Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma

The optimal use of "prophylactic" cranial irradiation (PCI) in patients with small cell lung cancer remains undetermined. This study reviews the impact of PCI, given at complete remission (CR), on neurologic relapse in 172 consecutive patients with small cell lung cancer treated in three sequential chemotherapy protocols at the University of Maryland Cancer Center. In the first study of 38 patients, none received PCI. In the second study of 109 patients, the first 28 achieving CR were randomized to 3000 rad of PCI in ten fractions (PCI+) or to observation (PCI-). Thereafter, based on interim analysis, all patients achieving CR received PCI. In the third study, to date, 25 patients achieving CR have received PCI. Overall, 169 patients were evaluable for neurologic relapse, and 30 of 90 patients achieving CR received PCI. Among all patients with CR, with adjustment for disease extent, there was a significant delay to any neurologic relapse (P = 0.01) and cerebral metastases (P = 0.02) for PCI+ compared to PCI- patients. Among PCI- patients with CR, cerebral metastases alone occurred in 28% as the sole site and in 33% as the initial site, whereas cerebral relapse occurred prior to systemic relapse in only one PCI+ patient with CR. Patient survival however, was not significantly altered by PCI. PCI at CR confers effective and worthwhile local control in the CNS, especially during periods of systemic response, and a small percentage of patients may benefit. Systemic drug resistance still determines overall survival.     

Prophylactic cranial irradiation in limited disease small-cell lung cancer in complete remission: a retrospective analysis

Recently a meta-analysis showed an improved survival probability of prophylactic cranial irradiation (PCI) in limited disease small-cell lung cancer (LD SCLC) in complete remission after chemotherapy. We evaluated treatment results of PCI+ and PCI- in these patients. Whether PCI (n = 65) or no PCI (n = 37) was administered did not depend either on patients or on tumour characteristics. After 2 years the incidence of brain metastases was 11% in PCI+ patients and 51% in PCI- patients. Both disease-free survival and overall survival were significantly longer after PCI. PCI reduces the incidence of brain metastases, prolongs brain metastases-free period, and overall survival in LD SCLC patients in complete remission after chemotherapy.     

Treatment of small cell lung cancer

The incidence of small cell lung cancer (SCLC) is declining in the United States (US). SCLC is nearly universally smoking-related and is very sensitive to both chemotherapy and radiation therapy. In contrast to non-small cell lung cancer (NSCLC), SCLC is staged as either limited-stage disease (LD) or extensive-stage disease (ED). Chemotherapy remains the essential component for treatment of all patients with SCLC, regardless of stage or performance status. In LD, the addition of radiation therapy improves survival over chemotherapy alone. However, the dose, timing and schedule of radiation are not well defined. Prophylactic cranial irradiation (PCI) reduces brain relapse rates, and modestly improves survival in patients in a clinical remission. Many chemotherapy agents and combinations result in high response rates in ED SCLC; however, median survival time remains 8-10 months. Cisplatin (or carboplatin) and etoposide is the standard doublet used in the United States. One study has shown cisplatin plus irinotecan to have a survival benefit over cisplatin plus etoposide, but confirmatory studies are needed. Patients with ED frequently relapse, and relapsed/refractory SCLC has a poor prognosis. The challenge remains to identify novel therapies and molecular targets to improve survival in SCLC.     

Brain metastases in patients with limited small cell lung cancer achieving complete remission. Correlation with TNM staging

We reviewed the brain metastases, after treatment, of 45 patients with limited small cell lung cancer who achieved complete remission by radiochemotherapy or curative operation. No patient received prophylactic cranial irradiation. The incidence of subsequent brain metastases was classified according to pretreatment staging as follows: two of 13 (15 percent) patients in stage I; two of ten (20 percent) in stage II; nine of 17 (53 percent) in stage IIIa; and four of five (80 percent) in stage IIIb. The brain metastases occurred from seven to 29 months after the start of treatment, and the median time of the occurrence was 13 months. Of 17 patients who developed brain metastases and who subsequently received cranial irradiation, there were two in whom relapse had occurred at no other site except the brain and who survived 26 and 79 months after the relapse, respectively. These data indicate that not all patients with limited SCLC achieving CR due to treatment necessarily benefit from PCI.     

Consideration of aggressive therapeutic strategies for primary testicular lymphoma

To evaluate the clinical features and treatment of primary testicular lymphoma, 45 cases were retrospectively evaluated. The median age of the patients was 59 years (range, 40-81) and most patients (76%) presented with Stages I-II. All patients underwent an orchiectomy, after which various treatments were given, chemotherapy alone in 37 patients (60%) and chemotherapy with involved field radiotherapy (IFRT) in 15 patients (33%). Prophylactic intrathecal chemotherapy was given to six patients; cranial irradiation was given in two patients. Eleven patients (24%) received prophylactic irradiation or surgery on the contralateral testis. In 40 patients able to be evaluated, complete response (CR) rate was 78%; 11 of 31 CR patients (36%) had relapsed. Relapse or disease progression was observed in 21 patients. The most frequent site (44%) was in the CNS. The median progression free survival and overall survival were 16 and 34 months, respectively. Ten patients who received prophylactic radiation to the contralateral testis had no relapse in this site. In six patients who received prophylactic intrathecal chemotherapy, there was no leptomeningeal progression, but brain parenchymal relapse occurred in two patients. In multivariate analysis, Stage I (P = 0.02) and additional IFRT after orchiectomy (P = 0.01) were found to be good prognostic factors. In conclusion, orchiectomy followed by intensive chemotherapy and IFRT including prophylaxis to the CNS and contralateral testis, should be considered as initial treatment in primary testicular lymphoma.     

Alternating chemotherapy, prophylactic cranial irradiation and late local thoracic irradiation for small-cell lung cancer

28 consecutive patients with small-cell lung cancer (SCLC) aged 48-78 years (with exclusion of 4 patients over 80 years) were treated with combination chemotherapy in the schedule AAA-BBB-AAA-BBB, where A consisted of cyclophosphamide 1,000 mg/m2, adriamycin 50 mg/m2, and etoposide 100 mg/m2 X 3, and B of cyclophosphamide 1,000 mg/m2, methotrexate 50 mg/m2 and vincristine 1 mg/m2 X 2. Patients in complete remission after 3 courses received prophylactic cranial irradiation, and thoracic irradiation was given after completion of chemotherapy. There were 3 toxic deaths. Of the patients with limited disease, 71% reached complete remission and 24% partial remission; in extensive disease these percentages were 36 and 45%, respectively. Three patients survived more than 2 years, 1 with recurrence of squamous cell carcinoma after 125 weeks. It is concluded that this scheme of combination chemotherapy is as effective as those reported earlier in remission rate and survival in SCLC. However, the addition of thoracic irradiation failed to prevent local relapse in 83% of the patients.     

Treatment of children with acute myeloid leukaemia who relapsed after allogeneic haematopoietic stem cell transplantation

Despite improvements in diagnosis and treatment, 30–40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo‐HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo‐HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease‐free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS . Of the 36 patients who received intensive chemotherapy after post‐HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5‐year DFS and OS were 32·6 ± 10·2% and 44·4 ± 11·1%, respectively. For all recipients of intensive chemotherapy, 5‐year OS was 31·6 ± 8·7%. Cumulative incidence of treatment‐related death was 14·4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2·42, 95% Confidence Interval 1·02–5·74, P = 0·045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post‐allogeneic transplant.     

Standard induction and low dose ara-C treatment in patients over 60 with AML or MDS

In this retrospective study, 61 induction treatment periods in 57 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were evaluated. According to the WHO performance status, 6 patients received no chemotherapy, 20 had low dose cytosine arabinoside (LD ara-C) induction courses, and 35 received standard induction consisting of daunorubicin and cytosine arabinoside. Untreated patients had a poor survival. Of the 20 patients with LD ara-C induction courses, 4 (20%) achieved complete remission (CR). Three patients (15%) died during induction. Of 35 patients with standard induction, 21 patients (60%) achieved CR. Toxicity was considerable - 11 patients (31%) dying during treatment. We conclude that patients over 60 yr of age with RAEB, RAEB-t or AML had a CR rate and survival comparable to those of younger patients if treated with standard induction chemotherapy at the cost of serious therapy-related complications. In patients who were judged not to be able to tolerate standard induction and who were subsequently treated with LD ara-C, complications occurred less frequently, but the CR rate was low and survival short.     

Long-term follow up of re-induction with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukemia previously treated with all-trans retinoic acid: results of 7 cases from a single institute

Seven patients experiencing first (n = 5) or second (n = 2) relapse of acute promyelocytic leukemia (APL) were treated with a new synthetic retinoid, Am-80. All 7 patients were previously treated with all-trans retinoic acid (ATRA). Am-80 was orally administered at a dose of 6 mg/m2 daily. Chemotherapy was combined in 3 patients because of leukocytosis. All 7 patients achieved a complete remission (CR) during periods ranging from 36-56 days (median 52 days). Adverse effects such as hyperlipidemia and skin lesions, were tolerable. After achieving CR, 3 patients underwent allogeneic bone marrow transplantation and 4 patients received only consolidation chemotherapy. In 2 of 3 patients who received allogeneic transplantation, relapse free survival has lasted for 9.7 and 28.3 months. Furthermore, in 2 of 4 patients who received only chemotherapy, relapse free survival has lasted for 84.7 and 90.1 months. Am-80 is an active agent for APL patients who have relapsed from ATRA-induced remission.     

Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal irradiation and stem cell transplantation for adult patients with lymphoblastic lymphoma

The therapeutic role of mediastinal radiotherapy and stem cell transplantation (SCT) in lymphoblastic lymphoma (LL) remains controversial. In a risk-oriented design, we adopted a flexible treatment program in which (1) patients with persistent mediastinal abnormality, evaluated by post-induction computed chest tomography, received mediastinal irradiation; and (2) those with persistence of minimal residual disease (MRD), evaluated by MRD analysis of the bone marrow, underwent SCT. Twenty-eight out of 30 patients (T-lineage, n?=?24; B-lineage, n?=?6) achieved a complete response. Of 21 patients with mediastinal mass, 13 (62%) achieved a complete response after chemotherapy alone, while 6 (28.5%) required additional irradiation. Eleven patients were evaluated for MRD: 6 were negative and 5 positive. On the basis of MRD findings and clinical risk characteristics, 14 patients underwent SCT, 13 received maintenance chemotherapy, and 1 had local radiotherapy. Five patients relapsed. Among the 14 non-irradiated patients with T-LL, the mediastinal recurrence rate was only 7%. After a median follow-up of 3.9?years, 21 patients who responded were alive without recurrence (75%). The projected 5-year survival, disease-free survival, and relapse rate were 72%, 77%, and 18%, respectively. This program induced high remission and survival rates, indicating the feasibility and the benefits potentially associated with a selective, response-oriented policy of mediastinal irradiation and a concurrent MRD-based strategy to assign adult LL patients to SCT.     

A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma ATL is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Preliminary results using zidovudine (AZT) and interferon-alpha (IFN) showed high response rate in ATL patients. We report a prospective phase II trial using AZT/IFN treatment for aggressive ATL. Nineteen ATL patients (15 acute and four lymphoma) were included in this study. Thirteen patients received AZT/IFN as initial treatment and six patients after initial chemotherapy. For the 17 patients with evaluable tumor, 13 responses were obtained with nine complete remissions (CR) and four partial remissions (PR). Response rate (RR) was 92% for patients who received AZT/IFN as initial treatment (58% CR and 33% PR). Toxicity was mild, mainly hematological. One patient died of fulminant viral hepatitis. Fifteen patients relapsed with a median event free survival (EFS) of seven months for the whole population (range 1-50+ months), 10 months for patients who received AZT/IFN as initial therapy and two months for patients who received initial chemotherapy. Median overall survival (OS) was 11 months for the whole population (range 1-82+ months) and 28 months for patients who entered CR. Three acute ATL showed prolonged CR (42, 52+ and 84+ months respectively) on maintenance therapy with AZT/IFN. This study confirms the efficacy and safety of AZT/IFN in ATL with high response and CR rates. Despite impressive prolonged CR of more than three years, most of the patients relapse stressing the need for additional therapy after achieving CR with AZT/IFN.     

A myelo dysplastic syndrome (refractory anemia with excess of blasts) occurred in a patient with small cell lung cancer during complete response

A myelo dysplastic syndrome (MDS), refractory anemia with excess of blasts (RAEB), that occurred in a patient with small cell lung cancer (SCLC) during a period of complete response (CR) was reported. A 66-year-old female patient was diagnosed as SCLC in March, 1985. Induction chemotherapy (CDDP, ADM, VCR, VP-16) achieved CR in May, 1985. She had received maintenance chemotherapy (CDDP, ADM, VCR (or VDS), VP-16) and chest irradiation (48.6 Gy) until May, 1988. The hematologic findings revealed MDS and she was admitted in June, 1989. She died one month after onset of MDS because of pneumonia. An autopsy showed no evidence of recurrence of small cell carcinoma in the primary site and other organs. There is a possibility of the risk of secondary leukemia following long term chemotherapy and irradiation in patients with SCLC, and the role of treatment after the achievement of CR in patients with SCLC remains to be clarified.     

Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation

The problem of brain metastasis from small cell carcinoma (SCC) of the lung has been appreciated for many years, but the magnitude of the problem has been underestimated. Recent studies have shown that the risk of brain metastasis increase as survival is prolonged. Although prophylactic cranial irradiation (PCI) has reduced the frequency of brain metastases, the effect on risk estimates of differences in the periods of observation was not evaluated. From 1974 through 1979, 131 patients with SCC of the lung who had no evidence of brain metastasis by radionuclide or computerized tomographic scan were treated in the Division of Therapeutic Radiology at the Medical College of Wisconsin Affiliated Hospitals. PCI was started in 1977; 57 patients received it and 74 did not. To correct for the differing periods of observation for the two groups, an actuarial calculation of the probability of brain metastasis was used. The calculated rate of clinical failure in the brain for patients who did not receive PCI was 28% at 12 months and 58% at 24 months. The calculated failure rate of the brain for patients who received PCI was 11% at 12 and 24 months. The difference in the probability of brain metastasis between the patients who did or did not receive PCI is highly significant (P less than 0.01). The true benefit of PCI becomes apparent only when the risk of intracranial metastasis is evaluated by methods that correct for incomplete followup. PCI eliminates the progressive increase in the risk of brain metastasis that accompanies increased survival and is important to maximize the probability for cure of patients with SCC.     

Retrospective analysis of treatment outcomes in 70 patients with t(8;21) acute myeloid leukemia

We conducted a retrospective study to evaluate outcomes and prognostic factors of newly diagnosed patients with t(8;21) acute myeloid leukemia (AML). There were 70 patients (43 men and 27 women) with a median age of 48 years old (range, 17～76 years old). Sixty-five patients achieved complete remission (CR) after induction chemotherapy. Fifty-seven patients received consolidation chemotherapy based on the policy of not performing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the time of first CR. Twenty-seven of the 57 patients relapsed (relapse rate, 47%). The median time from the achievement of the first CR to relapse was 307 days (96～1,256 days). A white blood cell count of more than 25,400/μl at diagnosis was associated with a higher relapse rate than a white blood cell count of less than or equal to 25,400/μl (75% vs. 43%, P=0.04). Nineteen of the 25 relapsed patients who received re-induction therapy experienced a second CR (second CR rate, 76%). Twenty-six patients (5 with first CR, 12 with second CR, and 9 without remission) received allo-HSCT. The five-year overall survival and disease-free survival rates were 61% and 45%, respectively. Patients with t(8;21) AML had a high CR rate, but about half of them relapsed. However, this report could not show prognostic factors for the identification of patients who should receive allo-HSCT at the time of their first CR.     

Role of prophylactic cranial irradiation in prevention of central nervous system metastases in small cell lung cancer. Potential benefit restricted to patients with complete response

The records of 332 patients with small cell lung cancer treated on National Cancer Institute protocols between 1970 and 1980 were reviewed to evaluate the association of prophylactic cranial irradiation with the development of central nervous system metastases and survival. Stage of disease, involvement of liver, bone marrow, and bone, and the degree of response to systemic therapy were prognostic features significantly associated with the development of central nervous system metastases. Prophylactic cranial irradiation had no influence on leptomeningeal, spinal, or epidural metastases, but a significant reduction In intracerebral metastases was observed. There was also a statistically significant improvement in overall survival in patients who received prophylactic cranial irradiation (p < 0.005), with actuarial two-year survival of 18 to 20 percent in patients who received prophylactic cranial irradiation and 5 percent in patients who did not receive prophylactic cranial irradiation. Among patients who achieved a complete response to systemic combination chemotherapy, with or without chest irradiation, fewer central nervous system metastases developed in those who received prophylactic cranial irradiation, (25 percent versus 52 percent at two years) and they survived longer (38 percent versus 16 percent at two years) than patients who did not receive prophylactic cranial irradiation, although neither difference was significant after adjustment for prognostic features. Central nervous system metastases were the first and only site of relapse from complete remission in 17 percent of patients with a complete response who did not receive prophylactic cranial irradiation, whereas no patient who received prophylactic cranial irradiation had a relapse solely in the central nervous system. These findings emphasize the need for a prospective study in which patients with a complete response randomly receive or do not receive prophylactic cranial irradiation after stratification for prognostic features, in patients who did not achieve a complete response to systemic therapy, there was no significant association between prophylactic cranial irradiation and the development of central nervous system metastases. The short survival of these patients and the high rate of central nervous system relapse over time (to nearly 100 percent for two-year survivors) argue against the use of prophylactic cranial irradiation in this subset of patients.     

Treatment of 61 patients with acute myelogenous leukemia at first relapse

Treatment results in the 61 adult patients with AML in first relapse were analyzed to establish a better strategy for this group of patients. These patients received reinduction chemotherapy during 1979-1988. Complete remission (CR) was obtained in 57.4% of the cases, and the probability of survival and remaining in CR at five years was 11.9% and 17.9%, respectively. The longer duration of initial remission was favorable factor for achieving second CR. Type of reinduction regimens which were different from those used in the initial induction phase did not influence the second CR rate. The use of different consolidation regimen appeared to favorably affect the survival and probability of remaining in CR.     

High dose chemotherapy with ABMT in soft tissue sarcomas: a report of 22 cases.

Twenty-two patients with locally advanced or metastatic soft tissue sarcomas received high dose chemotherapy with autologous bone marrow graft. Eleven patients receiving melphalan also received fractionated total body irradiation. Six patients (four in CR and two in PR) were intensified after first line therapy. Thirteen patients were grafted after chemosensitive relapse: seven in second CR, one in third CR, one in first PR, three in second PR and one in fourth PR. Three patients with primary refractory disease were intensified. The overall response rate in 66% in nine evaluable patients. The overall median survival and disease-free survival were 19 and 15 months, respectively. The actuarial survival rates at 2 and 5 years were 40% and 32% respectively. There was one treatment-related death due to infection. We conclude that high dose chemotherapy is feasible and provides reasonable response rates in patients with advanced soft tissue sarcomas.     

Autologous peripheral blood stem cell transplantation for acute myeloid leukemia

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.     

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.     

Hippocampal avoidance in prophylactic cranial irradiation for small cell lung cancer: benefits and pitfalls

Small cell lung cancers (SCLC) are a group of cancers that are clinically and pathologically different from other lung cancers. They are associated with high recurrence rates and mortality, and many patients present with metastatic disease. Approximately ten percent of SCLC patients have brain metastases at time of diagnosis, and the cumulative incidence of brain metastases increases to more than fifty percent at two years, even with optimal treatment. Hence, in patients without brain metastases at presentation, prophylactic cranial irradiation (PCI) is an important component of treatment along with systemic chemotherapy and radiotherapy. The goal of PCI is to decrease the incidence of subsequent symptomatic brain metastases in patients who show an initial response to the systemic treatment. Various clinical trials have evaluated the utility of PCI and found substantial benefit. Unfortunately, the long-term toxicity associated with PCI, namely the neuro-cognitive impairment that may develop in patients as a result of the radiation toxicity to the hippocampal areas of the brain, has raised concern both for patients and their treating physicians. Various techniques have been tried to ameliorate the neuro-cognitive impairment associated with PCI, including pharmacological agents and highly conformal hippocampal avoidance radiation. All of these have shown promise, but there is a lack of clarity about the optimal way forward. Hippocampal avoidance PCI appears to be an excellent option and a number of groups are currently evaluating this technique. Although there is clear benefit with this specialized radiation treatment, there are also concerns about the risk of disease recurrence in the undertreated hippocampal areas. This review attempts to compile the available data regarding the benefits and pitfalls associated with hippocampal avoidance PCI in the setting of SCLC.