bluuebunny/crossref_metadata_2025 huggingface dataset:
Tandem autotransplantation for the treatment of metastatic breast cancer.
Authors: Broun E R , Sridhara R , Sledge G W , Loesch D , Kneebone P H , Hanna M , Hromas R , Cornetta K , Einhorn L H
Published: February 2017

PURPOSE

To investigate the tolerability and impact on progression-free and overall survival of two consecutive cycles of high-dose chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) in patients with previously untreated metastatic breast cancer.

PATIENTS AND METHODS

Twenty-eight patients received conventional-dose induction therapy (ITx) followed by a planned two cycles of HDC with ABMT. Median age was 45 years (range, 34 to 60 years). Sites of disease were bone (seven patients), visceral (three), soft tissue (11), multiple (six), and CNS (one). The ITx regimens of cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), methotrexate, fluorouracil, prednisone, and tamoxifen (CAMFTP) (three patients); fluorouracil, doxorubicin, and cyclophosphamide (FAC; 11 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; four patients); or doxorubicin or mitoxantrone/cyclophosphamide (10 patients) were given to maximum response (three to five cycles). HDC was cyclophosphamide 6 g/m2, carboplatin 2 g/m2, and etoposide 625 mg/m2 with ABMT.

RESULTS

Of 28 patients, 24 received two (86%) cycles of HDC. Four received only one cycle due to persistent toxicity from course 1 (one patient), no response to course 1 (two), and death on course 1 (one). Grade 3 to 4 nonhematologic toxicities included mucositis (in one or both cycles in 21 of 28 patients; 75%), diarrhea, nausea, and vomiting. Reversible peripheral neuropathy was seen in 15 of 28 patients and was severe in one. Documented infections were seen in 19 of 52 cycles. There was one transplant-related death. Six patients were converted from partial remission (PR) to complete remission (CR) with HDC; two of 24 patients (8%) were converted from PR to CR with the second cycle of HDC. Progression-free survival rate is nine of 28 patients (32%) with median follow-up of 23 months (range, 13 to 36+ months). Eighteen of 28 patients (64%) have progressed at 1 to 17 months from ABMT.

CONCLUSION

Two cycles of HDC with ABMT was well tolerated with a high response rate in patients with metastatic breast cancer. The importance of the second cycle of HDC in this population is unclear.
Paclitaxel activity in heavily pretreated breast cancer: a National Cancer Institute Treatment Referral Center trial.
Authors: Abrams J S , Vena D A , Baltz J , Adams J , Montello M , Christian M , Onetto N , Desmond-Hellmann S , Canetta R , Friedman M A
Published: February 2017

PURPOSE

To provide paclitaxel, an investigational drug at the inception of this study, to women with chemotherapy-refractory metastatic breast cancer and to evaluate response and toxicity in these patients.

PATIENTS AND METHODS

Two hundred sixty-seven patients with progressive disease (PD) following at least two chemotherapy regimens for metastatic breast cancer and a contraindication to further doxorubicin treatment received paclitaxel either at 175 mg/m2 intravenously (IV) over 24 hours or at 135 mg/m2 if they had prior irradiation to 30% of marrow-bearing bone or a cumulative dose of mitomycin > or = 20 mg/m2.

RESULTS

In a subgroup of patients (n = 172) with measurable disease, four complete responses (CRs) and 36 partial responses (PRs) occurred, for an overall response rate of 23% (95% confidence interval [CI], 17% to 30%). No differences in response rates were noted according either to the number of prior chemotherapy regimens received or to whether patients were considered refractory to doxorubicin. The dose and schedule used in this trial resulted in febrile neutropenia in 45% of patients and a hospitalization rate of 49%.

CONCLUSION

Paclitaxel's activity in this multiinstitutional trial in heavily pretreated patients confirms the encouraging results attained in single-institution trials. Although at this dose and schedule paclitaxel may be considered too myelosuppressive for palliative care, supportive measures such as colony-stimulating factors and antibiotics were not used prophylactically. Current research efforts are focusing on whether paclitaxel's activity against breast cancer is dose- and/or schedule-dependent, and on what role it has in patients with less advanced disease.
Salvage chemotherapy with paclitaxel for recurrent primary brain tumors.
Authors: Chamberlain M C , Kormanik P
Published: February 2017

PURPOSE

To assess the safety and efficacy of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) given at a dose of 175 mg/m2 every 3 weeks as a 3- to 4-hour outpatient infusion to patients with recurrent malignant primary brain tumors who had received prior radiotherapy and at least one chemotherapy regimen containing nitrosoureas and who were no longer responding to therapy.

PATIENTS AND METHODS

Twenty patients (12 men and eight women), ages 19 to 69 years (median, 35), with recurrent primary brain tumors were treated according to a phase II protocol with intravenous Taxol. Tumor histologies included the following: anaplastic astrocytoma (n = 8), glioblastoma multiforme (n = 8), and anaplastic oligodendroglioma (n = 4). All patients had been previously treated with subtotal resection, limited-field radiotherapy (median dose, 60 Gy; range, 54 to 78 Gy), and nitrosourea-based chemotherapy. Taxol was administered intravenously at a dose of 175 mg/m2/d every 3 weeks with neurologic and neuroradiographic evaluation every 8 to 9 weeks. Complete blood cell counts were performed weekly.

RESULTS

A median of six cycles of Taxol (range, two to 12) were administered to 20 assessable patients. Toxicities included partial alopecia (n = 10), thrombocytopenia (n = 4), rate of Taxol administration-dependent bradycardia (n = 3), and nondisabling peripheral neuropathy (n = 1). No patient developed neutropenic fever or sepsis or required cytokine support. Two patients required blood-product support (platelet transfusions in both). Four patients (20%) demonstrated a partial response (PR) and seven (35%) had stable disease (SD) for a total response plus SD rate of 55%. The median time to tumor progression was 6 months (range, 2 to 20).

CONCLUSION

Taxol demonstrated modest efficacy with minimal toxicity in this heavily pretreated cohort of young patients with recurrent primary brain tumors.
Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.
Authors: Willson J K , Haaga J R , Trey J E , Stellato T A , Gordon N H , Gerson S L
Published: February 2017

PURPOSE

Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU.

PATIENTS AND METHODS

Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases.

RESULTS

Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed.

CONCLUSION

Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.
Lymph node staging standards in gastric cancer.
Authors: Bunt A M , Hogendoorn P C , van de Velde C J , Bruijn J A , Hermans J
Published: February 2017

PURPOSE

In tumor-node-metastasis (TNM) staging, no recommendations are provided on the number of lymph nodes to examine per N level. We investigated the relationship between number of nodes examined and probability of detecting metastases, and ultimately staging accuracy.

PATIENTS AND METHODS

Data from 473 curatively resected gastric cancer patients, from a randomized trial that compared the Western resection with limited and the Japanese resection with extended lymphadenectomy, were used.

RESULTS

Yields varied between zero to 67 in N1 and zero to 43 in N2. Yields correlated significantly with classification; the more nodes examined, the more likely the classification was N+. Calculating the probability of detecting metastases using either a likelihood-ratio estimate or an exponential model, this probability increased steeply in the lower range and more gradually in the higher range yield.

CONCLUSION

To standardize treatment results, we emphasize histologic examination of a fixed number of nodes per anatomically defined N level (20 in N1 and 15 in N2), corresponding with a probability to detect metastases of 60% to 65% and 40% to 45%, respectively. These yields are feasible in all resection specimens, while the extra increase in the chance of detecting metastases by examining more nodes does not compensate the effort to increase yields further. Thus, standardization of histologic TNM staging can improve and render comparison of surgical and adjuvant treatment modalities feasible.
Bone marrow-sparing and prevention of alopecia by AS101 in non-small-cell lung cancer patients treated with carboplatin and etoposide.
Authors: Sredni B , Albeck M , Tichler T , Shani A , Shapira J , Bruderman I , Catane R , Kaufman B , Kalechman Y
Published: February 2017

PURPOSE

The aim of this study was to evaluate the ability of the immunomodulator AS101 to prevent chemotherapy-induced neutropenia and thrombocytopenia and thus allow patients to receive full-dose antineoplastic agents according to protocol design. We also aimed to determine the production level of various hematopoietic growth factors in treated patients.

PATIENTS AND METHODS

This study of 44 unresectable or metastatic non-small-cell lung cancer (NSCLC) patients was an open-label prospective randomized study of standard chemotherapy alone versus chemotherapy plus AS101. Each patient received carboplatin (300 mg/m2 intravenously [IV] on day 1 of a 28-day cycle, and etoposide (VP-16) (200 mg/m2 orally) on days 3, 5, and 7 of each cycle. AS101 was administered at 3 mg/m2 three times per week starting 2 weeks before chemotherapy.

RESULTS

AS101, which manifested no major toxicity, significantly reduced neutropenia and thrombocytopenia and thus allowed all treated patients to receive full-dose antineoplastic agents, in contrast to only 28.5% of the control group. Continuous treatment with AS101 significantly reduced the number of days per patient of thrombocytopenia and neutropenia and did not provide protection to tumor cells as reflected by the higher overall response rate compared with the chemotherapy-alone arm. Interestingly, AS101 treatment also significantly prevented chemotherapy-induced alopecia. These effects correlate with the ability of AS101-treated patients to increase significantly the production of colony-stimulating factors (CSFs) interleukin-1 alpha (IL-1 alpha) and IL-6.

CONCLUSION

AS101 has significant bone marrow (BM)-sparing effects and prevents hair loss in chemotherapy-treated patients, with minimal overall toxicity. These effects are probably due to increased production of IL-1 alpha, IL-6, and granulocyte-macrophage (GM)-CSF.
Ethical considerations in oncology: balancing the interests of patients, oncologists, and society.
Authors: Smith T J , Bodurtha J N
Published: February 2017

BACKGROUND

Oncologists face ethical dilemmas every day in deciding about choice of treatment, continuation of treatments, events near the end of life, conflicts of interest, and risk management. Yet, many oncologists have limited training in ethics.

METHODS

Review of existing studies and definitions of useful terms. Case studies analyzed according to ethical principles.

RESULTS

Individual oncology cases can be analyzed according to ethical principles with benefit to the patient, physician, and possibly society. Ethics cannot resolve many of the thorny questions about allocation of resources, justice, or possible conflict of interest.

CONCLUSION

Oncology decision-making fits into formal ethical frameworks, and understanding both can help doctors and patients make difficult choices. Understanding of ethical principles can help daily practice, but does not solve current dilemmas of allocation of resources, unrealistic demands, etc. More formal collaboration between hospital ethics committees or personnel and clinical oncologists is recommended for the day-to-day decision-making process.
Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse.
Authors: Haffty B G , Reiss M , Beinfield M , Fischer D , Ward B , McKhann C
Published: February 2017

PURPOSE

To evaluate the prognostic significance of ipsilateral breast tumor recurrence (IBTR) with respect to the subsequent development of distant metastasis.

MATERIALS AND METHODS

Between January 1970 and December 1989, 973 patients with invasive breast cancer were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. The median follow-up time as of December 1993 was 8.6 years. A number of prognostic factors were tested as possible predictors of distant metastases, including whether a patient experienced IBTR. IBTRs were broken down by time to recurrence to determine whether the breast recurrence-free interval had any prognostic relevance with respect to the development of distant metastasis.

RESULTS

As of December 1993, out of the entire population of 973 patients, 73 patients had developed IBTR and 134 had developed distant metastases. The overall actuarial survival rate at 10 years was .71 +/- .02, with a 10-year actuarial breast recurrence-free rate of .84 +/- .02 and a 10-year distant metastasis-free rate of .77 +/- .02. The overall distant metastasis rate was higher in patients who experienced IBTR compared with patients who had never experienced IBTR. Furthermore, the time to IBTR had a significant effect on distant metastases. Of 32 patients who developed an IBTR within 4 years of original diagnosis, 16 (50%) developed distant metastases. In contrast, of 41 patients who developed later breast relapses (> 4 years from original diagnosis), only seven (17%) developed distant metastases (P < .01). Of 32 patients who developed early breast relapse, the 5-year survival rate following breast relapse was .50 +/- .01, compared with a 5-year post-breast relapse survival rate of .78 +/- .10 among 41 patients with later breast relapses (P < .05).

CONCLUSION

It appears that early IBTR is a significant predictor for distant metastases. Whether early breast tumor relapse is a marker for or cause of distant metastases remains a controversial and unresolved issue. Implications for adjuvant systemic therapy at the time of breast relapse are discussed.
Natural history of node-positive breast cancer: the curability of small cancers with a limited number of positive nodes.
Authors: Quiet C A , Ferguson D J , Weichselbaum R R , Hellman S
Published: February 2017

PURPOSE

The long-term outcome of node-positive breast cancer was analyzed to determine the risk of metastatic disease as a function of tumor size and number of positive nodes.

METHODS

From 1927 to 1987, 501 women with node-positive breast cancer were treated at the University of Chicago Medical Center. Patients were treated with radical, extended radical, or modified radical mastectomy. Forty-eight patients received multiagent chemotherapy, and 118 were treated with hormonal therapy. The mean survival duration is 120 months, with a maximal follow-up time of 485 months (40 years).

RESULTS

The number of nodes that contained metastatic disease and the pathologic size of the primary tumor were significant determinants of disease-free-survival (DFS) by multivariate analysis (P < .001). In patients with fewer than four positive nodes, tumor size was of prognostic importance, with small tumors more likely to be cured by local-regional therapy. The 20-year DFS rate for patients with one positive node was 69%; however, if the primary tumor was < or = 2 cm, the 20-year DFS rate was 81%, compared with 59% if the tumor was larger than 2 cm. Patients with two or three positive nodes had a 73% 20-year DFS rate if the tumor size was < or = 2 cm, compared with 53% 20-year DFS in patients with tumors larger than 2 cm.

CONCLUSION

In patients with T1 lesions with less than four nodes positive, the long-term DFS rate is comparable to that for node-negative breast cancer of the same size. Four or more nodes positive is an indicator of likely systemic disease.
Prediction of colorectal cancer relapse and survival via tissue RNA levels of matrix metalloproteinase-9.
Authors: Zeng Z S , Huang Y , Cohen A M , Guillem J G
Published: February 2017

PURPOSE

In this study, we investigated the association between matrix metalloproteinase (MMP)-9 RNA expression in primary colorectal cancer (CRC) and standard clinicopathologic variables and determined whether levels of MMP-9 RNA predict relapse and survival.

PATIENTS AND METHODS

Tumor and paired normal mucosa specimens from 71 primary CRC patients following resections were assessed. RNA levels were determined via Northern blot hybridization and quantitated with laser densitometry. Results were expressed as tumor/normal mucosa (T/N) fold-increase calculated after normalizing for RNA loading using 28S expression. Statistical analysis was performed using the SAS statistical package procedure. Kaplan-Meier survival curves were compared with the two-sided log-rank test.

RESULTS

The mean T/N MMP-9 RNA fold-increase was 9.4 +/- 1.0 (mean +/- SE) (P < .001). Overexpression of MMP-9 RNA correlated significantly with status of synchronous distant metastases (M stage) (P = .004) and Dukes' stage (P = .008). A T/N fold-increase of 5.0 was used to discriminate between high (> 5.0) and low (< or = 5.0) T/N MMP-9 expression. High T/N MMP-9 RNA expression was associated with a significantly shorter disease-free (P = .0001) and overall (P = .0002) survival duration. In univariate and multivariate analyses, T/N MMP-9 RNA level was found to be an independent prognostic factor for disease-free survival.

CONCLUSION

This report provides the first evidence that increased MMP-9 RNA production in primary human CRC may be a powerful, independent predictor of recurrence and outcome.
Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia.
Authors: Relling M V , Mahmoud H H , Pui C H , Sandlund J T , Rivera G K , Ribeiro R C , Crist W M , Evans W E
Published: February 2017

PURPOSE

Although epipodophyllotoxins are commonly used in contemporary treatment regimens for acute lymphoblastic leukemia (ALL), their potential role in CNS-directed therapy has received little attention. We prospectively studied 20 children during initial remission of ALL and 16 children at relapse to assess CSF penetration of etoposide.

METHODS

Simultaneous plasma and CSF concentrations were assessed at a median of 2.8 hours (range, 0.4 to 5.3) after an intravenous (i.v.) or oral dose in 41 paired samples.

RESULTS

Etoposide given at 300 mg/m2 i.v. to patients during first remission and at 50 or 25 mg/m2 orally to those in relapse resulted in median CSF levels of 0.175 mumol/L (range, .066 to 2.12), 0.011 mumol/L (range, .004 to .032), and 0.007 mumol/L (range, .003 to .014), respectively. The CSF etoposide concentration was > or = 10 nmol/L in 20 of 20, five of 10, and two of 11 courses following 300 mg/m2 i.v., 50 mg/m2 orally, and 25 mg/m2 orally, respectively, and was positively related to both the concurrent etoposide plasma concentration (R2 = .64) and to dose (R2 = .73). The median ratio of CSF to plasma concentration was 0.30% (range, 0.09% to 3.12%), which was not related to dose, plasma concentration, or time postdose at which samples were obtained, but was positively correlated with the CSF protein concentration (R2 = 0.43, P = .006). Both the absolute etoposide CSF concentrations (P = .008) and the ratio of CSF to plasma concentrations (P = .023) were higher among first-remission patients who had CSF leukemic blasts at diagnosis compared with those without CSF blasts.

CONCLUSION

Because etoposide concentrations as low as 10 nmol/L may be cytotoxic in vitro, prolonged daily oral low-dose (50 mg/m2) or conventional i.v. doses of etoposide may contribute to successful CNS-directed therapy in children with ALL.
Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points.
Authors: Tannock I F , Osoba D , Stockler M R , Ernst D S , Neville A J , Moore M J , Armitage G R , Wilson J J , Venner P M , Coppin C M , Murphy K C
Published: February 2017

PURPOSE

To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a randomized controlled trial.

PATIENTS AND METHODS

We randomized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone (10 mg daily). Nonresponding patients on prednisone could receive mitoxantrone subsequently. The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients (or complete loss of pain if initially 1 +) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart. Secondary end points were a decrease of > or = 50% in use of analgesic medication without an increase in pain, duration of response, and survival. Health-related quality of life was evaluated with a series of linear analog self-assessment scales (LASA and the Prostate Cancer-Specific Quality-of-Life Instrument [PROSQOLI]), the core questionnaire of the European Organization for Research and Treatment of Cancer (EORTC), and a disease-specific module.

RESULTS

Palliative response was observed in 23 of 80 patients (29%; 95% confidence interval, 19% to 40%) who received mitoxantrone plus prednisone, and in 10 of 81 patients (12%; 95% confidence interval, 6% to 22%) who received prednisone alone (P = .01). An additional seven patients in each group reduced analgesic medication > or = 50% without an increase in pain. The duration of palliation was longer in patients who received chemotherapy (median, 43 and 18 weeks; P < .0001, log-rank). Eleven of 50 patients randomized to prednisone treatment responded after addition of mitoxantrone. There was no difference in overall survival. Treatment was well tolerated, except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone. Most responding patients had an improvement in quality-of-life scales and a decrease in serum prostate-specific antigen (PSA) level.

CONCLUSION

Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer.
Detection of circulating neoplastic cells by reverse-transcriptase polymerase chain reaction in malignant melanoma: association with clinical stage and prognosis.
Authors: Mellado B , Colomer D , Castel T , Muñoz M , Carballo E , Galán M , Mascaró J M , Vives-Corrons J L , Grau J J , Estapé J
Published: February 2017

PURPOSE

Circulating melanoma cells can be detected in peripheral blood by means of tyrosinase mRNA amplification by reverse-transcriptase polymerase chain reaction (RT-PCR). We conducted a prospective study to evaluate the clinical significance of the presence of circulating neoplastic cells in the blood of patients with malignant melanoma (MM).

METHODS

A sensitive RT-PCR assay was used to detect tyrosinase mRNA in the peripheral blood of patients with stages I to IV melanoma. Healthy subjects or patients with other malignancies were used as negative controls.

RESULTS

Ninety-one assessable patients were included in the study. There was a statistically significant association between RT-PCR positivity and clinical stage. Circulating melanoma cells were detected in 36% of patients with localized disease (stages I and II), in 45% of patients with regional nodal involvement (stage III), and in 94% of patients with metastatic disease (stage IV) (P < .001). In stage II-III patients who were RT-PCR-positive for mRNA tyrosinase in blood, the recurrence rate and disease-free survival were significantly worse than patients who were RT-PCR-negative. In multivariate analysis, RT-PCR was an independent prognostic factor for recurrence in patients with nonmetastatic disease (P = .002).

CONCLUSION

The detection of circulating melanoma cells in peripheral blood by RT-PCR correlated with the clinical stage of patients with melanoma and was an independent prognostic factor for recurrence. Further studies are warranted to better assess the significance of this test in the evaluation of prognosis, early detection of relapse, and in monitoring the effectiveness of systemic therapy.
Successful management of low-stage neuroblastoma without adjuvant therapies: a comparison of two decades, 1972 through 1981 and 1982 through 1992, in a single institution.
Authors: Evans A E , Silber J H , Shpilsky A , D'Angio G J
Published: February 2017

PURPOSE

A review was undertaken of 119 children seen at the Children's Hospital of Philadelphia between 1972 and 1992 to assess the impact of adjuvant therapies for patients with low-stage neuroblastoma (NBL).

PATIENTS AND METHODS

Twenty-one of 119 International Neuroblastoma Staging System (INSS) stage 1, 2a, 2b, and 4s patients seen received initial adjuvant treatment postoperatively and 98 did not. The patients were further subdivided according to decade, age, presence of residual disease, and lymph node status. Outcomes were then compared.

RESULTS

The event-free survival (EFS) rate for those who received adjuvant therapy was 52% versus 86% for those who did not. The 5-year survival rate was 68% and 94%, respectively. Age (< or > 12 months), extent of residual disease, and status of lymph nodes did not influence survival. Over the two decades, the reasons for selecting treatment changed as new and powerful additional prognostic factors were identified; 71% of patients received no adjuvant treatment in the first decade, compared with 90% in the second. EFS rates for untreated patients by decade were 79% and 89%, and 5-year survival rates were 85% and 98%, respectively.

CONCLUSION

It is possible to define most low-stage NBL as favorable-even in patients with positive lymph nodes and gross residual disease-and to omit initial adjuvant treatments successfully.
Human papillomavirus DNA and antibodies to human papillomaviruses 16 E2, L2, and E7 peptides as predictors of survival in patients with squamous cell cervical cancer.
Authors: Viladiu P , Bosch F X , Castellsagué X , Muñoz N , Escribà J M , Hamsíkova E , Hofmannova V , Guerrero E , Izquierdo A , Navarro C , Moreo P , Izarzugaza I , Ascunce N , Gili M , Muñoz M T , Tafur L , Shah K V , Vonka V
Published: February 2017

PURPOSE

To assess whether human papillomavirus (HPV) DNA detection in cervical cancer specimens, or antibodies to selected HPV 16 peptides are predictors of tumor recurrence and long-term survival in patients with squamous cell invasive cervical cancer.

SUBJECTS AND METHODS

Four hundred seventy-one cases included in two population-based case-control studies underwent follow-up evaluation. The survival and cause of death were ascertained for 410 cases (87%), with a median follow-up time of 4.6 years after diagnosis. HPV DNA was assessed using an L1 polymerase chain reaction (PCR)-based system and Southern hybridization (SH) on scraped cytologic specimens or biopsies. HPV 16 antibodies to E2, L2, and E7 peptides were detected with enzyme-linked immunosorbent assay (ELISA).

RESULTS

Clinical stage was the only independent prognostic factor for recurrence or survival. Although seropositivity to HPV 16 E7/3 peptide predicted a twofold excess risk of mortality (adjusted hazards ratio [HRa] = 2.0; 95% confidence interval [CI], 1.2 to 3.3), the association was restricted to stage I (HRa = 6.6; 95% CI, 1.2 to 37.6) and II (HRa = 5.9; 95% CI, 2.1 to 16.5) patients. The presence of HPV DNA (HRa = 0.9; 95% CI, 0.5 to 1.5), different estimates of the HPV viral load and the HPV type identified were not predictors of tumor recurrence or survival.

CONCLUSION

The presence of antibodies to HPV 16 E7 proteins is of prognostic value in early-stage cervical cancer. Our results provide strong evidence that detection and typing of HPV DNA in cervical cells or tissues is not a prognostic factor for recurrence or survival.
Surveillance policy for stage I ovarian germ cell tumors.
Authors: Dark G G , Bower M , Newlands E S , Paradinas F , Rustin G J
Published: February 2017

PURPOSE

Surveillance for stage I male germ cell tumors (GCT) is well established as a standard practice; however, such a policy has not been evaluated for women with equivalent tumors. This study was designed to evaluate the management of grade II or higher stage Ia tumors by close surveillance to minimize treatment, while reserving chemotherapy for patients with residual or recurrent disease.

PATIENTS AND METHODS

Between 1973 and 1995, 24 patients with malignant stage Ia ovarian GCT were enrolled onto a surveillance program. The group consisted of nine patients with dysgerminoma, nine with pure immature teratoma, and six with endodermal sinus tumor (with or without immature teratoma). Treatment consisted of surgical resection without adjuvant chemotherapy, followed by a surveillance program of clinical, serologic, and radiologic review, and included a second-look procedure for patients enrolled after 1982.

RESULTS

All but one patient are alive and in remission after a median follow-up of 6.8 years. The 5-year overall survival is 95%, and the 5-year disease-free survival is 68%. Eight patients have required chemotherapy for recurrent disease or second primary ovarian GCT. This includes three patients with grade II immature teratoma and three patients with dysgerminoma, and a further two women with dysgerminoma who developed contralateral (presumed second primary) dysgerminoma 4.5 and 5.2 years after their first tumor. All but one, who died of a pulmonary embolus, have been successfully salvaged with chemotherapy.

CONCLUSION

Our experience emphasizes that patients with true stage Ia ovarian GCT are adequately managed by surgical resection followed by careful clinical, radiologic, and serologic surveillance. These patients do not require adjuvant chemotherapy or radiotherapy, thus avoiding the potential complications of secondary leukemia and infertility.
Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.
Authors: Brice P , Bastion Y , Lepage E , Brousse N , Haïoun C , Moreau P , Straetmans N , Tilly H , Tabah I , Solal-Céligny P
Published: February 2017

PURPOSE

To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b.

PATIENTS AND METHODS

Newly diagnosed follicular lymphoma patients with a low tumor burden (n = 193) were randomly assigned to one of three arms: arm 1, no initial treatment (n = 66); arm 2, prednimustine 200 mg/m2/d for 5 days per month for 18 months (n = 64); or arm 3, interferon alfa 5 MU/d for 3 months then 5 MU three times per week for 15 months (n = 63). Clinical characteristics were similar in the three arms.

RESULTS

Overall response rates with prednimustine and interferon alfa were 78% and 70%, respectively. The overall response to therapy, when deferred, was similar at 70%. With a median follow-up duration of 45 months after randomization, the median freedom-from-treatment (FFT) interval was 24 months in arm 1 and the interval of freedom from treatment failure (FFTF) was 40 months in arm 2 and 35 months in arm 3. The median overall survival time was not reached and the overall survival rate at 5 years was 78% in arm 1, 70% in arm 2, and 84% in arm 3. Therefore, deferred treatment does not adversely influence survival at 5 years. Patients who progressed within 1 year had a significantly shorter survival duration (median, 48 months).

CONCLUSION

Delayed treatment is feasible in patients with follicular lymphoma and a low tumor burden. For patients with early progression, more intensive therapy should be considered. For others, because delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment, the long-term toxicity of alkylating agents can be reduced.
Phase II trial of hepatic arterial infusion of fluorouracil and recombinant human interferon alfa-2b for liver metastases of colorectal cancer refractory to systemic fluorouracil and leucovorin.
Authors: Patt Y Z , Hoque A , Lozano R , Pozdur R , Chase J , Carrasco H , Chuang V , Delpassand E S , Ellis L , Curley S , Roh M , Jones D V
Published: February 2017

PURPOSE

To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV).

PATIENTS AND METHODS

Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days.

RESULTS

There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump.

CONCLUSION

HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.
Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience.
Authors: Curran D , Sahmoud T , Therasse P , van Meerbeeck J , Postmus P E , Giaccone G
Published: February 2017

PURPOSE

Identification of prognostic factors in patients with malignant pleural mesothelioma based on prospectively collected international data.

PATIENTS AND METHODS

From October 1984 to October 1993, 204 eligible adult patients with malignant pleural mesothelioma were entered into five consecutive prospective European Organization for Research and Treatment of Cancer (EORTC) phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel). The Cox model was used to assess 13 factors related to biology and disease history with respect to survival.

RESULTS

The median survival duration was 12.6 months from diagnosis and 8.4 months from trial entry. In the multivariate analysis, poor prognosis was associated with a poor performance status, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified into two groups: a good-prognosis group (1-year survival rate, 40%; 95% confidence interval [CI], 30% to 50%) and a poor-prognosis group (1-year survival, 12%; 95% CI, 4% to 20%).

CONCLUSION

These results may help to design new clinical trials in pleural mesothelioma by selecting more homogenous groups of patients.
Molecular genetics of familial cutaneous melanoma.
Authors: Haluska F G , Hodi F S
Published: February 2017

PURPOSE

A family history of melanoma is a significant risk factor for the disease, and recently several loci that determine susceptibility to the development of melanoma have been identified. The most important of these is p16/CDKN2A. We attempted to determine the degree to which the p16/CDKN2A gene has been implicated in the development of melanoma, and to identify other genetic factors that play a role as well.

METHODS

We reviewed the literature published since the isolation of p16/CDKN2A and identified 13 studies that report the status of the gene in melanoma samples and 12 reports that examine p16/CDKN2A in melanoma kindreds. We also reviewed associated studies on CDK4 and RB1 involvement in melanoma, and examined the role of p16/CDKN2A in other inherited cancers.

RESULTS

The evidence strongly implicates p16/CDKN2A in determining predisposition to malignant melanoma. Overall, approximately 20% of families that have been studied show mutations in the gene. However, because of clustering of sporadic cases in families, and potentially because of technical factors, this is likely an underestimate of the proportion of the genetic predisposition for melanoma that is due to p16/CDKN2A mutation. Rare families carry a mutated CDK4 gene that is also responsible for inherited melanoma.

CONCLUSION

The gene p16/CDKN2A is an important determinant of melanoma risk. A commercial test is presently available to assess the status of this locus. However, because of uncertainties regarding the interpretation of the results of p16/CDKN2A genetic testing, we do not recommend routine clinical use of this test at this time.
Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer.
Authors: Susini T , Baldi F , Howard C M , Baldi A , Taddei G , Massi D , Rapi S , Savino L , Massi G , Giordano A
Published: February 2017

PURPOSE

The retinoblastoma gene is the prototype of tumor-suppressor genes and has been shown to be involved in the pathogenesis and progression of several human malignancies. In this study, we determined the relation between the expression of a newly discovered retinoblastoma-related gene Rb2/p130 and outcome in patients with endometrial carcinoma.

PATIENTS AND METHODS

pRb2/p130 expression was determined immunohistochemically in specimens of endometrial carcinoma (stages I to IV) from 100 patients who underwent surgery as the first treatment. The pRb2/p130 status was analyzed in relation to the length of disease-free survival and disease-specific survival.

RESULTS

Decreased levels of pRb2/p130 in endometrial cancer cells was significantly associated with a decreased probability of remaining disease-free after treatment (P = .003) and with decreased probability of survival (P < .0001). In a multivariate analysis, pRb2/p130 status (P = .004), tumor stage (P = .009), and ploidy status (P = .02) were independent predictors of clinical outcome. The risk of dying of disease was increased substantially (risk ratio, 4.91; 95% confidence interval, 1.66 to 14.54) among patients with decreased levels of pRb2/p130 in tumor cells.

CONCLUSION

In patients with endometrial carcinoma who did not receive radiotherapy or chemotherapy before surgery, the presence of decreased levels of pRb2/p130 in tumor cells is associated with a significantly increased risk of recurrence and death of disease, independent of tumor stage and ploidy status.
Peripheral primitive neuroectodermal tumors in adults: documentation by molecular analysis.
Authors: Lawlor E R , Mathers J A , Bainbridge T , Horsman D E , Kawai A , Healey J H , Huvos A G , Bridge J A , Ladanyi M , Sorensen P H
Published: February 2017

PURPOSE

The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients.

PATIENTS AND METHODS

The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features.

RESULTS

Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET.

CONCLUSION

Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.
Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis.
Authors: Engels E A , Lau J , Barza M
Published: February 2017

PURPOSE

To perform a meta-analysis to estimate the efficacy of quinolone antibiotics in preventing infections, fevers, and deaths among cancer patients neutropenic following chemotherapy.

METHODS

We searched MEDLINE to identify randomized trials of quinolone prophylaxis, controlled either with no prophylaxis or trimethoprim/sulfamethoxazole (TMS) prophylaxis. We pooled relative risks for outcomes using a random-effects model.

RESULTS

Eighteen trials with 1,408 subjects were included. Compared with no prophylaxis, quinolones significantly reduced the incidence of gram-negative bacterial infections (relative risk, 0.21; 95% confidence interval [CI], 0.12 to 0.37), microbiologically documented infections (0.65; 0.50 to 0.85), total infections (0.54; 0.31 to 0.95), and fevers (0.85; 0.73 to 0.99). Quinolone prophylaxis did not alter the incidence of gram-positive bacterial, fungal, or clinically documented infections, or infection-related deaths. Results were similar for trials that used TMS as the control regimen. Among those who received quinolones, the incidence of infections due to quinolone-resistant organisms was 3.0% (95% CI, 1.7% to 5.2%) for gram-negative species and 9.4% (95% CI, 5.3% to 16.3%) for gram-positive species. Based on limited data, the incidence of quinolone-resistant infections was not higher among quinolone recipients than controls. With fever as outcome, blinded trials found quinolones less efficacious than did unblinded trials.

CONCLUSION

Quinolone prophylaxis substantially reduces the incidence of various infection-related outcomes, but not deaths, in these patients. Although this reduction in infections may translate into a decrease in morbidity, the reduction in fevers (and by extension, use of empiric antibiotics) appears small, and blinded trials provided less evidence for benefit than unblinded trials. Quinolone-resistant infections are uncommon, but continued vigilance is warranted.
Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group.
Authors: Gore M , Mainwaring P , A'Hern R , MacFarlane V , Slevin M , Harper P , Osborne R , Mansi J , Blake P , Wiltshaw E , Shepherd J
Published: February 2017

PURPOSE

We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy.

PATIENTS AND METHODS

Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer.

RESULTS

The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001).

CONCLUSION

We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.