Salvage Chemotherapy Regimens Research Articles

Continuous infusion intermediate-dose cytarabine, mitoxantrone, plus etoposide for refractory or early relapsed acute myelogenous leukemia

6711 Background: Little attention has been paid to continuous infusion of intermediate- to high-dose cytarabine to increase the duration of drug exposure. We conducted a prospective phase II clinical trial to evaluate the efficacy and toxicity of continuous infusion intermediate-dose cytarabine-based salvage chemotherapy regimen in refractory and early relapsed AML. Methods: The chemotherapy regimen consisted of cytarabine (1 g/m2/d, 24-h iv infusion, d 1–5), mitoxantrone (12 mg/m2/d, short iv infusion, d 1–3), and etoposide (150 mg/m2/d, short iv infusion, d 1–3). Results: Of 33 patients enrolled in this study, 19 had refractory leukemia and 14 had relapsed leukemia. Seventeen patients (51.5%) achieved complete remission (CR). The cause of treatment failure was resistant leukemia in 13 and indeterminate in 3. Common severe non-hematologic toxicities were febrile neutropenia (87.9%), metabolic abnormalities (51.5%), gastrointestinal toxicities (27.3%), and hepatic toxicities (21.2%). These toxicities were manageable. Median duration of CR was 117 days and median overall survival was 219 days with 2 surviving patients in CR on 664 days and 1145 days after salvage chemotherapy. Conclusions: Continuous infusion intermediate-dose cytarabine along with mitoxantrone and etoposide could induce CR in significant portion of the patients with refractory or early relapsed AML, but remission duration was short. Continued efforts to improve treatment outcomes in patients with refractory or relapse AML should be made. No significant financial relationships to disclose.

Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma

There is currently no standard salvage chemotherapy regimen in relapsed and refractory lymphoma. Gemcitabine is a novel nucleoside analogue, which acts synergistically with cisplatin both in vitro and in clinical studies. We evaluated the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) in 41 heavily pretreated patients with relapsed and refractory Hodgkin's and non-Hodgkin's lymphoma. The best-achieved response rate (RR) was 79% (95% CI 64–91), with a complete RR of 21%. In patients with chemo-resistant disease, the RR was 63%. Myelosuppression was the main toxicity, the incidence of Grade 3 or 4 anaemia, neutropenia and thrombocytopenia was 17.1, 61.0 and 53.7% respectively. Only one patient had neutropenic sepsis and none of the patients suffered from haemorrhage. Grade 3 or 4 nonhaematological toxicity was minimal and stem cell mobilisation was not inhibited. GEM-P is an effective salvage regimen and its use prior to autologous stem cell transplant warrants further investigation.

A Phase II Trial of Dexamethasone, High-Dose Cytarabine, and Cisplatin (DHAP) in Combination with Rituximab as Salvage Treatment for Patients with Refractory or Relapsed Aggressive Non-Hodgkin's Lymphoma.

Purpose: With commonly used salvage chemotherapy regimens like DHAP, response and overall survival rates are unsatisfactory. We designed a multicenter phase II trial to evaluate the safety and efficacy of the combination of rituximab with the DHAP regimen in patients who relapsed after or were resistant to a CHOP-like regimen.Methods: 61 patients with relapsed or resistant aggressive B-cell NHL were included in this trial so far. The median age was 61,5 years. 39 patients were in first relapse; 21 had recurrence during the first 12 months after treatment. 5 patients had second or subsequent relapse, 17 had primary refractory disease. Treatment consisted of rituximab infusions (375 mg/m2 per dose) on day 1 followed by dexamethasone 40 mg d3–6 (d 3–5 in first cycle), cytarabine 2 x 2000 mg/m2 d 4 (2 x 1000 mg/m2 in first cycle), 2 x 1000 mg/m2 for patients > 60 years of age (2 x 500 mg/m2 in first cycle), and cisplatin 25 mg/m2 d 3–6 (d3–5 in first cycle) for a maximum of 4 cycles. When hematological toxicity did not allow continuation of chemotherapy on day 22, rituximab was given as single agent on day 22 and the next cycle was postponed until day 29.Results: The overall response rate in evaluable patients was 54.0%. 29.0% of patients achieved a complete response, 25% of patients had a partial response, 15.0% of patients had stable disease. 31.0% of patients showed progressive disease. Patients in first relapse achieved an overall response of 67.0 % as opposed to only 27.0% in patients with refractory disease. Grade 3/ 4 nausea and vomiting were the only severe toxicities attributed to rituximab in one patient. Main toxicities were neutropenia and thrombocytopenia. Grade 3/ 4 nephrotoxicity occured in 2 patients. Survival data will be presented at the meeting.Conclusions: Interim analysis of the data suggests that the combination of rituximab with the DHAP regimen in the treatment of relapsed or refractory aggressive lymphoma is feasible and effective. In view of the unfavorable prognostic factors in our patient population, response rates (ORR = 54%) are encouraging and warrant further investigation.

VIP (Etoposide, Ifosfamide, Cisplatin) in Adult Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors

Despite the fact that Ewing sarcoma family of tumors (ET) is chemosensitive, long-term survival is extremely rare for patients with primary refractory or recurrent disease. There is no standard salvage chemotherapy regimen available in this context. In this study the authors reviewed their experience with the combination of etoposide, ifosfamide, and cisplatin in adult patients with recurrent or refractory disease. From February 1997 through December 2001, they evaluated the efficacy of etoposide (75 mg/m2/day for 5 days), ifosfamide (1,200 mg/m2/day for 5 days), and cisplatin (20 mg/m2/day for 5 days) combination chemotherapy (VIP regimen), as second-line salvage therapy in 27 patients with recurrent or refractory ET. All patients were evaluated for response, time to progression, and overall survival. Twenty-one male and 6 female patients with recurrent (n = 14) and refractory (n = 13) disease were treated with the VIP regimen. Median age was 18 years (range, 16-34 years). Twenty-two patients were previously treated with vincristine, Adriamycin, ifosfamide, and actinomycin-D; and 5 patients were treated with cyclophosphamide, Adriamycin, and vincristine. Sites of recurrent or progressive disease included local (n = 3), distant (n = 11), and both local and distant (n = 13). A total of 129 cycles of VIP were given (median, 5 cycles/patient; range, 1-14 cycles/patient). One patient (4%) had a complete response (CR) and 8 patients (30%) had a partial response (PR), for an overall response rate of 34%. The median number of cycles given to patients with CR + PR was 6 (range, 3-14 cycles). Nine patients (33%) had stable disease and 9 (33%) had disease progression. Median time to progression and median overall survival were 6.6 months and 8.1 months respectively for all patients, and 12.8 months and 14.2 months respectively for responders. There were no toxic deaths. Major toxicities included grade IV granulocytopenia in 19 patients and grades III/IV thrombocytopenia in 15 patients. At a median follow-up of 8 months (range, 2-56 months), 24 patients died of disease progression, 2 patients are alive with disease, and 1 patient is alive with no evidence of disease. The authors conclude that the VIP combination is active in patients with recurrent/refractory ET, with acceptable toxicity, and offers good palliation. Cisplatin-based combination chemotherapy merits further investigation, possibly as first-line treatment in this disease.

Phase II study of salvage therapy with high-dose tamoxifen and oral etoposide for recurrent malignant glioma

Background: Salvage chemotherapy regimens for patients with recurrent glioma are limited in their efficacy. Reports of antitumor activity of the oral agents etoposide (VP-16®, Immunex Corporation) and high-dose tamoxifen (Nolvadex®, AstraZeneca) prompted this Phase II study. Tamoxifen and etoposide may be synergistic in their antitumor effects. Both agents are administered orally, are well tolerated individually and do not have overlapping toxicities. We report the results of a Phase II study of this combination as salvage therapy for patients with recurrent glioma. Methods: Patients received tamoxifen at an escalating dose from 120 mg/day to 240 mg/day over a 1-week period, after which time etoposide 50 mg/m2/day for 3 weeks was added to the regimen. Patients remained on tamoxifen continuously and the etoposide was repeated after a 2-week break. This 10-week cycle was repeated until tumor progression or unacceptable toxicity occurred. Response assessments using neuroradiographic imaging and clinical eval...

Therapeutic efficacy of chemotherapy with VIP for small cell lung cancer

To evaluate the effect of combination chemotherapy with etoposide plus ifosfamide and cisplatin (VIP) for small cell lung cancer (SCLC). One-hundred and twenty patients with localized SCLC who never received chemotherapy were randomly divided into VIP regimen group and EP regimen group. The response and toxicity were evaluated after 3 cycle chemotherapy with VIP or EP respectively. In addition, salvage chemotherapy by VIP was given to 25 patients, who had progression or recurrence of the cancer after treatment with EP regimen, and the response was assessed after 3 cycles of the treatment. In 118 evaluable patients, response rate was 89.6% for VIP regimen group and 78.3% for EP regimen group. There was no remarkable difference of response rates between the two groups. Toxicity of the two regimens was similar. However, complete response rate for VIP regimen group (43.1%) was significantly higher than that for EP regimen group (25.0%) (P < 0.05). In 23 patients who were progressive or relapsed after treatment with EP regimen, the complete response, partial response, progression and total response were 13.0%, 39.1%, 47.8% and 52.2% respectively. VIP regimen may be used as the first-line chemotherapy for localized SCLC, its efficacy is superior to that of EP regimen. VIP can also be used as salvage chemotherapy regimen for patients with SCLC who failed to EP regimen chemotherapy.

Trisomy 4 as the sole karyotypic abnormality in a case of acute biphenotypic leukemia with T-lineage markers in minimally differentiated acute myelocytic leukemia

We report an unusual case of acute biphenotypic leukemia with trisomy 4. A 22-year-old woman presented with acute leukemia characterized by the presence of two cell populations (prothymocytic and myeloblastic). The leukemic cells were resistant to standard induction chemotherapy and were cleared from the bone marrow only after a salvage chemotherapy regimen. To our knowledge, this is the fourth reported case of acute biphenotypic leukemia with trisomy 4 and perhaps the first case with T-lineage markers and acute myelocytic leukemia.

Docetaxel: promising and novel combinations in ovarian cancer.

Despite considerable progress over the past two decades in the management of advanced ovarian cancer, the majority of patients with this type of malignancy still die from their disease, and the search for new and improved first-line and salvage chemotherapy regimens continues. As part of this work, the antitumour activity and effect on survival of new chemotherapy combinations containing the novel taxane docetaxel are being explored. Dual therapy with docetaxel plus a camptothecin (a topoisomerase inhibitor) has shown promise in second-line treatment, and preliminary data indicate good activity of docetaxel in combination with gemcitabine. Triple-therapy studies have produced mixed results, but encouraging activity has been reported when the anthracycline, epirubicin, is added to docetaxel and carboplatin – sequential therapy with docetaxel, cisplatin and epirubicin is currently being assessed. Combinations of docetaxel, carboplatin and gemcitabine may also be of future interest. Early efficacy and tolerability results with novel combination chemotherapy regimens involving docetaxel thus offer the promise of additional progress in the chemotherapy of advanced ovarian cancer, and further trials should be encouraged.

Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy?

The role of adjuvant chemotherapy in early-stage epithelial ovarian cancer (EOC) has been controversial. We have previously reported the cases of patients managed with a policy of observation only. We now present the salvage rate for the patients in that study who experienced relapse. One hundred ninety-four patients with stage I EOC presenting between 1980 and 1994 received no adjuvant chemotherapy, but were treated with platinum-based chemotherapy at relapse. We calculated the progression-free survival (PFS) and overall survival (OS) for the whole cohort and the salvage rate for those who experienced relapse. We defined salvage as freedom from relapse for 5 years after platinum treatment. Sixty-one (31%) of 194 patients experienced relapse, and 55 received platinum-based chemotherapy. Twenty-four percent were progression-free at 5 years after this treatment. Clear-cell histology and cyst rupture before the patients' original surgery were independent prognostic factors for PFS after salvage chemotherapy. The OS for all 194 patients is 72% at 10 years (median follow-up, 8.7 years), with an 80% disease-specific survival (DSS). We have shown that some patients with stage I EOC can be successfully treated with a salvage chemotherapy regimen after a policy of observation only. Interestingly, approximately 30% of stage I patients who die within 10 years do so from causes other than EOC (OS, 72%; DSS, 80%). Our findings need to be taken into consideration when the results from recent randomized trials of adjuvant chemotherapy in this patient population (International Collaborative Ovarian Neoplasm Trial 1/European Organization for Research and Treatment of Cancer Adjuvant Chemotherapy in Ovarian Neoplasm Trial) are being discussed with patients.

Ifosfamide salvage treatment before autologous stem cell transplantation in patients with refractory and relapsed Hodgkin’s lymphoma: a GELA experience

Ifosfamide salvage treatment before autologous stem cell transplantation in patients with refractory and relapsed Hodgkin’s lymphoma: a GELA experience

A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy

To evaluate the efficacy and toxicity of capecitabine as a salvage chemotherapy regimen in Chinese patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) previously treated with platinum-based chemotherapy, 17 patients with recurrent or metastatic NPC previously treated with platinum-based chemotherapy as adjuvant or palliative treatments received oral capecitabine at a dose of 1.25 G/m 2 twice daily in 3-week cycles consisting of 2 weeks of treatment followed by rest period of 1 week. Seven patients had local recurrence, seven had distant metastases, one had loco-regional recurrence, and two had both local/regional recurrence and distant metastases. Patients received a median number of three cycles of capecitabine (range: 1–6). The median follow-up was 7.5 months (range: 3–25.3). All patients were included in the efficacy and adverse events analysis. Three patients (17.6%) achieved partial response and one patient (5.9%) achieved complete response, with an overall response rate of 23.5% (95% confidence interval, 7–50%). The duration of response's were 4.2, 5, 6+, and 23.1+ months. Nine patients (52.9%) had stable disease whereas four (23.5%) had progressive disease. The median time to progression was 4.9 months. The median survival was 7.6 months. Five patients are still alive with an estimated 1-year survival rate of 35%. Treatment-related adverse events were generally mild except hand–foot syndrome which occurred in 58.8% of patients. Capecitabine is an effective salvage regimen in patients with recurrent and metastatic NPC. Capecitabine as a single agent or in combination with other chemotherapeutic agents or treatment modalities should be further studied in NPC.

Time-intensified dexamethasone/cisplatin/cytarabine:an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease

BackgroundAn important variable affecting outcome in relapsed and refractory Hodgkin’s disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 3–4 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkin’s lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD. Patients and methodsPatients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 1–4, cisplatin 100 mg/m2 i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m2 i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 µg/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT. ResultsThe median age of the 102 patients included was 34 years (range 21–64 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors forresponse to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 0–6) and 48% (mean duration 1.4 days, range 0–11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 × 106/kg CD34+ cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients. ConclusionsA brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.

Gemcitabine Alone or Combined with Cisplatin in Relapsed or Refractory Multiple Myeloma

Gemcitabine is a pyrimidine nucleoside analog with antitumor activity against solid tumor malignancies and leukemia. We evaluated its activity as a single agent and combining it with cisplatin in relapsed-refractory multiple myeloma (MM). Sixteen patients with advanced MM received intravenous gemcitabine 1250 mg/mq (days 1, 8 and 15) as a single agent for a total of 3 monthly courses. The responders received another three courses, and the non-responders received three courses of gemcitabine 1000 mg/mq (days 1, 8 and 15) plus cisplatin 80 mg/mq (day 1). No grade 4 hematological toxicity was seen after gemcitabine treatment, whereas ≥ 3 grade neutropenia and thrombocytopenia were seen in 21 and 13% of the gemcitabine-cisplatin infusions, respectively. Non-hematological toxicity was negligible for both the regimens. After three courses of gemcitabine as a single agent, the response rate was 31% (1 complete response, 1 partial response and 3 minimal response). Eight patients (50%) achieved stable disease and 3 (19%) had disease progression. Ten patients received gemcitabine-cisplatin and were evaluable for the response. Two patients progressed, four maintained stable disease whereas four patients, unresponsive to gemcitabine, obtained a response (3 partial response and 1 minimal response). With a median follow-up of 13 months (range 8-17.5), 7 patients (44%) died, 5 (31%) had disease progression, 1 (6%) relapsed, 1 was still in partial response (+11 months) and 2 (13%) had a stable disease. Median time to treatment failure (TTF) was 8 months (CI 95%: 7.6-8.4) and median overall survival (OS) was 16 months (CI95%: 10-22). These results showed that gemcitabine and gemcitabine-cisplatin were feasible regimens and well tolerated in advanced relapsed-refractory MM. The response rates, the TTF and OS were similar to other salvage chemotherapy regimens; nevertheless, the quality of response was modest particularly after gemcitabine alone. Better results might be obtained combining gemcitabine with other chemotherapy compounds or with biologically based therapies.

Polyethylene Glycol-Liposomal Doxorubicin

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.

Clinical Outcomes Associated with very Late Relapses in Diffuse Large Cell Lymphoma

While the majority of patients achieve complete remission (CR) following treatment for diffuse intermediate-grade and immunoblastic non-Hodgkin's lymphoma, many will eventually relapse. It is known that late-relapsing patients have a better prognosis than those who relapse earlier; however, the optimal choice of therapy and clinical outcomes in this former group remain uncertain. We report here our experience with patients who develop a very late relapse of their disease, defined as occurring in the fifth year or later from the time of original diagnosis following a period of continuous CR. The overall poor prognosis in this group of patients justifies the use of more aggressive treatment approaches in the future, such as high dose therapy with stem cell support, rather than conventional salvage chemotherapy regimens.

Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis.

Relapsed extragonadal germ cell tumors patients (EGGCT) are treated with identical salvage chemotherapy regimens, as are patients with metastatic testicular cancer. This investigation evaluates the results of second-line chemotherapy in nonseminomatous EGGCT and tries to identify prognostic factors for survival. We conducted a retrospective review of 142 patients treated at eleven European and American centers between 1975 and 1996. All had received cisplatin-containing regimens as induction treatment. Twenty-seven of 142 patients (19%) were long-term disease-free, 11% with primary mediastinal and 30% of patients with primary retroperitoneal disease. Median follow-up since start of salvage treatment was 11 months (range, 1 to 157) for all patients and 45 months (range, 6 to 157) for surviving patients. Forty-eight patients (34%) received high dose chemotherapy with autologous bone marrow transplant at relapse, and 10 of these patients (21%) are continuously disease-free. Primary mediastinal location (P =.003), sensitivity to cisplatin (P =.003), elevated beta-HCG at relapse (P: =.04), and normal LDH at diagnosis (P =.01) were shown to be significant negative prognostic factors for overall survival in univariate; mediastinal location [relative risk ratios (HR) = 1.9; 95% confidence intervals (CI), 1.2 to 3.0] and sensitivity to cisplatin [HR = 2.4; 95% CI, 1.1 to 5.2] were significant negative prognostic factors in multivariate analysis. Although current salvage strategies will cure between 20% and 50% of recurrent metastatic testicular cancer, relapsed nonseminomatous EGGCT patients appear to have an inferior survival rate, in particular in case of primary mediastinal location. Mediastinal primary tumor and inadequate response to cisplatin-based induction chemotherapy have been identified as independent negative prognostic factors, both associated with an approximately two-fold higher risk for failure of salvage treatment.

Chemotherapy with Irinotecan (CPT-11), a Topoisomerase-I Inhibitor, for Refractory and Relapsed Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11), a DNA topoisomerase-I inhibitor, is now widely used in the treatment of various solid tumors, including colorectal, gastric, breast, lung, and ovarian cancer. Despite the good response shown in the late phase-II study, CPT-11 was not often employed in the treatment of malignant lymphoma, mainly because of severe leukopenia and diarrhea caused by the recommended schedule: 40 mg/m2 of CPT-11 on days 1 to 3, 8 to 10, 15 to 17, then discontinued for at least 2 weeks. In clinical use, administration of CPT-11 had to be ceased on days 15 to 17 in almost all cases, and on days 8 to 10 in a considerable number of patients. Subsequently, a lower dose schedule (less than 40 mg/m2) was developed. Our phase II trial employing a reduced dose of CPT-11 on days 1 and 2, plus ADM on day 3 with 3-week interval in patients with refractory and relapsed NHL showed a fairly good response of relapsed B-cell lymphoma and a substantial response of T-cell lymphoma with acceptable toxicity. The combination of a topoisomerase-I inhibitor (CPT-11) and a topoisomerase-II inhibitor is an interesting concept for the treatment of NHL. Another phase II trial in combination with CPT-11 and other anti-cancer drugs, particularly cisplatin or topoisomerase-II inhibitors, is warranted. A superior salvage chemotherapy regimen could be found in the future by investigating combinations of low-dose CPT-11 and cisplatin or topoisomerase-II inhibitors.

High-dose Chemotherapy with Hematopoietic Stem Cell Transplantation is Effective for Nasal and Nasal-type CD56+ Natural Killer Cell Lymphomas

CD56+ natural killer (NK) cell lymphomas occur frequently in the nasal and nasopharyngeal regions and carry a poor prognosis. We have studied seven cases with NK-cell lymphomas. These lymphomas showed the following immunophenotype: CD56+, CD2+, sCD3 and Epstein-Barr virus-encoded small RNAs (EBERs)+. Six patients had localized (stage I or II) disease involving the nasopharyngeal region, while one had stage III disease. One patient with stage I disease achieved a complete remission (CR) after treatment with involved-field irradiation, but subsequently relapsed and died. The remaining six patients received combination chemotherapy as primary treatment: five patients with localized stage I or II disease and one patient with advanced stage III disease. Responses to initial chemotherapy were generally poor. These six patients received a variety of salvage chemotherapy regimens, but never achieved a CR. Subsequently, four of six patients showed a highly aggressive clinical course and died of disseminated disease within 1 year from the diagnosis. Three of six patients received high-dose chemotherapy supported by syngeneic, autologous or allogeneic peripheral blood stem cell transplantation. Two of the three transplant patients achieved a CR and are now surviving in continuous CR. Our clinical experience suggests that myeloablative high-dose chemotherapy and bone marrow rescue by hematopoietic stem cell transplantation may be an effective salvage treatment modality for refractory NK-cell lymphomas and could be considered as a part of the initial therapy for these patients.

High-dose chemotherapy with hematopoietic stem cell transplantation is effective for nasal and nasal-type CD56+ natural killer cell lymphomas.

CD56+ natural killer (NK) cell lymphomas occur frequently in the nasal and nasopharyngeal regions and carry a poor prognosis. We have studied seven cases with NK-cell lymphomas. These lymphomas showed the following immunophenotype: CD56+, CD2+, sCD3- and Epstein-Barr virus-encoded small RNAs (EBERs)+. Six patients had localized (stage I or II) disease involving the nasopharyngeal region, while one had stage III disease. One patient with stage I disease achieved a complete remission (CR) after treatment with involved-field irradiation, but subsequently relapsed and died. The remaining six patients received combination chemotherapy as primary treatment: five patients with localized stage I or II disease and one patient with advanced stage III disease. Responses to initial chemotherapy were generally poor. These six patients received a variety of salvage chemotherapy regimens, but never achieved a CR. Subsequently, four of six patients showed a highly aggressive clinical course and died of disseminated disease within 1 year from the diagnosis. Three of six patients received high-dose chemotherapy supported by syngeneic, autologous or allogeneic peripheral blood stem cell transplantation. Two of the three transplant patients achieved a CR and are now surviving in continuous CR. Our clinical experience suggests that myeloablative high-dose chemotherapy and bone marrow rescue by hematopoietic stem cell transplantation may be an effective salvage treatment modality for refractory NK-cell lymphomas and could be considered as a part of the initial therapy for these patients.

Combination Chemotherapy with Methotrexate, Etoposide, and Actinomycin D for High-Risk Gestational Trophoblastic Tumors

Objectives. The goal of this study was to evaluate the efficacy, toxicity, and survival of patients with high-risk gestational trophoblastic tumors (GTTs) treated with a methotrexate–etoposide–actinomycin D (MEA) regimen without cyclosphosphamide or vincristine.Methods. Thirty-nine consecutive patients with high-risk GTTs (28 were defined high risk by WHO criteria) were treated with primarily the MEA regimen. Among them, 27 patients had received no prior chemotherapy and 12 had received prior chemotherapy. Survival, causes of treatment failure, and toxicity were analyzed retrospectively.Results. After treatment with the MEA regimen, 29 of 39 patients achieved primary remission (74.4%), 8 developed resistance (20.5%), and 2 died of widespread metastases and chemotherapy-related toxicity. All 8 patients who developed resistance were treated with high-dose 5-fluorouracil and actinomycin D (FA); 6 were salvaged and 2 died of refractory disease. Three patients relapsed; 2 were controlled with FA or cisplatin-based chemotherapy and 1 who refused further treatment died. The disease-free survival rate was 87%. WHO grade 4 leukocytopenia and thrombocytopenia with the MEA regimen occurred in 5.3 and 6.4%, respectively, of the cycles; other toxic effects were acceptable and manageable.Conclusions. At present, MEA chemotherapy (without cyclophosphamide or vincristine) is our treatment of choice for patients with high-risk GTT. Its toxicity is predictable and manageable. For patients who become resistant to MEA, new salvage chemotherapy regimens are needed.