Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma.

BACKGROUND: Combined modality treatment consisting of chemotherapy followed by localised radiotherapy is the standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long- term adverse effects such as secondary malignancies the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. OBJECTIVES: To assess the effects of chemotherapy alone compared to chemotherapy plus radiotherapy in adults with early stage HL . SEARCH METHODS: For the or i ginal version of this review, we searched MEDLINE, Embase and CENTRAL as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology and International Symposium of Hodgkin Lymphoma) from January 1980 to November 2010 for randomised controlled trials (RCTs) comparing chemotherapy alone versus chemotherapy regimens plus radiotherapy. For the updated review we searched MEDLINE, CENTRAL and conference proceedings to December 2016. SELECTION CRITERIA: We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in patients with early stage HL. We excluded trials with more than 20% of patients in advanced stage. As the value of radiotherapy in addition to chemotherapy is still not clear, we also compared to more cycles of chemotherapy in the control arm. In this updated review, we also included a second comparison evaluating trials with varying numbers of cycles of chemotherapy between intervention and control arms, same chemotherapy regimen in both arms assumed. We excluded trials evaluating children only, therefore only trials involving adults are included in this updated review. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. As effect measures we used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RR) for response rates. Since not all trials reported PFS according to our definitions, we evaluated all similar outcomes (e.g. event-free survival) as PFS/tumour control. MAIN RESULTS: Our search led to 5518 potentially relevant references. From these, we included seven RCTs in the analyses involving 2564 patients. In contrast to the first version of this review including five trials, we excluded trials randomising children. As a result, we excluded one trial from the former analyses and we identified three new trials.Five trials with 1388 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with the same number of chemotherapy cycles in both arms. The addition of radiotherapy to chemotherapy has probably little or no difference on OS (HR 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, moderate- quality evidence), however two included trials had potential other high risk of bias due to a high number of patients not receiving planned radiotherapy. After excluding these trials in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved OS compared to chemotherapy alone (HR 0.31; 95% CI 0.19 to 0.52; P <0.00001, moderate- quality evidence). In contrast to chemotherapy alone the use of chemotherapy and radiotherapy improved PFS (HR 0.42; 95% CI 0.25 to 0.72; P = 0.001; moderate- quality evidence). Regarding infection- related mortality (RR 0.33; 95% CI 0.01 to 8.06; P = 0.5; low- quality evidence), second cancer- related mortality (RR 0.53; 95% CI 0.07 to 4.29; P = 0.55; low- quality evidence) and cardiac disease- related mortality (RR 2.94; 95% CI 0.31 to 27.55; P = 0.35;low- quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. For complete response rate (CRR) (RR 1.08; 95% CI 0.93 to 1.25; P = 0.33; low- quality evidence), there is also no evidence for a difference between treatment groups.Two trials with 1176 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with different numbers of chemotherapy cycles in both arms. OS is reported in one trial only, the use of chemotherapy alone (more chemotherapy cycles) may improve OS compared to chemotherapy plus radiotherapy (HR 2.12; 95% CI 1.03 to 4.37; P = 0.04; low- quality evidence). This trial also had a potential other high risk of bias due to a high number of patients not receiving planned therapy. There is no evidence for a difference between chemotherapy alone and chemotherapy plus radiotherapy regarding PFS (HR 0.42; 95% CI 0.14 to 1.24; P = 0.12; low- quality evidence). After excluding the trial with patients not receiving the planned therapy in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved PFS compared to chemotherapy alone (HR 0.24; 95% CI 0.070 to 0.88; P = 0.03, based on one trial). For infection- related mortality (RR 6.90; 95% CI 0.36 to 132.34; P = 0.2; low- quality evidence), second cancer- related mortality (RR 2.22; 95% CI 0.7 to 7.03; P = 0.18; low- quality evidence) and cardiac disease-related mortality (RR 0.99; 95% CI 0.14 to 6.90; P = 0.99; low-quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. CRR rate was not reported. AUTHORS' CONCLUSIONS: This systematic review compared the effects of chemotherapy alone and chemotherapy plus radiotherapy in adults with early stage HL .For the comparison with same numbers of chemotherapy cycles in both arms, we found moderate- quality evidence that PFS is superior in patients receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. The addition of radiotherapy to chemotherapy has probably little or no difference on OS . The sensitivity analysis without the trials with potential other high risk of bias showed that chemotherapy plus radiotherapy improves OS compared to chemotherapy alone.For the comparison with different numbers of chemotherapy cycles between the arms there are no implications for OS and PFS possible, because of the low quality of evidence of the results.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND: Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES: To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS: In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS: As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Identifying melanoma patients with 1-3 brain metastases who may benefit from whole-brain irradiation in addition to radiosurgery.

BACKGROUND/AIM: To develop a tool for estimating the risk of developing new cerebral lesions in 69 melanoma patients receiving radiosurgery for 1-3 cerebral metastases. PATIENTS AND METHODS: Ten factors were investigated: lactate dehydrogenase (LDH), radiosurgery dose, age, gender, performance status, maximum diameter, location and number of cerebral lesions, extra-cranial spread, time between melanoma diagnosis and radiosurgery. Two factors, number of lesions and extra-cranial spread, were included in the tool. Scoring points were achieved by dividing the 6-month rate of freedom from new cerebral lesions by 10. RESULTS: Sum scores were 9, 11, 12 or 14 points. Six-month rates of freedom from new brain metastases were 28%, 63%, 59% and 92% (p=0.002). Three prognostic groups were designed: A (9 points), B (11-12 points) and C (14 points). Freedom from new cerebral lesion rates were 28%, 60% and 92% (p<0.001). CONCLUSION: Group A and B patients should be considered for additional whole-brain radiotherapy (WBRT).

Radiosurgery alone for 1-3 newly-diagnosed brain metastases from melanoma: impact of dose on treatment outcomes.

BACKGROUND/AIM: To compare different doses of stereotactic radiosurgery (SRS) for 1-3 newly-diagnosed cerebral metastases from melanoma. PATIENTS AND METHODS: Fifty-four patients were assigned to dose groups of 20 Gy (N=36) and 21-22.5 Gy (N=18). Variables additionally analyzed were age, gender, Karnofsky Performance Score (KPS), lactate dehydrogenase (LDH) before SRS, number of cerebral lesions, extracranial lesions, time from melanoma diagnosis to SRS. RESULTS: The 12-month local control was 72% after 20 Gy and 100% after 21-22.5 Gy (p=0.020). Freedom from new cerebral metastases (p=0.13) and survival (p=0.13) showed no association with SRS dose. On multivariate analyses, improved local control showed significant associations with SRS doses of 21-22.5 Gy (p=0.007) and normal lactate dehydrogenase levels (p=0.018). Improved survival was associated with normal LDH levels (p=0.006) and KPS 90-100 (p=0.046). CONCLUSION: SRS doses of 21-22.5 Gy resulted in better local control than 20 Gy. Freedom from new brain metastases and survival were not significantly different.