When Prof Cathy Eng of the MD Anderson Cancer Centre in Texas meets a new patient with liver metastases, she initially tries to identify the goals of therapy with patients

Gary Culliton reports on remarks made by Associate Prof Cathy Eng, Medical Oncologist at the University of Texas MD Anderson Cancer Centre, at the recent Mater Hospital ‘Multimodality Management of Colorectal Liver Metastases: Collaborating Towards Cure’ meeting.

When Prof Cathy Eng of the MD Anderson Cancer Centre in Texas meets a new patient with liver metastases, she initially tries to identify the goals of therapy with patients. Surgical resection offers the only real potential for cure in colorectal liver metastases: this is less likely with systemic chemotherapy alone or with hepatic directed therapy.

Prof Eng spoke about neoadjuvant chemotherapy in the treatment of metastatic colorectal carcinoma at a recent meeting at Dublin’s Mater Hospital.

The meeting was entitled, ‘Multimodality Management of Colorectal Liver Metastases: Collaborating towards Cure’.

Prof Eng outlined treatment options for patients with liver metastases. She posed a number of questions, including the extent to which upfront biologic therapy was required in patients who were surgically resectable, in their two- to three-month period of neoadjuvant chemotherapy.

The aim is to use neoadjuvant chemotherapy to improve surgical resection outcomes. Predictive markers help in this regard. The majority of patients, unfortunately, will present with unresectable disease with a five-year survival of only 11 per cent, according to the American Cancer Society.

Studies done by Dr Rene Adam at Hôpital Paul Brousse in France looked at overall five-year survival of patients who were surgically resectable (48 per cent) compared with those who were initially considered unresectable but who were converted with the use of  neoadjuvant chemotherapy and received surgery (33 per cent). There was an improvement in 10-year survival. An analysis showed that — where there was stabilisation and partial response — this resulted in a benefit for overall survival. With current chemotherapy options, the response rates are 35-55 per cent.

Prof Eng considered results with the inclusion of biologic therapy. An Italian study (Falone et al: J Clin Oncol 2007 May 1;25(13):1670-6) looked at a surgically unresectable patient population. Patients over 75 years old were excluded. The primary endpoint was response rate. There was a difference in response (66 per cent) if folinic acid, 5-fluorouracil, oxaliplatin and irinotecan, or FOLFOXIRI, were used. This compared to therapy with folinic acid, 5-fluorouracil and irinotecan, or FOLFIRI, (41 per cent);  50 per pert of the patients had grade 3 or 4 neutropenia. Some did require G-CSF support: 36 per cent of patients who received FOLFOXIRI had an R0 surgical resection. This seemed to be very promising. FOLFOXIRI might not be suitable for elderly patients with multiple co-morbidities, however.
Liver metastases
The same Italian group (Masi et al, Ann Surg 2009 Mar;249(3):420-5) completed a pooled analysis of FOLFOXIRI based on three studies they had conducted on unresectable metastatic carcinoma patients with liver metastases. This involved 196 patients. They evaluated 71 patients for surgical resection; 37 patients went on to R0 resection. Eight of those patients had the addition of radiofrequency ablation (RFA). They reported a five-year progression-free survival (PFS) in a select patient population of 42 per cent.

In contrast, there was also a Greek study (Souglakos J et al, British Journal of Cancer, 2006) in similar patients who were randomised to FOLFIRI and FOLFOXIRI. This showed no difference in the primary endpoint of overall survival.

The European Organisation for Research and Treatment of Cancer (EORTC) study compared six cycles of FOLFOX (a chemotherapy regimen that incorporates folinic acid, fluorouracil, and oxalipatin), surgery, followed by adjuvant FOLFOX, versus surgery alone. This was in 364 resectable patients with one to four liver metastases.

The primary endpoint was progression-free survival. There was an absolute disease-free survival (DFS) benefit after three years for patients who received neoadjuvant FOLFOX (36.2 per cent) versus those treated with surgery alone (28.1 per cent). There was a comparative actual improvement in DFS of 8.1 per cent at three years. However, biologic therapy was not included and, as a result, it is not known who will respond to bevacizumab-based therapy. Furthermore, there are no predictive markers in colorectal cancer for anti-angiogenic therapy.

In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-naïve metastatic colorectal cancer patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI), or FOLFIRI alone. The difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone. The results were 8.9 months for the combination versus eight months for those given cetuximab.

KRAS mutation
The KRAS mutation is predictive of a very poor response to cetuximab therapy in colorectal cancer. When stratified, patients who were KRAS wild type and had received the combination (Cetuximab plus FOLFIRI), had PFS of 9.9 months versus 7.6 months for FOLFIRI. For overall survival, the combination was superior with 23.5 months, compared to 20 months.

A pooled analysis of prior European studies was published by DeRoock et al in JAMA in October 2010. This involved a total of 579 patients with the KRAS mutation on codon-13 (which represents fewer than 10 per cent of colorectal patients). The primary endpoint was overall survival. Despite having the KRAS mutation, those who received EGFR inhibition had an overall survival benefit of two months.

The CELIM trial involved patients with nonresectable disease (Folprecht et al, 2009) and 111 patients were studied. This looked at cetuximab with the addition of FOLFOX versus FOLFIRI, with a primary endpoint of response rate. There was no difference between the FOLFOX and FOLFIRI treatments. This was later broken down for those patients who had the presence of the KRAS wild type (the response rate went up to 70 per cent for the cetuximab combination with chemotherapy).

The BRAF mutation (which is downstream from KRAS) is present in less than 10 per cent of all colorectal carcinoma patients. The V600 mutation accounts for 90 per cent of the mutations. There is no current statistically-powered study that can definitely say that BRAF’s presence is predictive of benefit from EGFR inhibition. However, the presence of the BRAF mutation is prognostic.

When providing neoadjuvant chemotherapy in the hopes of attaining conversion status — so the patient can go on to surgical resection — care must be taken with the duration of chemotherapy provided. More than three months of chemotherapy is not recommended prior to resection. A retrospective study of 406 patients conducted at MD Anderson in Texas (Jean-Nicolas Vauthey et al, J Clin Oncology, 2006) found steatohepatitis is associated with increased 90-day mortality after hepatic surgery. Patients were provided a median of four months of chemotherapy.  Those who received irinotecan -based therapy were compared to those who received oxaliplatin-based therapy and those who received no therapy, prior to surgical resection.

In terms of current clinical trials, investigators are examining the differences between those patients who receive ‘up-front’ bevacizumab-based therapy versus those who receive cetuximab-based therapy

In patients with hepatic colorectal metastases (CRM), the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant, the authors recommended. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy. In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy. Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis.

“Treat only until surgical respectability, not until radiographic cure,” said Prof Eng.  A pooled analysis (Mitry et al, J Clin Oncol, 2008, Oct 20;26(30):4906-11. Epub 2008 Sep 15), which looked at 278 patients, considered adjuvant 5-FU based therapy (not oxaliplatin therapy). A trend in progression-free survival of 27.9 months versus 18.8 months was noted. There was no statistical difference in overall survival for adjuvant 5-FU based therapy. Irinotecan is not recommended in the adjuvant setting for liver resection.

Current trials
In terms of current clinical trials, investigators are examining the differences between those patients who receive ‘up-front’ bevacizumab-based therapy versus those who receive cetuximab-based therapy. Anti-VEGF therapy has been compared with anti-EGFR inhibition in the front-line setting. In the US, a trial (CALGB/SWOG 80405) is being conducted on metastatic colorectal carcinoma patients (some patients will have gone on to liver resection.)

A German group is examining FOLFIRI/cetuximab versus FOLFIRI/bevacizumab. There is a Phase 2 study which compares FOLFOXFIRI versus FOLFOX in the unresectable metastatic colorectal carcinoma patient with liver metastases. This is a study with 80 patients and the primary endpoint is a liver resection.

An Italian Phase 3 trial of 450 patients — which is comparing FOLFIRI against FOLFOXIRI — is going further and adding bevacizumab. The primary endpoint now is progression-free survival. In Spain, there is currently a study of FOLFIRI and panitumumab versus FOLFOX — comparing the two chemotherapy regimens and using an EGFR inhibition backbone.

Regarding novel agents, a study began last year in the US, where Dr Johanna C Bendell, at the Sarah Cannon Research Institute in Nashville, is examining FOLFOXIRI plus panitumumab. The NSABP C11 study is the largest intergroup study in the US. A Phase III study evaluating the role of perioperative chemotherapy in patients with potentially resectable hepatic colorectal metastases is available but is not enrolling well. Arm one is liver resection followed by standard chemotherapy; either FOLFOX or FOLFIRI. Arm two is neoadjuvant chemotherapy and surgical resection followed by adjuvant chemotherapy.

In terms of a prospective adjuvant study, a Dutch group is looking at capecitabine combined with oxaliplatin (CAPOX)/bevacizumab following liver resection, versus CAPOX.  The endpoint will be disease-free survival.

A UK group (FOCUS3: PI — Timothy Maughan) is also looking at biomarker analysis for metastatic or locally-advanced colorectal carcinoma patients.

They hope to enroll over 3,000 patients in a four-arm trial. The role of irinotecan is examined based on high/low topoisomerase  1 levels and whether or not the patient is KRAS or BRAF wild-type. This will allow study of those individuals who go on to liver resection. It also advances the field of looking at predictive markers and selecting the appropriate patients for treatment.

Routine surveillance of patients with Barrett’s oesophagus is of “doubtful value”, experts say, with research showing very few patients will develop oesophageal cancer.

A Danish study of 11,000 patients with Barrett’s oesophagus found their annual risk of oesophageal adenocarcinoma was just 0.12 per cent — considerably lower than that reported in previous studies.

While patients with Barrett’s oesophagus faced an 11-fold increased risk of developing oesophageal adenocarcinoma compared with the general population, the study authors said it was not enough to warrant routine monitoring.

“The risk of oesophageal adenocarcinoma among patients with Barrett’s oesophagus is so minor that in the absence of dysplasia, routine surveillance of such patients is of doubtful value,” the researchers wrote.

They studied all patients with Barrett’s oesophagus in Denmark between 1992 and 2009, with follow up of about five years.

Previous studies showed the annual incidence rate of adenocarcinoma among Barrett’s patients was about 0.5 per cent, but most studies involved only a few hundred patients and were subject to publication bias, the study authors said.

Dr Ellard added that the study provided reassurance for patients with Barrett’s that the risk of them developing adenocarcinoma was in fact extremely small.

New England Journal of Medicine 2011; 365:1375-83.

New research has shed light on why some breast-cancer patients experience neurological impairments, with evidence that certain areas of the brain are particularly vulnerable to chemotherapy.

Regardless of treatment history, all breast-cancer survivors had reduced activation in the left-middle dorso-lateral prefrontal cortex and premotor cortex, a US MRI study of executive function in 34 patients and 18 controls found.

But the subgroup of 25 women who underwent chemotherapy had the worst outcomes, including reduced left caudal lateral prefrontal cortex activation and reduced processing speed.

Specifically, reduced BA 8 activation was significantly linked with increased self-reported executive dysfunction in the chemotherapy group.

Writing in the Archives of Neurology, the authors said the left caudal lateral prefrontal region “may represent a novel biomarker of subjective executive dysfunction in chemotherapy-treated women”.

While some animal studies suggested the toxic nature of chemotherapy regimens might be responsible, the study authors found their own sample groups’ treatment programmes were too varied to address the relationship between the treatment protocol and brain function.

However, they did find that the effects of chemotherapy on the brain appeared to be exacerbated by increased age and lower educational level, suggesting cognitive reserve may play a role.

Meanwhile, the finding of decreased BA 10/46 and BA 6 function in all breast cancer patients, regardless of treatment, suggested non-chemotherapy factors such as abnormal endocrine function might be to blame, they said.

“Tamoxifen and menopause both result in oestrogen deficiency, which can impair brain and cognitive function,” they wrote, adding that this theory needed to be tested further.

Archives of Neurology,
2011;68:1447-53

The debate on whether non-steroidal anti-inflammatory drugs (NSAIDs) have a chemopreventive role to play have resurfaced, with the latest analysis finding users of NSAIDs have a significantly reduced risk for oesophageal cancers.

Compared to non-users, users of any NSAID had a 32 per cent reduced risk of oesophageal adenocarcinoma (EAC) and a 16 per cent reduced risk of oesophagogastric junctional adenocarcinoma (EGJA) the pooled analysis of six population-based studies with over 2,300 oesophageal cancer patients found.

Writing in Gastroenterology, the US authors said this effect seemed to be restricted to current NSAID users.

Increasing frequency of use correlated with decreasing risk of EAC, as did NSAID use for any duration, but there was little evidence of a relationship between increased frequency or duration and EGJA risk, the study authors found.

Use of aspirin only decreased risk of EAC by 24 per cent (CI, 3-40 per cent) and of EGJA by 16 per cent (CI, 0-31 per cent).

There was some evidence of decreasing risk of EAC with increasing frequency of aspirin use, although not with greater duration, and increased frequency or duration did not affect the risk of EGJA.

Non-aspirin NSAIDs were associated with a similar reduced risk for both cancers. Overall, the effect of all NSAIDs was slightly weaker for EGJA than for EAC.

However, the reviewers cautioned that reverse causation could in part explain the association between NSAIDs and EAC risk, since NSAIDs can lead to gastrointestinal tissue damage, resulting in patients with gastro-oesophageal reflux discontinuing NSAID use.

Gastroenterology 2011; doi:10.1053/j.gastro.2011.11.019

Oncogenetic analysis of female patients with a breast cancer risk and/or ovarian cancer risk

Dr John Greene and Prof Bryan Hennessy look at the role of anthracyclines in the treatment of breast cancer and how careful monitoring can limit any potential for cardiotoxicity.

Breast cancer is the most common female cancer in Ireland and the second most common cause of cancer death in women. Important risk factors for breast cancer are age, gender, hormonal factors and family history.

The treatment of early breast cancer includes the treatment of local disease with surgery, radiation therapy or both, and the treatment of systemic disease with one or a combination of chemotherapy, endocrine therapy or biologic therapy. The indication for, timing and type of therapy are based upon tumour characteristics such as histology, stage and immunohistochemistry; patient characteristics such as age and menopausal status; and other comorbidities.

Adjuvant systemic therapy is given following primary surgery for early breast cancer to prevent breast-cancer recurrence and to improve overall survival.

Anthracyclines have been used in the treatment of early breast cancer for more than 30 years and have been the subject of many trials. A meta-analysis of randomised trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed that anthracycline-based regimens have efficacy in the adjuvant treatment of patients with early breast cancer and that they are superior to older nonanthracycline-containing regimens, such as cyclophosphamide, methotrexate and fluorouracil (CMF).

Anthracycline-based chemotherapy regimens such as doxorubicin and cyclophosphamide (AC) were shown to reduce breast-cancer death rates by approximately 38 per cent for women younger than 50 years at diagnosis, and by approximately 20 per cent for those aged 50 to 69 years at diagnosis, irrespective of the use of tamoxifen, oestrogen receptor (ER) status, nodal status and other tumour characteristics. These findings are reflected in current clinical practice and a wide variety of adjuvant anthracycline-containing chemotherapy regimens are in general use.

HER2 protein
Approximately 20 per cent of breast cancers overexpress the HER2 protein, a surface membrane tyrosine kinase receptor, and this is nearly always due to amplification of the HER2 gene. Patients may be selected for treatment with HER2-targeting agents, such as trastuzumab, on the basis of HER2 status and adjuvant trastuzumab has been shown in several trials to improve survival in patients with HER2-positive early breast cancer.

The CALGB 8869 study suggested that HER2 status might also predict breast cancer responsiveness to anthracyclines in the adjuvant setting. This analysis looked retrospectively at patients randomly assigned to an anthracycline-containing regimen and found that patients had significantly longer disease-free survival and overall survival if their tumours showed HER2 overexpression.

This was confirmed in a second large study from Canada, which showed that amplification of HER2 in breast-cancer cells is associated with breast cancer responsiveness to anthracycline-containing chemotherapy in the adjuvant setting. Indeed, a phase III randomised study (NSABP B46) is now investigating if doxorubicin can be omitted from an adjuvant anthracycline regimen containing docetaxel, doxorubicin and cyclophosphamide (TAC) without impairing outcomes in patients with HER2-negative breast cancer.

However, the role of HER2 amplification as a predictive factor for sensitivity to anthracyclines may be related to the proximity of the HER2 gene to the topoisomerase II α (TOP2A) gene, and not due to the presence of HER2 overexpression per se. The HER2 and TOP2A genes lie next to each other on the long arm of chromosome 17 and are frequently coamplified.

Anthracyclines are believed to target an enzyme which is encoded by TOP2A that is involved in DNA replication and repair. Breast cancer cells with TOP2A amplification are known to be more sensitive to anthracyclines, whereas cells that do not amplify TOP2A appear to be more resistant to anthracyclines.

Most experts currently continue to recommend the use of anthracyclines in many patients with both HER2-positive and negative breast cancer. Almost all patients entering the large Herceptin Adjuvant (HERA) trial, which looked at adjuvant trastuzumab for patients with HER2-positive breast cancer, had been treated with an anthracycline-containing adjuvant regimen.

However, the BCIRG006 trial compared an adjuvant nonanthracycline regimen (docetaxel, carboplatin and trastuzumab (TCH)) with anthracycline-containing regimens (doxorubicin, cyclophosphamide and docetaxel (AC-T) with and without trastuzumab) in patients with HER2-positive early breast cancer. Data from the trial indicated that disease-free survival and overall survival were significantly better in both trastuzumab-containing arms compared to the control arm.

There was no significant difference in efficacy between the two trastuzumab-containing arms but there were fewer cardiac events and secondary leukaemias in the non-anthracycline arm. The non-anthracycline containing regimen (TCH) is thus an acceptable adjuvant chemotherapy regimen in patients with HER2-positive early breast cancer.

The cardiac toxicity of anthracyclines is well described and reported. Acute cardiotoxicity may present with arrhythmias, ECG changes or signs of acute pericarditis. Early cardiotoxicity usually peaks at three months after the last anthracycline administration. Patients are usually asymptomatic but there may be a decline in left ventricular ejection fraction detected using echocardiography.

Late cardiotoxicity tends to occur 10 to 15 years after completion of anthracycline treatment. Congestive heart failure is known to be closely associated with cumulative dose. By reducing the cumulative dose of the anthracycline, the overall incidence of congestive heart failure has reduced, however data from long-term survivors of childhood cancer have shown that cardiac damage may only become detectable years later.

In addition to limiting the lifetime cumulative dose of anthracycline, other approaches have been investigated, including the use of adjunctive cardioprotective agents that can be used concurrently with anthracyclines

Martin et al reported a 10-year update of the BCIRG 001 study, and their data showed significant decreases of more than 20 per cent in left ventricular ejection fraction in more than 15 per cent of patients 10 years after treatment with adjuvant anthracyclines.

The emergence of newer agents that may be used in combination with anthracyclines in patients with breast cancer has given rise to newer concerns about the cardiac toxicity of anthracyclines, and a range of different cardiovascular toxicities have been associated with these drugs. These include hypertension and thrombotic events associated with angiogenesis inhibitors such as bevacizumab, and congestive heart failure with drugs that target HER2.

Trastuzumab is associated with significant cardiotoxicity when used concurrently with doxorubicin in patients with metastatic breast cancer. However, the incidence of adverse cardiac events is low when trastuzumab is used in combination with nonanthracycline-based adjuvant chemotherapy or as monotherapy in the adjuvant setting after completion of anthracycline-based chemotherapy.

Data from the HERA trial indicated that not many patients had to discontinue trastuzumab because of cardiac disorders and most patients with cardiac dysfunction recovered within six months. The cardiac safety of lapatinib, an oral reversible tyrosine kinase epidermal growth factor receptor and HER2 inhibitor, has been assessed using prospective data collected in a number of clinical studies.

Lapatinib was given as monotherapy or in combination with other drugs. Data from studies revealed a low level of cardiotoxicity, with usually asymptomatic events or a reversible decrease in left ventricular ejection fraction. Rates of events were similar whether or not patients were pretreated with anthracyclines or trastuzumab. Certain strategies may limit anthracycline-induced cardiotoxicity. A careful history and examination should elicit any possible cardiac risk factors that may prevent a patient from receiving an anthracycline-based chemotherapy regimen.

Some studies have shown that the use of liposomal anthracyclines allows substantially higher cumulative doses with similar anti-cancer effects to the free anthracyclines but a lower incidence of heart failure and myocardial damage and may be considered for use in certain patients. A nonanthracycline regimen containing a taxane may also be considered as an alternative regimen in the adjuvant setting in certain circumstances.

Indeed, one study has shown that four cycles of docetaxel and cyclophosphamide (TC) was superior to four cycles of standard doxorubicin and cyclophosphamide (AC) as adjuvant chemotherapy for early breast cancer.

Other approaches
In addition to limiting the lifetime cumulative dose of anthracycline, other approaches have been investigated, including the use of adjunctive cardioprotective agents that can be used concurrently with anthracyclines. Dexrazoxane is an EDTA-like chelator that may prevent anthracycline damage; however, the actual mechanism underlying the cardioprotective effect of dexrazoxane against anthracycline cardiotoxicity remains uncertain.

The efficacy of dexrazoxane was addressed in a meta-analysis of six randomised trials. Dexrazoxane given with an anthracycline significantly reduced the incidence of clinical and subclinical cardiotoxicity. Despite the apparent cardiac benefit, a number of issues have created uncertainty about the role of dexrazoxane in both adults and children, including the possibility of a lower response rate to chemotherapy and enhanced myelosuppression.

The American Society of Clinical Oncology guidelines recommend against the use of dexrazoxane in patients who will receive anthracyclines in the adjuvant setting, but that it may be considered in patients with metastatic disease who have received prior doxorubicin and may benefit from continued treatment.

Anthracyclines have been shown in numerous randomised trials over many years to be one of the most effective groups of agents for the treatment of breast cancer. Because not all patients benefit from anthracyclines, better ways of detecting patients who will have a response to anthracycline treatment need to be investigated. More personalised treatments which allow treatment to be tailored for individual patients are clearly important.

Genetic assays show great promise, but need to be reliable and validated if patients are to be selected for certain drugs based on these tests. The 21-gene recurrence score (Oncotype Dx) can be used to predict the risk of recurrence in patients with newly-diagnosed, node-negative, oestrogen receptor (ER)-positive, HER2-negative breast cancer and to allow physicians to more accurately identify patients who will not benefit from adjuvant chemotherapy. Cardiotoxicity is an important but uncommon side effect of anthracyclines, and careful evaluation and monitoring should limit this adverse effect. At present, anthracyclines still remain a mainstay of chemotherapy treatment in early breast cancer.

References available on request.

l Dr John Greene is a Registrar in Medical Oncology and Prof Bryan Hennessy is a Consultant Medical Oncologist at Beaumont Hospital, Dublin.

Many women did not regain their pre-morbid physical activity levels several years after ovarian cancer diagnosis, new research shows.

Low physical activity may simply be a consequence of poor well-being but, alternatively, physical activity may improve the psychosocial health of this group, according to the study. The researchers looked at physical activity in women with ovarian cancer and its association with decreased distress and improved quality of life.

The study documented levels of and changes in physical activity before and after ovarian cancer diagnosis and explored associations with psychosocial outcomes.

Almost 40 per cent of women decreased their physical activity in the first year after diagnosis.

Approximately 25 per cent still had lower levels after two-to-three years and at over four years. Recent physical activity level was inversely associated with depression and positively associated with quality of life.

In addition, women who maintained or increased their physical activity after diagnosis had better mean depression and quality of life scores than women who decreased physical activity or remained inactive. Among women who received chemotherapy shortly prior to completing the lifestyle questionnaire, high versus low or medium physical activity was associated with significantly lower mean depression scores during both periods of treatment and non-treatment.

Psycho-Oncology Nov 2011, Vol 20, Issue 11, p1137–1249.

Each 10g increase in dietary and cereal fibre intake reduces an individual’s risk of colorectal cancer (CRC) by about 10 per cent, but fibre from fruit and vegetables contributes little to the risk reduction, a large meta-analysis concludes.

Those who consumed three servings of whole grains each day (90g) had a 20 per cent lower risk of colorectal cancer compared with those who consumed less, with even higher intakes linked with further risk reductions, the analysis of seven cohort studies involving almost 800,000 people found.

Reviewing another nine studies involving more than 1.5 million participants, the UK researchers found no reduction in CRC among those who consumed greater amounts of vegetable fibre and a borderline-significant reduction among those who consumed more fruit fibre.

The associations with dietary fibre were robust, however, with an analysis of 16 prospective studies involving almost two million people showing a significant dose-response effect.

The study authors said their results lent support to recommendations to increase the intake of dietary fibre to prevent CRC.

“However, they suggest a particular benefit of increasing cereal fibre and whole grain intake,” they said, adding that doing so would likely reduce the risk of cardiovascular disease, diabetes, obesity and mortality.

Since the last large pooled analysis that failed to find a dose-response relationship, a number of very large studies had been completed, which were incorporated into the present analysis, they said.

They noted that it would be helpful if future studies reported more detailed results, including those for subtypes of figure, and stratified other risk factors to rule out residual confounding.

BMJ 2011; doi: 10.1136/bmj.d6617.

Most claims from cancer survivors that mammography screenings saved their lives are unfounded, a study suggests, after finding the test has only a minor impact on mortality.

Women with screen-detected breast cancer are instead either diagnosed early, with no effect on their mortality, or overdiagnosed, a statistical analysis claims.

Using the US Cancer Institute’s surveillance analysis software, researchers estimated the risk of dying from breast cancer, with and without mammography, in women of various ages.

They found the probability that a 50-year-old woman with screen-detected breast cancer avoided dying because of mammography was 13 per cent, assuming mammography reduced breast-cancer mortality by 20 per cent. This number fell to 3 per cent if it was assumed that mammography screening reduced breast-cancer mortality by 5 per cent. Similar analyses of women of different ages all produced probability estimates below 25 per cent, the study authors said.

“The so-called popularity paradox of screening is driven, in part, by the presumption that every screen-detected breast cancer survivor has had her ‘life saved’ because of screening,” said the authors. “Our analyses suggest this is an exaggeration.”

Archives of Internal Medicine 2011; doi:10.1001/archinternmed.2011.476.

Intrauterine device (IUD) use might act as a protective cofactor in cervical carcinogenesis, a new study has found. Cellular immunity triggered by the device might be one of several mechanisms that could explain findings by a Catalan group led by Dr Xavier Castellsagué.

A strong inverse association was found between frequent use of IUDs and cervical cancer. A protective association was noted for squamous-cell carcinoma, adenocarcinoma and adenosquamous carcinoma, but not among human papilloma virus (HPV)-positive women. No association was found between IUD use and detection of cervical HPV DNA among women without cervical cancer.

A pooled analysis was conducted of individual data from two large studies by the International Agency for Research on Cancer and Institut Català d’Oncologia research programme on HPV and cervical cancer. One study included data from 10 case-control studies of cervical cancer done in eight countries. The other included data from 16 HPV prevalence surveys of women from the general population in 14 countries.

The Lancet Oncology, Vol 12; Issue 11, 1023-1031

Ovarian cancer might be thought of as a disease of DNA instability. However, unlike in other cancers, there are no overwhelmingly evident driver mutations in ovarian cancer

Gary Culliton reports on a recent meeting on ‘Advances in Ovarian Cancer’, where delegates got the latest updates on clinical trials into the causes and treatment of the disease.

Worldwide, there are 220,000 new cases of ovarian cancer and 140,000 deaths each year, it was revealed at the ‘Advances in Ovarian Cancer’ meeting in Dublin’s Mater Private Hospital recently.

Dr Robert Soslow, Gynaecologic Pathologist at New York’s Memorial Sloan-Kettering Cancer Center, made the case that ovarian cancer constituted a number of separate diseases. Among these were high-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma and low-grade serous carcinoma.

Many high-grade serous carcinomas probably arise in the fallopian tube, the delegates heard. BRCA1 mutation gives rise to serous carcinomas with characteristic morphological features. These features may facilitate recognition of tumours with a relatively better prognosis due to platinum sensitivity, anti-tumour immunity or ‘de-bulkability’. They also allow recognition of at-risk tissues in the index patient and in at-risk family members.

Ovarian cancer might be thought of as a disease of DNA instability. However, unlike in other cancers, there are no overwhelmingly evident driver mutations in ovarian cancer (Levine D, TCGA). A study limited to Stage III/IV BRCA-associated ovarian cancer found median survival of 7.5-to-eight years (Chetrit, JCO, 2008). Some of this improvement may be due to better responses to platinum-based chemotherapy, Dr Noah Kauff, of the Gynaecology and Clinical Genetics service at Memorial Sloan-Kettering, said.

Platinum sensitivity is associated with improved survival. However, even in the absence of platinum sensitivity, BRCA mutation status was associated with improved outcome (Gallagher DJ, Ann Oncol, 2011).

Poly ADP ribose polymerase (PARP) inhibitors are a major class of drugs in this disease. Patients who have the best response to PARP are also those patients who are platinum-sensitive. Among BRCA-mutated patients, a 200mg twice-daily dose of olaparib showed a 28 per cent response rate and a seven-month progression-free interval. With a dose of 400mg, people who had finished platinum-sensitive recurrence therapy with gemcitabine/carboplatin were examined (Lederman, ASCO, 2011). A total of 22 per cent of these carried the BRCA1 or BRCA2 mutation. Those patients with the mutation did better than those without it.

There was a near doubling of progression-free survival (PFS) from 4.8 months to 8.4 months in those patients who remained on olaparib.

Current standards
Dr Paul Sabbatini, Attending Medical Oncologist at Memorial Sloan-Kettering, focuses his clinical practice on women with gynaecological malignancies.

His research focuses on the period of remission after initial treatment of ovarian cancer with chemotherapy. Dr Sabbatini looked at current standards for ovarian cancer treatment and primary therapy. He reviewed research presented at ASCO 2011 and offered a preview of how clinical treatment might change.

Dr Sabbatini looked at the remission population, proposing that the second remission population was one in which much could be learned about new therapies and where new agents that prolong remissions might be of value (Dizon et al, Journal of Clinical Oncology 2002).

The disease does not start in a systematic way and Dr Sabbatini said that he considers it is unlikely that early imaging studies will ever be sufficient. He expects that biomarkers such as YKL-40 and HE4 will be of interest in the unselected population.

In terms of primary treatment of ovarian cancer, the standard approach is maximum de-bulking surgery and then standard taxane and platinum-based chemotherapy. If the patient is optimally de-bulked (maximum diameter of residual less than 1cm), PFS of 24-to-28 months and overall survival of 52-to-65 months is possible. If suboptimal, overall survival consistently ranges around 38 months.

The most recent randomised trials suggested it was not helpful to return for more surgery after chemotherapy, where surgical de-bulking in the beginning could not be attempted because there was too much disease.

The Gynaecologic Oncology Group (GOG) 182-ICON5 was the first study to consider whether adding gemcitabine, liposomal doxorubicin or topotecan to primary therapy might secure any benefit. Mixing and matching standard chemotherapy at the beginning of a patient’s course of treatment is unlikely to change events or downstream endpoints, Dr Sabbatini said. This trial showed there was nothing better than carboplatin and paclitaxel in the upfront setting (Bookman, J Clinical Oncology, 2009).

Upfront treatment
Intraperitoneal (IP) therapy has to be considered in upfront treatment of ovarian cancer. Three studies support the notion that IP therapy has benefits in ovarian cancer. Alberts et al (NEJM, 1996) found there was an eight-month survival advantage with IV cyclophosphamide with either intravenous or intraperitoneal cisplatin. Maurie Markman (JCO, 2001) administered IV paclitaxel. A high dose of IV carboplatin was introduced to de-bulk people before intraperitoneal cisplatin treatment. There was a 10-month survival advantage.

Deborah Armstrong (NEJM, 2006) was more straightforward and used IV paclitaxel with IV cisplatin. This study looked at weekly paclitaxel too (IP paclitaxel was also administered on day eight). Toxicity was high. In the GOG 182-ICON5 trial, some 46 per cent of people had grade III/IV toxicity.

With a dose reduction of cisplatin from 100mg down to 75mg, the toxicity profile changed significantly.

The neuropathy decreased substantially.

Ovarian cancer has more vascular endothelial growth factor (VEGF) in its acidic form than any other tumour type that has been examined. Like many tumours, low VEGF in this disease predicts higher survival and high VEGF predicts lower survival. Bevacizumab has a single-agent response rate, which is quite atypical in ovarian cancer.

The major trial for platinum-sensitive patients reported at ASCO was the OCEANS study (Carol Aghajanian, ASCO 2011). It looked at gemcitabine and carboplatin, with or without bevacizumab. It considered a robust platinum-sensitive group.

The response rate was significantly higher in patients receiving bevacizumab (79 per cent versus 57 per cent). There was a four-month PFS advantage for giving bevacizumab and interim survival data for platinum-sensitive recurrent patients showed an advantage of 29 versus 35 months.

The study concluded that these drugs prolong PFS. Thrombolic events, central nervous system bleeding and neutropaenia were not significantly different.

Ovarian cancer has more vascular endothelial growth factor (VEGF) in its acidic form than any other tumour type that has been examined

The GOG218 study compared giving: A) paclitaxel, carboplatin and placebo; B) paclitaxel, carboplatin plus bevacizumab solely during chemotherapy; and C) paclitaxel, carboplatin and continued bevacizumab through chemotherapy and maintenance (for up to 22 cycles). About 30 per cent of patients were optimal and 40 per cent were sub-optimal. The rest were stage IV.

Bevacizumab rose to the top in the Gynaecologic Oncology Group study. The response rate was higher.  A decision was made to add this agent to front-line therapy in a bid to improve outcome. The proportion of patients with PFS at six months was 40 per cent, clearly higher than anything else. The ICON7 trial produced similar data to this. There was an increase in median PFS of 10.3 months to 14.1 months — a 3.8-month advantage for continuing the bevacizumab for 22 cycles of therapy. The same benefit accrued if bevacizumab was given later.

Also looking at upfront therapy for ovarian cancer, the ICON7 trial included high-risk, early-stage patients, as well as Stage III and IV patients. The dose here was half that in the Gynaecologic Oncology Group study. The PFS in favour of the bevacizumab arm was 19.8 months, compared to 17.4 months (ASCO 2011). This represented a 2.8-month PFS advantage for continuing bevacizumab for 12 cycles.

Data presented at ESMO 2010 showed no survival advantage for bevacizumab. However, this was updated this year. An emerging survival difference was reported among a stratum of patients who were suboptimally de-bulked at the beginning or who had bulky disease when they started treatment. There was a survival difference among this high-risk group — 28 months versus 36 months. Thus, while there appeared to be no survival advantage in the low-risk group, there was a survival advantage in the high-risk group (patients with bulk disease when they started their therapy).

Pilot study
A pilot study used IP cisplatin and IP paclitaxel with standard IP bevacizumab (Konner, MSKCC 2007). Hypertension was 10 per cent lower. The GOG 0252 trial showed this combination could be given without risk of toxicity. The GOG 0252 study used weekly paclitaxel in two of the arms, versus the standard three-week paclitaxel schedule. Carboplatin was substituted for cisplatin. Bevacizumab was in all three arms of this trial.

A Japanese study (JGOG, Kalsumata, Lancet, 2009) looked at paclitaxel and carboplatin therapy every three weeks, versus weekly paclitaxel. A major progression-free advantage for weekly paclitaxel — 17 to 28 months — was observed. There was an overall survival advantage of 72 per cent versus 65 per cent.

GOG 0262 — which has not reported – is an important trial for upfront treatment. Weekly paclitaxel was compared to three-weekly paclitaxel. The bevacizumab treatment was made optional. Sorafenib had some activity, as did temsirolimus.

Dr Sabbatini then considered relapse therapy. Taxane therapy, etoposide, vinorelbine and altretamine are among the standard agents that have activity in relapsed ovarian cancer. Paclitaxel, topotecan, liposomal doxorubicin and gemcitabine have been compared, one to another, in Phase III trials. For single-agent therapy, there is a 20-30 per cent response rate if the patient is platinum sensitive. For patients who are platinum resistant, there is a 15-20 per cent response rate.

The only single-agent drug that was added to the list at ASCO this year was trabectedin, which had a 23 per cent platinum-sensitive response rate.

Platinum sensitivity
There are three randomised trials that lend themselves to advice about how to treat people with platinum-sensitive, recurrent ovarian cancer. The first one (ICON4/AGO-OVAR, Parmar M et al, Lancet 2003) compared paclitaxel and carboplatin to carboplatin alone. This showed both a PFS and an overall survival advantage. The AGO group looked at gemcitabine/carboplatin versus carboplatin. There was a three-month progression-free advantage for the doublet.

There were updated data about platinum-sensitive groups at ASCO. The CALYPSO trial, presented at ASCO last year, compared liposomal doxorubicin combined with carboplatin, versus carboplatin combined with paclitaxel. A PFS advantage of 11.3 months was demonstrated. At ASCO this year, it was revealed that overall survival was 31.5 months in both arms.

Moreover, there was no difference in PFS in a very-platinum-sensitive subgroup of the trial. “It’s possible to retreat people with platinum-sensitive disease, particularly with either liposomal doxorubicin/carboplatin or with gemcitabine/carboplatin,” said Dr Sabbatini. “These patients can be spared additional alopecia and neuropathy. Paclitaxel can be used later.”

As patients are retreated with carboplatin, platinum hypersensitivity is frequently an issue. One approach used is to desensitise people after they have a reaction. A group is looking at the possibility of prophylactically moving people to a desensitisation schedule before they have had a reaction (O’Cearbhall, Gynecologic Oncology 2010). A randomised, prospective trial on this has started.

Among 77 patients re-treated with carboplatin, 17 per cent had a hypersensitivity reaction. Among 174 people who had been prophylactically converted using the desensitisation schedule, the hypersensitivity rate was 3.4 per cent. This compared to 21 per cent of patients who remained on the standard schedule. Minimising hypersensitivity would become more important as more platinum-based doublet therapy was recommended for patients with platinum-sensitive disease, Dr Sabbatini said.

It was clear that platinum-based combination therapy was the most highly responsive regimen, Dr Sabbatini concluded.