Intermediate Prognosis Patients Research Articles

Conditional survival of stage III non-seminoma testis cancer patients

PurposeIn many primaries other than non-seminoma testis cancer, the risk of death due to cancer decreases with increasing disease-free interval duration after initial diagnosis and treatment. This effect is known as conditional survival and is relatively unexplored in stage III non-seminoma patients, where it may matter most in clinical decision-making. We examined the effect of disease-free interval duration on overall survival in stage III non-seminoma patients. Materials and MethodsWithin the Surveillance, Epidemiology, and End Results Database (2004–2018), stage III non-seminoma patients were identified. Multivariable Cox regression analyses and conditional survival models were applied. ResultsOf 2,092 surgically treated stage III non-seminoma patients, 385 (18%) exhibited good vs. 558 (27%) intermediate vs. 1,149 (55%) poor prognosis. In multivariable Cox regression models, poor prognosis group independently predicted overall mortality (HR 3.3, P < 0.001). In conditional survival analyses based on 36 months’ disease-free interval duration, 5-year overall survival estimates were as follows: good prognosis patients 96 vs. 89% at initial diagnosis without accounting for disease-free interval duration (Δ=+7); intermediate prognosis patients 94 vs. 85% at initial diagnosis without accounting for disease-free interval duration (Δ=+9); poor prognosis patients 94 vs. 65% at initial diagnosis without accounting for disease-free interval duration (Δ=+29). ConclusionsConditional survival estimates based on 36 months’ disease-free interval duration provide a more accurate and more optimistic outlook for stage III non-seminoma patients than predictions defined at initial diagnosis, without accounting for disease-free interval duration.

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

PURPOSEThe classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.MATERIALS AND METHODSData on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.RESULTSCompared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.CONCLUSIONPFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib

BackgroundThe Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib. Patients and MethodsPatients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan-Meier methods, and Pearson χ2 tests. ResultsThe patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression-free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05). ConclusionINTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.

Impact of extrascrotal symptoms on treatment outcome in patients with nonseminomatous germ cell tumor with intermediate or poor prognosis.

384 Background: The International Germ Cell Consensus (IGCC) classification is based on primary tumor localization, presence of non-pulmonary visceral metastases, and serum tumor marker levels, not the general condition of patients. The present study aimed to identify novel prognostic factors for nonseminomatous germ cell tumors (NSGCTs) with IGCC intermediate or poor prognosis. Methods: We retrospectively analyzed 399 patients with germ cell tumors (GCT) treated at Tohoku University Hospital between 1979 and 2011. Of these, 52 and 61 patients with NSGCTs were classified as having intermediate and poor prognosis, respectively. Several clinical parameters were reviewed, including age, IGCC prognosis group, kind of induction chemotherapy, and extra-scrotal symptoms at presentation. Extra-scrotal symptoms were defined as symptoms other than scrotal swelling, such as abdominal pain, lumbago, and dyspnea. Survival was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to assess potential predictors of outcome. Results: The median age of the 113 patients was 30. Median length of follow-up was 57 months. At presentation, 12 (23%) patients with intermediate prognosis and 32 (52%) patients with poor prognosis had extra-scrotal symptoms. In the intermediate prognosis group, the five year overall survival (OS) of patients with extra-scrotal symptoms was significantly worse than that of patients without symptoms (95% vs. 63%, p= 0.0008), but there was no significant difference in five year OS between patients with and without extra-scrotal symptoms in the poor prognosis group (60% vs. 66%, p= 0.265). On multivariate analysis, the presence of extra-scrotal symptoms (hazard ratio [HR] = 2.48, p= 0.0184) and induction chemotherapy not including etoposide (HR = 12.0, p&lt; 0.0001) were independent predictors of inferior OS. Conclusions: The presence of extra-scrotal symptoms was associated with inferior OS, particularly in patients with intermediate prognosis. Intermediate-prognosis patients with extra-scrotal symptoms should be recognized as having poor prognosis.

Heterogeneity of intermediate prognosis patients (pts) with metastatic renal cell cancer (mRCC) treated with sunitinib.

446 Background: The Memorial Sloan Kettering Cancer Center risk model (MSKCC) stratifies pts with mRCC into 3 prognostic groups based on 5 risk factors. The Intermediate Prognosis (INTMP) risk group is characterized by the presence of 1 or 2 factors, equivalent to 15 possible distinct entities. This heterogeneity suggests that the efficacy of tyrosine kinase inhibitors may be less predictable in the INTMP than in the other groups. Methods: We identified 548 patients with INTMP mRCC from a pooled analysis of patients treated with sunitinib in 6 prospective phase II and III clinical trials. Statistical analysis was performed using Cox regression and Kaplan-Meier methods and Pearson chi-square tests. Results: Most INTMP pts were male (69%), with clear cell carcinoma (93%), good ECOG performance status (PS) (60.5% PS 0; 38% PS 1; 1.5% PS 2) and median age 60. There were 325 pts (56%) with 1risk factor, and the most common were &lt;1 year from diagnosis (38%); low hemoglobin (Hg) (29%), or both (16%). Objective response rate (RR) was 35.4%, progression free survival (PFS) was 8.4 months (m) and overall survival (OS) was 20.5 m. The 325 (59.3%) pts with one risk factor fared better than the 223 (40.7%) patients with two: PFS 10.7 vs 6.5 m, HR 0.684(95% CI 0.563-0.832, p&lt;0.001); OS 26.3 vs 14.1 m, HR 0.522 (95% CI 0.420-0.648, p&lt;0.001). RR was similar (38.5% vs 30.9%, p=0.071). Sunitinib was more effective in pts with PS 0: PFS 9.7 vs 7.8 m, HR 0.797 (95% CI 0.654-0.972, p=0.0242); OS 24.7 vs 14.0 m, HR 0.529 (95% CI 0.426-0.657, p&lt;0.001), RR 38.9% vs 30.1%, (p=0.036). The most common grade 3/4 adverse events (AE) were fatigue (17%), hypertension (10%), hand foot skin reaction (9%), and nausea (4%). Overall, 17% of patients discontinued due to AE, and the overall pattern of AEs did not vary among the subgroups. Conclusions: MSKCC INTMP is a heterogeneous group comprised mostly of pts with low Hg and/or &lt; 1 year from diagnosis. PFS and OS are superior in pts with 1 vs. 2 risk factors, and PS is also an important factor in the INTMP group. Sunitinib is active and well-tolerated in INTMP pts. Clinical trial information: NCT00077974, NCT00083889, NCT00137423, NCT00267748, NCT00338884, NCT00054886.

The role of AHI1 and CDKN1C in cutaneous T‐cell lymphoma progression

Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin. Recent reports suggest that AHI1 is overexpressed in a subset of CTCL-derived cell lines, where it downregulates the expression of CDKN1C tumor suppressor gene. In the current work, we test the expression of these genes in 60 patients with Mycosis Fungoides and Sezary Syndrome by RT-PCR and correlate our findings with 6 years of clinical follow-up. These findings reveal that AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients. Kaplan-Meier analysis documents that downregulation of CDKN1C is associated with poor disease outcome in patients with CTCL, while upregulation of AHI1 shows a weak association with aggressive disease course.

Renal cancer treatment in Spain: An online survey.

397 Background: Renal cancer incidence has increased in the last decades. Many treatment options have also been developed in this period. Knowledge about oncologists' attitudes in the management of this disease could help to implement better treatment protocols. Methods: An online survey about therapeutic options for renal cancer was developed by an expert committee. Oncologists with expertise on the treatment of genitourinary malignancies that fulfilled all inclusion criteria in Spain were listed (n=200) and 80 were randomly selected to complete the survey. Survey items considered renal carcinoma management in the daily clinical practice. The questionnaire posed multiple tests, protocols, or therapeutic options. Results: From the 80 selected oncologists, 53 responded to the online survey (66% response rate). The mean number of newly diagnosed cases per year was 201 (SD: 12) patients of whom 15 corresponded to renal carcinoma. Seventy nine per cent of participants reported to apply a protocol for treatment decisions, being the NCCN recommendations the most frequently followed (54.7%). Surprisingly, local or European recommendations were scarcely used. When asked about management of metastatic disease, most physicians (83%) reported that they would use sunitinib as the preferred first line treatment for good or intermediate prognosis patients. If further treatment would be required, 69.8% (n=37) and 79.2% (n=42) of oncologists would recommend a change in the mechanism of action by switching to an mTOR inhibitor (everolimus) for first and further relapses, respectively. Regarding the management of first line non-clear cell histologies, almost half of the physicians would utilize a TKI, while 38% would prefer an mTOR inhibitor. Conclusions: NCCN are the most frequently followed recommendations. There is agreement among oncologists about which treatment should be used for renal carcinoma after first line treatment failure by switching the mechanism of action of the selected treatment. The management of non-clear cell patients remains a matter of debate with no consensus among the participants. No significant financial relationships to disclose.

Phase I/II Trial of a COX-2 Inhibitor With Limited Field Radiation for Intermediate Prognosis Patients Who Have Locally Advanced Non–Small-Cell Lung Cancer: Radiation Therapy Oncology Group 0213

BackgroundTreatment of patients who have locally advanced non–small-cell lung cancer and compromised performance status or weight loss (WL) is challenging. This study was conducted to test a low toxicity treatment regimen in this cohort. Patients and MethodsPatients were treated with concurrent celecoxib and thoracic radiation therapy to 45 Gy in 15 fractions or 60 to 66 Gy in 30 to 33 fractions. Eligible patients had inoperable or unresectable stage IIB, IIIA/B NSCLC, performance status 2 and/or greater than 5% WL. In the phase I portion of the study, the starting dose of celecoxib was 200 mg twice daily with one dose escalation to 400 mg twice daily. Celecoxib was continued for 2 years or until progression. ResultsThe phase I component accrued eight patients each at 200 mg twice daily and 400 mg twice daily. Twice daily 400 mg was chosen for the phase II component, which enrolled five patients and was closed early because of poor accrual. We were able to analyze 18 patients. Performance status ratings were 0, 1, and 2 in 7, 7, and 4 patients, respectively. Median age was 72 years. WL of greater than 5% was noted in 10 patients (56%). Four of 10 had WL greater than or equal to 20%. Median follow-up and survival was 10 months. Overall survival rates at 1 and 2 years were 44.4% [95% confidence interval (CI), 21.6%–65.1%] and 22.2% (95% CI, 6.9%–42.9%), respectively. Progression-free survival at 1 year was 33.3% (95% CI, 13.7%–54.5%). Toxicities matched those expected with thoracic radiotherapy alone. ConclusionConcurrent thoracic radiation therapy and celecoxib was well tolerated. The sample size was too small to draw conclusions regarding efficacy.

Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Unexpected High Lung Toxicity from Radiation Pneumonitis in a Phase I/II Trial of Concurrent Erlotinib with Limited Field Radiation for Intermediate Prognosis Patients with Stage III or Inoperable Stage IIB Non–small-cell Lung Cancer(NSCLC)

Unexpected High Lung Toxicity from Radiation Pneumonitis in a Phase I/II Trial of Concurrent Erlotinib with Limited Field Radiation for Intermediate Prognosis Patients with Stage III or Inoperable Stage IIB Non–small-cell Lung Cancer(NSCLC)

Medroxyprogesterone, interferon alfa‐2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis

Few randomized trials have compared the survival benefit of interferon-alfa over controls in metastatic renal cell carcinoma, and none has been performed using interleukin-2. The Programme Etude Rein Cytokines (PERCY) Quattro trial was designed to evaluate both cytokines for their survival benefit to intermediate prognosis patients, who represent the majority of candidates for these treatments. Patients were randomized in a 2-by-2 factorial design to medroxyprogesterone acetate 200 mg daily, interferon-alfa 9 million IU 3 times a week, subcutaneous interleukin-2 9 million IU daily, or a combination of both cytokines. Tumor response was evaluated at Week 12 and Month 6; progression-free patients received further identical treatment for a maximum of 3 additional months. Primary endpoint was overall survival; secondary endpoints were disease-free survival, response rate, toxicity, and quality of life. Survival was analyzed on an intent-to-treat basis. From January 2000 to July 2004, 492 patients were enrolled. Analysis was performed after a 29.2-month median follow-up (range, 0 months to 54.6 months). There were no significant survival differences between the 244 interferon-alfa-treated patients and 248 noninterferon-alfa patients (hazard ratio, 1.00; 95% CI, 0.81-1.24) or between the 247 interleukin-2 and 245 noninterleukin-2-treated patients (hazard ratio, 1.07; 95% CI, 0.87-1.33; log rank, 0.99 and 0.52, respectively). Grade 3-4 toxicities were significantly more frequent in cytokine-treated patients than in medroxyprogesterone-treated patients. Subcutaneous interleukin-2 and/or interferon-alfa provide no survival benefit in metastatic renal cancers of intermediate prognosis, and they induce a significant risk of toxicity. Newly available angiogenesis inhibitors should be preferred for these patients.

Predicting recurrence following post-chemotherapy retroperitoneal lymph node dissection for residual fibrosis or teratoma

4551 Background: The current recommendation for the management of patients with the histologic finding of fibrosis or teratoma at PC-RPLND is surveillance. We evaluated men at our institution who underwent PC-RPLND for metastatic non-seminomatous germ cell tumor (NSGCT) to determine predictors of disease recurrence. Methods: From 1989 through 2003, a total of 532 men underwent PC-RPLND for metastatic NSGCT at our institution. Of these, 473 (89%) had either fibrosis or teratoma present in the RPLND specimen. Following IRB approval, clinical and pathologic data were obtained from our prospective surgical database. A Cox regression model was constructed to evaluate variables that may predict for recurrence of viable NSGCT following PC-RPLND and a prognostic index was developed. Freedom from disease recurrence was analyzed using the Kaplan Meier method. Results: Of the 473 patients with fibrosis or teratoma, all patients underwent complete resection of all residual retroperitoneal masses, however 35 (7%) did not undergo a full PC-RPLND. With a median follow-up of 41 months, 47 (10%) patients relapsed with viable NSGCT. The 2- and 5- year probability of freedom from recurrent viable GCT for the entire cohort was 90% and 89%, respectively. In our multivariable model only post-chemotherapy nodal size &gt; 5cm (p = 0.008), clinical stage III (p = 0.002), and absence of a full PC-RPLND (p = 0.002) were independent predictors for recurrence with viable NSGCT. Based on these three adverse predictors, a prognostic index was developed with favorable patients having no risk factors, intermediate prognosis patients with one risk factor, and poor prognosis patients having 2 or more risk factors. Favorable, intermediate, and poor prognosis patients had a 2-year progression free probability of 97% (95% CI 95–99%), 90% (95% CI 85–95%), and 66% (95% CI 54–78%), respectively (p &lt; 0.001). Conclusions: This data suggests that patients who have a high risk of reucrrence with viable GCT should undergo more frequent follow-up during the first 2-years with serum tumor markers and imaging. Additionally, this data suggests that an incomlete RPLND is not sufficient surgery for men with metastatic NSGCT. These men should undergo a bilateral RPLND. No significant financial relationships to disclose.

Survival of non-seminomatous germ cell cancer patients according to the IGCC classification: An update based on meta-analysis

The International Germ Cell Consensus (IGCC) Classification distinguishes patients with non-seminomatous germ cell tumours (NSGCT) with a good, intermediate or poor prognosis, with a reported 5-year overall survival of 92%, 80% and 48%, respectively. Since the IGCC classification was based on patients treated between 1975 and 1990, we aimed to investigate whether survival has improved for more recently treated patients. We did a systematic search of the literature and included studies on survival of patients with NSGCT, treated after 1989 and classified according to the IGCC classification. Survival estimates of selected studies were pooled using meta-analytic techniques. We included 10 papers, describing 1775 patients with NSGCT with good ( n = 1087), intermediate ( n = 232), or poor ( n = 456) prognosis. Pooled 5-year survival estimates were 94%, 83% and 71%, respectively. Since the publication of the IGCC classification, there was a small increase in survival for good and intermediate prognosis patients, and a large increase in survival for patients with a poor prognosis. This increase is most likely due to both more effective treatment strategies and more experience in treating NSGCT patients.

Treatment of testicular tumours based on risk factors.

Germ cell cancer is highly sensitive to cisplatinum-based chemotherapy, resulting in cure rates of over 90% for patients with minimal metastatic disease or low tumour markers, 70% for patients with intermediate prognosis features, and 50% for patients with poor prognosis criteria. Whereas current clinical studies aim to improve the survival of patients with poor prognosis by means of high-dose chemotherapy, or the survival of intermediate prognosis patients by more intensive chemotherapy, for patients with good prognosis the reduction of doses, number of drugs or cycles is investigated to reduce the short-term and, in particular, long-term treatment sequelae. However, apart from these clinical studies, the current treatment standard of three cycles of platinum/etoposide/bleomycin for good prognosis patients and four cycles for intermediate and poor prognosis patients with advanced germ cell cancer has not been changed by recent trial results. The excellent cure rate with cisplatinum-based chemotherapy in the case of early metastatic disease with three cycles of platinum/etoposide/bleomycin as well as the high efficacy of adjuvant chemotherapy with two cycles of platinum/etoposide/bleomycin in the case of microscopic disease did change the treatment standards in stage I and II non-seminomatous germ cell cancer, with defined treatment options depending on prognostic factors. The treatment of testicular cancer based on prognostic factors is mandatory in all stages of seminoma and non-seminoma; however, molecular biological factors might make a major contribution to a more precise determination of prognosis and therefore enable a tailored selection of an individual treatment in the future.

A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia

In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which intermediate prognosis patients (stage B) received either an indefinite course of chlorambucil (0.1 mg/kg/d) or 12 cycles of the COP regimen (vincristine, cyclophosphamide, and prednisone). We present the results of the third interim analysis based on 291 patients (151 in the chlorambucil group and 140 in the COP group) with a mean follow-up of 53 months at the reference date of June 1, 1987. At this date, 129 deaths were observed, 65 in the chlorambucil group and 64 in the COP group; there was no improvement in overall survival with the COP regimen (P = .44) even after adjusting for both prognostic and imbalanced factors (P = .24). The 3-year and 5-year overall survival rates were, respectively, 69% and 44% in the chlorambucil group as compared with 73% and 43% in the COP group. The median survival times were 58 months in the chlorambucil group and 57 months in the COP group. Moreover, no significant difference was observed between the two treatment groups in terms of either treatment response, 9-month status, time to disease progression to stage C, or causes of death.

A Randomized Clinical Trial of Chlorambucil Versus COP in Stage B Chronic Lymphocytic Leukemia

In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which intermediate prognosis patients (stage B) received either an indefinite course of chlorambucil (0.1 mg/kg/d) or 12 cycles of the COP regimen (vincristine, cyclophosphamide, and prednisone). We present the results of the third interim analysis based on 291 patients (151 in the chlorambucil group and 140 in the COP group) with a mean follow-up of 53 months at the reference date of June 1, 1987. At this date, 129 deaths were observed, 65 in the chlorambucil group and 64 in the COP group; there was no improvement in overall survival with the COP regimen (P = .44) even after adjusting for both prognostic and imbalanced factors (P = .24). The 3-year and 5-year overall survival rates were, respectively, 69% and 44% in the chlorambucil group as compared with 73% and 43% in the COP group. The median survival times were 58 months in the chlorambucil group and 57 months in the COP group. Moreover, no significant difference was observed between the two treatment groups in terms of either treatment response, 9-month status, time to disease progression to stage C, or causes of death.

EFFECTIVENESS OF "CHOP" REGIMEN IN ADVANCED UNTREATED CHRONIC LYMPHOCYTIC LEUKAEMIA

This paper gives the first interim results of a randomised clinical trial of several drug regimens for the treatment of chronic lymphocytic leukaemia. Patients were classified as being in stage A, B, or C depending on clinical findings and peripheral blood picture. Good prognosis patients—ie, stage A (n=455)—were randomised to receive either no treatment or a course of chlorambucil. Intermediate prognosis patients—ie, stage B (n=224)—received either chlorambucil or the COP regimen (cyclophosphamide, vincristine, and prednisone). Poor prognosis patients—ie, stage C (n = 60)- received either COP or CHOP (COP plus doxorubicin). The first six courses of polychemotherapy were given every month and the other six every 3 months. 93 deaths were recorded at the time of the analysis. Stages A and B patients did not show significant differences in survival rates between treatment groups. In stage C patients 2-year survival rates were 44% with COP and 77% with CHOP (p=0·0013, one-sided log-rank test). Disease status, as assessed by staging at 9 months, was also better with CHOP than with COP. These results led to the termination of the trial and its replacement by one in which CHOP is given to intermediate prognosis patients.