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Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

Purpose: The WHO guidelines on cancer pain management recommend a sequential three-step analgesic ladder. However, conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids., Patients and Methods: In a multicenter, 28-day, open-label randomized controlled study, adults with moderate cancer pain were assigned to receive either a weak opioid or low-dose morphine. The primary outcome was the number of responder patients, defined as patients with a 20% reduction in pain intensity on the numerical rating scale., Results: A total of 240 patients with cancer (118 in the low-dose morphine and 122 in the weak-opioid group) were included in the study. The primary outcome occurred in 88.2% of the low-dose morphine and in 57.7% of the weak-opioid group (odds risk, 6.18; 95% CI, 3.12 to 12.24; P < .001). The percentage of responder patients was higher in the low-dose morphine group, as early as at 1 week. Clinically meaningful (≥ 30%) and highly meaningful (≥ 50%) pain reduction from baseline was significantly higher in the low-dose morphine group (P < .001). A change in the assigned treatment occurred more frequently in the weak-opioid group, because of inadequate analgesia. The general condition of patients, which was based on the Edmonton Symptom Assessment System overall symptom score, was better in the morphine group. Adverse effects were similar in both groups., Conclusion: In patients with cancer and moderate pain, low-dose morphine reduced pain intensity significantly compared with weak opioids, with a similarly good tolerability and an earlier effect., (© 2015 by American Society of Clinical Oncology.)

Purpose: This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor (HR) -positive/human epidermal growth factor receptor 2 (HER2) -negative operable breast cancer., Methods: Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses., Results: Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P = .040)., Conclusion: The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor-positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed.

Purpose: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes)., Patients and Methods: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily., Results: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019)., Conclusion: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

Purpose: Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696)., Patients and Methods: Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) > or = 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m(2) weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m(2) added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral alpha .05, 355 events were needed and 400 patients planned., Results: Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS > or = 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity., Conclusion: The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.

Purpose: No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials., Methods: This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed., Results: Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance., Conclusion: This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.

Purpose: In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program)., Patients and Methods: Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively., Results: The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses., Conclusion: When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

Purpose: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated., Patients and Methods: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months., Results: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response., Conclusion: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

Purpose: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil., Patients and Methods: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNalpha-2a; 3 MU, three times weekly) for 12 months or observation., Results: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P =.07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P =.45), failure-free survival (P =.07), or progression-free survival (PFS; P =.5). Eighty-eight patients were randomly assigned to either IFNalpha-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS., Conclusion: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNalpha maintenance treatment did not prolong response duration.

Purpose: We explored the feasibility, toxicity, and preliminary results of a chemotherapy (CT) regimen, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), derived through hybridization, shortening, and intensification of a corresponding 10-drug alternating combination CAD/MOPP/doxorubicin, bleomycin, and vinblastine (ABV), effective in treatment of advanced Hodgkin's disease (HD)., Patients and Methods: Hybridization involved all drugs except CCNU and mechlorethamine, which were administered in alternating cycles; the length of therapy was reduced from nine to six cycles. The average projected drug doses during the six cycles were increased by 42%, with an overall 1.54 dose-intensification; epidoxorubicin was substituted for doxorubicin at equivalent tumoricidal doses. Radiotherapy (RT) was optional and its indications were limited., Results: Eighty assessable patients with previously untreated, advanced or unfavorably presenting HD were treated in nine cooperating institutions between 1988 and 1991. RT was delivered to 22 patients. Remissions were complete (CR) in 75 patients (93%), partial in three (4%), and null in two (3%). The median relative dose-intensity was 0.71 for the overall regimen. Three of five patients who failed to achieve CR, and two of the four who relapsed, received lower relative dose-intensive cycles. Nonhematologic toxicity was acceptable, but there was considerable hematologic toxicity. Fatal gastrointestinal bleeding was seen in one patient., Conclusion: Caution is advised due to the short median follow-up period. Nevertheless, in addition to the excellent response rate, (1) the results were reached through abbreviation, intensification, and hybridization of an existing alternating regimen; (2) RT had limited use in this program, which may have contributed to lowering the risk of second tumors; and (3) the results were obtained in a multicenter study (a condition that often impairs results from clinical trials).