Reporter: Ritu Saxena, Ph.D.
With the number of cancer cases plummeting every year, there is a dire need for finding a cure to wipe the disease out. A number of therapeutic drugs are currently in use, however, due to heterogeneity of the disease targeted therapy is required. An important criteria that needs to be addressed in this context is the –‘tumor response’ and how it could be predicted, thereby improving the selection of patients for cancer treatment. The issue of tumor response has been addressed in a recent editorial titled “Tumor response criteria: are they appropriate?” published recently in Future Oncology.
The article talks about how the early tumor treatment response methods came into practice and how we need to redefine and reassess the tumor response.
Defining ‘tumor response’ has always been a challenge
WHO defines a response to anticancer therapy as 50% or more reduction in the tumor size measured in two perpendicular diameters. It is based on the results of experiments performed by Moertel and Hanley in 1976 and later published by Miller et al in 1981. Twenty years later, in the year 2000, the US National Cancer Institute, with the European Association for Research and Treatment of Cancer, proposed ‘new response criteria’ for solid tumors; a replacement of 2D measurement with measurement of one dimension was made. Tumor response was defined as a decrease in the largest tumor diameter by 30%, which would translate into a 50% decrease for a spherical lesion. However, response criteria have not been updated after that and there a structured standardization of treatment response is still required especially when several studies have revealed that the response of tumors to a therapy via imaging results from conventional approaches such as endoscopy, CT scan, is not reliable. The reason is that evaluating the size of tumor is just one part of the story and to get the complete picture investigating and evaluating the tissue is essential to differentiate between treatment-related scar, fibrosis or microscopic residual tumor.
In clinical practice, treatment response is determined on the basis of well-established parameters obtained from diagnostic imaging, both cross-sectional and functional. In general, the response is classified as:
- Complete remission: If a tumor disappears after a particular therapy,
- Partial remission: there is residual tumor after therapy.
For a doctor examining the morphology of the tumor, complete remission might seem like good news, however, mission might not be complete yet! For example, in some cases, with regard to prognosis, patients with 0% residual tumor (complete tumor response) had the same prognosis compared with those patients with 1–10% residual tumor (subtotal response).
Another example is that in patients demonstrating complete remission of tumor response as observed with clinical, sonographic, functional (PET) and histopathological analysis experience recurrence within the first 2 years of resection.
Adding complexity to the situation is the fact that the appropriate, clinically relevant timing of assessment of tumor response to treatment remains undefined. An example mentioned in the editorial is – for gastrointestinal (GI) malignancies, the assessment timing varies considerably from 3 to 6 weeks after initiation of neoadjuvant external beam radiation. Further, time could vary depending upon the type of radiation administered, i.e., if it is external beam, accelerated hyperfractionation, or brachytherapy.
Abovementioned examples remind us of the intricacy and enigma of tumor biology and subsequent tumor response.
Conclusion
Owing to the extraordinary heterogeneity of cancers between patients, and primary and metastatic tumors in the same patients, it is important to consider several factors while determining the response of tumors to different therapie in clinical trials. Authors exclaim, “We must change the tools we use to assess tumor response. The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics.”
Future perspective
Editorial points out that the oncologists, radiotherapists, and immunologists all might have a different opinion and observation as far as tumor response is considered. For example, surgical oncologists might determine a treatment to be effective if the local tumor control is much better after multimodal treatment, and that patients post-therapeutically also reveal an increase of the rate of microscopic and macroscopic R0-resection. Immunologists, on the other hand, might just declare a response if immune-competent cells have been decreased and, possibly, without clinical signs of decrease of tumor size.
What might be the answer to the complexity to reading tumor response is stated in the editorial – “an interdisciplinary initiative with all key stakeholders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prognosis.”
Sources:
Editorial : Björn LDM Brücher et al Tumor response criteria: are they appropriate? Future Oncology August 2012, Vol. 8, No. 8, 903-906.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981, 47(1),207–214.
Related articles to this subject on this Open Access Online Scientific Journal:
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Dr. Sanexa
you have brought up an interesting and very clinically relevant point: what is the best measurement of response and 2) how perspectives among oncologists and other professionals differ on this issues given their expertise in their respective subspecialties (immunologist versus oncologist. The advent of functional measurements of tumors (PET etc.) seems extremely important in the therapeutic use AND in the development of these types of compounds since usually a response presents (in cases of solid tumors) as either a lack of growth of the tumor or tumor shrinkage. Did the authors include an in-depth discussion of the rapidity of onset of resistance with these types of compounds?
Thanks for the posting.
Dr. Williams,
Thanks for your comment on the post. The editorial brings to attention a view that although PET and other imaging methods provide vital information on tumor growth, shrinkage in response to a therapy, however, there are more aspects to consider including genetic and molecular characteristics of tumor.
It was an editorial review and the authors did not include any in-depth discussion on the rapidity of onset of resistance with these types of compounds as the focus was primarily on interpreting tumor response.
I am glad you found the contents of the write-up informative.
Thanks again!
Ritu
Thank you for your wonderful comment and interpretation. Dr.Sanexa made a brilliant comment.
May I allow myself putting my finger deeper into this wound ? Cancer patients deserve it.
It had been already pointed out by international experts from Munich, Tokyo, Hong-Kong and Houston, dealing with upper GI cancer, that the actual response criteria are not appropriate and moreover: the clinical response criteria in use seem rather to function as an alibi, than helping to differentiate and / or discriminate tumor biology (Ann Surg Oncol 2009):
http://www.ncbi.nlm.nih.gov/pubmed/19194759
The response data in a phase-II-trial (one tumor entity, one histology, one treatment, one group) revealed: clinical response evaluation according to the WHO-criteria is not appropriate to determine response:
http://www.ncbi.nlm.nih.gov/pubmed/15498642
Of course, there was a time, when it seemed to be useful and this also has to be respected.
There is another challenge: using statistically a ROC and resulting in thresholds. This was, is and always be “a clinical decision only” and not the decision of the statistician. The clinician tells the statistician, what decision, he wants to make – the responsibility is enormous. Getting back to the roots:
After the main results of the Munich-group had been published 2001 (Ann Surg) and 2004 (J Clin Oncol):
http://www.ncbi.nlm.nih.gov/pubmed/11224616
http://www.ncbi.nlm.nih.gov/pubmed/14990646
the first reaction in the community was: to difficult, can’t be, not re-evaluated, etc.. However, all evaluated cut-offs / thresholds had been later proven to be the real and best ones by the MD Anderson Cancer Center in Houston, Texas. Jaffer Ajani – a great and critical oncologist – pushed that together with Steve Swisher and they found the same results. Than the upper GI stakeholders went an uncommon way in science: they re-scrutinized their findings. Meanwhile the Goldstandard using histopathology as the basis-criterion had been published in Cancer 2006.
http://www.ncbi.nlm.nih.gov/pubmed/16607651
Not every author, who was at the authorlist in 2001 and 2004 wanted to be a part of this analysis and publication ! Why ? Everyone should judge that by himself.
The data of this analysis had been submitted to the New England Journal of Medicine. In the 2nd review stage process, the manuscript was rejected. The Ann Surg Oncol accepted the publication: the re-scrutinized data resulted in another interesting finding: in the future maybe “one PET-scan” might be appropriate predicting the patient’s response.
Where are we now ?
The level of evidence using the response criteria is very low: Miller’s (Cancer 1981) publication belonged to ”one single” experiment from Moertel (Cancer 1976). During that time, there was no definition of “experiences” rather than “oncologists”. These terms had not been in use during that time.
Additionally they resulted in a (scientifically weak) change of the classification, published by Therasse (J Natl Cancer Inst 2000). Targeted therapy did not result in a change so far. In 2009, the international upper GI experts sent their publication of the Ann Surg Oncol 2009 to the WHO but without any kind of reaction.
Using molecular biological predictive markers within the last 10years all seem to have potential.
http://www.ncbi.nlm.nih.gov/pubmed/20012971
http://www.ncbi.nlm.nih.gov/pubmed/18704459
http://www.ncbi.nlm.nih.gov/pubmed/17940507
http://www.ncbi.nlm.nih.gov/pubmed/17354029
But, experts are aware: the real step breaking barriers had not been performed so far. Additionally, it is very important in trying to evaluate and / predict response, that not different tumor entities with different survival and tumor biology are mixed together. Those data are from my perspective not helpful, but maybe that is my own Bias (!) of my view.
INCORE, the International Consortium of Research Excellence of the Theodor-Billroth-Academy, was invited publishing the Editorial in Future Oncology 2012. The consortium pointed out, that living within an area of ‘prove of principle’ and also trying to work out level of evidence in medicine, it is “the duty and responsibility” of every clinician, but also of the societies and institutions, also of the WHO.
Complete remission is not the only goal, as experts dealing with ‘response-research’ are aware. It is so frustrating for patients and clinicians: there is a rate of those patients with complete remission, who develop early recurrence ! This reflects, that complete remission cannot function as the only criterion describing response !
Again, my heartly thanks, that Dr.Sanexa discussed this issue in detail.
I hope, I found the way explaining the way of development and evaluating response criteria properly and in a differentiated way of view. From the perspective of INCORE:
“an interdisciplinary initiative with all key stake¬holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prognosis.”
Dr. Brucher,
First of all thanks for expressing your views on the ‘tumor response’ in a comprehensive way. You are the first author of the editorial review one of the prominent people who has taken part in the process of defining tumor response and I am glad that you decided to write a comment on the writeup.
The topic has been explained well in an immaculate manner and that it further clarifies the need for the perfect markers that would be able to evaluate and predict tumor response. There are, as you mentioned, some molecular markers available including VEGF, cyclins, that have been brought to focus in the context of squamous cell carcinoma.
It would be great if you could be the guest author for our blog and we could publish your opinion (comment on this blog post) as a separate post. Please let us know if it is OK with you.
Thanks again for your comment
Ritu
Thank you all to the compelling discussions, above.
Please review the two sources on the topic I placed at the bottom of the post, above as post on this Scientific Journal,
All comments made to both entries are part of thisvdiscussion, I am referring to Dr. Nir’s post on size of tumor, to BB comment to Nir’s post, to Larry’ Pathologist view on Tumors and my post on remission and minimally invasive surgery (MIS).
Great comments by Dr. Williams, BB and wonderful topic exposition by Dr. Ritu.
Aviva,
Thats a great idea. I will combine all sources referred by you, the post on tumor imaging by Dr. Nir and the comments made on the these posts including Dr. Brucher’s comments in a new posts.
Thanks
Ritu
Great idea, ask Larry, he has written two very long important comments on this topic, one on Nir’s post and another one, ask him where, if it is not on MIS post. GREAT work, Ritu, integration is very important. Dr, Williams is one of our Gems.
Assessing tumour response it is not an easy task!Because tumours don’t change,but happilly our knowlege(about them) does really change,is everchanging(thans god!).In the past we had the Recist Criteria,then the Modified Recist Criteria,becausa of Gist and other tumors.At this very moment,these are clearly insuficient.We do need more ,new validated facing the reality of nowadays.A great,enormoust post Dr Ritu!Congratulations!
[…] Judging the ‘Tumor response’-there is more food for thought (pharmaceuticalintelligence.com) […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette