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 trialThe Lancet Oncology|21|P. 969-977

Chemo doorstep drops help to keep cancer patients safe

Thousands of patients with cancer have had chemotherapy delivered to their doors so that they can more safely receive treatment during the coronavirus pandemic.

Up to 10,000 chemo home deliveries were made over three months at the peak of the outbreak, avoiding the need for patients to venture out and risk infection when their immune system was low. The drops are part of the COVID-friendly treatments introduced in response to the pandemic which have helped to ensure that 85,000 people could start treatment between March and June.

Full detail at NHS England

Testicular cancer: one cycle of chemo just as effective

Cullen, M., et al |2020|The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis|European Urology|

European Urology has published a paper based on a study that looked at the efficacy of one cycle of chemotherapy for patients with testicular cancer rather than two.  While standard treatment in Europe involves two cycles of chemotherapy the researchers of this trial  show that one cycle has few adverse effects and comparable outcomes
to those seen with two cycles. 

Abstract
Background: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2 ), and cisplatin (BE360P) chemotherapy, or surveillance.
Objective: To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P.
Design, setting, and participants: A total of 246 patients with vascular invasion–positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study.
Intervention: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1–3, and cisplatin 50 mg/m2 on days 1–2, plus antibacterial and granulocyte colony stimulating factor prophylaxis.
Outcome measurements and statistical analysis: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of 5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr.
Results and limitations: The median follow-up was 49 mo (interquartile range 37–60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3–
3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3–4 febrile neutropenia occurred in 6.8% of participants.
Conclusions: BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population.
Patient summary: Removing the testicle fails to cure many patients with high-risk primary testicular cancer  since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes
to those seen with two cycles

 

The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of  Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in 
High-risk, Stage 1 Nonseminomatous or Combined Germ Cell
Tumours of the Testis

In then news:

BBC News Testicular cancer: ‘Kinder’ chemotherapy is ‘just as effective’

Scientists discover new breakthrough in cancer hair loss treatment

University of Manchester| September 2019 |Scientists discover new breakthrough in cancer hair loss treatment

Scientists at the University of Manchester have discovered that damage in the hair follicle causing by taxanes cancer drugs which can cause permanent hair loss, can be prevented. Taxanes are very important anti-cancer drugs commonly used to treat, for example, patients with breast or lung carcinoma and particularly cause anxieties among breast cancer patients for the very distressing and sometimes long-lasting hair loss taxanes can induce. 

Source Purba et al 2019
Image source: Purba et al 2019

Lead author of the study Dr Talveen Purba explains:

Dr Purba emphasises: “A pivotal part of our study was to first get to grips with how exactly hair follicles responded to taxane chemotherapy, and we found that the specialised dividing cells at the base of the hair follicle that are critical for producing hair itself, and the stem cells from which they arise, are most vulnerable to taxanes. Therefore, we must protect these cells most from undesired chemotherapy effects – but so that the cancer does not profit from it.”

The team hope that their work will support the development of externally applicable medicines that will slow or briefly suspend cell division in the scalp hair follicles of patients undergoing chemotherapy to mitigate against chemotherapy-induced hair damage. This could complement and enhance the efficacy of existing preventive approaches i.e. scalp cooling devices (Source: University of Manchester)

The full new story is available from the University of Manchester

Full reference: Purba, T. S. et al 2019| CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane‐induced alopecia| EMBO molecular medicine| https://doi.org/10.15252/emmm.201911031

Abstract

Taxanes are a leading cause of severe and often permanent chemotherapy‐induced alopecia. As the underlying pathobiology of taxane chemotherapy‐induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell‐rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy‐induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy‐induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell‐protective therapy in taxane‐based oncotherapy, and provides preclinical proof‐of‐principle in a healthy human (mini‐) organ that G1 arrest therapy can limit taxane‐induced tissue damage.

 

The article can be read online or downloaded

 

 

 

 

A solution to less toxicity in chemotherapy treatment?

Oh, H. J., Aboian, et al |2019| 3D Printed Absorber for Capturing Chemotherapy Drugs before They Spread through the Body|  ACS Central Science| 

A study that describes  the development of 3D printed porous absorbers for capturing excess chemotherapy drugs that are not taken up by the targeted tumor to prevent toxic side effects is published in the journal ACS Central Science.  So far the research has not been conducted in human subjects but the early work could potentially offer a way to make chemotherapy less harmful to the body. 

Abstract

Despite efforts to develop increasingly targeted and personalized cancer therapeutics, dosing of drugs in cancer chemotherapy is limited by systemic toxic side effects. We have designed, built, and deployed porous absorbers for capturing chemotherapy drugs from the bloodstream after these drugs have had their effect on a tumor, but before they are released into the body where they can cause hazardous side effects. The support structure of the absorbers was built using 3D printing technology. This structure was coated with a nanostructured block copolymer with outer blocks that anchor the polymer chains to the 3D printed support structure and a middle block that has an affinity for the drug. The middle block is polystyrenesulfonate which binds to doxorubicin, a widely used and effective chemotherapy drug with significant toxic side effects. The absorbers are designed for deployment during chemotherapy using minimally invasive image-guided endovascular surgical procedures. We show that the introduction of the absorbers into the blood of swine models enables the capture of 64 ± 6% of the administered drug (doxorubicin) without any immediate adverse effects. Problems related to blood clots, vein wall dissection, and other biocompatibility issues were not observed. This development represents a significant step forward in minimizing toxic side effects of chemotherapy.

The full article is available to download from ACS Central Science

In the news:

BBC News ‘Less toxic’ chemotherapy hope

Research supports less chemotherapy after bowel cancer surgery

NIHR | June 2018 | Research supports less chemotherapy after bowel cancer surgery

New research funded by the NIHR shows that patients with bowel cancer may only need half of the number of sessions of chemotherapy than they currently receive. The international clinical research trial indicates that people with bowel cancer who are currently given 6 months of chemotherapy may only need three months of treatment (Source: NIHR).
drip-2016247_1920

The full story is available at NIHR 

Background

6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.

Methods

The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.

Findings

6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7%  for the 3 month group and 77·1%  for the 6 month group, giving a hazard ratio of 1·006 (0·909–1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).

Interpretation

In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.

The findings have now been published in the journal Lancet Oncology where the article can now be downloaded

Full reference:

Iveson, Timothy J et al.| 2018| 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial|The Lancet Oncology | Vol. 19| Issue 4| P.  562 – 578

Three-month course of chemotherapy as effective as six months following surgery for bowel cancer

NIHR   | March 2018  |Three-month course of chemotherapy as effective as six months following surgery for bowel cancer

NIHR and MRC in partnership  have funded international clinical trial, which has evaluated the effectiveness of a three-month course of adjuvant oxaliplatin/fluoropyrimidine combination chemotherapy for colorectal cancer versus the standard six-month treatment regimen. The trial’s findings indicate that the shorter duration treatment leads to similar survival outcomes with better quality of life for patients and therefore might represent a new standard of care.

chemotherapy-448578_1920
The research team led by the Cancer Research UK Clinical Trials Unit in Glasgow, recruited more than  6,000 patients with high-risk stage II or stage III colorectal cancer from 244 centres across Europe, Australia and New Zealand. The participants in the trial  received either a three or six month course of chemotherapy and were followed up for a minimum of three years.

Three years later, 76.7% of patients who received treatment over three months were disease free compared to 77.1% of patients treated over six months. Patients treated over three months had fewer side effects and reported a better quality of life as well as reduced peripheral neuropathy.

Chief Investigator Dr Tim Iveson, Consultant Medical Oncologist at University Hospital Southampton NHS Foundation Trust and Honorary Associate Professor at the University of Southampton, said: “Bowel cancer is the fourth most common cancer in the UK with 41,000 new cases each year. Bowel cancer can be cured by surgery and chemotherapy. Approximately 2,500 patients per year currently receive up to six months of post-operative chemotherapy. Reducing chemotherapy duration to three months will save the NHS £5000 per patient – a total saving to the NHS of £12.5 million pounds per year.

Dr Iveson added: “The impact on patients is important, as by having a shorter course of chemotherapy patients have fewer side effects.  Based on these results, three months of post-operative chemotherapy should be considered as the new standard care for many patients with bowel cancer.”

The full unedited news item is available from NIHR  here

Summary

Background

6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.

Methods

The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.

Findings

6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1–78·2) for the 3 month group and 77·1% (75·6–78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909–1·114, test for non-inferiority p equal to 0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).

Interpretation

In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.

Funding

Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.

 

Full reference:
Iveson, T. J., et al  |    2018  | 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial The Lancet Oncology  |  Vol. 19  | 4 | P.562–78

The full article can be read in The Lancet here

New chemotherapy approach offers breast cancer patients a better quality of life

The chemotherapy drug capecitabine gives patients a better quality of life and is as effective at preventing breast cancer from returning as the alternative regimen called CMF, when given following epirubicin. | ScienceDaily | Cancer Research UK

Around 4,400 patients on the TACT2 clinical trial were treated with the chemotherapy drug epirubicin followed by either capecitabine or CMF, after surgery.

Researchers at The Institute of Cancer Research, London, and the Cancer Research UK Edinburgh Centre found that capecitabine resulted in patients experiencing fewer side effects and having a better quality of life, and it was as effective at preventing cancer’s return as CMF.

Most patients experienced some side effects regardless of the treatment they were given. But those taking CMF were more likely to experience severe side effects including early menopause, nausea, infection, thrombosis, and anemia.

During the trial, patients were followed up after 12, 18 and 24 months, and then yearly for at least 10 years, to see if their cancer had returned and to monitor side effects. More than 85 per cent of patients did not experience their cancer returning for at least five years.

More detail at

Link to the research:

Cameron, D., et al.  Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. The Lancet Oncology.