The optimal radiation volume after first-line chemotherapy in Hodgkin lymphoma

Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT); however, this has not been clinically validated. The need for irradiation or optimal radiation volume after chemotherapy are not defined. The treatment results of 296 Hodgkin's disease patients receiving ABVD or BEACOPP-21 chemotherapy with consequent EFRT demonstrate CR/PR > or = 80% and 99% local disease control rate. Beam therapy with EFRT is possible to use if dose levels don't exceed 30 Gy. Higher doses demands reduction of volume of radiating target. In our opinion the optimum program of beam therapy involves 2 stages with maximal possible dose level EFRT followed by additional INRT. Those approaches offer perspectives for Hodgkin's disease treatment.     

Mitoxantrone, methotrexate, and 5-fluorouracil combination chemotherapy as first-line treatment in stage IV breast cancer

Fifty patients with Stage IV breast cancer were entered into a prospective Phase II trial of combination chemotherapy that consisted of mitoxantrone (10 mg/m2), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) given in a 3-weekly schedule. Objective response to treatment was seen in 18 of 48 assessable patients (38%). Responses were seen predominantly in the lung and pleura and the node and soft tissue sites of disease. The median duration of response was 7 months. Toxicity from treatment consisted predominantly of reversible leukopenia. Other toxicities such as nausea and alopecia occurred in less than one half of the patients in the study group. The combination was well-tolerated, and appears to be moderately effective.     

Management of advanced prostate cancer after first-line chemotherapy.

Hormone refractory prostate cancer (HRPC) causes substantial morbidity and mortality. There are increasing options for both first- and second-line therapy in the palliative treatment of patients with HRPC. Medications to control symptoms should first be optimized in patients with late-stage disease, and radiotherapy applied to dominant painful bone lesions. Docetaxel, mitoxantrone, satraplatin, and ixabepilone are active chemotherapeutic agents in the first- and/or second-line setting for patients with HRPC, and this may be true also of older drugs such as oral cyclophosphamide and vinorelbine. Radioisotopes such as strontium and samarium are useful for treatment of more generalized bone pain. Third-line hormonal maneuvers including glucocorticoids, ketoconazole, and estrogens can lead to further palliation in some patients, and there are provocative data that chemotherapy might restore hormonal sensitivity in a subset of patients.     

Effect of combination chemotherapy,duration of methotrexate administration,and Patient's age on methotrexate pharmacokinetics

Summary The kinetics of methotrexate were studied in a group of 59 patients after infusion of high doses. From the triexponential analysis of the serum concentration curve, rate constants and relative concentrations in non-circulating pools were calculated, using a linear mammillary three-compartment model. No significant variation as a function of dose (300–6,000 mg/m²) was observed. In circumstances the rapidly exchanging pool was a reflection of the circulating pool, suggesting that it is an extravascular, protein-bound pool of methotrexate. Considerable variations of the relative concentration and rate constants of the slowly exchanging pool were observed to be a function of the duration of methotrexate infusion, the presence of other drugs, and the patient's age. If this compartment is assumed to include the target cells for methotrexate, then the large variations observed could be responsible for individual differences in toxicity and/or effectiveness.     

Extending the duration of first-line chemotherapy in metastatic breast cancer: a perspective review

The treatment of metastatic breast cancer is mainly palliative, but optimal management might result in survival improvement as well. For this reason, many trials have attempted to optimize the therapeutic approach in this disease setting. Among the possible options, chemotherapy represents the backbone of the treatment and survival improvements that have been shown by the use of modern chemotherapeutic agents. Whereas the type of chemotherapy is generally dictated by patient characteristics and those of their disease, substantial controversy still remains on how long chemotherapy should be administered after disease control is achieved. In this review, we have analysed all available evidence on the duration of first-line chemotherapy in advanced breast cancer.     

Cisplatin, epirubicin, and lonidamine combination regimen as first-line chemotherapy for metastatic breast cancer: a pilot study

 We assessed the activity and tolerability of a cisplatin, epirubicin, and lonidamine combination regimen as first-line chemotherapy in 28 advanced breast cancer patients. The schedule of treatment was as follows: 60 mg/m² epirubicin followed by 40 mg/m² cisplatin given on days 1 and 2 every 21 days, with 450 mg lonidamine being given per os (three tablets) on days of chemotherapy administration and in the period intervening between one cycle and the next. Patients received a median of 5 (range 1 – 6) cycles. Overall, 22 patients were evaluable for response and 28, for toxicity. Four patients refused to continue the treatment after the first course, one was lost to follow-up, and one died due to toxicity (septic shock). The incidence of grade 3/4 nausea and vomiting was found to be greater than that expected with epirubicin and lonidamine alone. The addition of cisplatin resulted in an increase in platelet and hemoglobin toxicities, whereas the WBC toxicity did not differ from that expected with epirubicin and lonidamine. The hematological toxicity was found to be cumulative, leading to treatment delay in about 50% of patients at the fifth and sixth courses. The activity of this cytotoxic regimen was noteworthy, with the overall response rate being 81.8% (31.8% complete responses and 50.0% partial responses) in evaluable patients. This response rate decreased to 64.2% when all registered patients were included according to an intent-to-treat analysis. In conclusion, the association of cisplatin, epirubicin, and lonidamine given on the schedule described herein, appears to be very active but substantially toxic. We are now testing this combination in a randomized comparison, with the cisplatin dose being reduced to 30 mg/m² given on days 1 and 2. Received: 1 January 1997 / Accepted: 22 July 1997     

Optimal duration of first-line chemotherapy for advanced gastric cancer: data from the AGAMENON registry

Clinical and Translational Oncology - The optimal duration of first-line chemotherapy for patients with advanced gastric cancer is unknown. Diverse clinical trials have proposed different...     

Phase II study of capecitabine and cisplatin as first-line combination therapy in patients with gastric cancer recurrent after fluoropyrimidine-based adjuvant chemotherapy

To evaluate the efficacy and safety of capecitabine and cisplatin in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant therapy. Patients with histologically confirmed and measurable advanced gastric cancer that had relapsed after fluoropyrimidine-based adjuvant chemotherapy received oral capecitabine (1250 mg m(-2) twice daily, days 1-14) and intravenous cisplatin (60 mg m(-2) over 1 h, day 1) every 3 weeks. In total, 32 patients were enrolled, of whom 30 were evaluable for efficacy and 32 for safety. A median of 5 cycles (range 1-10) was administered. One patient achieved a complete response and eight had partial responses, giving an overall response rate of 28% (95% CI, 13-44%). The median time to progression and median overall survival were 5.8 months (95% CI, 4.1-7.5 months) and 11.2 months (95% CI, 5.5-16.9 months), respectively. Grade 3 neutropenia and thrombocytopenia were observed in 38 and 6% of patients, respectively. Grade 2/3 nonhaematological toxicities included diarrhoea (19%), stomatitis (19%) and hand-foot syndrome (31%). No grade 4 toxicity, neutropenic fever or treatment-related deaths occurred. Capecitabine in combination with cisplatin was effective and well tolerated as first-line treatment in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant chemotherapy.     

Salvage chemotherapy using a combination of fludarabine and cyclophosphamide for refractory or relapsing indolent and aggressive non-Hodgkin's lymphomas

The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/m2) and cyclophosphamide (300 mg/m2) for 3 consecutive days followed by G-CSF (5 microg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen. The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this "failure" regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients.     

Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer

Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC). From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good.     

Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy

BACKGROUND:

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first‐line palliative chemotherapy. There are, however, no published studies concerning second‐line treatment of the disease. Temozolomide has shown clinical effect in well‐differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first‐line treatment.

METHODS:

Twenty‐five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.

RESULTS:

One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression‐free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.

CONCLUSIONS:

Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first‐line chemotherapy. These results indicated that temozolomide may be used as second‐line treatment in PDEC. Cancer 2011;. © 2011 American Cancer Society.     

Outcome of second-line treatment after first-line chemotherapy with the GONO FOLFOXIRI regimen

PurposeFOLFOXIRI demonstrated higher efficacy compared to 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) as first-line treatment of metastatic colorectal cancer. We evaluated the outcome of second-line treatments among 196 patients treated with first-line FOLFOXIRI in three consecutive trials conducted by the Gruppo Oncologico Nord Ovest group.Patients and MethodsOne hundred seventy-two of 196 patients so far progressed and 136 (79%) received second-line therapies: 32 (24%) were rechallenged with FOLFOXIRI, 52 (38%) were treated with irinotecan- or oxaliplatin-based doublets, and 52 (38%) received fluoropyrimidine plus mytomicin C or single-agent chemotherapy. Only 10 patients received bevacizumab (3) or cetuximab (7) with chemotherapy. Activity and efficacy data were collected and subgroup analyses were performed according to the regimen administered.ResultsOverall response rate (RR) was 23%; median progression-free survival (PFS) and overall survival (OS) were 5.9 and 13.2 months, respectively. At an exploratory subgroup analysis, retreatment with FOLFOXIRI was associated with longer PFS (8.2 versus 6.3 months; P = .003, hazard ratio [HR] = 0.61) and OS (19.3 versus 14.0 months; P = .02, HR = 0.57) compared with doublets; single-agent chemotherapy or fluoropyrimidine plus mytomicin C was significantly lower in terms of RR (8%), PFS (3.0 months), and OS (8.7 months) compared with FOLFOXIRI or doublets.ConclusionsFirst-line FOLFOXIRI does not impair the efficacy of second-line treatments. In some patients rechallenge with FOLFOXIRI may represent a valid option, although potential imbalances in prognostic factors due to better patient selection should be considered.     

Successful treatment of disseminated extragonadal germ cell cancer with intensive conventional chemotherapy after first-line high-dose chemotherapy

High-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) support has been investigated as a first-line treatment in patients with poor risk germ cell cancer. However, effective management of patients with residual cancer after HDCT has not been well addressed, and the outcome in such patients is poor. Here, we report a case of disseminated germ cell cancer successfully treated with intensive conventional chemotherapy after HDCT. A 31-year-old man presented with a bulky mass at the retroperitoneum, which had invaded the lumbar and sacral vertebra, and multiple lung and liver metastases. The patient's serum beta subunit of human chorionic gonadotrophin (β-hCG) was elevated to 2600 IU (cut-off value <0.1 IU). At the time of diagnosis of poor risk germ cell cancer of extragonadal origin, he underwent two cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy and PBSC harvest followed by three cycles of HDCT with PBSC transplantation. The liver metastases disappeared. The retroperitoneal bulky mass and multiple lung metastases shrank but were still present, and the serum β-hCG level was not completely normalized. An additional three courses of BEP and five courses of VIP (cisplatin, ifosfamide, etoposide) normalized the β-hCG level. Pathological evaluation of the residual masses revealed no viable cancer cells at either site. The patient is alive without disease recurrence 5 years after completion of chemotherapy.     

Optimal duration of first-line chemotherapy for advanced non-small cell lung cancer: A systematic review with meta-analysis

BackgroundThe optimal duration of first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) has been a matter for debate for nearly 20 years. In order to elucidate this issue, a meta-analysis comparing the different durations of same treatments was performed.MethodsWe searched for all published randomised controlled trials (RCTs) comparing different durations of first-line treatment of advanced NSCLC. The MEDLINE, EMBASE, LILACS and CENTRAL databases were searched for RCTs comparing a defined number of cycles of chemotherapy versus continuing treatment until disease progression, or a defined number of cycles versus a higher number of cycles of the same chemotherapy. Trials including biological agents were excluded.ResultsSeven trials that included 1559 patients were analysed. Treatment for more than 4 cycles was associated with a non-statistically significant decrease in the hazard of mortality relative to shorter treatment (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.84–1.11; P = .65). In those treated with third-generation chemotherapy through the whole study time, treatment for more than 4 cycles was associated with a non-statistically significant increase in mortality (HR = 1.08; 95% CI = 0.90–1.28; P = .28). Patients receiving more chemotherapy had significant longer progression-free survival (HR = .75; 95% CI = 0.60–0.85; P < 0.0001) than the group with shorter duration of treatment. In an intent-to-treat analysis, there was no difference in the overall response rate between the groups (odds ratio (OR) = 0.78; 95% CI = 0.60–1.01; P = .96). Longer treatment was associated with more severe leucopaenia but with no significant increase in non-haematological toxicities.ConclusionsIn patients with advanced NSCLC the use of more than 4 cycles of first-line chemotherapy with third-generation regimens significantly increases progression-free survival but not overall survival and is associated with higher incidence of adverse events. There is no evidence to support continuous chemotherapy until progression in patients with lung cancer.