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Immuno-PCI: A proposal for the implementation of “seed and soil” concept in the treatment of peritoneal carcinomatosis from colorectal cancer
Medical Hypotheses xxx (2014) xxx–xxx
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Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer Fotios Seretis a, Charalampos Seretis b,⇑ a b
Medical School of Patras, University of Patras, Greece 2nd Department of General Surgery, 401 General Army Hospital of Athens, Greece
a r t i c l e
i n f o
Article history: Received 5 March 2014 Accepted 1 May 2014 Available online xxxx
a b s t r a c t The advent of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has revolutionized the approach to peritoneal carcinomatosis of colorectal cancer origin in appropriately selected cases. However, the high postoperative morbidity and mortality following the procedure underlines the need for optimizing the patient selection criteria, finally aiming to establish a patient-tailored approach. The introduction of tools enabling the quantification of the peritoneal spread of the metastatic deposits has been of paramount importance in the decision-making and the estimation of the prognosis. However, we believe that it is high time to attempt a further evolution of the current practice, by incorporating in the above mentioned quantification scores parameters indicative of the immune-response against the disease progression, fact which will probably reflect more accurately the dynamics of cancer progression and will sequentially be a crucial step towards individualized treatment of peritoneal carcinomatosis. Ó 2014 Published by Elsevier Ltd.
Introduction
The hypothesis
Peritoneal carcinomatosis (PC) from colorectal cancer is emerging as a form of metastatic colorectal cancer (mCRC) amenable to treatment and even cure. The concept of complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) appears to be an aggressive loco-regional therapy with acceptable morbidity and mortality [1]. The complexity of the procedure itself and the prolonged recovery period after this intervention highlights the implementation of solid criteria for patient selection and surrogate endpoints to guide treatment escalation or de-escalation, without however compromising the oncological outcomes. The standardization of CRS + HIPEC, although still premature, has recently emerged as an important first step towards this direction [2]. Despite these efforts HIPEC is still not an integral part of every multidisciplinary decision-making due to the fact that the natural course of peritoneal carcinomatosis from colorectal cancer is still largely unknown, thus hindering an effective treatment plan with CRS + HIPEC at its very center. An increasing body of evidence has also recently shown that the immune response of the host in colorectal cancer patients is a powerful predictor of outcomes [3,4].
Our aim is to propose a concept of combining a score for peritoneal carcinomatosis extent of disease, namely Peritoneal Cancer Index (PCI), with an inflammation-based prognostic score to construct a tool that shall be used for prognosis estimation and/or therapeutic decision-making in patients with peritoneal carcinomatosis of colorectal cancer origin.
⇑ Corresponding author. Postal address: Kanellopoulou & Katehaki Av, Athens 11525, Greece. Tel.: +30 6937236655. E-mail address: [email protected] (C. Seretis).
An initial and fundamental step in our approach is the concept of quantification and objective measurement of metastatic disease burden. With regards to peritoneal involvement from mCRC, a lot
Evaluation of the hypothesis To evaluate our hypothesis, we conducted a literature search in PubMed database, presenting in an accumulative way the currently available evidence regarding the significance of quantifying the extent of peritoneal carcinomatosis in the natural course of the disease and the clinical and decision-making, along with the current knowledge supporting the emerging role of assessing the systemic inflammation as a prognostic factor in colorectal cancer and we attempted to merge them under a unifying approach. The concept of measuring metastatic disease burden
http://dx.doi.org/10.1016/j.mehy.2014.05.010 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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of work has already been done in this field and peritoneal carcinomatosis scores have been reported and even compared by Cashin et al. [5] in terms of better describing the metastatic cancerous load in the peritoneum. The most widely used score is the Peritoneal Carcinomatosis Index (PCI) reported by Sugarbaker et al. [6], which also has the largest amount of published data behind it, thus making it the reasonable candidate for the disease quantification part of our proposed approach. The comparative study of different prognostic scores validated the efficacy of PCI but also reported on better predictive value of Colorectal Peritoneal Score (COREP) score when compared to PCI [5]. However, COREP score relies strongly on signet ring histology of the tumor and serum tumor markers baseline values, as well as their serial changes. In the study showing the inferiority of PCI compared to COREP, 9 out of the total 56 patients of the study cohort had cancer of signet ring histology (16%). When considering that signet ring histology comprises 1% of colorectal adenocarcinomas [7] then the cohort reported in the Cashin study is not only small numbered but also not representative of the actual histological variability. Therefore, it is of no surprise to report superiority of a signet ring histology-based prognostic score in a small cohort of patients with signet ring histology over-representation. Apart from this argument, relying on tumor cell markers appears probably a misleading approach unable to describe the dynamics of cancerous disease and guide treatment and decision making [8,9]. Moreover, PCI was the analytical tool used to compare outcomes between colorectal metastasis liver surgery (standard of care for mCRC) and peritoneal carcinomatosis from colorectal cancer, which is another aspect of mCRC [10]. Despite the notion that involvement of the peritoneum per se in metastasis has a different biology compared to liver metastasis [11], a recently reported study by Elias et al. provides proof that metastatic disease quantification, although naïve, is simple and robust enough to guide possibly patient selection and decision-making [12]. An additional argument in favor of PCI as ‘‘the disease quantification’’ part of our proposed immuno-PCI is that it reflects only disease burden and does not describe tumor or host characteristics, which we hope to encompass in its immune component. Tumor biology under-represented in the PCI will hopefully be described in the immuno-PCI, thus excluding the need for an alternate score that only partially represents the two entities but ultimately only provides limited information to the clinician because of intrinsic limitations and trade-offs between disease burden and host-tumor interactions when constructing the score in the first place. Peritoneum: a host exemplifying tumor cell-host interactions or just another space for cancer to spread? Peritoneal carcinomatosis is beginning to emerge as merely another form of mCRC with data on its incidence, prognosis and coexistence with liver metastatic disease just recently published [13]. The complexity and the unpredictability of the natural course of the disease calls for implementing tools to assess effectively the peritoneum as a potential cancer host, which facilitates peritoneal carcinomatosis or as an unfriendly environment for tumor cells, which prevents effective tumor implantation and colonization. The current research and practice in the field so far has focused on identifying the invasion of peritoneal barrier by tumor deposits. Synchronous peritoneal carcinomatosis at the time of CRS + HIPEC, synchronous isolated ovarian metastases, perforated primary tumor were reported in a meta-analysis of 4395 patients to predict tumor spread in the peritoneal cavity [14]. Similar reports about T4 [15,16] colorectal tumors point to a still largely prevalent notion, namely that cancer spreads only in anatomic continuity and that the course of the disease can be accurately predicted only by the disruption of anatomic planes. However, this concept might be
an oversimplification in light of data showing no prognostic significance for positive peritoneal cytology in colorectal cancer [17]. A gradient between intraperitoneal and systemic cytokines in peritoneal malignancy patients [18] suggests an active role of peritoneum and/or the local inflammatory response in effective peritoneal niche initiation and proliferation. In support of this notion is the lack of prognostic significance of visible cardiophrenic angle lymph nodes which, although associated with concurrent peritoneal carcinomatosis, failed to exert any positive or negative effects on survival after CRS + HIPEC [19]. These findings suggest that peritoneal disease burden which is quantified by PCI might represent a dynamic equilibrium between tumor burden (PCI) and host-related parameters that are not fully understood when only the extent of disease (the equilibrium outcome meaning) is taken into consideration. Performing elaborate studies at the molecular level to elucidate these complex interactions might not be applicable in the clinical setting [20]. What we need in our opinion is a tool that -despite not going into exhaustive detail about tumor biology- shall be sensitive enough to characterize the final outcome of host-tumor cell interactions not as a mere static picture of the disease dynamics (as is the case in most cancer staging systems). On the contrary, quantifying host-tumor cell interactions may have prognostic and even predictive information for the clinician about different patients with the same disease burden who ‘‘unexpectedly’’ progress differently. Inflammatory scoring: the key player to understand disease dynamics? The most potent and robust marker to better describe these complex host-tumor cell interactions with a reasonable trade-off between tumor biology understanding and host-related processes seems to be the immune system. An increasing body of evidence has recently emerged in colorectal cancer suggesting that systemic inflammation assessment through ‘‘easy to use, quantitative and reproducible scores, such as Neutrophil to Lymphocyte Ratio (NLR) [21], modified Glasgow prognostic score (mGPS) [4] and combined NLR and platelet count (COP-NLR) [22] have powerful prognostic implications for colorectal cancer prognosis. It is of great interest that systemic inflammation scores show significant prognostic value across all stages and most importantly stage IV of colorectal cancer [23–26], suggesting that they reflect tumor biology as well as host-tumor cell interactions. To our knowledge no data exist on inflammation scoring solely in peritoneal carcinomatosis from colorectal cancer. However, the durability of inflammatory scoring across all stages of colorectal cancer, its prognostic significance shown in stage IV whether a palliative [23] or curative approach [27] is undertaken and the notion that peritoneal metastasis is a form of mCRC treatable like colorectal liver metastases under certain conditions and indications [10] make inflammatory scoring in peritoneal colorectal metastasis reasonable. A recent study reporting the existence of a gradient between intraperitoneal cytokines and the levels of these cytokines in the serum of patients with peritoneal surface malignancies [18], confirms the very existence of an inflammatory response in peritoneal cavity in colorectal carcinomatosis. Measuring cytokines might not be easily implemented in the clinical practice but this can be substituted for one of the aforementioned inflammatory scores, because they can be easily applied in the peritoneal cavity and reflect the same immunologic processes [28–30]. Although this may seem an oversimplification, it should be regarded as a reasonable compromise between robustness and scientific accuracy that outweighs loss of perhaps elaborate information with a holistic and integrative approach of complex balances robust enough to enable clinical decision making. These data point to the necessity of applying the aforementioned inflammatory scores as baseline in patients with peritoneal carcinomatosis from colorectal cancer, obtaining
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
F. Seretis, C. Seretis / Medical Hypotheses xxx (2014) xxx–xxx
a powerful prognostic and even predictive tool for their survival. Routine preoperative laboratory investigations can easily provide an estimation of the systemic inflammation profile in the peripheral blood of peritoneal carcinomatosis patients, bearing in mind, however, that what more accurately shall depict intraperitoneal phenomena is intraperitoneal sampling. It is intraperitoneal samples that should ideally be used to calculate intraperitoneal inflammatory scores, namely ‘‘intraperitoneal mGPS, intraperitoneal NLR, intraperitoneal COP-NLR’’. Constructing the immuno-PCI: an integrative approach Having solidified from a theoretical point of view the concept of immuno-PCI, what remains to be done is to propose a way to construct it. PCI component has been well described in the literature [31] and since it is probably the most widely used peritoneal carcinomatosis staging system a lot of data exist for retrospective validation of immuno-PCI in large patient cohorts and many institutions. With regards to the immune component, the aforementioned inflammation scoring systems are easy to calculate from peritoneal fluid. PCI calculation can only be done in the operating room during exploratory laparotomy or staging laparoscopy [32,33] as radiology currently lacks high diagnostic accuracy [34]. This provides with a window of opportunity for peritoneal cytology and immune scoring of the peritoneal cavity without subjecting the patient to the risks and harms of an additional invasive staging procedure. When it comes to which of the aforementioned inflammatory prognostic scores should be used, evidence probably favors mGPS [3], although no specific data exist about intraperitoneal application of these scores. However, this can be easily overcome as all these scores can be calculated in standard peritoneal fluid analysis and therefore validated as candidates for the immune component of the immuno-PCI. The score with the best accuracy for peritoneal metastases should be then used to construct and finalize immuno-PCI. The statistical methodology that should be used is out of the purposes of this review whose aim is to provide the theoretical basis for the immuno-PCI concept. The paradigms of the novel Tumor-Node-Metastasis (TNM) staging system proposed for peritoneal mesothelioma [35] and the nomogram proposed by Elias et al. for combined liver and peritoneal colorectal metastases [12] pave in our opinion the way forward for the implementation of our proposed strategy as well. The idea behind the aforementioned TNM for mesothelioma and the nomogram by Elias was to stratify patients characteristics, namely PCI for mesothelioma or number of liver metastases + PCI, into groups based on similar prognosis. It is now a widespread notion that patients can be grouped into separate groups based on their PCI. Furthermore, patient survival has been shown to be predicted by the aforementioned inflammatory scores with the various cutoffs adopted. The concept of immuno-PCI is fundamentally an attempt to merge the predictive power of immune scores with the predictive power of PCI. This can be done, in our opinion, when bearing the nomogram of Elias et al. in mind. To construct this model, Elias et al. used as one part of the nomogram the PCI score. The other part was the number of liver metastases. This part can be substituted for in the immuno-PCI with the inflammatory scores. Exhaustive description of statistical analyses, fitting of the model, bootstrapping of data and statistical adjustments for the statistical weights of PCI and immune scores in the proposed predictive model are beyond the aims of our proposal due to lack of raw data to actually implement it and internally validate it. Therefore, one part of the immuno-PCI will be the PCI; the other part coud be either mGPS, NLR or COP-NLR, which could be compared for their predictive accuracy in future studies. The immune component that when combined with PCI yields the best predictive accuracy shall be the final selection. It is this final immuno-PCI that in
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our opinion encompasses all the aforementioned concepts for disease biology of peritoneal metastases from colorectal cancer. Immuno-PCI: why bother? Although relatively easy to construct and validate though retrospective review of existing data under this novel perspective, the true power of immuno-PCI will be recognized only if it can answer real clinical questions and help clinicians with a stratification tool for their patients into the different treatment modalities. The first gap in clinical practice that immuno-PCI might answer is to balance and unify under a single decision making tool the different cutoffs for PCI clinicians propose to implement CRS + HIPEC or not [36–38]. In one of the largest cohorts reported including 523 patients with peritoneal carcinomatosis of colorectal origin (40), 83% of whom having peritoneum-confined disease (no liver metastases), there was hardly any separation of the overall survival curves in the group of patients with PCI 7–12 and PCI 12–19 [39]. Clearly in favor of prolonged survival was a PCI of <7 while a PCI >19 implicated the worst prognosis. Apart from the obvious fact that little disease is a good thing and that very extensive disease is a poor prognostic sign, this study revealed also a great gap in our ability to accurately determine prognosis in the intermediate group (PCI 7–19), which constituted 49% of the patients in this study. It is exactly in this grey zone that the different PCI cutoffs in the literature appear as described above and it is exactly this grey zone where immuno-PCI will hopefully bring the most help for clinical decision making. Another possible aspect of immuno-PCI might be predicting peritoneum confined cancer recurrence. An increased immunoPCI might reflect a tumor implantation/re-growth-prone peritoneum. It has been reported that high PCI score predicts peritoneal recurrence due to an associated high probability of incomplete cytoreduction (CC0/CC1) which is critical for loco-regional control of the disease [40]. A recurrence-promoting inflammatory environment in the peritoneum is a notion not far from a recent paper pointing to inflammatory infiltrate in colorectal cancer as powerful predictor of recurrence [41]. It is these interactions and processes we hope to even vaguely describe and implement into clinical practice making the logical assumption that peritoneal inflammatory cytology reflects local inflammatory phenomena at the metastases sites, phenomena which could be not otherwise be described for every single peritoneal metastasis. The implementation of immuno-PCI in detecting peritoneal recurrence bears the promise to stratify more accurately patients into second-look surgery approaches, which even under less strict selection criteria currently have shown impressive results [42,43]. Constructing a tool to measure and host-tumor cell interactions in a practical way might have an additional benefit; it could set a common pathway to integrate peritoneal carcinomatosis from colorectal cancer of different histological types. Recent reports about tumor histology determining colorectal cancer prognosis [44,45] have emerged in the literature. As our understanding of the complexity of the cancer as seed (different tumor sub-populations, different histological types) especially with the advent of elaborate data from high throughput screening technologies we might be confronted with patient cohorts too divided to enable therapeutic decision making in a disease consortium where data are already scarce and heterogeneous [11]. The immuno-PCI concept reflects the ‘‘final disease severity level’’ to which multiple tumor and host related events converge and can therefore be used as the common language to communicate outcomes from the ‘‘many’’ types of colorectal cancer into a unified approach. This seems to be a gap in the peritoneal carcinomatosis field that immuno-PCI might answer in an effective, practical and not exhaustive way.
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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F. Seretis, C. Seretis / Medical Hypotheses xxx (2014) xxx–xxx
Limitations Limitations in our approach emerge from the fact that its concept has not been proven yet, at least in the suggested finalized form. However, the novelty and the proposed clinical benefits of the immuno-PCI concept might account for skepticism. Another limitation of our concept might arise from scarcity of data to construct it. The simplicity of our proposal which requires clinical data of the most naive nature (intraperitoneal neutrophil count, albumin etc.) still does not account for difficulties in obtaining the necessary data. A reasonable preliminary proposal to overcome this barrier is to substitute peritoneal immune scores with the scores calculated from serum values. This approach should, however, be exploited in peritoneum-confined mCRC patients as metastatic disease at other sites might confound the results. Should this preliminary pilot approach prove immuno-PCI as concept, then getting the data prospectively is probably the way forward. Ambiguous results from the proposed pilot (systemic immuno)-PCI study should be interpreted with caution bearing in mind that inflammatory changes in the peritoneum might not appear at least in the beginning systemically [18], which could erroneously turn down immuno-PCI concept before it is actually tested. Consequences of the hypothesis Integrating the qualitive characteristics of the immuno-reaction against peritoneal carcinomatosis, which reflect the biological aggressiveness of the disease, in the currently used prognostic tools which only quantify the extent of peritoneal carcinomatosis will optimize risk stratification and will enable to tailor our decision-making, particularly when referring to the implementation of CRS + HIPEC. Conclusions We proposed a simple way to implement the ‘‘seed and soil concept’’ in peritoneal carcinomatosis from colorectal cancer and proposed a new tool to stage peritoneal carcinomatosis from colorectal cancer more accurately. Immuno-PCI is composed of the seed (PCI) and the soil component (namely immune scoring in the peritoneal cavity) and bears the promise to merge the sophisticated knowledge of medical oncology with the power of locoregional control strategies of surgical oncology. This is in our opinion a novel concept that will help to optimize the decision-making for patients and take CRS + HIPEC into the very center of colorectal peritoneal carcinomatosis treatment strategies. Financial support None. Conflict of interest statement The authors have no competing interests to declare. References [1] Jafari MD, Halabi WJ, Stamos MJ, Nguyen VQ, Carmichael JC, Mills SD, et al. Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the American college of surgeons national surgical quality improvement program. JAMA Surg 2014;149:170–5. [2] Turaga K, Levine E, Barone R, Sticca R, Petrelli N, Lambert L, et al. Consensus guidelines from the american society of peritoneal surface malignancies on standardizing the delivery of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol 2013 [Epub ahead of print].
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Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer Fotios Seretis a, Charalampos Seretis b,⇑ a b
Medical School of Patras, University of Patras, Greece 2nd Department of General Surgery, 401 General Army Hospital of Athens, Greece
a r t i c l e
i n f o
Article history: Received 5 March 2014 Accepted 1 May 2014 Available online xxxx
a b s t r a c t The advent of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has revolutionized the approach to peritoneal carcinomatosis of colorectal cancer origin in appropriately selected cases. However, the high postoperative morbidity and mortality following the procedure underlines the need for optimizing the patient selection criteria, finally aiming to establish a patient-tailored approach. The introduction of tools enabling the quantification of the peritoneal spread of the metastatic deposits has been of paramount importance in the decision-making and the estimation of the prognosis. However, we believe that it is high time to attempt a further evolution of the current practice, by incorporating in the above mentioned quantification scores parameters indicative of the immune-response against the disease progression, fact which will probably reflect more accurately the dynamics of cancer progression and will sequentially be a crucial step towards individualized treatment of peritoneal carcinomatosis. Ó 2014 Published by Elsevier Ltd.
Introduction
The hypothesis
Peritoneal carcinomatosis (PC) from colorectal cancer is emerging as a form of metastatic colorectal cancer (mCRC) amenable to treatment and even cure. The concept of complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) appears to be an aggressive loco-regional therapy with acceptable morbidity and mortality [1]. The complexity of the procedure itself and the prolonged recovery period after this intervention highlights the implementation of solid criteria for patient selection and surrogate endpoints to guide treatment escalation or de-escalation, without however compromising the oncological outcomes. The standardization of CRS + HIPEC, although still premature, has recently emerged as an important first step towards this direction [2]. Despite these efforts HIPEC is still not an integral part of every multidisciplinary decision-making due to the fact that the natural course of peritoneal carcinomatosis from colorectal cancer is still largely unknown, thus hindering an effective treatment plan with CRS + HIPEC at its very center. An increasing body of evidence has also recently shown that the immune response of the host in colorectal cancer patients is a powerful predictor of outcomes [3,4].
Our aim is to propose a concept of combining a score for peritoneal carcinomatosis extent of disease, namely Peritoneal Cancer Index (PCI), with an inflammation-based prognostic score to construct a tool that shall be used for prognosis estimation and/or therapeutic decision-making in patients with peritoneal carcinomatosis of colorectal cancer origin.
⇑ Corresponding author. Postal address: Kanellopoulou & Katehaki Av, Athens 11525, Greece. Tel.: +30 6937236655. E-mail address: [email protected] (C. Seretis).
An initial and fundamental step in our approach is the concept of quantification and objective measurement of metastatic disease burden. With regards to peritoneal involvement from mCRC, a lot
Evaluation of the hypothesis To evaluate our hypothesis, we conducted a literature search in PubMed database, presenting in an accumulative way the currently available evidence regarding the significance of quantifying the extent of peritoneal carcinomatosis in the natural course of the disease and the clinical and decision-making, along with the current knowledge supporting the emerging role of assessing the systemic inflammation as a prognostic factor in colorectal cancer and we attempted to merge them under a unifying approach. The concept of measuring metastatic disease burden
http://dx.doi.org/10.1016/j.mehy.2014.05.010 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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of work has already been done in this field and peritoneal carcinomatosis scores have been reported and even compared by Cashin et al. [5] in terms of better describing the metastatic cancerous load in the peritoneum. The most widely used score is the Peritoneal Carcinomatosis Index (PCI) reported by Sugarbaker et al. [6], which also has the largest amount of published data behind it, thus making it the reasonable candidate for the disease quantification part of our proposed approach. The comparative study of different prognostic scores validated the efficacy of PCI but also reported on better predictive value of Colorectal Peritoneal Score (COREP) score when compared to PCI [5]. However, COREP score relies strongly on signet ring histology of the tumor and serum tumor markers baseline values, as well as their serial changes. In the study showing the inferiority of PCI compared to COREP, 9 out of the total 56 patients of the study cohort had cancer of signet ring histology (16%). When considering that signet ring histology comprises 1% of colorectal adenocarcinomas [7] then the cohort reported in the Cashin study is not only small numbered but also not representative of the actual histological variability. Therefore, it is of no surprise to report superiority of a signet ring histology-based prognostic score in a small cohort of patients with signet ring histology over-representation. Apart from this argument, relying on tumor cell markers appears probably a misleading approach unable to describe the dynamics of cancerous disease and guide treatment and decision making [8,9]. Moreover, PCI was the analytical tool used to compare outcomes between colorectal metastasis liver surgery (standard of care for mCRC) and peritoneal carcinomatosis from colorectal cancer, which is another aspect of mCRC [10]. Despite the notion that involvement of the peritoneum per se in metastasis has a different biology compared to liver metastasis [11], a recently reported study by Elias et al. provides proof that metastatic disease quantification, although naïve, is simple and robust enough to guide possibly patient selection and decision-making [12]. An additional argument in favor of PCI as ‘‘the disease quantification’’ part of our proposed immuno-PCI is that it reflects only disease burden and does not describe tumor or host characteristics, which we hope to encompass in its immune component. Tumor biology under-represented in the PCI will hopefully be described in the immuno-PCI, thus excluding the need for an alternate score that only partially represents the two entities but ultimately only provides limited information to the clinician because of intrinsic limitations and trade-offs between disease burden and host-tumor interactions when constructing the score in the first place. Peritoneum: a host exemplifying tumor cell-host interactions or just another space for cancer to spread? Peritoneal carcinomatosis is beginning to emerge as merely another form of mCRC with data on its incidence, prognosis and coexistence with liver metastatic disease just recently published [13]. The complexity and the unpredictability of the natural course of the disease calls for implementing tools to assess effectively the peritoneum as a potential cancer host, which facilitates peritoneal carcinomatosis or as an unfriendly environment for tumor cells, which prevents effective tumor implantation and colonization. The current research and practice in the field so far has focused on identifying the invasion of peritoneal barrier by tumor deposits. Synchronous peritoneal carcinomatosis at the time of CRS + HIPEC, synchronous isolated ovarian metastases, perforated primary tumor were reported in a meta-analysis of 4395 patients to predict tumor spread in the peritoneal cavity [14]. Similar reports about T4 [15,16] colorectal tumors point to a still largely prevalent notion, namely that cancer spreads only in anatomic continuity and that the course of the disease can be accurately predicted only by the disruption of anatomic planes. However, this concept might be
an oversimplification in light of data showing no prognostic significance for positive peritoneal cytology in colorectal cancer [17]. A gradient between intraperitoneal and systemic cytokines in peritoneal malignancy patients [18] suggests an active role of peritoneum and/or the local inflammatory response in effective peritoneal niche initiation and proliferation. In support of this notion is the lack of prognostic significance of visible cardiophrenic angle lymph nodes which, although associated with concurrent peritoneal carcinomatosis, failed to exert any positive or negative effects on survival after CRS + HIPEC [19]. These findings suggest that peritoneal disease burden which is quantified by PCI might represent a dynamic equilibrium between tumor burden (PCI) and host-related parameters that are not fully understood when only the extent of disease (the equilibrium outcome meaning) is taken into consideration. Performing elaborate studies at the molecular level to elucidate these complex interactions might not be applicable in the clinical setting [20]. What we need in our opinion is a tool that -despite not going into exhaustive detail about tumor biology- shall be sensitive enough to characterize the final outcome of host-tumor cell interactions not as a mere static picture of the disease dynamics (as is the case in most cancer staging systems). On the contrary, quantifying host-tumor cell interactions may have prognostic and even predictive information for the clinician about different patients with the same disease burden who ‘‘unexpectedly’’ progress differently. Inflammatory scoring: the key player to understand disease dynamics? The most potent and robust marker to better describe these complex host-tumor cell interactions with a reasonable trade-off between tumor biology understanding and host-related processes seems to be the immune system. An increasing body of evidence has recently emerged in colorectal cancer suggesting that systemic inflammation assessment through ‘‘easy to use, quantitative and reproducible scores, such as Neutrophil to Lymphocyte Ratio (NLR) [21], modified Glasgow prognostic score (mGPS) [4] and combined NLR and platelet count (COP-NLR) [22] have powerful prognostic implications for colorectal cancer prognosis. It is of great interest that systemic inflammation scores show significant prognostic value across all stages and most importantly stage IV of colorectal cancer [23–26], suggesting that they reflect tumor biology as well as host-tumor cell interactions. To our knowledge no data exist on inflammation scoring solely in peritoneal carcinomatosis from colorectal cancer. However, the durability of inflammatory scoring across all stages of colorectal cancer, its prognostic significance shown in stage IV whether a palliative [23] or curative approach [27] is undertaken and the notion that peritoneal metastasis is a form of mCRC treatable like colorectal liver metastases under certain conditions and indications [10] make inflammatory scoring in peritoneal colorectal metastasis reasonable. A recent study reporting the existence of a gradient between intraperitoneal cytokines and the levels of these cytokines in the serum of patients with peritoneal surface malignancies [18], confirms the very existence of an inflammatory response in peritoneal cavity in colorectal carcinomatosis. Measuring cytokines might not be easily implemented in the clinical practice but this can be substituted for one of the aforementioned inflammatory scores, because they can be easily applied in the peritoneal cavity and reflect the same immunologic processes [28–30]. Although this may seem an oversimplification, it should be regarded as a reasonable compromise between robustness and scientific accuracy that outweighs loss of perhaps elaborate information with a holistic and integrative approach of complex balances robust enough to enable clinical decision making. These data point to the necessity of applying the aforementioned inflammatory scores as baseline in patients with peritoneal carcinomatosis from colorectal cancer, obtaining
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
F. Seretis, C. Seretis / Medical Hypotheses xxx (2014) xxx–xxx
a powerful prognostic and even predictive tool for their survival. Routine preoperative laboratory investigations can easily provide an estimation of the systemic inflammation profile in the peripheral blood of peritoneal carcinomatosis patients, bearing in mind, however, that what more accurately shall depict intraperitoneal phenomena is intraperitoneal sampling. It is intraperitoneal samples that should ideally be used to calculate intraperitoneal inflammatory scores, namely ‘‘intraperitoneal mGPS, intraperitoneal NLR, intraperitoneal COP-NLR’’. Constructing the immuno-PCI: an integrative approach Having solidified from a theoretical point of view the concept of immuno-PCI, what remains to be done is to propose a way to construct it. PCI component has been well described in the literature [31] and since it is probably the most widely used peritoneal carcinomatosis staging system a lot of data exist for retrospective validation of immuno-PCI in large patient cohorts and many institutions. With regards to the immune component, the aforementioned inflammation scoring systems are easy to calculate from peritoneal fluid. PCI calculation can only be done in the operating room during exploratory laparotomy or staging laparoscopy [32,33] as radiology currently lacks high diagnostic accuracy [34]. This provides with a window of opportunity for peritoneal cytology and immune scoring of the peritoneal cavity without subjecting the patient to the risks and harms of an additional invasive staging procedure. When it comes to which of the aforementioned inflammatory prognostic scores should be used, evidence probably favors mGPS [3], although no specific data exist about intraperitoneal application of these scores. However, this can be easily overcome as all these scores can be calculated in standard peritoneal fluid analysis and therefore validated as candidates for the immune component of the immuno-PCI. The score with the best accuracy for peritoneal metastases should be then used to construct and finalize immuno-PCI. The statistical methodology that should be used is out of the purposes of this review whose aim is to provide the theoretical basis for the immuno-PCI concept. The paradigms of the novel Tumor-Node-Metastasis (TNM) staging system proposed for peritoneal mesothelioma [35] and the nomogram proposed by Elias et al. for combined liver and peritoneal colorectal metastases [12] pave in our opinion the way forward for the implementation of our proposed strategy as well. The idea behind the aforementioned TNM for mesothelioma and the nomogram by Elias was to stratify patients characteristics, namely PCI for mesothelioma or number of liver metastases + PCI, into groups based on similar prognosis. It is now a widespread notion that patients can be grouped into separate groups based on their PCI. Furthermore, patient survival has been shown to be predicted by the aforementioned inflammatory scores with the various cutoffs adopted. The concept of immuno-PCI is fundamentally an attempt to merge the predictive power of immune scores with the predictive power of PCI. This can be done, in our opinion, when bearing the nomogram of Elias et al. in mind. To construct this model, Elias et al. used as one part of the nomogram the PCI score. The other part was the number of liver metastases. This part can be substituted for in the immuno-PCI with the inflammatory scores. Exhaustive description of statistical analyses, fitting of the model, bootstrapping of data and statistical adjustments for the statistical weights of PCI and immune scores in the proposed predictive model are beyond the aims of our proposal due to lack of raw data to actually implement it and internally validate it. Therefore, one part of the immuno-PCI will be the PCI; the other part coud be either mGPS, NLR or COP-NLR, which could be compared for their predictive accuracy in future studies. The immune component that when combined with PCI yields the best predictive accuracy shall be the final selection. It is this final immuno-PCI that in
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our opinion encompasses all the aforementioned concepts for disease biology of peritoneal metastases from colorectal cancer. Immuno-PCI: why bother? Although relatively easy to construct and validate though retrospective review of existing data under this novel perspective, the true power of immuno-PCI will be recognized only if it can answer real clinical questions and help clinicians with a stratification tool for their patients into the different treatment modalities. The first gap in clinical practice that immuno-PCI might answer is to balance and unify under a single decision making tool the different cutoffs for PCI clinicians propose to implement CRS + HIPEC or not [36–38]. In one of the largest cohorts reported including 523 patients with peritoneal carcinomatosis of colorectal origin (40), 83% of whom having peritoneum-confined disease (no liver metastases), there was hardly any separation of the overall survival curves in the group of patients with PCI 7–12 and PCI 12–19 [39]. Clearly in favor of prolonged survival was a PCI of <7 while a PCI >19 implicated the worst prognosis. Apart from the obvious fact that little disease is a good thing and that very extensive disease is a poor prognostic sign, this study revealed also a great gap in our ability to accurately determine prognosis in the intermediate group (PCI 7–19), which constituted 49% of the patients in this study. It is exactly in this grey zone that the different PCI cutoffs in the literature appear as described above and it is exactly this grey zone where immuno-PCI will hopefully bring the most help for clinical decision making. Another possible aspect of immuno-PCI might be predicting peritoneum confined cancer recurrence. An increased immunoPCI might reflect a tumor implantation/re-growth-prone peritoneum. It has been reported that high PCI score predicts peritoneal recurrence due to an associated high probability of incomplete cytoreduction (CC0/CC1) which is critical for loco-regional control of the disease [40]. A recurrence-promoting inflammatory environment in the peritoneum is a notion not far from a recent paper pointing to inflammatory infiltrate in colorectal cancer as powerful predictor of recurrence [41]. It is these interactions and processes we hope to even vaguely describe and implement into clinical practice making the logical assumption that peritoneal inflammatory cytology reflects local inflammatory phenomena at the metastases sites, phenomena which could be not otherwise be described for every single peritoneal metastasis. The implementation of immuno-PCI in detecting peritoneal recurrence bears the promise to stratify more accurately patients into second-look surgery approaches, which even under less strict selection criteria currently have shown impressive results [42,43]. Constructing a tool to measure and host-tumor cell interactions in a practical way might have an additional benefit; it could set a common pathway to integrate peritoneal carcinomatosis from colorectal cancer of different histological types. Recent reports about tumor histology determining colorectal cancer prognosis [44,45] have emerged in the literature. As our understanding of the complexity of the cancer as seed (different tumor sub-populations, different histological types) especially with the advent of elaborate data from high throughput screening technologies we might be confronted with patient cohorts too divided to enable therapeutic decision making in a disease consortium where data are already scarce and heterogeneous [11]. The immuno-PCI concept reflects the ‘‘final disease severity level’’ to which multiple tumor and host related events converge and can therefore be used as the common language to communicate outcomes from the ‘‘many’’ types of colorectal cancer into a unified approach. This seems to be a gap in the peritoneal carcinomatosis field that immuno-PCI might answer in an effective, practical and not exhaustive way.
Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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Limitations Limitations in our approach emerge from the fact that its concept has not been proven yet, at least in the suggested finalized form. However, the novelty and the proposed clinical benefits of the immuno-PCI concept might account for skepticism. Another limitation of our concept might arise from scarcity of data to construct it. The simplicity of our proposal which requires clinical data of the most naive nature (intraperitoneal neutrophil count, albumin etc.) still does not account for difficulties in obtaining the necessary data. A reasonable preliminary proposal to overcome this barrier is to substitute peritoneal immune scores with the scores calculated from serum values. This approach should, however, be exploited in peritoneum-confined mCRC patients as metastatic disease at other sites might confound the results. Should this preliminary pilot approach prove immuno-PCI as concept, then getting the data prospectively is probably the way forward. Ambiguous results from the proposed pilot (systemic immuno)-PCI study should be interpreted with caution bearing in mind that inflammatory changes in the peritoneum might not appear at least in the beginning systemically [18], which could erroneously turn down immuno-PCI concept before it is actually tested. Consequences of the hypothesis Integrating the qualitive characteristics of the immuno-reaction against peritoneal carcinomatosis, which reflect the biological aggressiveness of the disease, in the currently used prognostic tools which only quantify the extent of peritoneal carcinomatosis will optimize risk stratification and will enable to tailor our decision-making, particularly when referring to the implementation of CRS + HIPEC. Conclusions We proposed a simple way to implement the ‘‘seed and soil concept’’ in peritoneal carcinomatosis from colorectal cancer and proposed a new tool to stage peritoneal carcinomatosis from colorectal cancer more accurately. Immuno-PCI is composed of the seed (PCI) and the soil component (namely immune scoring in the peritoneal cavity) and bears the promise to merge the sophisticated knowledge of medical oncology with the power of locoregional control strategies of surgical oncology. This is in our opinion a novel concept that will help to optimize the decision-making for patients and take CRS + HIPEC into the very center of colorectal peritoneal carcinomatosis treatment strategies. Financial support None. Conflict of interest statement The authors have no competing interests to declare. References [1] Jafari MD, Halabi WJ, Stamos MJ, Nguyen VQ, Carmichael JC, Mills SD, et al. Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the American college of surgeons national surgical quality improvement program. JAMA Surg 2014;149:170–5. [2] Turaga K, Levine E, Barone R, Sticca R, Petrelli N, Lambert L, et al. Consensus guidelines from the american society of peritoneal surface malignancies on standardizing the delivery of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol 2013 [Epub ahead of print].
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Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010
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Please cite this article in press as: Seretis F, Seretis C. Immuno-PCI: A proposal for the implementation of ‘‘seed and soil’’ concept in the treatment of peritoneal carcinomatosis from colorectal cancer. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.05.010