The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

https://escholarship.org/content/qt7gf847t7/qt7gf847t7.pdf?t=qaejdd

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00222-3.pdf

Expanding global access to radiotherapy

http://static.guim.co.uk/ni/1432986420413/Ann-Oncol-2015.pdf

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

Global colorectal cancer burden in 2020 and projections to 2040

www.thelancet.com/oncology Vol 17 March 2016 e96 Women with atypical glandular cells (AGC) identifi ed at cervical screening remain at heightened risk of developing invasive cervical cancer for up to 15·5 years compared with women with normal cytology, according to new research. The investigators examined the records of 3 024 340 Swedish women who had undergone cervical cytology testing from 1980 to 2011. 14 625 were diagnosed with AGC on their fi rst abnormal screening, of whom 65 633 were diagnosed with high grade squamous intraepithelial lesions (HSIL), and 244 168 were diagnosed with low grade squamous intraepithelial lesions (LSIL). Within 6 months of diagnosis, 1·4% of women with AGC, 2·5% of women with HSIL, and 0·2% of women with LSIL were found to have cervical cancer. For up to 15·5 years, the cumulative incidence of invasive cervical cancer, mainly adenocarcinoma, for women with AGC was 2·6% (95% CI 2·3–2·9). Beyond the fi rst 6 months, their risk of developing invasive cervical cancer remained higher than women with either HSIL or LSIL for up to 6·5 years. But, whereas 85·9% of women with HSIL, and 43·2% of women with LSIL, were followed up within 6 months with histological assessment, only 53·8% of women with AGC underwent such testing. “We need more attention and closer follow-up of women with AGC”, said co-author Par Sparen (Karolinska Institutet, Stockholm, Sweden). In view of the small number of aff ected women, such follow-up should be feasible. Sweden, with a population of about 10 million, sees around 1300 women diagnosed with AGC every year, of which 30–35 are likely to develop cervical cancer within 15 years. “We should be thinking of any glandular changes more in the way we think of high grade abnormalities than low grade ones”, agrees Peter Sasieni (Queen Mary University of London, London, UK). He cautioned that this might result in some over-treatment—glandular tumours can be tricky to fi nd. “There is certainly the question of what is the best way of sampling once you have seen something in the glandular cells”, added Sasieni. Another issue is that of diff erent risk profi les among women diagnosed with AGC. It is not clear whether the two glandular cytological categories in the British classifi cation system directly correspond to the Swedish AGC. Questions also remain over the clinical stage at which women with AGC tend to be diagnosed with cancer. “We have some limited staging data for the last 10 years, and we hope to look into this”, said Sparen.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(16)00112-1.pdf

Atypical glandular cells and risk of cervical cancer

A new study has found that 272 (9%) of 2938 cancer survivors continued to smoke 9 years after being diagnosed. Smoking prevalence was highest for those who had had bladder cancer (17%) and lung cancer (15%). Survivors who still smoked tended to smoke heavily, averaging 15 cigarettes per day. “There is probably a higher level of dependence among those who are still smoking”, suggested lead author Lee Westmaas (American Cancer Society, Atlanta, Georgia, USA). His team used cross-sectional data from a longitudinal study on longterm cancer survivors in the USA, all of whom were initially diagnosed between January, 2000, and September, 2003 (mean time since diagnosis 8·9 years; SD 0·7). Of the 1209 former smokers, 137 (11%) had quit since their diagnosis. By adding this number to the number of current smokers, the authors calculated that 33·5% of smokers had quit. This proportion compares favourably with that of smokers quitting in the general US population (around 19%). But there is a proviso: “Post-diagnosis smoking is associated with increased all-cause mortality, decreased overall survival, and increased cancer mortality compared with never smoking”, noted the authors. So substantial numbers of continuing smokers are likely to have died in the time between diagnosis and the study. These deaths would lower the quit rate and imply that 9% is probably an underestimate for those who continue to smoke after diagnosis. Some oncologists might be reluctant to broach tobacco cessation with patients whose cancer is not strongly associated with smoking—they might feel that the patient has enough to worry about without additional pressure. In the UK, which faces similar issues with cancer survivors continuing to smoke as the USA, NICE guidance recommends that all hospitals maintain on-site stopsmoking services. But this guidance has yet to be fully implemented. “Many hospitals use in-reach communitybased stop-smoking services”, explains Andrew Furber (Faculty of Public Health, London, UK). “These services cannot develop relationships with clinicians and oncologists and identify the opportunities to intervene in the way that an on-site service can”. After patients have left hospital they should continue to be off ered support. “We need to keep checking for smoking status among survivors, and provide interventions at every point when we interact with them, whether it is close to diagnosis or later on”, concluded Westmaas.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(14)70393-6.pdf

Cancer survivors continue to smoke

www.thelancet.com/oncology Vol 17 May 2016 e185 Uganda’s only external beam radiotherapy machine has recently broken down. The Cobalt-60 machine was donated to Mulago National Referral Hospital (Kampala, Uganda) by the International Atomic Energy Agency (IAEA) in 1995. A new machine has been ordered from the IAEA, but Jackson Orem (Uganda Cancer Institute, Kampala, Uganda), estimates it will be at least six months before it arrives. Around 2000 patients, many of whom travel from neighbouring countries, undergo radiotherapy at Mulago Hospital every year. “Having one country lose the ability to give radiotherapy has a multicountry, rippling effect throughout cancer care in sub-Saharan Africa”, points out Peter Kingham (Memorial Sloan Kettering, New York, NY, USA). “It really shows how tenuous the supply line and availability is”. Over half of the nations in Africa have no radiotherapy services at all. Where they do exist, services are scarce. Nigeria (population 180 million) usually has to manage with 2–4 functional radiotherapy machines. “Patients travel throughout the country to whichever machine happens to be working at the time”, said Kingham. Most of Uganda’s radiotherapy patients have cervical cancer. The country has one of the highest rates of the disease in the world, and 80% of patients present with late-stage disease. Radiotherapy is predominantly used as a palliative measure. “We have an elaborate system of palliative care that we can now fall back on”, said Orem. He added that for cervical cancer patients, clinicians can request treatment with Uganda Cancer Institute’s newly installed high dose bracytherapy equipment. A lack of radiotherapy means that women with breast cancer must have mastectomies instead of lumpectomies, but this is not contrary to common practice in Uganda. “In most developing countries, including Uganda, mastectomy is still the norm rather than the exception”, points out Orem. Uganda’s public healthcare system does provide for sending patients for treatment abroad if necessary, although the interrupted radiotherapy services are not likely to result in a sizeable exodus. Orem views the demise of the Cobalt-60 machine as a setback, rather than a catastrophe. The Uganda Cancer Institute has ambitious plans to establish bunkers containing advanced treatment technologies such as linear accelerators. “I am quite sure that in a short time the landscape for treatment for patients with cancer who require radiotherapy will be quite diff erent in Uganda”, Orem said.

Radiotherapy challenges in Uganda

Ipilimumab, a GLA-4 inhibitor, significantly prolongs overall survival in patients with advanced melanoma who have had com plete lymphnode dissection, according to a new study. The invest i gators assigned patients with stage III melanoma, who had under gone surgery within the previous 12 weeks, to receive either 10 mg/kg ipilimumab for 3 weeks for four doses, then every 3 months for up to 3 years (n=471) or the placebo (n=476). The primary endpoint was recurrence-free survival: at 5 years 40·8% of patients in the ipilimumab group were recurrence free compared with 30·3% of patients in the placebo group (HR 0·76 [95% CI 0·64–0·89; p<0·001). The proportion of patients who were free of distant metastases was also higher in the ipilimumab group (48·3%) compared with placebo (38·9%; HR 0·76 [95·8% CI 0·64–0·92]; p=0·002). Overall survival in the ipilimumab group was higher than in the placebo group: 65·4% versus 54·4% (hazard ratio [HR] 0·72 [95·1% CI 0·58–0·88]; p=0·001). “You see these benefi ts both in patients with sentinel-node positive disease, and with palpable nodal disease”, said fi rst author Alexander Eggermont (Gustave Roussy Cancer Campus Grand Paris, Villejuif, France). Five deaths were attributed to ipilimumab and over half the patients in the treatment group stopped taking it because of adverse events. 40% of patients did not go beyond four doses of ipilimumab, and 13% lasted the entire 3-year treatment schedule. Yet this did not aff ect survival, raising the question of whether four doses might be all that is needed. Paul Lorigan (Christie NHS Foundation Trust, Manchester, UK) suggested that ipilimumab’s toxicity is a surrogate for activity. “So the patients who are getting more toxicity are getting more benefi t, and they are getting this benefi t fairly early on”, he explained. “It is a question of managing the toxicity.” This is particularly important for adjuvant therapies, where the risk-benefi t calculations diff er from those involving therapies that target advanced, metastatic disease. Eggermont stresses the value of keeping in mind the fact that symptoms such as diarrhoea in patients taking ipilimumab might be drug-related. This could help facilitate prompt clinical intervention—most of the serious adverse events associated with ipilimumab can be eff ectively treated with corticosteroids. Two ongoing trials are examining the effi cacy of anti-PD-1 agents as adjuvant therapies for melanoma.

Talha Khan Burki

Papers

Atypical glandular cells and risk of cervical cancer

Cancer survivors continue to smoke

Radiotherapy challenges in Uganda

Ipilimumab prolongs survival in advanced melanoma.

T-DM1 for residual, invasive, HER2-positive breast cancer