Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer.
Mismatch repair deficiency is found in 15% to 20% of sporadic (noninherited) colorectal cancers and in nearly all colorectal cancers associated with Lynch syndrome, which constitute up to 5% of all colorectal cancers. Mismatch repair deficiency is also found in other tumor types including stomach, small bowel, endometrial, prostate, and ovarian cancer. Testing for mismatch repair deficiency is widely available and could enable identification of a larger population of patients who might benefit from pembrolizumab and other PD-1 drugs.
That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.
In a small, proof-of-principle study recently published in The New England Journal of Medicine and presented at the American Society of Clinical Oncology’s annual meeting, the Johns Hopkins researchers reported that they could predict the benefit of an anti-PD-1 inhibitor called pembrolizumab (Keytruda®) by scanning patients’ tumor samples for defects in mismatch repair. Regardless of their type of cancer, patients whose tumors were mismatch repair deficient were more likely to respond to the immune-boosting, anti-PD-1 drug than those with tumors proficient in mismatch repair. In fact, the worse the tumor cells were at repairing DNA, the better the patients fared on anti-PD-1 therapy!
This may all sound counterintuitive. However, researchers say it supports the hypothesis that immunotherapy may be most effective against tumors with many mutations. (In the new study, the tumor cells deficient in mismatch repair contained more than 20 times as many mutations, on average, than tumor cells proficient in mismatch repair.) The idea is that the greater the number of DNA glitches in a tumor cell, the more abnormal proteins it will produce—and the more abnormal proteins that are generated, the greater the odds that the body’s immune cells will regard the tumor cells as “foreign” and target them for destruction.
To test this hypothesis, Vogelstein, Luis Diaz, Jr., and their colleagues initiated a phase II clinical trial to evaluate pembrolizumab, which is already approved by the Food and Drug Administration for treating certain patients with melanoma, in 32 patients with advanced colorectal cancer. Some of the patients had tumors that were mismatch repair deficient; others had tumors proficient in mismatch repair. The researchers also enrolled nine people with cancers of the pancreas/bile duct, uterus, small bowel, and stomach that tested positive for mismatch repair defects. The patients, all of whom had not responded to at least one previous cancer treatment, were administered the anti-PD-1 drug intravenously every two weeks.
After at least 20 weeks of anti-PD-1 therapy, the researchers found that colorectal tumors shrank in about 40 percent of patients in the mismatch repair deficient group, compared to none in the mismatch repair proficient group. Furthermore, 78 percent of the mismatch repair deficient group was free of tumor progression at 20 weeks, compared to 11 percent of the mismatch repair proficient group.
According to the researchers, the average overall survival time for colorectal patients in the mismatch repair deficient group has not yet been reached because some are still responding well to anti-PD-1 therapy, more than a year after the study started. In contrast, average overall survival among patients in the mismatch proficient group was reported to be only 5 months.
As for the patients with other types of mismatch repair deficient cancer, their tumors shrank at rates similar to those seen in mismatch repair deficient colorectal cancer. However, such patients tended to respond faster to anti-PD-1 therapy than the colorectal cancer patients. And, unlike the colorectal group, a complete remission of cancer was observed in one patient—a woman with uterine cancer. No treatment-related deaths occurred in the study, with the most serious adverse reaction being pneumonitis (inflammation of the lung) in one patient.
The team will continue to follow these patients and enroll more volunteers to see if their findings hold up in a larger study. They also hope to start similar trials for some of the many other types of cancer, such as prostate and ovarian, known to contain mismatch repair deficiencies in a small percentage of tumors. Another area of scientific exploration is whether patients whose tumors contain other types of DNA repair deficiencies, such as those caused by POLD, POLE, and MYH mutations, might also benefit from anti-PD-1 therapy.
This research is just one of many outstanding examples of how decades of research by NIH-supported basic, translational, and clinical scientists continue to move us towards the era of precision medicine. NIH’s National Cancer Institute recently took a major step in that direction by announcing the Molecular Analysis for Therapy Choice, or NCI-MATCH trial. This pioneering clinical study will precisely match patients from as many as 2,400 sites across the country to one of more than 20 targeted drugs or drug combinations based on the particular molecular abnormalities of their individual tumors . With this and many other new efforts envisioned by the Precision Medicine Initiative, it seems as though a future of more precise, individualized approaches to the diagnosis, treatment, and prevention of cancer and many other diseases is now within sight.
For hundreds of years the Scottish Highlands have resounded to the names of their famous clans: MacDonald, Campbell, Fraser, and many more. Each clan is a complex, branching family tree, starting from a single person but evolving over the years into a plethora of related but distinct groups.
Trying to untangle the different branches of a clan is a complicated and painstaking job for genealogists, poring over detailed histories and dusty parish records. But the family trees they construct from this information reveal the story of a clan’s evolution over time.
Now Charles Swanton and his team at the Francis Crick Institute, funded by Cancer Research UK, have carried out a similar painstaking analysis of data from more than 2,500 cancers, covering nine different tumour types.
Their study, published in the journal Science Translational Medicine, reveals the genetic relationships between different groups of cancer cells within an individual tumour, shedding light on the evolutionary processes at work as cancer grows and spreads within the body and how we might harness them to treat the disease more effectively in future.
A new study has just been published in the journal Frontline Gastroenterology. This shows a highly inconsistent approach to the management of patients at elevated risk of hereditary colorectal cancer (CRC) in the United Kingdom (UK).
The British Society of Gastroenterology (BSG) Cancer Group designed a national survey to determine how we might understand and improve the service for these patients.
What is already known on this topic? Genetic factors contribute about 35% of all colorectal cancer (CRC) risk. There is good evidence that the correct management of patients with an elevated hereditary risk is a highly effective method of preventing CRC. This can be achieved by screening according to guidelines and the development of a high quality service with clear patient pathways. However in some studies there is evidence of an inconsistent approach to the management of those patients, with low risk patients being screened too often, and high risk patients not frequently enough. There is also a low referral rate to genetic services for high risk patients.
What this study adds? Responses to this national survey suggest a poor understanding of the current guidelines amongst clinicians and variable clinical pathways for patients. There is also a perception that another unspecified clinician is undertaking this work. This may explain the wide variation in care and low adherence to guidelines in the United Kingdom (UK).
How might it impact on clinical practice in the foreseeable future? We recommend the development of clear structures and the provision of a high quality service to these patients through national audit, development of quality standards and education of physicians and surgeons in the UK. Each hospital should develop a lead clinician for the delivery of these services. Only in this way will this ad hoc approach to the management of hereditary CRC be improved.
Objectives: The British Society of Gastroenterology (BSG) Cancer Group designed a survey to determine how we might understand and improve the service for patients at elevated risk of hereditary colorectal cancer (CRC).
Design and Setting: United Kingdom (UK) gastroenterologists, colorectal surgeons, and oncologists were invited by email to complete a 10 point questionnaire. This was cascaded to 1,793 members of the Royal College of Radiologists (RCR), Association of Cancer Physicians (ACP), the Association of Coloproctology of Great Britain and Ireland (ACPGBI), as well as BSG members.
Results: Three hundred and eighty-two members responded to the survey, an overall response rate of 21.3%. Although 69% of respondents felt there was an adequate service for these higher risk patients, 64% believed that another clinician was undertaking this work. There was no apparent formal patient pathway in 52% of centres, and only 33% of centres maintain a registry of these patients. Tumour block testing for Lynch Syndrome is not usual practice. Many appeared to be unaware of the BSG/ACPGBI UK guidelines for the management of these patients.
Conclusions: There is wide variability in local management and in subsequent clinical pathways for hereditary CRC patients. There is a perception that they are being managed by ‘another’, unspecified clinician. National guidelines are not adhered to. We therefore recommend improved education, well defined pathways and cyclical audit in order to improve care of patients with hereditary CRC risk.
When a child is diagnosed with cancer, one of the first questions the parents ask is “Will my other children get cancer?” A new study from Huntsman Cancer Institute (HCI) at the University of Utah suggests the answer to that question depends on whether a family history of cancer exists. The research results were published online in the International Journal of Cancer and will appear in the November 15 print issue.
The study, led by Joshua Schiffman, M.D., medical director of HCI’s High Risk Pediatric Cancer Clinic and a pediatric hematologist/oncologist in in the Department of Pediatrics at the University of Utah, examined the family medical history of 4,482 children diagnosed with cancer over a 43-year period to determine the cancer risk in their relatives.
The research team found that when children were diagnosed with any kind of cancer at age 18 or younger, the risk to their parents, siblings, or children for childhood cancer doubled compared to families with no childhood cancer patients. If the cancer diagnosis came when the child was age 4 or less, the risk to close relatives for childhood cancer increased almost four times.
“No one had previously studied the question, so we simply told parents there was no evidence of increased risk to the other children,” said Schiffman. “Now we can give an evidence-based answer — the risk depends on your family history of cancer.”
This is the first study that uses the Utah Population Database (UPDB) to broadly examine the risk of all types of cancer in relatives of children with cancer. This unique resource at the University of Utah links genealogies and cancer registry data from Utah to medical records and vital records, including Utah death certificates.
“Because our data came from the UPDB, the assessment of family history in our study does not rely on self- or family-reported medical history,” said lead author Karen Curtin, Ph.D., a genetic epidemiologist and UPDB assistant director. “Self-reporting of family medical history depends on an individual’s memory, while our data comes from the statewide Utah Cancer Registry that records nearly all cancer cases, which reduces possible errors in reporting family cancers.”
The team also assessed known inherited genetic syndromes in adult relatives of pediatric cancer patients. They found cancers associated with Li-Fraumeni Syndrome (LFS) seemed to be driving the increased risk to relatives in families with a history of cancer.
“Not all children’s cancers are hereditary,” said Schiffman. “But the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5-10% generally cited in adult hereditary cancers, and likely even more than 20%.
“LFS is one of the most devastating cancer syndromes,” said Schiffman. “It causes a variety of cancers in both children and adults. For people with LFS, the lifetime risk of getting cancer is 80% to 90%, but with increased and early screening for tumors, there’s early indication of a very high survival rate, perhaps even approaching100%. In a previous study, LFS patients who did not receive early screening only had a 20% survival rate.”
Although childhood cancer rarely occurs in the population, based on their findings, the authors recommended collection of three generations of family medical history for all newly diagnosed pediatric cancer patients and referral of families with a history of early-onset cancers in children or adults for genetic counseling. In addition, parents of children diagnosed with cancer before age five with a family history of cancer should be advised of the potential for increased risk to other children in the family.
“We want to encourage the taking of a family history as part of routine care. With all cancers, but perhaps especially with childhood cancers, so many other questions seem so urgent, a family history may not seem to be the most pressing issue,” said co-author Wendy Kohlmann, director of HCI’s Genetic Counseling Program. “When families are referred into genetic counseling, we can provide them with more information about the risks and actions they can take.”
“For families with previously unidentified LFS, following these recommendations could actually save the lives of multiple family members if at risk individuals are identified and early cancer surveillance programs implemented,” Schiffman said.
This article provides a historical overview of the online database (www.insight-group.org/mutations) maintained by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.
The InSiGHT colorectal cancer hereditary mutation database can be found here
Introduction IGF1 may be important for colorectal cancer risk because of its role in cell growth and differentiation. High IGF1 serum levels have been associated with increased risk of colorectal cancer. Variations in these serum levels have been associated with a CA repeat microsatellite 1 kilobase upstream of the transcription start site. We sought to determine the association of germline variation of the IGF1 gene with colorectal cancer predisposition by performing a large case-control study.
Methods Genescan 500 was used to differentiate alleles of the IGF1 microsatellite among 2143 colorectal cancer cases (enriched for family history) and 1715 controls from the CORGI (COloRectal Gene Identification) study, with subsequent 100% confirmation of about 5% of genotypes by direct sequencing. Associations of genotypes with the following clinicopathological features were tested: sex; site of tumour; Dukes stage; age of onset; presence of adenomas. Using genotype data obtained from the Hap550 platform by colleagues1 plus the genotypes at the insertion/deletion, we reconstructed haplotype blocks around the IGF1 gene in the controls using 68 tagging SNPs.
Results All the alleles confer increased risk for colorectal neoplasia except ‘192′ (192 copies of CA repeat), which is a protective allele (allelic OR for ‘192′ =1.199; 95% CI 1.09 to 1.32; p = 0.000152). The population attributable risk (PAR) for the risk ‘allele’ (ie, where ‘X’=not ‘192′) is 2.94%. The risk alleles occurred more frequently in more advanced Dukes’ stage tumours (p=0.039, χ2). Several SNPs in close linkage disequilibrium with IGF1 are also significantly associated with colorectal neoplasia risk.
Conclusion This study demonstrates a novel association of IGF1 microsatellite with colorectal cancer risk. The association is stronger with advanced stage colorectal cancers, and in colonic rather than rectal cancers. This microsatellite is in linkage disequilibrium with other significant SNPs in the promoter region of this gene.
Gut 2011;60:A116-A117 doi:10.1136/gut.2011.239301.246
Family History of Bowel `Cancer Clinic, West Middlesex University Hospital, London, UK; Cancer Medicine, Imperial College, London, UK; Molecular and Population Genetics, Cancer Research UK, London, UK
Introduction Progressive loss of cell cycle control is an important feature on the adenoma-carcinoma sequence of colorectal cancer. Cyclin-dependent kinase inhibitor 1A (P21/CDKN1A) is an important target of the TGFβ signalling pathway, and it is commonly under-expressed as colorectal neoplasia develop. The aim of this study was to identify low penetrance germline variation in this gene which predisposes individuals to colorectal cancer.
Methods Variation in the coding region of CDKN1A was determined in fifty colorectal cancer cases with a strong family history and 50 controls were tested using the Lightscanner and direct sequencing. 15 tagging SNPs around CDKN1A were typed in the CORGI cases and controls as part of a genome-wide analysis using the Illumina Hap550 platform in 930 cases and 960 controls performed by colleagues (Tomlinson et al 2007). Allele-specific expression of the gene was examined using quantitative reverse transcriptase PCR linked to SNPs in an upstream promoter region.
Results A novel amino-acid changing variant Phe22Leu was identified in a single colorectal cancer patient. Six patients were identified in the case group and 5 in the control group with Arg31Ser. In the association study the two most significant SNPs lie in an upstream promoter region and are in linkage disequilibrium, both are risk alleles for colorectal cancer (OR 1.13; 95% CI 1.06 to 1.2).
p ( χ2)
There were significant differences in expression between CDKN1A and the controls in 94 samples (p=0.037, Student’s t test), demonstrating linkage of these upstream polymorphisms to allele-specific expression of CDKN1A.
Conclusion Rare variants of P21/CDKN1A are an infrequent cause of predisposition to colorectal neoplasia. A promoter region upstream of the CDKN1A is associated with prediposition to colorectal neoplasia, and is linked to allele-specific expression of this gene.
A new £100m project will map the DNA of up to 100,000 patients with cancer and other rare diseases.
The genetic data will help researchers to develop new drugs and tests that could help save thousands of lives.
Britain should “push the boundaries” and become the first country to introduce genetic sequencing to its mainstream health service, according to the prime minister David Cameron.
He said: “Britain has often led the world in scientific breakthroughs and medical innovations, from the first CT scan and test-tube baby through to decoding DNA. By unlocking the power of DNA data, the NHS will lead the global race for better tests, better drugs and above all better care.We are turning an important scientific breakthrough into a potentially life-saving reality for NHS patients across the country.”
He added: “If we get this right, we could transform how we diagnose and treat our most complex diseases not only here but across the world, while enabling our best scientists to discover the next wonder drug or breakthrough technology.”
Dr Harpal Kumar, Cancer Research UK’s chief executive, welcomed the plans: “This work will uncover a wealth of new information which doctors and scientists will use to learn more about the biology of the disease and to develop new ways to prevent, diagnose and effectively treat cancer.
“We’re very excited about personalised medicine – some targeted treatments, such as imatinib, a drug for chronic myeloid leukaemia are already helping to treat patients more effectively – and we’re working hard, with many others – to develop new treatments, and to ensure the NHS can effectively deliver a more personalised cancer treatment service.”
He added: “We hope that this vital investment, together with other measures, such as continued support to diagnose cancers earlier, when treatment is more likely to be successful, will be an important step towards saving more lives from cancer, sooner.
“But, it will be some time before everyone with the disease will be able to have treatment based on the genetic make-up of their cancer.”
The NHS already analyses single genes in cancer tests to determine the chances of particular patients having side-effects from treatment.
Professor Dame Sally Davies, the government’s chief medical officer, explained: “At the moment, these tests focus on diseases caused by changes in a single gene.
“This funding opens up the possibility of being able to look at the three billion DNA pieces in each of us so we can get a greater understanding of the complex relationship between our genes and lifestyle.”
The £100m earmarked from the project, which stems from existing NHS budgets, will be spent on training genetic scientists, mapping patients’s DNA, and creating systems for handling the information.
The Human Genome Project, which made an initial ‘rough draft’ of the human genetic sequence in 2011, cost approximately £500m.
But technological advances have cut costs dramatically, meaning the procedure can now be performed for under £1,000 per person, and officials believe the new £100m DNA mapping investment could reduce prices further still.
All patients will be asked for permission before their DNA is sequenced, with all subsequent data anonymised before it is stored.
Alongside the DNA mapping announcement, the government also allocated £100m of new science funding in the Autumn Statement to the life sciences sector.
The money will help build research capabilities for synthetic biology, facilities for manufacturing cell and biological medicines such as antibodies and vaccines.
Science minister David Willetts said: “Life sciences is one of the most truly international sectors – so if we are to continue to be a world player and compete in the global race we must do everything we can to support it.
“In the past year, our initiatives have attracted more than £1 billion of private sector investment to the UK. We can see clear evidence the UK is succeeding in creating the right environment to attract global investment to our shores and continue to be world leader in life sciences.”
Neoplasia and cancer pathogenesis posters
PWE-067 Recessively inherited non-polyposis colorectal cancer: genotype and phenotype
K J Monahan1,2, K Pack2, C Cummings1, H J W Thomas1, I P M Tomlinson2
Introduction: Patients diagnosed before 50 years of age have a likely strong genetic or environmental aetiological factor. There is good evidence from population studies1 that recessive inheritance is common in young colorectal cancer patients.
Methods: A cohort of 133 colorectal cancer patients were diagnosed under the age of 50 years who did not have multiple polyps or a family history suggestive of dominant inheritance. They were identified and recruited from the Bobby Moore Database in the Family Cancer Clinic, St Mark’s Hospital, Harrow. MUTYH was screened for germline mutations. As these patients fulfilled Bethesda criteria they were tested for hereditary non-polyposis colorectal cancer (HNPCC) by microsatellite instability analysis and immunohistochemistry of mismatch repair proteins. Immunohistochemistry was also performed on β-catenin and P53. Loss of heterozygosity of the APC locus at 5q21–22 was tested using a set of microsatellite markers. Sequencing was used to identify somatic mutations in KRAS and BRAF.
Results: Forty-four patients (33%) had cancers proximal to the splenic flexure, 79 (59%) distal and had 11 (8%) synchronous colorectal cancers. Thirty-seven patients (28%) had an affected sibling and 33 (25%) patients had a second-degree relative with cancer at any site. The median age of diagnosis of colorectal cancer was 39 years (range 14–49 years of age). Twenty-six patients (20%) were found to harbour sequence variation in the MUTYH gene but none of these variants were likely to be pathogenic, and there was no difference in the frequency of these compared to a control group of 50 patients. Eighty percent of tumours were found to be microsatellite stable. 20/30 cancers had nuclear localisation of β-catenin and 21/30 had nuclear localisation of P53 antibodies on immunohistochemistry. Loss of heterozygosity of the APC locus at 5q21–22 was present in 14/30 cases. Thus Wnt pathway activation is likely by over half of this group of cancers. Four cancers had BRAF V600E mutations and five had KRAS codon 12 or 13 mutations.
Conclusion: In a cohort of 133 young colorectal cancer patients without multiple polyps, most tumours demonstrated Wnt pathway activation and other somatic changes consistent with the classical adenoma-to-carcinoma sequence. Germline mutations in the colorectal neoplasia predisposition gene MUTYH appear to be rare events in such patients. The majority of recessive inheritance in young patients is probably caused by mutations in unknown predisposition genes.
This trial is looking at the chemotherapy drug methotrexate for people with a MSH2 gene fault who have cancer that started in the bowel, stomach, womb (endometrium), bladder, or lining of the urinary system (urothelium) and has spread.
Every cell contains DNA. This is the genetic information which controls how cells behave. In cancer cells, the DNA is changed or damaged. Cancers can have different types of changes in the DNA. One of these is when a gene called MSH2 is not working properly.
Doctors often use chemotherapy to treat cancer. But sometimes the cancer comes back after treatment and spreads elsewhere in the body.
Methotrexate is a chemotherapy drug that is used to treat some types of cancer. We know from research that methotrexate kills cancer cells when the MSH2 gene is not working properly. Researchers want to find out if it will help people with a faulty MSH2 gene who have cancer that has spread.
The aims of this trial are to
Who can enter
You can enter this trial if you
You cannot enter this trial if you
This phase 2 trial will recruit 56 people. Everybody taking part will have methotrexate.
You have methotrexate as an injection into a vein. The treatment only takes a few minutes. You have another injection a week later and then 2 weeks without any treatment. Each 3 week period is called a cycle of treatment. You have up to 6 cycles of treatment. But if the treatment is helping you, your doctor may talk to you about having it for longer.
During the trial, the researchers will take samples of blood, urine and a hair follicle (such as from an eyebrow). And they will get a sample of the tissue taken when you had surgery to remove your cancer or when you had a biopsy.
The researchers will use the samples to try to find substances they can measure in the body to help them tell how well the treatment is working. They call these substances biomarkers. And they will use the blood samples to look at your genes. This is to learn more about how genetic changes can lead to cancer and whether certain changes affect how people respond to treatment.
The trial team may also ask your permission to take an extra biopsy during treatment. This is to learn more about what effect the treatment has on the genetic make up of your cancer. If you don’t want to have this extra biopsy, you don’t have to. You can still take part in the trial.
All samples will be stored safely and may be used in the future, but only for research purposes.
You will be asked to fill out a questionnaire before you start treatment, just before the 2nd and 4th cycle of chemotherapy, and every 3 months for a year after you finish treatment. The questionnaire will ask about any side effects you have had and how you have been feeling. This is called a quality of life study.
The trial team will also ask you to fill out a short questionnaire which asks about other members of your family who have had cancer.
People taking part in this trial may also be asked to join extra studies looking at PET scans and MRI scans. Doctors want to find out if these scans can provide more information about bowel cancer with a faulty MSH2 gene.
You may be able to take part in one or both of these studies. Whether or not you are asked to take part will depend on where you are having your treatment and also where in your body the cancer is.
You will see the doctors and have some tests before you start treatment. The tests include
You go to hospital twice in each 3 week cycle of treatment. You have regular blood tests. And after 9 weeks of treatment you have a CT scan to check that your cancer has not got any bigger. If the scan shows the cancer has grown, you will stop having the trial treatment and the doctors will discuss other treatment options with you. If the cancer has stayed the same size or got smaller, you will have the next 3 cycles of treatment and then another CT scan.
After you finish treatment you will see the trial doctors and have a CT scan every 3 months for up to 1 year.
If you do take part in the MRI or PET scan study (or both), you will have extra scans
Having an MRI scan takes about 15 to 30 minutes. If you have PET scans, you have an injection of a small amount of a radioactive drug first. Then you have to wait an hour before having the scan. The scan itself can take up to an hour.
The side effects of methotrexate include
There is more information about the side effects of methotrexate on CancerHelp UK.
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