Colorectal Cancer by sdfgsg234

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									                               CANCER THERAPEUTICS

Colorectal                                                                               Improving outcomes
                                                                                         after surgery

Cancer                                                                                   The use of chemotherapy following surgery, a procedure
                                                                                         known as adjuvant therapy, is well established for
New therapies for colorectal cancer                                                      patients with colorectal tumours involving local lymph
                                                                                         nodes (Duke’s C cancer). With Duke’s C cases, adjuvant
Colorectal cancer is one of most common cancers                                          therapy has been shown to reduce the chance of
worldwide and in the UK alone, over 35,000 new                                           relapse and improve survival following surgery to
cases are diagnosed each year.                                                           remove the primary colorectal tumour. In contrast, for
                                                                                         those patients with no regional lymph node involvement
                                                                                         (Duke’s B cancer), the role of adjuvant chemotherapy
                                                                                         has been far less clear. However, data from two large
                                                                                         randomised Phase III trials, QUASAR (UK led) and
                                                                                         MOSAIC (European) now indicate that adjuvant
                               Stages of colorectal cancer                               chemotherapy is beneficial for Duke’s B patients.

                                A significant number of patients present with early      Bolus versus a continuous infusion of
                                stage colorectal cancer and are suitable for             adjuvant chemotherapy?
                                potentially curative surgery. However, a proportion of   Currently, the standard length of time of adjuvant
                                these patients are at risk of cancer recurrence and      chemotherapy using bolus (ie repeated short injections)
                                strategies to identify these subgroups and develop       5-fluorouracil (5FU) is 6 months. However, there is
                                preventive therapeutic strategies have been a key        debate over the optimal duration of treatment and on
David Cunningham
MD FRCP                         area in attempting to improve outcomes from the          whether or not adjuvant chemotherapy given as a

Professor David
                                disease.                                                 constant continuous infusion might provide better
Cunningham is a                 Approximately 25% of patients with colorectal            suppression of the growth of cancer cells. This question
Consultant in Medical
Oncology and Head of the        cancer will present with advanced disease or             has been addressed in the SAFFA randomised Phase III
Gastrointestinal Unit at The
Royal Marsden NHS
                                develop metastatic disease despite earlier therapy.      multicentre UK study. The SAFFA study was designed
Foundation Trust                The development of effective treatments for this         and conducted by the Gastrointestinal Unit, and
                                group of patients is also of paramount importance.       compared whether 3 months of continuous infusion of
                                                                                         5FU was equivalent to 6 months of bolus 5FU in

                                 The Royal Marsden                                       patients following surgery for colorectal cancer. The
                                                                                         results, presented and discussed at the 2004 American
                                 Gastrointestinal Unit                                   Society for Clinical Oncology (ASCO) annual meeting,

                                 has a critical role in                                  indicated equivalence between the two treatments and
                                                                                         importantly, that shortening the duration of
                                 contributing to, and                                    chemotherapy with infused 5FU did not compromise

                                 in leading research                                     patient outcomes.
                                                                                            An analysis of the Duke’s B patients in the SAFFA
                                 into the treatment of                                   study has also been undertaken. Duke’s B patients, with

                                 colorectal cancer, both                                 at least one of a defined set of risk factors, who are
                                                                                         treated with adjuvant chemotherapy, are predicted to
                                 in the national and                                     have a poorer outcome than patients who do not have

                                 international arenas.                                   at least one of a defined set of risk factors. Such
                                                                                         knowledge may help select patients from this group for
                                                                                         adjuvant therapy.
    The duration of                                          prospective data on this issue. At the Royal Marsden,
                                                             the Gastrointestinal Unit is running a Phase II non-
    adjuvant chemotherapy                                    randomised study of capecitabine (an oral pro-drug

    is an important area of                                  of 5FU) plus oxaliplatin, a highly active chemotherapy
                                                             combination in colorectal cancers, pre- and post-liver
    research and further                                     resection, and will eventually provide some of the

    studies are being                                        first data with this drug combination in this
                                                             important setting.
    designed worldwide
                                                             Making progress with
    to address this issue.                                   new drugs
                                                             The emergence of several new drugs – including
Therapy before surgery                                       capecitabine, oxaliplatin and irinotecan – in the last
                                                             decade has had a great impact on the treatment of
Treatment of potentially operable tumours before
                                                             colorectal cancer. Various combinations, schedules and
surgery has advantages in certain groups of patients.
                                                             use as first line and salvage therapies have improved
Advances in surgical techniques, including total
                                                             survival and quality of life for sufferers of the disease.
mesorectal excision, have improved rates of relapse in
                                                             However, new approaches are desperately needed to
rectal cancers but further progress is needed. The
                                                             achieve further improvements in care.
EXPERT study designed and undertaken by the
Gastrointestinal Unit, aims to investigate the use of pre-
operative therapy to reduce the rate of relapse in rectal        As we begin to gain a
cancers. Here, high definition magnetic resonance
imaging (MRI) has been used to identify patients with
                                                                 greater understanding
operable rectal cancer that displays features indicative         of the biological
of high-risk relapse. These high-risk relapse patients
have been treated using combination chemotherapy
                                                                 processes governing
(capecitabine and oxaliplatin), followed by                      the development of
chemoradiotherapy and then subsequent surgery. This
approach has resulted in a high rate of tumour shrinkage
                                                                 colorectal cancer, new
and successful surgery and the results of the study were         therapeutic targets have
presented at the 2005 ASCO Gastrointestinal Symposium
held in Miami, USA, in January.
                                                                 been identified and
Liver metastases in colorectal cancer
                                                                 exciting new treatments
The liver is the most common site for secondary spread           for colorectal cancer
from colorectal cancer and in a significant proportion of
patients is the only organ involved. A small proportion
                                                                 successfully developed.
of patients have liver metastases that can be removed
by surgery, a strategy known to improve disease-free
time and which may potentially result in cure.
   However, it is recognised that chemotherapy,
particularly including oxaliplatin, may improve the
operability of liver metastases and therefore further
improve outcomes. Nevertheless, there are currently no




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Figure 1.                                                                             The study was published in the New England Journal of
Targeting the epidermal       External                              Cetuximab         Medicine in July 2004 and has served as a catalyst for the
growth factor receptor       domains of
(EGFR). Cetuximab             the EGFR                                                implementation of several new Phase II and III studies of
(Erbitux) binds to the
external domains of the                                                               cetuximab in combination with chemotherapy agents
                            Cell
EGFR, whereas gefitinib   membrane                                                    both in the first and second line treatment of colorectal
(Iressa) binds to the
internal domains of the                                                               cancer. It has provided a significant contribution to
EGFR. Either molecule         Internal
can therefore block                                        Gefitinib                  developing effective therapies for patients with pre-
                             domains of
activation of the EGFR,       the EGFR                                                treated cancer, a group that is assuming greater
interfering with the
subsequent function                                                                   importance. Furthermore, other ways to target EGFR are
of the cancer cell.
                                                                                      in development; gefitinib (Iressa) is a drug that acts on
                            Triggering the EGFR of cancer
                            cells can result in subsequent:                           the inner portion of the EGFR (Figure 1) and a trial
                            • cell growth
                            • cell survival                                           combining this drug with chemotherapy in patients with
                            • invasion and tumour metastasis
                            • tumour blood vessel growth                              colorectal cancer has recently been completed in the
                                                                                      unit. The results are awaited with interest.

                          Cetuximab (Erbitux) – an inhibitor of the                   Bevacizumab: interfering with the blood
                          epidermal growth factor receptor                            supply to tumours
                          The epidermal growth factor receptor (EGFR) is a cell       For decades we have known that tumours are able to
                          membrane receptor whose activation is thought to            stimulate their own blood supply in order to continue to
                          contribute to cancer development and progression.           grow, a process called tumour angiogenesis. The blood
                          EGFR has a portion of the molecule that is outside the      supply is often chaotic and inefficient in delivering
                          cell and a portion within the cell (Figure 1). Cetuximab    oxygen to the tumour. The lack of oxygen further
                          is a monoclonal antibody that targets the outer portion     stimulates new tumour blood vessel growth. One of the
                          of EGFR, thereby blocking its activation (Figure 1). This   main stimulants of angiogenesis is a small molecule
                          has generated a huge amount of interest in colorectal       called vascular endothelial growth factor (VEGF).
                          cancers known to overexpress EGFR. On the basis of a        Bevacizumab is a drug that targets VEGF and therefore
                          pivotal randomised Phase II European trial led by           interferes with the growth of new vessels.
                          Professor Cunningham, cetuximab was licensed for use           A large Phase III study in the USA published last
                          in EGFR positive, irinotecan-refractory colorectal cancer   year indicated that adding bevacizumab to
                          in June 2004.                                               chemotherapy in patients receiving treatment for the
                             The trial randomised patients with colorectal cancer     first time resulted in improved response to treatment
                             resistant to irinotecan therapy (many of whom were       and survival. The Gastrointestinal Unit is currently
                             heavily pre-treated) between irinotecan plus             recruiting patients with colorectal cancer into several
                             cetuximab or cetuximab alone treatment options.          international trials of bevacizumab and chemotherapy
                             Responses to therapy were seen in both groups, with      to further characterise potential benefits of this exciting
                             a larger benefit seen in the irinotecan plus             new therapy.
                             cetuximab group (response rate of 23%). Cetuximab
                             was therefore able to reverse resistance to prior
                             irinotecan chemotherapy in a proportion of patients
                             and provide a further treatment option to those
                             patients for whom further therapy is extremely
                             limited. An example of a response to cetuximab
                             monotherapy is shown in Figure 2.
                                                                              CANCER THERAPEUTICS

                                                                Baseline
Future directions                                                                                                      Figure 2.
                                                                                                                       Response of liver
The new targeted therapies, including cetuximab and                                                                    metastases (indicated
                                                                                                                       by white arrows) to
bevacizumab are very much in the spotlight and the next                                                                cetuximab in a patient
year is likely to see the development of these treatments                                                              with advanced
                                                                                                                       colorectal cancer.
in both advanced and early stage colorectal cancer. The
Gastrointestinal Unit aims to be at the forefront of this
research and a number of projects utilising these and
other novel agents are in development:
   A multicentre European study of cetuximab in
   combination with chemotherapy and radiotherapy as
   curative treatment for rectal cancers is planned and
   will be led and managed by the Gastrointestinal Unit.        Same patient after 6 weeks of cetuximab chemotherapy

   Increasingly, combining targeted agents in an
   attempt to knock out several cancer mechanisms
   simultaneously will be a key area of research.
   It is also crucial to identify which patients are most
   likely to respond to these therapies on the basis of
   individual tumour characteristics, in order that
   therapeutic management can be tailored to
   the individual.
The identification of appropriate patients for therapy
and inclusion in clinical trials is vital to the continuing
progress in clinical research made by the
Gastrointestinal Unit. Here, we acknowledge the
willingness of our patients to participate in clinical trials
in colorectal cancer. We continue to aim to provide them
with an ongoing and strong multidisciplinary
environment and a commitment from all members of
the research team.

                                                                                                                       Professor David
                                                                                                                       Cunningham and
                                                                                                                       the medical team




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