Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset

BackgroundWorldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible.Patients and methodsBetween January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified.ResultsOf the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5–10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7–44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0–16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3–3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9–12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4–30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system.ConclusionOur simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.     

Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: should we operate?

The significance of residual lung metastasis from malignant gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy is unknown. We currently do not advocate resection of these masses. Here, we investigate the outcome of these patients. Patients with residual lung abnormalities after the completion of treatment for GTN were compared to those who had a complete radiological resolution of the disease. None of the residual masses post-treatment were surgically removed. In all, 76 patients were identified. Overall 53 (70%) patients had no radiological abnormality on CXR or CT after completion of treatment. Eight (11%) patients had residual disease on CXR alone 15 patients had residual disease on CT (19%). During follow-up, two patients (2.6%) relapsed. One of these had had a complete radiological response post-treatment whereas the other had residual disease on CT. Patients with residual lung lesions after completing treatment for GTN do not appear to have an increased chance of relapse compared to those with no residual abnormality. We continue to recommend that these patients do not require pulmonary surgery for these lesions.     

Classification systems in Gestational trophoblastic neoplasia - Sentiment or evidenced based?

The classification system for Gestational trophoblastic neoplasia (GTN) has proved a controversial topic for over 100 years. Numerous systems simultaneously existed in different countries, with three main rival classifications gaining popularity, namely histological, anatomical and clinical prognostic systems.Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide consensus on the optimal classification system, largely due to a lack of high quality data proving the merit of one system over another. Remarkably, a validated, prospectively tested classification system is yet to be conducted.Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO classification system, and its ability to identify patients most likely to develop primary chemotherapy resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6.This review aims to examine the historical basis of the GTN classification systems and critically appraise the evidence on which they were based. This culminates in a critique of the current FIGO/WHO prognostic system and discussion surrounding clinical preference versus evidence based practice.     

Hepatic arteriogram for gestational trophoblastic tumor: is it useful?

The presence of liver metastasis will be staged as IV in the FIGO 1992 Gestational Trophoblastic Tumor (GTT) staging. This study was to determine the role of hepatic arteriogram (HAG) in the management of GTT. It is a retrospective analysis of 309 patients treated from 1981 to 2001. Patients were restaged according to the FIGO 1992 classification with or without taking into account the HAG result. Outcome measures including mortality, drug resistance and recurrence of disease, as well as treatment with and without the HAG result were compared. Eighty-one (26.2 percent) patients had HAG and 11 (3.6 percent) also had ultrasound (USG) features of liver metastasis. Interval between diagnosis and treatment were significantly different between USG and HAG positive groups (Mann-Whitney U test, P < 0.05). Seventeen (5.5 percent) of the 309 patients died of the disease and 7 (41.2 percent) of them had liver metastasis. Three (27.3 percent) of the 11 patients who had USG features of liver metastasis died of the disease; mortality is significantly higher than those without USG features of metastasis (Chi-square test, P < 0.05). Patients classified as medium to high risk with or without taking HAG as a feature of liver metastasis were associated with higher mortality and recurrent rate (Chi-square test, P < 0.05). On the other hand, the chance of drug resistance was higher in the medium to high risk group after reclassifying all HAG positive patients as negative for liver metastasis (Chi-square test, P < 0.05). HAG evidence of liver metastasis did not correlate with patient mortality. HAG was not an appropriate investigation in the management of GTT.     

Can we conquer cancer in the twenty-first century?

The twentieth century recorded the greatest advance in the control of human disease. From the beginning of recorded time, the human life-span changed little until the twentieth century. In the USA, it increased from 47.3 years in 1900 to 76.4 years in 2000. The answer to the question of "Can we cure cancer in the twenty-first century?" requires an appreciation of the contemporary nature of our knowledge. At the beginning of the twentieth century, major problems were nutrition and infection. By 1950, the major causes of mortality and morbidity were still infectious diseases, such as syphilis, tuberculosis, poliomyelitis, and influenza. The 1950s and 1960s were the golden age of control of infectious diseases, while cancer, because of the aging of the population and the strong association between cancer and age, has become the major healthcare problem of the twenty-first century. Until 1960, no one had proposed or demonstrated that a systemic or metastatic form of cancer could be cured. In only 35-40 years not only have techniques for the early detection, prevention, and surgical and radiation therapy treatments improved, but at least 15-20% of patients with systemic/metastatic cancers can be cured with our current primitive systemic treatments. Prior to 1943, there was no chemotherapy. Prior to 1948, no one had described complete regression of a systemic cancer. There were no multi-institution, randomized clinical trials prior to 1949. Additionally, combination chemotherapy, new drugs, bone marrow transplantation, broad-spectrum antibiotics to control infections, and platelets to control hemorrhage have been added in the past 50 years. The pace of progress extrapolates to a prediction of cancer control in the twenty-first century. The human genome has been sequenced, and it will be possible to identify expression profiles not only for malignant cells but for their normal counterparts. It is certain that interventions specific for control of the malignant transformation will be identified. An example of gene-directed therapy is in acute promyelocytic leukemia where trans-retinoic acid is effective and contributes to cure. The signal transduction inhibitors, small molecules bioavailable orally and specific for interfering with signals resulting from ligand-receptor interactions, are a dramatic advance. Because cancer is a genetic disorder, the expanding field of genomics will certainly accelerate our progress toward the control of cancer. Finally, the twenty-first century will be an era of enhanced communication. The computer has given us the internet. Our communication in cyberspace is not only universal but instantaneous. Increases in the speed at which knowledge can be exchanged and the enormous capacity for storing new knowledge in cyberspace ensure that the pace of progress that we saw in the twentieth century will accelerate in the twenty-first. To address the question in the title of this paper, I believe that it is not a question of whether, but only of when.     

The management and outcome of women with post-hydatidiform mole ‘low-risk' gestational trophoblastic neoplasia,but hCG levels in excess of 100?000?IU?l?1

Background:

Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l⁻¹ can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group.

Methods:

Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l⁻¹ and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded.

Results:

Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l⁻¹ and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%.

Conclusion:

Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l⁻¹ can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l⁻¹ should receive multi-agent chemotherapy from the outset.     

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.     

HDAC inhibitor-based therapies: Can we interpret the code?

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. One of the most promising approaches towards drugs that modulate epigenetic processes has been seen in the development of inhibitors of histone deacetylases (HDACs). HDACs regulate the acetylation of histones in nucleosomes, which mediates changes in chromatin conformation, leading to regulation of gene expression. HDACs also regulate the acetylation status of a variety of other non-histone substrates, including key tumour suppressor proteins and oncogenes. Histone deacetylase inhibitors (HDIs) are potent anti-proliferative agents which modulate acetylation by targeting histone deacetylases. Interest is increasing in HDI-based therapies and so far, two HDIs, vorinostat (SAHA) and romidepsin (FK228), have been approved for treating cutaneous T-cell lymphoma (CTCL). Others are undergoing clinical trials. Treatment with HDIs prompts tumour cells to undergo apoptosis, and cell-based studies have shown a number of other outcomes to result from HDI treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. However, our understanding of the key pathways through which HDAC inhibitors affect tumour cell growth remains incomplete, which has hampered progress in identifying malignancies other than CTCL which are likely to respond to HDI treatment.     

Can Paneth cell metaplasia in cecum indicate the presence of colorectal epithelial neoplasia?

The main purpose of the present study was to investigate the relationship between the incidence of Paneth cells in cecal mucosa and the incidence of colorectal epithelial neoplasias. Using endoscopic biopsy specimens, obtained from cecum of 375 subjects in cases of total colonoscopy, we examined the incidence of Paneth cells in the cecal mucosa. In the present study, Paneth cells were present in the human cecal mucosa (47.7%, 179/375 subjects) regardless of age. Paneth cells were found more frequently in the subjects with colorectal epithelial neoplasia (57.3%, 90/157 subjects) than in the subjects without colorectal epithelial neoplasia (40.8%, 89/218 subjects) (p<0.01, chi(2) test). Our results suggest that the incidence of Paneth cells in cecal mucosa indicate some changes in the environment with tumorigenesis of the colorectal region according to the function of Paneth cells, proposed by other investigators.     

Can surgeons improve survival in stage IV melanoma?

Successful systemic management of stage IV melanoma continues to be elusive because of the paucity of effective therapies. This has fueled the continued interest in surgical resection. Several single-institution studies and a current, large, multi-institutional phase III trial have demonstrated a survival benefit for patients who underwent surgical resection for melanoma metastases. Incorporating these results into new approaches using multimodality treatment may enhance survival in patients with stage IV melanoma.