Curing metastatic cancer: lessons from testicular germ-cell tumours

Most metastatic cancers are fatal. More than 80% of patients with metastatic testicular germ-cell tumours (TGCTs), however, can be cured using cisplatin-based combination chemotherapy. Why are TGCTs more sensitive to chemotherapeutics than most other tumour types? Answers to this question could lead to new treatments for metastatic cancers.     

Improved survival of patients with metastatic breast cancer receiving combination chemotherapy

Groups of patients with newly diagnosed metastatic breast cancer who were consecutively registered into a breast cancer clinic beginning January 1956 (210 patients), January 1966 (210 patients), and January 1975 (251 patients), were analyzed to determine the impact on survival of the various treatment modalities utilized in each decade. Comparisons of survival were made among subgroups of patients with similar prognostic features. Except for patients with very poor performance status, all subgroups showed a significantly improved survival in the 1970s compared with the earlier decades. Combination chemotherapy was considered to be the major factor in the survival improvement.     

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors

BackgroundTo report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.Patients and methodsWe conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS.ResultsWith a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001.ConclusionThe MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort.     

Improved survival for patients with de novo metastatic prostate cancer in the last 20 years

IntroductionDuring recent years, several new life-prolonging therapeutic options have been introduced for patients with metastatic prostate cancer (mPCa). The aim of the present study was to evaluate the changes in the survival of patients diagnosed with mPCa prior to and in the early period of the implementation of these new agents.Patients and methodsThe study population consisted of 207 men diagnosed in 1997 and 316 men diagnosed in the period 2007–2013 with de novo mPCa and managed with initial endocrine therapy. Men were followed for overall survival and PCa-specific survival.ResultsAt the time of diagnosis, men diagnosed in the period 2007–2013 had less co-morbidity, lower prostrate-specific antigen levels and lower clinical tumour categories than men diagnosed in 1997. A significantly higher proportion of men diagnosed in 1997 were managed with surgical castration (57% versus 9%). Only one patient diagnosed in 1997 received second-line therapy compared with 81 men (26%) diagnosed in the period 2007–2013. The median overall survival was significantly longer for men diagnosed between 2007 and 2013 compared with men diagnosed in 1997 (39.4 months versus 24.2 months, p < 0.0001). Likewise, the cumulative incidence of PCa-specific death was higher among men diagnosed in 1997 compared with men diagnosed between 2007 and 2013, with 5-year cumulative incidences of 72% and 47%, respectively (p < 0.0001).ConclusionSurvival in men diagnosed with metastatic PCa has improved significantly over time. The improved survival can in part be explained by lead-time bias, but also by the introduction of new life-prolonging treatments.     

Improved survival after pulmonary resection of metastatic colorectal carcinoma

While hepatic resection of metastatic colorectal carcinoma is accepted as effective in selected patients, resection of metastases to other solid organs has not gained wide acceptance. We retrospectively reviewed the records of 49 patients who had resection of isolated pulmonary (18 patients) and hepatic (31 patients) metastases from the large bowel, comparing disease-free survival and overall survival. Tumor parameters analyzed included Dukes' stage, deoxyribonucleic acid (DNA) flow cytometry, and number of metastases. Dukes' B and diploid tumors had longer disease-free survival and overall survival than did Dukes' C and aneuploid tumors, though the difference was not significant. Patients with a single lung metastasis had a significantly longer disease-free survival (P = .02) than did patients with multiple metastases. Mean and median survival were longer in patients with lung metastases. Five-year actuarial survival was 19% for patients with liver metastases and 47% for patients with lung metastases. Resection of isolated pulmonary metastases from the large intestine results in survival comparable to or better than resection of hepatic metastases. An aggressive surgical approach is warranted in patients with isolated resectable pulmonary metastases of colorectal carcinoma.     

Ten-year survival in patients with metastatic prostate cancer

The objective of this analysis is to identify baseline covariates that predict which patients will be long-term survivors with metastatic prostate cancer. We analyzed data from Southwest Oncology Group (SWOG) S8894, a clinical trial in men with newly diagnosed metastatic prostate cancer, to evaluate pretreatment characteristics associated with 10-year survival. There were 1286 eligible patients randomized to this study. Of these, 794 have been followed for > or = 10.5 years and are included in the analyses. Proportional odds models were used to predict 3 survival categories (survival for < 5 years, 5 up to 10 years, and > or = 10 years). Baseline patient and disease characteristics investigated were protocol treatment (flutamide vs. placebo), severity of disease, SWOG performance status (PS), bone pain, Gleason score, race, age, and prostate-specific antigen (PSA) level at study entry. Of the 794 evaluable patients, 77% lived < 5 years, 16% lived 5 up to 10 years, and 7% lived > or = 10 years. Factors predicting a statistical significant association with longer survival (P < 0.05) included minimal disease, better PS, no bone pain, lower Gleason score, and lower PSA level. All but PS were also significant in multivariate analyses. However, only 13% of patients (5 of 38) who lived > or = 10 years were correctly predicted in their survival category based on the model, whereas 98% (405 of 414) who died within the first 5 years were correctly predicted. Although statistically significant baseline characteristics were identified in this clinical trial, they did not accurately predict the survival interval to which a patient belonged.     

Extending survival with chemotherapy in metastatic breast cancer

Metastatic breast cancer (MBC) remains essentially incurable, and goals of therapy include the palliation of symptoms, delay of disease progression, and prolongation of overall survival time without negatively impacting quality of life. Anthracycline and taxane-based therapies have traditionally shown the highest degree of activity in MBC. Though numerous randomized clinical trials have shown improvements in overall response rates, few have found clear survival benefits. In recent years, however, there has been a small but growing series of clinical trials demonstrating modest, but meaningful survival advantages in metastatic disease. A common feature in many of these trials has been the use of a taxane, and more recently, a taxane combined with an antimetabolite. In addition, the development of targeted biologic agents active against MBC, such as trastuzumab and bevacizumab, has demonstrated great potential for enhancing the effects of chemotherapy and producing meaningful survival improvements. The role of the taxanes, antimetabolites, and biologics in extending survival in MBC is discussed.     

Gonadal dysfunction in patients treated for metastatic germ-cell tumors

The effects of chemotherapy on endocrine function were assessed in 22 previously treated patients with germ-cell tumors and compared with the endocrine function of six previously untreated patients. Baseline and stimulated serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, thyroid-stimulating hormone (TSH), prolactin, and thyroxine (T4) were obtained. Baseline LH levels were elevated in both groups of patients, whereas basal FSH levels were significantly elevated only in treated patients (P less than .001). Following gonadotropin-releasing hormone (GnRH), levels of LH (P = .051) and FSH (P = .003) were greater in treated patients than in untreated control patients. No abnormalities of thyroid function or prolactin responsiveness were observed. Patients younger than 25 years of age at the time of treatment had lower serum levels of LH and FSH following chemotherapy than patients older than 25. Evidence for partial recovery of gonadal function was present with patients treated more than 18 months before study having lower levels of LH and FSH than those patients studied less than 18 months after treatment. These data demonstrate that frequent gonadal dysfunction exists in untreated patients with germ-cell tumors and that chemotherapy induces additional injury to both Leydig cells and the germinal epithelium. Further studies with long-term follow-up are necessary to define the pattern of gonadal recovery and to assess the potential sequelae of endogenous gonadotropin hypersecretion.     

Laparoscopic retroperitoneal lymph-node dissection in metastatic nonseminomatous germ-cell tumors

ObjectivesTo support laparoscopic post-chemotherapy retroperitoneal lymph-node dissection (L-PC-RPLND) as a potential new standard, we report on a large dataset of patients systematically undergoing L-PC-RPLND.Patients and methodsPatients with unilateral residual mass (≥1 cm), normalized markers, limited encasement (<30%) of gross retroperitoneal vessels underwent unilateral L-PC-RPLND with no adjuvant chemotherapy. Surgical performances, histology, hospital stay, complications within 30 days and follow-up visits were recorded. Multivariable linear and logistic regression models were used.ResultsBetween February 2011 and January 2021, 151 consecutive patients underwent L-PC-RPLND. Median size of the residual mass was 25 mm (interquartile range [IQR] 20–35 mm). Overall median operative time was 208 min (IQR 177–241) and was 51 min longer (p-value <0.001) for right L-PC-RPLNDs. Eleven procedures were converted to open surgery. Median number of removed and positive nodes was 11 (IQR 8–16) and 1 (IQR 1–2), respectively. Mean hospital stay was 2 days (IQR 2–3). Nine complications (6%) occurred: two were Clavien-Dindo grade III. Definitive pathology revealed post-pubertal teratoma in 65.6%, fibro-necrotic tissue in 23.8%, teratoma with malignant somatic component in 6.6% and viable tumour in 4.0% patients. In multivariable linear regression models, fibro-necrotic tissue (32 min, CI 8.5–55.5; p < 0.01) and residual volume (1.05 min, CI 0.24–1.85; p < 0.01) achieved independent predictor status for longer operative time. All patients, but one, are alive and disease-free after a median follow-up of 22 months (IQR 10, 48).ConclusionL-PC-RPLND, when adequately planned, is safe and effective for most patients with low to medium volume residual masses.     

Chemotherapy in patients with metastatic or relapsed germ-cell tumours

The optimal treatment in patients with poor prognosis germ-cell tumours (GCT), according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification, and in patients with refractory or relapsed disease after cisplatin-based chemotherapy is controversial. As the majority of patients will suffer systemic relapses, chemotherapy is the mainstay of treatment. However, the question of whether or not to use conventional-dose or high-dose chemotherapy (HDCT) in these patients arises. Prognostic factors have recently been recognised to aid in this decision. However, reliable data on chemotherapy as primary treatment in poor prognosis patients and as the first-salvage attempt in patients with relapsed or refractory GCT are lacking. This report reviews the recent developments in first-line and salvage HDCT strategies and discusses the role of predictive factors for treatment outcome.     

Genetic polymorphisms and metastatic breast cancer survival

Variability of disease progression and survival exists among metastatic breast cancer patients. Treatment efficacy may be dependent on genetic variants in DNA repair and cell-cycle regulatory genes. This study examined three genetic variants in DNA repair and cell-cycle control genes (XRCC1, XRCC3 and CCND1) in 95 patients treated with high-dose chemotherapy. They found that all three were significantly associated with disease progression and survival independently, and that combinations of these variants progressively worsened breast cancer survival. Prior to identifying these genetic variants as prognostic indicators, replication of results in large randomized trials using standard treatment regimens is warranted.     

Methotrexate for relapse of metastatic non-seminomatous germ-cell tumours

Twelve patients with metastatic non-seminomatous germ-cell tumours who relapsed after 3-9 courses (median 7) of cis-platin containing combination chemotherapy, were treated with moderately high-dose methotrexate (1 g m-2) and folinic acid rescue. There was one partial response and the remaining eleven patients showed progression of disease. The patient that responded was one of two patients treated at the time of first relapse. It is concluded that methotrexate does not have a useful role in the salvage treatment of germ-cell tumours relapsing after cis-platin-containing chemotherapy or in patients who are primarily resistant to cis-platin-containing regimes.     

Fifteen-year trends in metastatic breast cancer survival in Greece

In the metastatic setting, a detected time trend to improved prognosis could be attributed to the corresponding recent advances in the therapeutic approaches. The aim of the current study was to first assess, in a large cohort of well over a thousand patients, the time trends in survival in MBC for the last 15 years and second to explore its association to prognostic factors affecting outcome including therapeutic regimen. This meta-analysis uses individual patient data collected from all the trials on MBC (6 nonrandomized, 4 randomized) conducted by HeCOG from 1991 through 2006. Four 4-year time periods (1991–1994, 1995–1998, 1999–2002, and 2003–2006) were constructed for exploration of time trends in survival according to the patient’s date of metastatic diagnosis. Different first line regimens in the 10 trials include anthracycline monotherapy (epirubicin, in the early 1990s) and taxane-containing regimens either as monotherapy or in different combinations with anthracyclines or other drugs. In two phase II studies and in the last randomized study, trastuzumab was administered in all the patients with HER2 overexpressing tumors. In this study, information is based on a total of 1361 patients with a median follow up of 3.7 years and median survival of 1.9 years (median survival 1.28, 1.68, 2.20, and 2.57 years for 1991–1994, 1995–1998, 1999–2002, and 2003–2006, respectively). Survival improved significantly across diagnosis time periods, by 25, 44, and 51%, respectively, in each time period (1995–1998: HR = 0.75, P = 0.004; 1999–2002: HR = 0.56, P < 0.001; 2003–2006: HR = 0.49, P < 0.001) as compared to the first time period (1991–1994). The effect of metastatic diagnosis time period remains almost unchanged in the presence of the following significant prognostic factors: performance status, hormonal receptor status, previous adjuvant chemotherapy, previous adjuvant hormonal treatment, visceral metastasis at entry, and number of metastatic sites. When exploring the effect of new systemic treatment introduction, taking into account the same significant prognostic factors, the effect of diagnosis time period disappears, and the survival improvement is explained directly by the introduction of new agents (hormonal treatment for metastatic disease: yes vs. no: HR = 0.72, P < 0.001; taxanes at first line: yes vs. no: HR = 0.69, P = 0.002; trastuzumab at first line: yes vs. no: HR = 0.63, P < 0.001). The results of this study provide significant evidence of improvement in prognosis of MBC patients within the last 15 years, taking into account all the important significant prognostic factors, and this improvement can be attributed to the use of new systemic treatment agents in the management of the disease.     

Improved survival for fallopian tube cancer

BACKGROUND.

Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer.

METHODS.

The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan‐Meier method.

RESULTS.

A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer‐specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48‐0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5‐year survival for stage III FT cancer was 54% (95% CI, 48%‐60%), compared with 30% (95% CI, 29%‐31%) for OV.

CONCLUSIONS.

Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers. Cancer 2008. © 2008 American Cancer Society.     

Effect of chemotherapy on survival in metastatic breast cancer

Summary In order to assess the impact of modern combination chemotherapy on overall survival of metastatic breast cancer patients, we retrospectively analysed survival data of those patients who presented with breast cancer and developed metastases at our clinic from 1971–78 inclusive. Our results indicate a trend towards improved survival from onset of first distant metastasis after 1975. Assessment of survival by treatment modality revealed significantly longer survival from first metastasis for those patients receiving predominantly endocrine treatment compared to chemotherapy, median survival being 32.5 versus 23 months for endocrine therapy and chemotherapy respectively. Patients receiving adriamycin in combination with other drugs, had longer survival from first metastasis than those patients receiving chemotherapy without adriamycin (median survival being 25 versus 18.5 months respectively). These differences are most probably due to patient selection. On the basis of these results it would appear that chemotherapy may be improving short-term survival in some patients, but is making no major impact on long-term survival. Address for reprints: Dr. A.H.G. Paterson, Dept. of Medicine, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.