Materiały źródłowe

• #1 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7866161/

  Patients with cancer of unknown primary site suffer the burden of an uncertain disease, which is characterized by the impossibility to identify the tissue where the tumor has originated. […] Therefore, patients with cancer of unknown primary have reduced therapeutic opportunities and poor prognosis. […] The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. […] Most CUP patients (~80%) do not respond to chemotherapy and have a median overall survival of 6 to 10 months, but a fraction of all cases, about 20%, are characterized by a favorable prognosis due to their potential chemosensitivity and long-term disease control. […] According to these criteria, they are classified into two prognostic subgroups, defined as favorable (15-20%) and unfavorable CUPs (80-85%).

• #2 Defining prognosis in Cancer of Unknown Primary (CUP) | Oncopedia

  https://www.oncopedia.wiki/contributions/defining-prognosis-in-cancer-of-unknown-primary

  Cancer of unknown primary (CUP) are heterogenous, undifferentiated metastatic tumours in which the primary lesion responsible for metastatic spread cannot be identified, despite a thorough diagnostic work up. Diagnosing CUP, therefore, is especially challenging, and fewer than 20% of patients survive beyond 1 year following initial diagnosis. […] The unfavourable CUPs accounts for the 80% of CUP tumors and have the worse prognosis. […] Most patients with CUP, however, (80-85%) have an unfavourable prognosis, and are treated with empiric chemotherapy, with a poor survival expectation of 4 to 10 months. […] Patients with good PS status (1) and normal lactate dehydrogenase level have a better outcome (life expectancy of 1 year) than those with poor PS (2) and raised LDH level (median overall survival of 4 months).

• #3 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://ouci.dntb.gov.ua/en/works/4NoQ32jl/

  Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. […] The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. […] Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. […] Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. […] Cancer of unknown primary (CUP) is a metastatic lesion with difficult identification of the primary tumor site using standard diagnostic approaches.

• #4 Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

  https://ouci.dntb.gov.ua/en/works/4NoQ32jl/

  Although the incidence of CUP is not high, this type of cancer often shows a high aggressiveness and therapy resistance and results in poor patient survival. […] CUP has always posed major challenges both in its diagnosis and management, leading to the hypothesis that it is rather a distinct entity with specific genetic and phenotypic aberrations, considering the regression or dormancy of the primary tumour; the development of early, uncommon systemic metastases; and the resistance to therapy. […] The diagnosis of CUP mainly depends on the standard evaluation comprising a thorough medical history; complete physical examination; histopathologic morphology and algorithmic immunohistochemistry assessment; and CT scan of the chest, abdomen, and pelvis. […] However, physicians and patients do not fare well with these criteria and often perform additional time-consuming evaluations to identify the primary tumour site to guide treatment decisions. […] The development of molecularly guided diagnostic strategies has emerged to complement traditional procedures but has been disappointing thus far. […] CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis.

• #5 Survival Rates for a Cancer of Unknown Primary | American Cancer Society

  https://www.cancer.org/cancer/types/cancer-unknown-primary/detection-diagnosis-staging/survival-statistics.html

  Survival rates tell you what portion of people with the same type and stage of cancer are still alive a certain amount of time (usually 5 years) after they were diagnosed. […] When all types of CUP are included, the average survival time is about 9 to 12 months after diagnosis. But this can vary widely depending on many factors, including the cancer cell type, where the cancer is found, how far the cancer has spread, a persons general health, the treatments received, and how well the cancer responds to treatment. […] Survival statistics can sometimes be useful as a general guide, but they may not accurately represent any one persons prognosis (outlook). This is because survival rates are often based on previous outcomes of large numbers of people who had the disease, but they cant predict what will happen in any particular persons case. Your doctor is familiar with your situation; ask how these numbers may apply to you.

• #6 Metastatic Cancer With Unknown Primary Site: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/280505-overview

  Median survival in patients with cancer of unknown primary origin ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%. In those with multiple organ involvement and poor performance status, the median survival is only 3-4 months; the 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Factors associated with a poor prognosis include the following: […] Approximately 15-20% of patients with CUP have a favorable prognosis. In these cases, treatment corresponds to that of the equivalent known primary tumor. Favorable-risk CUPs are as follows: Single metastatic deposit or oligometastatic disease amenable to local ablative treatment; In women, isolated axillary nodal metastases; In women, peritoneal adenocarcinomatosis of a serous papillary histologic type; In men, blastic bone metastases or IHC/serum prostate-specific antigen (PSA) expression; Squamous cell carcinoma involving non-supraclavicular cervical lymph nodes (head-and-neck); Adenocarcinoma with a colorectal immunohistochemical (CK7-negative, CK20-positive, CDX2-positive) or molecular profile; Carcinoma with a renal-cell histologic and immunohistochemical profile.

• #7 Survival for cancer of unknown primary (CUP) | Cancer Research UK

  https://www.cancerresearchuk.org/about-cancer/cancer-unknown-primary-cup/survival

  Survival for cancer of unknown primary (CUP) depends on many factors. No one can tell you exactly how long you will live. […] Your doctor can give you more information about your own outlook (prognosis). […] Generally for all those with CUP: almost 25 out of 100 people (almost 25%) survive their cancer for 1 year or more; around 15 out of 100 people (around 15%) survive their cancer for 5 years or more. […] These 1 and 5 year statistics are for net survival. Net survival estimates the number of people who survive their cancer rather than calculating the number of people diagnosed with cancer who are still alive. […] Your outlook depends on several factors. It is best to talk to your own specialist. They should be able to give you a broad idea about your outlook. Even then, it is very difficult for your specialist to be accurate. […] There are some factors that might mean that people with cancer of unknown primary (CUP) have a better outlook. […] Other factors that affect your outlook include how well your cancer responds to the treatment, how widespread your cancer is, and your general health and level of fitness.

• #8 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://www.mdpi.com/resolver?pii=cancers13030451

  Patients with cancer of unknown primary site suffer the burden of an uncertain disease, which is characterized by the impossibility to identify the tissue where the tumor has originated. […] Therefore, patients with cancer of unknown primary have reduced therapeutic opportunities and poor prognosis. […] Most CUP patients (~80%) do not respond to chemotherapy and have a median overall survival of 6 to 10 months, but a fraction of all cases, about 20%, are characterized by a favorable prognosis due to their potential chemosensitivity and long-term disease control. […] The prognostic model developed by the French CUP Group (GEFCAPI) further classify unfavorable CUPs on the basis of two parameters: the performance status and the pre-treatment serum lactate dehydrogenase levels (LDH). […] The subgroup characterized by a good performance status (0–1) and normal LDH levels when treated with a platinum-based doublet chemotherapy regimen (in combination with gemcitabine or taxane) experiences a median survival of 12 months.

• #9

  https://journals.lww.com/md-journal/fulltext/2021/12030/successful_treatment_using_immunotherapy_in.67.aspx

  Cancer of unknown primary (CUP) means that the primary focus cannot be found after preliminary clinical evaluation. It accounts for 2.3% to 5% of newly diagnosed cancer cases. Due to the lack of standard treatment, CUP is usually associated with poor prognosis and is the third to fourth most common cause of cancer-related deaths. […] There is no recommended standard treatment for most CUPs, which leads to their poor prognoses. By performing NGS for patients and targeting immune-related positive predictors, immunotherapy combined with chemotherapy may prolong the overall survival of patients. This case report suggests that immunotherapy combined with chemotherapy is feasible and effective in patients with CUP. […] According to SEOM clinical guidelines, SCC only accounts for 5% of CUP patients, and patients were divided into favorable and unfavorable groups. Patients in the favorable group can be treated similarly to patients with equivalent known primary focus and have a better prognosis. On the contrary, the unfavorable subgroups account for 80% of cases and have the characteristics of visceral disease, high tumor burden, and short survival time.

• #10 Prognosis and survival for cancer of unknown primary | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/cancer-of-unknown-primary/prognosis-and-survival

  A prognosis is the doctors best estimate of how cancer will affect someone and how it will respond to treatment. Survival is the percentage of people with a disease who are alive at some point in time after their diagnosis. Prognosis and survival depend on many factors. […] The following are prognostic and predictive factors for cancer of unknown primary (CUP). […] Favourable-risk CUPs have a better prognosis. Poor-risk CUPs have a poorer prognosis. […] A person diagnosed with CUP who has a good performance status has a better prognosis than someone who has a poor performance status. […] People diagnosed with CUP who have normal lactate dehydrogenase (LDH) levels in their blood have a better prognosis than people with high levels of LDH. […] People with CUP who were assigned female at birth tend to have a better prognosis than people with CUP who were assigned male at birth. […] People younger than 65 years of age have a better prognosis.

• #11 Cancer of Unknown Primary Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/unknown-primary/hp/unknown-primary-treatment-pdq

  The prognosis for patients with CUP is poor. Approximately 30% of patients are alive at 1 year. CUP is represented by a heterogeneous group of diseases, all of which have presented with metastasis as the primary manifestation. Although most diseases are relatively refractory to cytotoxic treatments, molecular and genetic diagnostics can identify targeted therapies that may result in a much better prognosis. In each instance, the clinician must consider distinct clinical and pathological details when selecting appropriate, and potentially curative, management. […] Survival is worse for patients with any of the following characteristics: Adenocarcinoma or undifferentiated carcinoma histology, Extranodal presentation, Older age, Hepatic or adrenal involvement, Poor performance status, Elevated serum lactate dehydrogenase (LDH).

• #12 Cancer of Unknown Primary Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/unknown-primary/hp/unknown-primary-treatment-pdq

  Patients who present with a normal LDH and an Eastern Cooperative Oncology Group performance status of 0 or 1 have a much better prognosis than those with a high LDH or worse performance status. […] Most patients with newly diagnosed cancer of unknown primary (CUP) are considered to have an unfavorable prognosis. […] Cytotoxic chemotherapy can be a palliative therapy, but the choice of drugs has been based on a few small clinical studies, with no randomized trials establishing their benefit over best supportive care.

• #13 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7866161/

  The prognostic model developed by the French CUP Group (GEFCAPI) further classify unfavorable CUPs on the basis of two parameters: the performance status and the pre-treatment serum lactate dehydrogenase levels (LDH). […] The subgroup characterized by a good performance status (0-1) and normal LDH levels when treated with a platinum-based doublet chemotherapy regimen (in combination with gemcitabine or taxane) experiences a median survival of 12 months. […] The subgroup presenting a performance status 2 and elevated LDH levels is characterized by a dismal median survival of four months; for these patients, the situation is critical and because the primary goal for them is to improve their quality of life, treatment mainly consists of palliative care, symptom control, or low-toxicity chemotherapy regimens.

• #14 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://www.mdpi.com/resolver?pii=cancers13030451

  The subgroup presenting a performance status ≥2 and elevated LDH levels is characterized by a dismal median survival of four months; for these patients, the situation is critical and because the primary goal for them is to improve their quality of life, treatment mainly consists of palliative care, symptom control, or low-toxicity chemotherapy regimens. […] A meta-analysis evaluated the impact on CUP survival of platinum, taxane, or new-generation compounds (gemcitabine, vinca alkaloids or irinotecan) regimens, in monotherapy or in combination; of note, no chemotherapy agent was found to effectively prolong CUP patient survival. […] An indication of a site of origin in these patients, or an approach based on personalized medicine, may assist the physicians in the selection of the best treatment options, potentially improving CUPs prognosis and survival.

• #15 Defining prognosis in Cancer of Unknown Primary (CUP) | Oncopedia

  https://www.oncopedia.wiki/contributions/defining-prognosis-in-cancer-of-unknown-primary

  A Canadian open registry study of patient samples collected from 2000-2005 looked at survival outcome differences based on treatments using knowledge of the primary tumour site for patients with CUP and known primary site. Patients with a known primary had considerably better outcomes (median overall survival of 11.9 months) than those with an unknown site (1.9 months). […] As Fizazi notes, the problem with prognostic factors is that they’re not super helpful. […] The primary end point of 1-year overall survival was 9.8 months in the site-specific guided therapy arm and 12.5 months in the empirical arm, a difference that was not statistically significant. Ultimately, molecular testing did not enable patients to do better as compared to just starting on standard chemotherapy. […] Ultimately it is still unclear whether molecular profiling increases the accuracy of identifying the primary site, and it does not seem to drastically improve targeted treatment decisions.

• #16 Accurate identification of primary site in tumors of unknown origin (TUO) using DNA methylation | npj Precision Oncology

  https://www.nature.com/articles/s41698-025-00805-z

  Tumor of unknown origin (TUO) is a heterogeneous group of tumors characterized by the presence of metastatic disease without an identified site of primary tumor at presentation. They account for 36% of all metastatic cancer diagnoses and represent a significant unmet clinical burden. Patients with TUO typically have a poor prognosis, with a median survival time of less than one year. Definitive diagnosis of the primary site allows for more specific therapy and is associated with improved overall survival and disease-free survival. […] The classifier presented here offers substantial advantages over previous models. Namely, it provides similar specificity, sensitivity, and accuracy (generally all 0.85 across studies) while including additional useful features. […] The presented TUO classifier exhibited high classifier support in most validation samples, with 85% having classifier scores 0.9. In addition, only 0.2% of validation samples received an equally high score and an incorrect classification, indicating a very low occurrence of highly confident yet incorrect classifications.

• #17 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7866161/

  An indication of a site of origin in these patients, or an approach based on personalized medicine, may assist the physicians in the selection of the best treatment options, potentially improving CUPs prognosis and survival. […] It has been recently hypothesized that primary-oriented specific treatments would significantly improve CUP patients prognoses. […] However, randomized, prospective clinical trials have failed in demonstrating a clinical benefit for CUP patients from the use of molecularly directed therapies; therefore, current international and national guidelines do not recommend a routine use of tissue-of-origin predictors in CUP management, only a case-by-case evaluation. […] Despite the remarkable progress in the pathological assessment of metastatic tumors observed in the last decade, cancers of unknown primary remain an enigma which current diagnostic procedures cannot easily solve.

• #18 Cancer of Unknown Primary: Challenges and Progress in Clinical Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7866161/

  Overall, there is a rising consensus in recommending molecular profiling, either based on coding or non-coding transcripts or epigenetic modifications, for tissue-of-origin prediction. […] Such biomarkers could potentially endorse the access to more specific therapies and improve patients life expectancy.

• #19 Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning | Nature Medicine

  https://www.nature.com/articles/s41591-024-02915-w

  Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. […] Despite the employment of a variety of combined chemotherapies, the majority of patients have a very poor prognosis, with only 20% achieving a median survival of 10 months. […] Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P=0.006). […] Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted. […] Accurate prediction of primary sites by pathologists and oncologists is a top priority for effective and personalized treatment. […] Among patients newly diagnosed with CUP, a substantial portion present with pleural or peritoneal metastasis.

• #20 Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning | Nature Medicine

  https://www.nature.com/articles/s41591-024-02915-w

  It has been reported that 720% of patients with respiratory or gastrointestinal tumors are diagnosed with pleural and peritoneal effusions, many of whom have synchronous peritoneal or pleural carcinomatosis. […] Previous studies revealed that serous effusions may develop without any history of cancer and present as the initial manifestation of cancer in 10% of patients with malignant effusions. […] Our model achieved robust performance across five testing sets and outstanding accuracy versus a group of four pathologists. […] For oncologists, under certain circumstances this offers valuable information regarding the selection of therapy. […] For those 310 patients who underwent palliative chemotherapy or targeted drugs, in the concordant group 75 achieved clinical partial response (PR) by imaging evaluation, 91 achieved stable disease (SD) and 48 demonstrated progressive disease (PD). […] Kaplan-Meier survival analysis showed that the concordant group had significantly better overall survival compared with the discordant group (median overall survival 27 months (95% CI 25-34) versus 17 months (95% CI 15-23); log-rank test, P=0.006).

• #21 Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial | Journal for ImmunoTherapy of Cancer

  https://jitc.bmj.com/content/10/5/e004822

  Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. […] Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile. […] This is the first phase 2 study of pembrolizumab in patients with carcinoma of unknown primary. Non-progression rate at 27 weeks (primary endpoint) was 28%. Objective response was seen in 20%, disease control in 44% of evaluable patients and 28% were progression free at 27 weeks. […] Pembrolizumab has encouraging clinical activity with an acceptable safety profile in patients with previously treated CUP. […] CUP is a life-threatening malignancy with limited treatment options. […] In this study, pembrolizumab demonstrated an NPR-27 and ORR of 28% and 20%, respectively, in treatment refractory CUP with a safety profile consistent with prior reports.

• #22 Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial | Journal for ImmunoTherapy of Cancer

  https://jitc.bmj.com/content/10/5/e004822

  Although our exploratory biomarker analyses are limited by size and are hypothesis generating, they lend some important insights. Both PD-L1 and TIL was associated with response. […] In conclusion, pembrolizumab was well-tolerated and had encouraging (although somewhat limited) efficacy as a single agent in patients with CUP refractory to prior systemic therapy; though patient selection for PD-L1 expression and TILs may enrich for patients more likely to derive clinical benefit.

• #23

  https://journals.lww.com/md-journal/fulltext/2021/12030/successful_treatment_using_immunotherapy_in.67.aspx

  The PS score of our patient was 1, her baseline LDH was elevated, the abdominal lesion was large and grew fast, and she belonged to the unfavorable group. TP53 and KRAS mutations all suggest a poor prognosis. Therefore, this patient is unlikely to benefit from chemotherapy alone. […] After chemotherapy and immunotherapy, the patient’s lesions were significantly reduced, her general state improved, and her PS score was 0. The patient benefited significantly.

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