Metastatic adenocarcinoma of unknown primary site. A randomized study of two combination chemotherapy regimens

doi:10.1016/0277-5379(87)90443-3

European Journal of Cancer and Clinical Oncology

Volume 23, Issue 11, November 1987, Pages 1645-1648

European Journal of ...

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Abstract

Of 101 patients with symptomatic adenocarcinoma or undifferentiated carcinoma of unknown primary site, 95 were evaluable for the effects of two randomized chemotherapy regimens. Forty-eight patients received combination doxorubicin and mitomycin C (DM) and 47 received combination cisplatin, vinblastine and bleomycin (PB). Response rates were not significantly different between the two treatment groups, 42% for DM and 32% for PVB, with an overall response rate of 37.1%. Survival differences for DM and PVB treated groups were not significantly different, with 18 weeks and 25 weeks median survivals respectively. Toxicities were unequal for the two treatment groups with increased haematological toxicity for DM and greater gastrointestinal toxicity for PVB.

The authors conclude both therapies were of limited efficacy in the treatment of ACUP patients and emphasize that only symptomatic patients should be considered for such therapies.

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Cited by (65)

Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?
2021, Cancer Treatment Reviews
Citation Excerpt :
They should be selected according to local expertise and facilities and considering toxicity profiles and patient comorbidities. Table 1 presents all existing randomized trials specifically studying CUP patients, with the regimens and their respective median overall survival and response rates when available [11,74–89]. As described, the prognostic classification (based on performance status and LDH levels) separates a favourable prognosis subgroup (median survival of 12 months) from a poor prognosis subgroup (median survival of 4 months); for the latter, best supportive care should also be considered upfront in the management algorithm [3,13].
The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group.
CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient’s outcomes. In that regard, CUP patients’ outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis.
The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the “true” CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group.
Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials.
Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes.
Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis
2009, Cancer Treatment Reviews
Citation Excerpt :
Of those, upon further detailed screening, we found 10 articles reporting on eligible clinical trials. The 10 trials19–28 were published from 1980 to January 2009 (Table 1). We found no trials that compared systemic treatment to best supportive care.
To synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP).
PubMed and the Cochrane Library Central Registry of Controlled Trials.
We retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals.
Ten articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane).
No type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing.
A Clinical Review of the Investigation and Management of Carcinoma of Unknown Primary in a Single Cancer Network
2007, Clinical Oncology
Citation Excerpt :
This survival is similar to the median survival in the current cohort of CUP patients (chemotherapy: 13.0 months; 95% CI 7.4–18.6). Four published randomised controlled studies were identified during the period 1987–2003 [34–37]. One study showed a non-statistically significant difference in survival favouring mitomycin C, epirubicin and cisplatin over mitomycin C alone [37] (9.4 months vs 5.4 months; P = 0.05).
Carcinoma of unknown primary (CUP) is a common encounter in oncological practice and represents 2.0–6.0% of all invasive malignancies. Evidence to support particular therapeutic strategies in this patient population is scarce, and empirical therapies are frequently derived from research on patients where the primary tumour site is known.
This retrospective study reviewed the management of all patients recorded to have a diagnosis of CUP in a single cancer centre over a period of 12 months. Health records were reviewed documenting the CUP subtype, the investigations carried out both in the referring cancer unit and subsequently at the cancer centre and the recommended treatment (type and regimen), together with survival. The outcomes were examined in respect to a number of prognostic factors. Statistical tests were considered significant at P < 0.05.
One hundred and sixty-six patients were recorded to have a diagnosis of CUP, representing 3.7% of all referrals to the cancer centre. The median age of patients was 68 years (range 32–94 years), and 52.0% were women. The three most common CUP subgroups were CUP-liver/multiple sites (25.0%), CUP-bone (21.0%) and CUP-brain (16.0%). The remaining subgroups occurred at frequencies of less than 10% each. Histological confirmation was only obtained in 55.0% of cases. Even within a single subtype, 41 patients with CUP-liver/multiple sites underwent a total of 19 different investigations before any treatment being given. Forty-seven (28.0%) patients received radiotherapy, 30 (18.0%) received chemotherapy and 58 (35.0%) received supportive care alone. Nine different 5-fluorouracil-containing regimens were used in 11 patients treated with chemotherapy for CUP-liver. The overall median survival for all patients was 4.0 months. Survival was better in patients with a good performance status (0–1) and absent liver metastases (median survival 15.0 months; 95% confidence interval 8.0–22.1) and those who received chemotherapy (median survival 13.0 months; 95% confidence interval 7.4–18.6). Multivariate analysis confirmed female gender (P = 0.006), a good performance status (0/1) (P < 0.0001) and absent liver metastases (P = 0.002) as favourable prognostic indicators.
The appropriate management of patients with CUP is unclear and this study revealed a high degree of variation in clinical practice. This area is in urgent need of clinical research to ensure that the treatment of CUP is evidence based. Until such time, clinical recommendations are suggested for the investigation and treatment of such patients. Therapeutic progress will be facilitated by designating a clinical lead for CUP in each clinical network.
Hepatic metastases from carcinomas of unknown primary site: Experience of the montpellier cancer center
2005, Gastroenterologie Clinique et Biologique
Hepatic metastases are often present at diagnosis of carcinoma of unknown primary site (CUP). The objective of this study was to describe the diagnostic and therapeutic strategies used.
One hundred and eighteen patients were treated at the Cancer Center of Montpellier from 1993 to 2002 for CUP initially metastatic to the liver. Initial chararcteristics, diagnostic tests, chemotherapies and outcome were retrospectively recorded.
The most frequent histological types observed were adenocarcinoma, undifferentiated, neuroendocrine and squamous-cell carcinomas. Hepatic metastases revealed the cancer in 66 patients and were isolated in 32 patients. Other metastatic sites involved lymph nodes, lung and bone. Pretreatment computed tomography scans of the chest, abdomen and pelvis evaluation were available for more than 80% of patients. Colonoscopy, gastroscopy and bronchoscopy were performed in 58, 56 and 26% of patients respectively. One hundred and seven patients had received at least a front-line of chemotherapy. Seventy-four patients had received platin salt-based chemotherapy, 67 in front-line treatment and 10 in second line. In first-line chemotherapy, overall response rates with or without platin were 19.4 and 20% respectively. One hundred and two of 111 deaths were due to disease progress and seven toxic-related deaths occurred. The median survival was 6.6 months, and 7.8 and 4.6 months in the with or without platin groups respectively (P = 0,35). The median survival for treated patients was 7 months. Multivariate analysis identified two prognostic factors: serum lactodehydrogenase level and performance status.
According to this study, pretreatment evaluations, which were very extensive in some patients, were insufficient to identify the primary site of liver metastases. Because of the poor prognostic, chemotherapy, in absence of clinically demonstrated benefit, has to be reserved for patients with better prognosis. Prospective trials are needed to determine whether use or not of cisplatin should be proposed for standard protocols.
Les métastases hépatiques sont fréquemment présentes lors d’un diagnostic de carcinome de primitif inconnu (CAPI). La prise en charge diagnostique et thérapeutique de ces malades au pronostic sombre est rapportée dans cette étude.
Cent dix-huit malades ont été traités au Centre Régional de Lutte contre le Cancer de Montpellier de 1993 à 2002 pour un CAPI avec métastases hépatiques initiales. Leurs caractéristiques, les examens préthérapeutiques réalisés, les chimiothérapies reçues et l’évolution ont été analysés de façon rétrospective.
Les types histologiques les plus fréquemment retrouvés étaient l’adénocarcinome, les carcinomes indifférenciés, endocrines et épidermoïdes. Dans 66 cas, les lésions hépatiques étaient révélatrices; et chez 32 malades, elles restaient isolées. Les autres sites retrouvés étaient les adénopathies, le poumon, et l’os. Lors du diagnostic, plus de 80 % des malades ont bénéficié d’un scanner thoracoabdominopelvien. Les coloscopies, gastroscopies et bronchoscopies ont été réalisées dans respectivement 58, 56 et 26 % des cas. Cent-sept patients ont reçu au moins une ligne de chimiothérapie. Les sels de platine ont été administrés chez 74 patients dont 67 en première ligne et 10 en seconde ligne. En première ligne, les taux de réponse objective après chimiothérapie avec et sans platine étaient respectivement de 19,4 et 20 %. Cent-deux des 111 décès sont imputables à la progression tumorale et sept aux chimiothérapies. La médiane de survie globale était de 6,6 mois, sans différence significative entre les groupes avec et sans sel de platine (7,8 et 4,6 mois P = 0,35). En analyse multifactorielle, deux variables indépendantes de mauvais pronostic sont retrouvées: l’élévation des lacto-déhydrogénases sériques et l’altération de l’état général. La survie des malades ayant reçu une chimiothérapie était de 7 mois.
Cette étude montre que des explorations parfois extensives n’ont pas permis de retrouver le site primitif des métastases hépatiques. La chimiothérapie, dont l’impact sur la survie n’est pas démontré, doit être réservée aux malades de meilleur pronostic. L’inclusion dans des essais thérapeutiques prospectifs doit être encouragée afin de déterminer la place notamment des sels de platine.
A case of unknown primary cancer with a tumor formed in the retroperitoneum: A case report
2020, Tokai Journal of Experimental and Clinical Medicine
Clinical practice of carcinoma of unknown primary
2018, Japanese Journal of Cancer and Chemotherapy

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European Journal of Cancer and Clinical Oncology

Abstract

References (18)

Undifferentiated carcinoma in young men: the atypical teratoma syndrome

Lancet

Metastatic adenocarcinomas of unknown primary site

Treatment of the patient with adenocarcinoma of unknown origin

Cancer

Adenocarcinoma of unknown primary origin: impact of chemotherapy on survival

South Med J

Cis-diammedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer

Ann Intern Med

Extragonadal germ cell malignancy: value of tumor markers in metastatic carcinoma in young males

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung

Cisplatin, vindesine and bleomycin (CVB) combination chemotherapy in advanced non small cell lung cancer

Cancer

Cited by (65)

Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?

Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis

A Clinical Review of the Investigation and Management of Carcinoma of Unknown Primary in a Single Cancer Network

Hepatic metastases from carcinomas of unknown primary site: Experience of the montpellier cancer center

A case of unknown primary cancer with a tumor formed in the retroperitoneum: A case report

Clinical practice of carcinoma of unknown primary