BMJ: Cancer of unknown primary

Lee, M.S. & Sanoff, H. K. (2020)| 371| m4050|Cancer of unknown primary| BMJ|
http://dx.doi.org/10.1136/bmj.m4050

Abstract

Cancers of unknown primary (CUPs) are histologically confirmed, metastatic
malignancies with a primary tumor site that is unidentifiable on the basis of standard
evaluation and imaging studies. CUP comprises 2-5% of all diagnosed cancers
worldwide and is characterized by early and aggressive metastasis. Current standard
evaluation of CUP requires histopathologic evaluation and identification of favorable
risk subtypes that can be more definitively treated or have superior outcomes.
Current standard treatment of the unfavorable risk subtype requires assessment of
prognosis and consideration of empiric chemotherapy. The use of molecular tissue
of origin tests to identify the likely primary tumor site has been extensively studied,
and here we review the rationale and the evidence for and against the use of such
tests in the assessment of CUPs. The expanding use of next generation sequencing
in advanced cancers offers the potential to identify a subgroup of patients who have
actionable genomic aberrations and may allow for further personalization of therapy.

The full text of the artilce is available from BMJ

[NICE Technology Appraisal Guidance] Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia

NICE | 09 December 2020 | Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia

Evidence-based recommendations on venetoclax (Venclyxto) with obinutuzumab for untreated chronic lymphocytic leukaemia in adults.

Full details from NICE

NIHR: Breast cancer screening for women in their forties could save lives

NIHR| December 2020 | Breast cancer screening for women in their forties could save lives

The Lancet Oncology has recently published the findings of a NIHR- funded longitudinal study that followed two groups of women who either received an annual mammography or were part of the NHS Breast Screening Programme. The trial began in 1990 and the research team randomly assigned 160,000 women into the two groups.

Recently published research from the long-term NIHR-funded UK Breast Screening Age Trial (UK Age Trial) provides further evidence of the benefits and risks of earlier screening for women.  Led by Professor Stephen Duffy, the trial began in 1990 and randomly assigned 160,000 women aged 39–42 to receive annual mammography or the usual NHS Breast Screening Programme. These women have now been followed up for around 23 years and the latest results have been published in The Lancet Oncology.

Currenlty the UK’s breast cancer screening programme offers mammograms to women aged between 50 and 70 years every three years. However, it is still unclear whether screening women from 40 years old is beneficial. Women in their forties are not routinely invited for screening because their risk of developing breast cancers is lower. However, the types of cancers that do develop in younger women are often more aggressive and progress more quickly. In these cases, earlier diagnosis and treatment would greatly benefit those patients. Source: NIHR

Full review is available from the NIHR

Primary paper available from The Lancet Oncology

Duffy, S. W., Vulkan, D., Cuckle, H., Parmar, D., Sheikh, S., Smith, R. A., … & Myles, J. (2020). Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. The Lancet Oncology, 21(9), 1165-1172.

Summary

Background

The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40–48 years on breast cancer mortality.

Methods

We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39–41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant’s first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151.

Findings

160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8–24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58–0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79–1·22]; p=0·86).

Interpretation

Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality.

Source: NIHR

Primary paper available from The Lancet Oncology

[NICE Technology appraisal guidance] Pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma

NICE | November 2020 | Pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma

Evidence-based recommendations on pembrolizumab (Keytruda) for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD L1 with a combined positive score (CPS) of 1 or more.

 NICE interactive flowchart – Upper aerodigestive tract cancer

Full details are available from NICE

[NICE Guidline] Isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma

NICE|Isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma | Technology appraisal guidance [TA658]| Published date: 18 November 2020

Evidence-based recommendations on isatuximab (Sarclisa) with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma in adults.

Further details are available from NICE

See also:

NICE

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NIHR: First-line chemotherapy for ovarian cancer given once every three weeks may preserve quality of life

NIHR | November 2020| First-line chemotherapy for ovarian cancer given once every three weeks may preserve quality of life

NIHR’s latest evidence feature focuses on research that studied the chemotherapy treatment women with a new diagnosis of ovarian cancer receive, this type of cancer is usually treated every three weeks with chemotherapy containing the medicines carboplatin and paclitaxel. Although a recent Japanese studied reported better outcomes without reducing quality of life for weekly chemotherapy, the researchers behind this study found that patients who received weekly paclitaxel had poorer quality of life during treatment. They were also more likely to have nerve damage that lasted up to 18 months.

Taken together with the lack of progression-free survival benefit, their findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer.

What’s new?

1438 women with ovarian cancer were asked about their quality of life at regular intervals for up to five years after starting treatment. They completed written questionnaires on factors such as emotional well-being, fatigue and nerve pain.

Nine months after patients entered the trial, the researchers found:

• Patient well-being fell during chemotherapy but then improved over the following months regardless of which treatment was given
• When researchers looked at well-being scores during and after treatment, those on weekly treatment experienced lower quality of life compared to those receiving treatment every three weeks
• Nerve damage caused by paclitaxel was worse in the weekly treatment arms and persisted for longer. It started later than in women receiving chemotherapy every three weeks
• Patients having weekly treatment reported slightly increased levels of fatigue compared to those treated every three weeks but this was not significant.

Although survival was similar for patients on all treatment plans, well-being data shows a different story. The study suggested weekly schedules were harder for patients to tolerate and caused long-lasting toxicity compared to less frequent chemotherapy.

The researchers believe that three-weekly chemotherapy should remain the standard of care for most newly-diagnosed ovarian cancer patients.

It is not known why paclitaxel causes nerve damage. The researchers in this study believe long-lasting nerve damage and numbness are likely because the total amount of paclitaxel given is higher for people taking weekly treatment (Source: NIHR)

Primary paper:

Blagden, S.P. (2020) et al. Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial| The Lancet Oncology|21|P. 969-977

University of Leeds: ‘First of its kind’ lung cancer trial

University of Leeds | November 2020| ‘First of its kind’ lung cancer trial

Scientists from the UK universities of Leeds, Newcastle, Manchester and Glasgow have been awarded funding of £900,000 by Cancer Research UK; the CONCORDE trial will explore the use of new drugs alongside standard radiotherapy in the hope of improving survival for people with advanced non-small cell lung cancer (NSCLC).

The team of researchers hope that the new drugs will make radiotherapy more effective, increase its ability to eradicate tumour cells and potentially offer new hope to lung cancer patients (Source: University of Leeds)

Full details of the trial are available from the Leeds press release

NICE recommends new chemotherapy-free treatment option for people with untreated chronic lymphocytic leukaemia

NICE | November 2020 | NICE recommends new chemotherapy-free treatment option for people with untreated chronic lymphocytic leukaemia

NICE has recommended a new chemotherapy-free treatment option for people with untreated chronic lymphocytic leukaemia (CLL) in final draft guidance.

The recommendation of venetoclax plus obinutuzumab is set to benefit more than 1,000 people each year. The new fixed 12-month chemotherapy-free treatment will be offered to people with CLL who have not received any prior treatments.

CLL, a type of cancer that affects white blood cells, is the most common of the chronic leukaemias and accounts for around 30% of all leukaemias affecting adults. In England there were 3,157 new cases of CLL in 2017.

Venetoclax plus obinutuzumab will be offered as a first-line treatment to people with CLL, with certain genetic abnormalities (such as a 17p deletion or TP53 mutation). For those without a 17p deletion or TP53 mutation, venetoclax plus obinutuzumab will be offered to those people with untreated CLL for whom fludarabine plus cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) is unsuitable.

NICE has also recommended venetoclax plus obinutuzumab as a new treatment option via the Cancer Drugs Fund, for people with untreated CLL without a 17p deletion or TP53 mutation for whom FCR or BR is suitable. This is so more evidence can be gathered on its cost effectiveness in this group (Source: NICE).

Full news story is available from NICE

ICR: What are the biggest issues in drug discovery and development?

Institute of Cancer Research | November 2020 | What are the biggest issues in drug discovery and development?

A panel of academic and industry experts have called on the NHS to pay less for drugs used to treat cancer. The summit held last summer by the Institute of Cancer Research (ICR) brought leading organisations from across the academic, charity, pharmaceutical and medical sectors.

The Summer Summit brought together experts from 16 leading academic institutions, charities, stakeholder groups and pharmaceutical companies and calls for a ‘variable pricing’ model based on the benefits they deliver to patients. The peer organistaions that participated in the summit, reached consensus and they identify several measures that will improve the current system of developing drugs, these are some of the solutions proposed to some of the biggest issues in drug discovery and development.

• Increasing incentives to discover and develop innovative treatments
• Enabling companies to work together more easily
• Flexible pricing for new medicines
• Improving the creation and use of biomarker tests
• New indicators of effectiveness to speed up clinical trials

The stakeholders at the summit also developed a nine point plan looking at practical recommendations to improve access to new cancer treatment.

The fuull blog post is available from The Institute of Cancer Research

The list of consensus statements is available from The Institute of Cancer Research

See also:

BMJ NHS should vary price it pays for cancer drugs to improve access, say experts

BMJ: Mortality due to cancer treatment delay: systematic review and meta-analysis

BMJ (2020) | Mortality due to cancer treatment delay: systematic review and meta-analysis| 371| m4087

A month long delay in treating cancer is associated with increased mortality for seven types of cancer: bladder, breast, colon, rectum, lung, cervical cancer, and head and neck cancer; delays longer than four weeks are even more detrimental.

For surgery, this is a 6-8% increase in the risk of death for every four week delay. This impact is even more marked for some radiotherapy and systemic indications, with a 9% and 13% increased risk of death for definitive head and neck radiotherapy and adjuvant systemic treatment for colorectal cancer, respectively.

The investigators acknowledge that their results reflect the impact of delay on large and expectedly heterogeneous populations with varying risks of recurrence. Therefore, these estimates are best used at a policy and planning level for modelling, rather than for individual risk prediction (Source: Hanna, et al. 2020).

Abstract

Objective To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways.

Design Systematic review and meta-analysis.

Data sources Published studies in Medline from 1 January 2000 to 10 April 2020.

Eligibility criteria for selecting studies Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models.

Results The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings.

Conclusions Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Visual abstract available from The BMJ, Hanna et al(2020)

Mortality due to cancer treatment delay: systematic review and meta-analysis