highest in most of the randomised phase III study in the first-line setting”, Mok said.

He noted that the PFS curves began to separate at 5–6 months and this resulted in a 2-year PFS rate of 30.6% for dacomitinib-treated patients and 9.6% for their gefitinib-treated counterparts.

Subgroup analysis favoured dacomitinib with the exception of nonAsian patients, who had an insignificant HR for PFS of 0.89, whereas there was a significant HR of 0.51 for their Asian counterparts. However, exploratory analysis of the 72 nonAsian patients who responded to treatment failed to explain this difference.

An objective response was achieved by a comparable 74.9% of dacomitinib-treated patients versus 71.6% of gefitinib-treated patients, but the dacomitinib patients had a significantly longer duration of response, at a median 14.8 versus 8.3 months.

Analysis of the objective response rate by change in tumour size suggested that the improved duration of response may be explained by the greater change in tumour size experienced by patients given dacomitinib.

Overall survival data are yet to mature, Mok said, noting that just 36.9% of events had occurred at data cut off in July 2016.

Safety analysis revealed that patients given dacomitinib had higher rates of grade 3 diarrhoea (8.4 vs 0.9%), Paronychia (7.5 vs 1.3%), dermatitis acneform (13.7 vs 0%) and Stomatitis (3.5 vs 0.4%). One patient given dacomitinib had grade 5 diarrhoea.

However, patients given gefitinib had higher rates of grade 2 (10.7 vs 2.2%) and grade 3 (8.5 vs 0.9%) alanine aminotransferase elevation than dacomitinib-treated patients.

Serious adverse events (SAEs) occurred in a comparable 27.3% of the dacomitinib group versus 22.3% of the gefitinib-treated patients, but the rate of treatment-related SAEs were higher in the dacomitinib arm, reported in 9.3% and 4.5%, respectively. The corresponding rates of permanent discontinuation and treatment-related deaths were 9.7% versus 6.7% and 0.9% versus 0.4%.

Dose modification was required after a median of 2.8 months of dacomitinib and lasted 11.3 months, with reduction to a 30 mg/day dose required in 38.3% of patients and to 15 mg/day in 27.8%, affecting 66.1% of patients overall.

By contrast, 8.0% of patients given gefitinib required a dose reduction to 250 mg every 2 days after a median of 3.3 months and this lasted for 5.2 months.

However, Tony Mok emphasized that the high efficacy, good tumour response and efforts to manage toxicity resulted in improved patient quality of life (QoL) in both treatment groups with regard to management of tumour symptoms, such as cough, dyspnoea and pain, with a slight benefit for dacomitinib.

Dacomitinib was associated with poorer QoL with regard to treatment-related symptoms but both treatments were neutral with regard to the global QoL measure.

Reference

Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial. J Clin Oncol; 35: 2017 (suppl; abstr LBA9007).

FOLFOXIRI–Bevacizumab ORR Allows Secondary Resection For Metastatic CRC

FOLFOXIRI–Bevacizumab ORR Allows Secondary Resection For Metastatic CRC
Surgery is feasible in a significant proportion of patients with initially unresectable metastatic colorectal cancer after FOLFOXIRI–bevacizumab regimen

Date: 30 May 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Colon Cancer / Rectal Cancer

medwireNews: Almost 40% of patients with unresectable metastatic colorectal cancer (CRC) may be eligible for surgery after treatment with fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) plus bevacizumab, say researchers who analysed data gathered from 11 clinical trials.

“Our findings show that FOLFOXIRI-[bevacizumab] represents a very effective therapeutic combination associated with a significant ORR [objective response rate]”, report Fausto Petrelli, from Piazzale Ospedale in Treviglio, Italy, and team in JAMA Oncology.

Data were available for 889 patients with initially unresectable CRC metastases, 877 of whom were evaluated for clinical response. The rate of liver-limited metastatic disease varied between the trial groups from 18–100%.

The pooled ORR for FOLFOXIRI–bevacizumab regimen was 69.0%. This resulted in conversion to surgery in 39.1% of the patients, with 28.1% achieving R0 resection at all surgical sites, the team says.

Pooled data available for six trials gave a median overall survival of 30.2 months, while pooled findings from nine trials gave a median progression-free survival of 12.4 months.

The researchers say that the survival outcomes, “although not striking, are highly consistent with those reported in the phase 3 TRIBE trial, probably reflecting the poor prognostic baseline characteristics of a population of patients with extensive metastatic involvement who were unselected for secondary resection intent.”

Fausto Petrelli et al conclude: “For patients with molecularly unselected and surgically unresectable metastatic CRC, triplet chemotherapy plus bevacizumab is able to not only control disease dissemination but induce rapid and deep cytoreduction that may translate into consistent probabilities to undergo secondary resection.

“Therefore, a multidisciplinary approach to advanced CRC is crucial to guarantee an optimal integration of highly active upfront treatments with surgical procedures to ultimately improve patients’ long-term outcome.”

Reference

Tomasello G, Petrelli F, Ghidini M, et al. FOLFOXIRI plus bevacizumab as conversion therapy for patients with initially unresectable metastatic colorectal cancer. A systematic review and pooled analysis. JAMA Oncol; Advance online publication 25 May 2017. doi:10.1001/jamaoncol.2017.0278