Molecular tumor profiling is a promising diagnostic technique to determine the tissue of origin in patients with carcinoma of unknown primary site (CUP). However, the clinical value of these ...molecular predictions is unknown. We used tumor profiling results to direct site-specific therapy for patients with CUP.
Tumor biopsy specimens from previously untreated patients with CUP were tested with a 92-gene reverse transcriptase polymerase chain reaction cancer classification assay. When a tissue of origin was predicted, patients who were treatment candidates received standard site-specific first-line therapy.
Of 289 patients enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. Sites most commonly predicted were biliary tract (18%), urothelium (11%), colorectal (10%), and non-small-cell lung (7%). Two hundred twenty-three patients were treatment candidates, and 194 patients received assay-directed site-specific treatment. In these 194 patients, the median survival time was 12.5 months (95% CI, 9.1 to 15.4 months). When the assay predicted tumor types that were clinically more responsive, the median survival was significantly improved when compared with predictions of more resistant tumors (13.4 v 7.6 months, respectively; P = .04).
In this large prospective trial, molecular tumor profiling predicted a tissue of origin in most patients with CUP. The median survival time of 12.5 months for patients who received assay-directed site-specific therapy compares favorably with previous results using empiric CUP regimens. Patients with CUP predicted to have more responsive tumor types had longer survival compared with patients with less responsive tumor types. Molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation.
PURPOSE Tracheoesophageal fistulae are rare complications of thoracic cancers and their treatments. Novel antiangiogenic agents in cancer treatment such as bevacizumab potentially impact wound ...healing and may contribute to tracheoesophageal fistula development. PATIENTS AND METHODS We conducted two independent phase II clinical trials in small-cell lung cancer and non-small-cell lung cancer using bevacizumab in combination with chemotherapy and radiation. Both trials were intended to assess preliminary efficacy and safety outcomes. Results For the limited-stage small-cell lung cancer trial, 29 patients were enrolled beginning April 2006, and closed early due to toxicity in March 2007 (14-month median follow-up). The locally advanced, non-small-cell lung cancer trial opened with enrollment limited to five patients in February 2007, and closed early due to safety in December 2007. In each trial, we observed tracheoesophageal fistulae development and related morbidity and mortality, prompting early trial closures, US Food and Drug Administration warnings, and a change in bevacizumab labeling. CONCLUSION The current data from the final reports from these two trials suggest bevacizumab and chemoradiotherapy are associated with a relatively high incidence of tracheoesophageal fistulae formation in both small-cell lung cancer and non-small-cell lung cancer settings. Strategies to safely incorporate novel antiangiogenic agents into combined-modality therapy in lung cancer are needed.
Molecular tumor profiling (MTP) is a potentially powerful diagnostic tool for identifying the tissue of origin in patients with cancer of unknown primary (CUP). However, validation of the accuracy ...and clinical value of MTP has been difficult because the anatomic primary site in most patients is never identified.
From March 2008 through January 2010, clinicopathologic data from 171 CUP patients who had MTP (CancerTYPE ID; bioTheranostics, Inc, San Diego, CA) performed on archived material were evaluated. The accuracy of MTP diagnoses was evaluated by comparison with (1) latent primary tumor sites found months/years later; (2) initial single diagnoses by immunohistochemistry (IHC); and (3) additional directed IHC and/or clinicopathologic findings evaluated after MTP diagnoses.
A single MTP diagnosis was made in 144 of 149 patients with adequate tumor specimens. Eighteen of 24 patients with latent primaries discovered months to years later had correct diagnoses by MTP (75%), and these diagnoses compared favorably with IHC. Single IHC diagnoses matched MTP diagnoses in 40 of 52 patients (77%). IHC predictions of 2 or more possible primaries compared poorly with MTP diagnoses. However, additional targeted IHC and clinical/histologic evaluation supported the MTP diagnosis in 26 of 35 patients (74%). Clinical features were usually consistent with MTP diagnoses (70%).
The diagnostic accuracy of this MTP assay was supported by a high level of agreement with identified latent primaries (75%), single IHC diagnoses (77%), and additional directed IHC and/or clinical/histologic findings (74%) prompted by the MTP diagnoses. MTP complements standard pathologic evaluation in determining the tissue of origin in patients with CUP, particularly when IHC is inconclusive.
•Over the last five years, CUP research involved primarily retrospective studies.•Prospective studies and clinical trials constituted a small proportion of CUP research.•The main topics were ...diagnostics (genomics) and treatment (empiric therapy).•Ongoing trials focus on multiple tumour types and are primarily phase II single-arm trials.•Two clinical trial designs are suggested to improve the quality of CUP research.
Research on therapeutic strategies for patients with unknown primary cancer (CUP) has been underwhelming. This paper summarized and evaluated the CUP therapeutic research over the previous five years. Based on this evaluation, recommendations for clinical trial designs are made to improve the impact of CUP research on patients.
Published and ongoing research were evaluated. PubMed was searched from January 1, 2015, to November 1, 2021. The start date of 2015 was chosen to identify research published after ESMO issued new diagnostic and therapeutic guidelines. The US National Library of Medicine indexed ongoing clinical trials.
Of the 244 CUP studies indexed in PubMed, 11.9% were prospective studies, and 4.9% were clinical trials. The review protocol deemed 65 publications eligible for full-text review. Eleven studies evaluating therapeutic regimens were retained. The two prospective studies and non-randomized trials showed promising outcomes for site-specific treatments. Randomized clinical trials were less promising; however, the trials had recruitment challenges resulting in biased accrual and the inability to keep pace with advancing diagnostics and therapeutics. Most of the 35 ongoing studies were phase II single-arm trials assessing immune checkpoint inhibitors (ICI) or site-specific therapies among CUP patients with suspected favorable prognoses.
Our evaluation suggests two prospective clinical trial designs that addressed recent study design and recruitment challenges. A visionary approach uses a multi-arm, multistage randomized trial to address rapid advancements in diagnosis and therapy. A pragmatic approach utilizes a single-arm trial with historical controls to overcome comparison group and recruitment challenges.
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib ...versus erlotinib in unselected patients with advanced non-small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens.
One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted.
There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio HR, 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade ≥ 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively).
In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib.
Cancers of unknown primary (CUP) are among the most common causes of death due to cancer, are associated with a poor prognosis and have few therapeutic options available. Molecularly-guided ...site-specific treatments were explored based on the assumption that CUP are similar in their response to treatment of predicted primary tumours. Given the discordant results between these studies, a meta-analysis using a random-effects model and the inverse variance method was performed. MEDLINE and conference abstracts of American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings were searched from inception until November 2019. A trend towards improved OS was noted with site-specific versus empiric treatment for CUP (HR = 0.73; 95% confidence interval (CI) 0.52–1.02). There was significant heterogeneity across the four studies (I 2 = 79%; p = 0.002) but no significant difference was noted between the treatment effect in the two subgroups (randomised vs. non-randomised; p = 0.07). The test for overall effect for progression free survival, which had only been reported for the two randomised studies, was not statistically significant (HR = 0.93; 95% CI 0.74–1.17), with little heterogeneity between studies (I 2 = 0%; p = 0.77). The results of this meta-analysis highlight the significant heterogeneity between the prospective studies comparing molecularly tailored to empiric therapy for CUP and the need for other randomised studies including only primary tumors with available effective therapies.
•This paper is a meta-analysis of the trials evaluating site-specific treatments in CUP.•No significant survival benefit with site-specific versus empiric chemotherapy.•There was significant heterogeneity across the prospective studies.•Current evidence is insufficient to recommend site-specific therapy in CUP.•However, certain patients with CUP may still benefit from tailored treatments.
Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in ...this multicenter phase II trial.
Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib.
One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib.
Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.
To evaluate the efficacy of chemotherapy with paclitaxel, carboplatin, and etoposide in advanced adult poorly differentiated neuroendocrine carcinomas.
Patients eligible for this multicenter, phase ...II trial had metastatic poorly differentiated neuroendocrine carcinoma and had received no previous treatment. Patients with a variety of known primary sites (excepting small-cell lung cancer) and patients with unknown primary site were eligible. Patients received four courses of chemotherapy with paclitaxel, carboplatin, and etoposide, administered at 3-week intervals. After completing four courses of treatment, patients with objective response or stable disease received three courses (24 weeks) of weekly paclitaxel.
Seventy-eight patients were treated; 62% had unknown primary site. Forty-one patients (53%) had major responses (complete response rate, 15%), and five patients remain disease free from 18 to 66 months after therapy. Response rates were similar regardless of histology (small-cell v poorly differentiated carcinoma) or primary site. The median, 2-year, and 3-year survivals for the entire group were 14.5 months, 33%, and 24%, respectively. Myelosuppression was the major toxicity, as has been reported previously with this regimen.
This prospective phase II trial provides additional evidence that this family of relatively uncommon carcinomas is initially chemosensitive, with a high overall response rate to combination chemotherapy and a minority of complete responses. The three-drug regimen evaluated in this trial is moderately toxic, and has no obvious efficacy advantages when compared with standard platinum/etoposide regimens. Treatment for advanced poorly differentiated neuroendocrine carcinoma should parallel treatments used for small-cell lung cancer.
Carcinoma of unknown primary site (CUP) is diagnosed in approximately 3 % of patients with advanced cancer, and most patients have traditionally been treated with empiric chemotherapy. As treatments ...improve and become more specific for individual solid tumor types, therapy with a single empiric combination chemotherapy regimen becomes increasingly inadequate. Gene expression profiling (GEP) is a new diagnostic method that allows prediction of the site of tumor origin based on gene expression patterns retained from the normal tissues of origin. In blinded studies in tumors of known origin, GEP assays correctly identified the site of origin in 85 % of cases and compares favorably with immunohistochemical (IHC) staining. In patients with CUP, GEP is able to predict a site of origin in >95 % of patients versus 35–55 % for IHC staining. Although confirmation of the accuracy of these predictions is difficult, the diagnoses made by IHC staining and GEP are identical in 77 % of cases when IHC staining predicts a single primary site. GEP diagnoses appear to be most useful when IHC staining is inconclusive. Site-specific treatment of CUP patients based on GEP and/or IHC predictions appears to improve overall outcomes; patients predicted to have treatment-sensitive tumor types derived the most benefit. GEP adds to the diagnostic evaluation of patients with CUP and should be included when IHC staining is unable to predict a single site of origin. Site-specific treatment, based on tissue of origin diagnosis, should replace empiric chemotherapy in patients with CUP.
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