Including Induction Chemotherapy Research Articles

Serum CA 19–9 level as a surrogate marker for prognosis in locally advanced pancreatic cancer (LAPC)

15514 Background: Assessing the efficacy of treatment for locally advanced pancreatic cancer (LAPC) via CT is inadequate; radiologic responses are uncommon. We hypothesized that serum CA 19–9 level may serve as an alternative surrogate marker for treatment efficacy in LAPC. Methods: We conducted an analysis of 143 patients with LAPC treated at MDACC. Baseline, final, nadir and change in CA 19–9 levels were correlated with overall survival (OS). Factors included in our model were treatment regimen, grade, age, race and sex. Analysis was conducted using Kaplan-Meier product-limit survival probability estimates and log-rank tests. For the final multivariate Cox regression related to OS, non-significant variables were eliminated using a step-down fashion. Results: The median age was 62.4 years; 50.3% were male. 98 pts were treated on investigational protocols while 45 received non-protocol therapy. Treatments included induction chemotherapy (n=96), concurrent chemoradiation (n=116), and maintenance chemotherapy after chemoradiation (n=29). OS was 13.2 months (95% CI= 11.2, 17.6). On univariate analysis, age (p=0.02) and elevated final CA 19–9 (p<0.0001) correlated with worsened OS while decreased CA 19–9 (p<0.0001) and delivery of second line chemotherapy (p=0.02) correlated with improved OS. On multivariate analysis, the use of second-line chemotherapy correlated with an improved OS (HR 0.61, CI 0.38–0.98, p=.04) while an elevated post-treatment CA 19–9 correlated with worsened OS (HR 1.12, CI 1.05–1.19, p=.0004). In a Kaplan-Meier analysis patients with CA 19–9 improvement (n=90), a 50% decline correlated with improved OS (p=0.01). A Cox hazard ratio (univariate) for this group was 0.46 (CI 0.25, 0.85 p=.01). Conclusion: LAPC patients with elevated CA 19–9 levels after treatment have a poor prognosis; therefore, these patients should be considered for second-line chemotherapy. CA 19–9 decline by 50% or more is associated with an improved outcome. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, Merck, sanofi-aventis

Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: Optimal compliance and promising 4-year results

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.

Homoharringtonine and Low-Dose Cytosine Arabinoside Combined with G-CSF or GM-CSF Administered in Patients with Advanced Myelodysplastic Syndromes and Relapsed or Refractory Acute Myeloid Leukemia.

According to the FAB classification of myelodysplastic syndromes (MDS), subgroups of refractory anemia with excess blasts(RAEB) and refractory anemia with excess blasts in transformation(RAEB-t) are considered as high-risk MDS or advanced MDS which tend to involve into acute myeloid leukemia(AML). Even though various strategies have been in use, chemotherapy remains the main treatment option. With low remission rates, short duration of remission and high relapse rates, conventional chemotherapy for high-risk MDS and AML transforming from MDS is generally unsatisfactory. Relapsed or refractory AML, geriatric AML and secondary AML have a poor response to the classical induction chemotherapy. Studies indicate that CRs have occurred(8∼56%) at the cost of a high incidence of deaths from toxicity(24%∼64%). Although allogeneic stem cell transplantation could potentially be curative, it is appropriate for only a small subset of patients. This challenges us to work towards new reasonable therapeutic strategies. In vitro, studies have confirmed that granulocyte colony stimulating factor(G-CSF) can enhance the cytotoxic effects of S-phase-specific drugs such as Ara-C by the mechanism of driving myeloid leukemic cells of resting G0-phase into the cell cycle as well as intensifying the metabolism of Ara-C and anthracyclines in the leukemic cell. Recently the regimen of low-dose Ara-C and aclarubicin in combination with G-CSF(CAG regimen) has presented both well-tolerated and highly effective in treating the above categories of AML and MDS. The reported overall CR rate is 35∼75%. We designed a combination chemotherapy of homoharringtonine, low-dose cytarabine and G-CSF or GM-CSF(HAG priming regimen) for remission induction in this study which enrolled 42 patients with advanced MDS or AML between January 2002 and July 2005. 42 patients who received HAG chemotherapy were followed up till April 2006. Clinical and laboratory data of all these patients, which concerned with a)medical interventions including induction chemotherapy, post-remission treatment, and management of complications, etc; b)follow up for conditions of remission, relapse-free survival and overall survival after HAG induction therapy; c)adverse events following HAG induction therapy, were recorded in detail. Among Forty appraisable patients, 20 of them (50%) achieved complete remission (CR), including 66.7% patients with MDS-RAEB and 46.2% patients with refractory or relapsed AML. The fact of 80% patients with AML-M1 achieved CR, demonstrates a better response than those with other subtypes of AML. The overall response rate was 52.5%. After a follow-up of 6—47 months(median 23) from the date of remission, the median times of relapse-free survival and overall survival were 7.0±1.1 and 28±12.3 months, respectively. Meanwhile, these patients aged under 60-year-old who have achieved complete remission and received regular post-remission treatment showed a better survival rate. Myelosuppression was the most significant toxicity. More than 80% of patients experienced neutropenia or thrombocytopenia of grade III to IV after the first induction therapy. The incidences of infection and hemorrhage in the total of 64 induction courses were 43.8%(28/64) and 37.5%(24/64), respectively. Nonhematologic adverse-effects were minimal.

Paradigms in chemoradiotherapy

The efficacy of radiation in locally advanced non- small cell lung cancer (NSCLC) is limited. In a search for improving the outcome, particular attention has focused on the possibility of combining radi- ation with chemotherapy. The two most frequently used combined modality strategies include induction chemotherapy (chemotherapy preceding radiation) and concurrent chemoradiation. The former allows for drug delivery in full doses and in principle aims at a reduction of micrometastatic disease, whereas the latter is believed to improve locoregional control by making tumour cells more vulnerable to radiotherapy. The results of phase III trials of induction chemo- therapy were equivocal; nevertheless, three large trials using platinum-based regimens demonstrated significant survival benefit. The role of single agent platinum compounds (believed to be radiosensitising agents) applied concurrently with radiotherapy is controversial. Improved survival with this strategy was demonstrated in two studies, but several other studies were negative. Concurrent application of multidrug platinum-based chemotherapy in conventional sched- ules has been found relatively toxic yet feasible in selected patients. The direct comparison of sequential versus concurrent use of chemotherapy and radiation demonstrated the superiority of the latter, but at the expense of higher acute in-field toxicity. More recently, several new agents, including taxanes, vinorelbine and gemcitabine, have appeared promising in NSCLC. Their role in combined modality regimens warrants further clinical research. Chemotherapy as an adjunct to radiation has become a standard in fit patients with locally advanced NSCLC. The gain from the combined modality approach, however, is modest on average and should be weighted against increased early and late toxicity. Further studies built upon recent positive results should focus on identifying the means of optimal interactions between the two modalities. This research should define the most effective types and doses of anti-cancer agents as well as the optimal features of radiotherapy. Additionally, the knowledge of the biological characteristics of individual tumours, in particular their expected response to therapy, may contribute to further progress.

A phase II study of induction chemotherapy followed by concurrent chemoradiotherapy in elderly patients with locally advanced non-small-cell lung cancer

The optimal management of unresectable locally advanced non-small-cell lung cancer in older patients has not been defined to date. The present phase II study was planned to evaluate the activity and safety of platinum-based induction chemotherapy followed by concurrent chemoradiotherapy in elderly patients with locally advanced non-small-cell lung cancer. Patients received two cycles of paclitaxel (175 mg/m) and carboplatin (area under the curve: 5) day 1, every 3 weeks. Chemoradiotherapy (thoracic radiation therapy) was initiated on day 42 and consisted of 1.8 Gy daily, five times per week over 5 weeks (45.0 Gy target dose) followed by 10 2.0 Gy daily fractions. Concomitant chemotherapy was weekly paclitaxel 50 mg/mq followed by weekly carboplatin at an area under the curve of 2. The eligibility for patients: age 70 or older and histologically documented untreated non-small-cell lung cancer, locally advanced, unresectable, stage III A N2 bulky or III B. Thirty consecutive patients were enrolled onto the study. The median age was 73 (range 70-76). According to the intention-to-treat analysis, 1 month after the end of combined chemoradiotherapy, we observed complete and partial responses in one and 19 of the 30 patients, respectively, for an overall response rate of 66% (95% confidence interval, 45-76%). Median progression-free survival was 8.7 months (95% confidence interval, 3.4-37.8) and median survival was 15 months (95% confidence interval, 4.2-52.1). During the treatment, 12 patients (40.0%) experienced grade 3-4 neutropenia, two patients neutropenic fever, and three patients grade 3 anaemia and grade 3 thrombocytopenia, respectively. Grade 3 oesophagitis, during concomitant radiotherapy, was observed in six patients (20.0%). No treatment-related mortality was reported. The investigated sequential approach including induction chemotherapy followed by concurrent chemoradiotherapy appears safe and seems a reasonable chance for the treatment of locally advanced non-small-cell lung cancer in the elderly population.

Induction Therapy with Paclitaxel and Carboplatin Followed by Hyperfractionated Radiotherapy plus Weekly Concurrent Chemotherapy and Subsequent Consolidation Therapy in Unresectable Locallyadvanced Non-Small-Cell Lung Cancer

The purpose of this pilot study was to determine the safety and feasibility of a complete integrated approach, including induction chemotherapy with carboplatin/paclitaxel followed by accelerated hyperfractionated radiotherapy with concurrent chemotherapy, and then by consolidation chemotherapy for locally advanced stage III non-small cell lung carcinoma. Systemic doses of carboplatin AUC 6 and paclitaxel (200 mg/m2), 3 weeks out of 4, were planned as induction and consolidation chemotherapy. Weekly carboplatin AUC of 2 plus paclitaxel (50 mg/m2) were given during thoracic radiotherapy. Eighteen patients were enrolled: 10 were evaluated at the end of chemoradiation and 8 received consolidation chemotherapy. On an intent-to-treat basis, 55% of patients achieved a response after induction therapy, whereas chemoradiation and consolidation therapy increased the response rate by 33% and 16%, respectively. No patient experienced grade > 3 acute hematologic toxicity during systemic-dose chemotherapy. With the exception of one episode of a severe cardiac adverse event, non-hematologic toxicity was similarly tolerable. Severe acute adverse events observed during concurrent chemoradiation were mainly represented by esophagitis, resulting in interruption of the radiotherapy in 25% of patients. More notably, only one patient experienced serious non-hematologic late toxicity. Although the present approach seemed feasible, our data did not support any possible advantage in favor of this three-phase integrated treatment, and therefore the design will not be investigated in a subsequent phase II study.

Phase II Study of Induction Chemotherapy with Gemcitabine plus 5-Fluorouracil Followed by Gemcitabine-Based Concurrent Chemoradiotherapy for Unresectable Locally Advanced Pancreatic Cancer

To evaluate the efficacy and tolerability of a new treatment approach including induction chemotherapy (CT) and concurrent chemoradiotherapy (CRT) in unresectable, locally advanced pancreatic cancer (LAPC). Twenty-four patients with LAPC were enrolled in the study. They first received induction CT consisting of 5-fluorouracil (5FU) (500 mg/m2) and gemcitabine (1000 mg/m2), which were given weekly for 3 weeks of every 4. Patients showing a response or disease stabilization after 2 cycles of induction CT received CRT consisting of external beam radiotherapy (50.4-54 Gy in fractions of 1.8 Gy/day) and gemcitabine (350 mg/m2, weekly for 6 weeks). Patients without disease progression received 2 additional cycles of CT consisting of 5FU plus gemcitabine with the same doses and schedule as given in the induction CT. After the end of the study, 2 (8%) and 5 (21%) patients showed complete and partial responses, respectively. Five patients (21%) had disease stabilization. The grade 3 and 4 toxicities associated with CT were neutropenia (21%) and thrombocytopenia (4%). The grade 3 and 4 toxicities occurring in patients who received CRT were neutropenia (24%), thrombocytopenia (24%), diarrhea (18%), and nausea (12%). The median progression-free survival for all patients was 6 months (95% CI, 3.6-8.4), and the median overall survival was 11 months (95% CI, 8.16-13.84). The CRT approach of this study is moderately active and has an acceptable toxicity profile. However, the incorporation of combination CT into CRT at the present schedule could not produce any additional benefit over CRT alone. Newer agents with more systemic activity are clearly warranted.

Surgery for Small Cell Lung Cancer.

Retrospective analyses have shown that, following surgical resection, patients with early-stage small cell lung cancer have a survival rate comparable to that seen with non-small cell lung cancer, especially if combined modality therapy is used. Surgery has been employed in three specific instances: primary surgery followed by postoperative chemotherapy and, when indicated, mediastinal irradiation for tumors presenting as peripheral nodules; multimodality therapy including induction chemotherapy followed by surgery; and radiotherapy in "resectable," very limited disease and "salvage surgery" for patients with limited disease previously treated, recurring at the primary site. The results of such surgery in very selected patients yields the best reported results in the treatment of small cell lung cancer. These approaches are worthy of further study.

Concurrent Chemoradiotherapy for Unresectable Stage III Non–Small Cell Lung Cancer

Over the last two decades, several approaches to multimodality therapy have been investigated in patients with advanced unresectable non-small cell lung cancer. These include induction chemotherapy and concurrent chemoradiotherapy. Both approaches have been shown to be superior to radiation therapy alone. However, in several randomized trials, concomitant chemoradiotherapy was shown to be superior to the induction chemotherapy approach. It has been hypothesized that the addition of systemic dose sequential chemotherapy to concurrent chemoradiotherapy, either as induction or as consolidation chemotherapy, might further improve survival rates. Recently, the Cancer and Leukemia Group B reported on a randomized phase III trial directly evaluating the addition of two cycles of carboplatin and paclitaxel to concurrent chemoradiotherapy. In this study, induction chemotherapy failed to further improve survival rates of concurrent chemoradiotherapy. A previously conducted randomized phase II study also suggested no benefit from the addition of induction chemotherapy to concomitant chemoradiotherapy. Favorable phase II data have been published supporting the use of consolidation chemotherapy. However, to date, no large randomized study evaluating a possible benefit from consolidation chemotherapy has been completed. In addition to evaluating optimal sequencing strategies of combined modality therapy, current investigations are also focusing on the integration of novel agents, including chemotherapeutic and targeted therapies. Currently ongoing trials involving novel approaches are reviewed here.

Short-schedule cisplatin and vinorelbine as induction chemotherapy in stage IIIA(N2)-IIIB non small cell lung cancer (NSCLC)

7267 Background: Multimodality therapy including induction chemotherapy is the standard treatment for locally advanced NSCLC. Aim of this study was to evaluate the activity and the influence on resectability of a short, intensive schedule of cisplatin and vinorelbine as induction chemotherapy for patients (pts) with stage IIIA(N2)-IIIB NSCLC. Methods: Between 8/01 and 6/04 48 pts with pathological stage IIIA(N2)-IIIB were enrolled in a single institution. Three courses of cisplatin 50 mg/m2 days 1,2 and vinorelbine 25 mg/m2 days 1,3 were given every three weeks with prophylactic G-CSF from day 11 to 15. In absence of disease progression, pts were evaluated for resection and underwent surgery and/or radiotherapy (RT). Results: Pts characteristics were: stage IIIA/IIIB 15/33, M/F 43/5, PS 0/1 31/17. One CR (IIIA) and 37 PR (14/15 IIIA, 23/33 IIIB) were observed, for a RR of 79%. Twenty-six of 48 pts (54%), of which 13/33 stage IIIB (39%), underwent complete resection with 17/26 (65%) downstaged by chemother...

Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer

The aim of this study was to analyse prognostic factors for disease free interval (DFI) and overall survival (OS) among patients with larynx and hypopharynx cancer requiring a total laryngectomy. Three groups of patients were studied according to the type of treatment they received. Fifty-eight patients had total laryngectomy, 71 patients had organ preservation treatment including induction chemotherapy followed by exclusive radiotherapy, 26 patients received induction chemotherapy followed by salvage total laryngectomy. The studied potential prognostic factors were age, gender, performans status, primary tumor localization, T status, N status, tumor volume and tumoral EGFR level (fmol/mg protein). The multivariate analysis showed that both N status and tumor volume were significant for DFI and OS. EGFR level was significant only for patients treated by induction chemotherapy and exclusive radiotherapy (p = 0.05 and 0.05 for DFI and OS length, respectively). Among this group, patients with tumor EGFR levels lower and higher than 100 fmol/mg protein had 53% versus 22% and 51% versus 18% 5-year of DFI and OS rates, respectively (Log rank test: p = 0.001 and 0.0001). EGFR determination appears to be a powerful prognostic parameter for patients treated by induction chemotherapy followed by exclusive radiotherapy. Laryngectomy seems to erase the prognostic impact of EGFR expression. These results profile the use of EGFR targeting therapy for this category of patients.

Results of multimodal treatment for desmoplastic small round cell tumors

Purpose: Desmoplastic small round cell tumors (DSRCTs) are rare aggressive neoplasms that frequently present with large symptomatic intraabdominal masses. We examined the effects of multimodal therapy including induction chemotherapy, aggressive surgical debulking, and external beam radiotherapy on patients with DSRCT. Methods: Institutional Review Board permission was obtained. Sixty-six patients were diagnosed by histology, immunohistochemistry, and or cytogenetics as having DSRCT at our institution from July 1, 1972, to July 1, 2003. Data were collected on patient demographics, presenting symptoms, tumor location and extent, treatment regimen, and overall survival. Results: A majority of patients were male (91%), Caucasian (85%), and with a median age of 19 (7-58) years old at diagnosis. The most common presenting complaint was an intraabdominal mass (64%). In 63 patients (96%), the primary tumor was located in the abdomen or pelvis. Thirty-three (50%) had positive lymph nodes and 27 (41%) had distant parenchymal metastases at diagnosis. Overall, 3- and 5-year survivals were 44% and 15%, respectively. Twenty-nine of these patients (44%) underwent induction chemotherapy (P6), surgical debulking, and radiotherapy. Three-year survival was 55% in those receiving chemotherapy, surgery, and radiotherapy vs 27% when all 3 modalities were not used ( P < .02). Gross tumor resection was highly significant in prolonging overall survival; 3-year survival was 58% in patients treated with gross tumor resection compared to no survivors past 3 years in the nonresection cohort ( P < .000 01). Ten patients (15%) have no evidence of disease with a median follow-up of 2.4 years (range, 0.4-11.2 years). Conclusions: Multimodal therapy results in improved survival in patients with DSRCT. Aggressive surgical resection of these extensive intraabdominal neoplasms correlates with improved patient outcome.

Preoperative chemotherapy is essential for conservative surgery of Askin tumors

J Thorac Cardiovasc Surg 2003;125:428-9

Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Non-Small Cell Lung Cancer

Multiple concepts of combined modality therapy for locoregionally advanced inoperable non-small cell lung cancer have been investigated. These include induction chemotherapy, concomitant chemoradiotherapy, and intensified radiation therapy schedules. To date, induction chemotherapy has been validated in randomized prospective trials versus radiotherapy alone. Concomitant chemoradiotherapy has led to promising results when combination chemotherapy regimens were used in the phase II setting. In addition, concomitant chemoradiotherapy has been shown to be superior to induction chemotherapy in direct comparison. Finally, accelerated radiotherapy has been shown to lead to improved locoregional control and survival in one randomized study. Based on these observations, the Cancer and Leukemia Group B (CALGB study 9431) investigated the addition of either vinorelbine, paclitaxel, or gemcitabine to cisplatin. In this trial, patients with locally advanced and inoperable non-small cell lung cancer received two cycles of induction chemotherapy with an additional two cycles of concomitant chemoradiotherapy utilizing the same agents accompanied by standard radiation to a total dose of 66 Gy. One hundred eighty-seven patients were entered on this study. An early analysis showed the median survival time was 17 months for all patients entered on the trial. In the context of other CALGB studies, the data from this trial are encouraging, and the regimens used warrant further study.

48. Combined chemotherapy and radiation in locally advanced NSCLC

In locally advanced inoperable NSCLC radiotherapy has traditionally been considered the mainstay of treatment. Unfortunately, in most instances this method does not allow for eradication of bulky tumor in the thorax and does not prevent uncontrolled systemic disease. In consequence the prognosis of these patients is dismal and has remained essentially unchanged within the last decades. The five-year survival rates after irradiation varies between 3 and 10%. During the last decades several approaches have been tested to improve this outcome. Of those, particular attention has focused on combining chemotherapy and radiation. Two most frequently used strategies have included induction chemotherapy followed by radiation, or concurrent chemoradiation. The results of a few phase III trials comparing radiation alone with radiation supplemented by chemotherapy have demonstrated modest yet significant survival benefit from the combined approach. Two recent studies suggested that concomitant chemoradiation might be more effective than chemotherapy preceding radiation. The gain from the concurrent use of both modalities should however be weighted against increased toxicity. Further studies built upon recent positive results should focus on identifying means of optimal interactions between the two modalities. This research should define the most effective types and doses of anticancer agents as well as the optimal features of radiotherapy.

Concomitant radiochemotherapy with cisplatin-etoposide with or without surgery in stage III non-small cell lung cancers: results of a pilot study in 67 patients

This pilot phase II study was aimed at determining the feasibility, toxicity, response rate, local control, and survival of concomitant chemotherapy with cisplatin-etoposide and radiotherapy in stage IIIA or IIIB non small-cell lung cancer (NSCLC). Between February 1992 and February 1994, 67 patients with either medically or technically inoperable stage III NSCLC were treated with concomitant chemoradiotherapy. Thoracic radiotherapy was administered to a median dose of 60 Gy over 6 weeks. Concomitant chemotherapy consisted of cisplatin 20 mg/m2/day plus etoposide 50 mg/m2/day from day 1 to day 5, every 4 weeks over four cycles. Medically operable patients were evaluated for surgical resection after a 45-Gy irradiation and two cycles of concomitant chemotherapy. Only 14 patients could undergo subsequent surgery. With a median 49-month and a minimum 34-month follow-up, the overall survival rate was 42% at 2 years, and 34% at 4 years. The median survival was 19 months and the actuarial local control rate was 57% at 3 years. Toxicity was mainly associated with myelosuppression and esophagitis, but could be treated and was of short duration. Concomitant chemoradiotherapy with cisplatin and etoposide at this dose level provides a well tolerated outpatient regimen that results in high local control rate and encouraging survival at 2.4 years. A similar regimen is being compared in a phase III trial including induction chemotherapy followed by radiotherapy.

Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) accounts for 25% of childhood cancer. Clinical and biological parameters define prognostic categories and therapeutic approaches. For the majority of children with B-progenitor ALL, age (1-9 yrs) and white blood count (WBC<50,000) indicate standard risk disease; WBC>50,000 and age>9 yrs. define eligibility for high-risk protocols. Infants (<1 yr. old) are high-risk, frequently associated with chromosomal t(4;11) translocation and extramedullary disease. T-cell immunophenotype is usually associated with clinical high-risk features, including older age, high WBC, and extramedullary disease. T-cell immunophenotype is usually associated with clinical high-risk features, including older age, high WBC, and extramedullary disease. Current regimens include induction chemotherapy, consolidation (often including high-dose systemic methotrexate, MTX), and continuation phases; intensification or reinduction is incorporated for high-risk disease. Preventive CNS therapy is a critical component of therapy. Intrathecal (IT) chemotherapy (MTX +/- cytosine-arabinoside and hydrocortisone) and systemic agents provide adequate CNS therapy in standard risk patients. The "threshold" for using preventive cranial irradiation (Crl, 18 Gy) varies among protocols, but systematically includes those with T-cell ALL and WBS>50,000; other criteria may include B-progenitor ALL with WBC>100,000,philadelphia chromosome positive ALL, residual marrow disease at day 7, or male gender, For the 5% of children with CNS leukemia at diagnosis (defined as CSF with 5 or greater WBC/uL and positive cytology), Crl is administered at does of 18 to 24 Gy. Recent series show a CNS relapse rate approximating 5% Reinduction chemotherapy, IT therapy, and subsequent craniospinal irradiation ( typically 24, Gy Crl, 15 Gy spine) achieve durable secondary disease control in greater than 60% of cases with isolated CNS relapse. High-dose systemic MTX has virtually eliminated testicular relapse. CNS toxicities (including leukoencephalopathy) relate to systemic and IT MTX as well as Crl. Late neuropsychologicral data following Crl at 18 Gy show little intellectual deficit compared with children receiving MTX- based preventive therapy alone. Neuroendocrine dysfunction is apparent in long-term survivors following Crl at 24 Gy. The relative efficacy and toxicities of Crl versus more intensive MTX-based regimens are yet controversial. Overall disease-free survival in ALL approximates 70% in contemporary series.

Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center.

To review the 20 years of experience at M. D. Anderson Cancer Center with a combined-modality approach against inflammatory breast carcinoma. A total of 178 patients with inflammatory breast carcinoma were treated in the past 20 years at M. D. Anderson Cancer Center by a combined-modality approach under four different protocols. Each protocol included induction chemotherapy, then local therapy (radiotherapy or mastectomy), then adjuvant chemotherapy, and, if mastectomy was performed, adjuvant radiotherapy. Chemotherapy consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without vincristine and prednisone (VP). In protocol D, patients received an alternate adjuvant chemotherapy regimen, methotrexate and vinblastine (MV), if they did not have a complete response (CR) to induction chemotherapy. The median follow-up of live patients in group A was 215 months, in group B 186 months, in group C 116 months, and in group D 45 months. An estimated 28% of patients were currently free of disease beyond 15 years. At the time of analysis, 50 patients were alive without any evidence of disease. A further 12 patients died of intercurrent illness, and 15 patients were followed beyond 10 years without recurrence of disease. Among initial recurrence, 20% of patients had local failure, 39% systemic failure, and 9% CNS recurrence. Initial response to induction chemotherapy was an important prognostic factor. Disease-free survival (DFS) at 15 years was 44% in patients who had a CR to induction chemotherapy, 31% in those who had a partial response (PR), and 7% in those who had less than a PR. There was no improvement in overall survival (OS) or DFS among patients who underwent alternate chemotherapy (MV) compared with those who did not. Using surgery and radiotherapy as opposed to radiotherapy alone as local therapy did not have an impact on the DFS or OS rate. These long-term follow-up data show that with a combined-modality approach a significant fraction of patients (28%) remained free of disease beyond 15 years. In contrast, single-modality treatments yielded a DFS of less than 5%. Thus, using combined-modality treatment (chemotherapy, then mastectomy, then chemotherapy and radiotherapy) is recommended as a standard of care for inflammatory breast carcinoma.

Combined chemotherapy and radiotherapy versus surgery and postoperative radiotherapy for advanced hypopharyngeal cancer

Background Although the standard therapy for locally advanced hypopharyngeal cancer remains surgery and postoperative radiotherapy (RT), alternative treatment approaches include induction chemotherapy and RT. The purpose of this retrospective study was to compare the long-term outcome of these treatments performed in a single institution. Methods Twenty-six patients with advanced, resectable, squamous cell carcinoma of the hypopharynx were treated with induction chemotherapy and definitive RT (group I), reserving laryngectomy for salvage. The induction phase of therapy consisted of 2–3 cycles of cisplatin-based chemotherapy followed by conventional fractionated RT to doses of 66–70 Gy. The outcomes of this group of patients were compared with the outcomes of 30 patients with hypopharyngeal cancer who were treated at our institution with surgery and postoperative RT (group II). The median follow-up times of the surviving patients in groups I and II were 5 and 9 years, respectively. Results The local recurrence-free survival at 5 years from the completion of therapy for group I was 50%, compared with 69% for group II (p = .41). Among patients with T3–T4 primary tumors, the 5-year local control rates were 58% and 59% for groups I and II, respectively (p = .78). The likelihood of larynx preservation, free of local disease at 5 years for group I, was 52%. The 5-year neck recurrence-free survival for groups I and II were 47% and 69%, respectively (p = .66). Among patients with N2–N3 stage disease, the 5-year incidence of neck failure for groups I and II were 73% and 68%, respectively (p = .74). The 5-year distant metastases-free survival for groups I and II were 67% and 57%, respectively (p = .19). The 5-year disease-free survival rates for groups I and II were 30% and 42%, respectively (p = .9). The 5-year overall survival rates for groups I and II were 15% and 22%, respectively (p = .65). Conclusions Nonsurgical therapy for advanced-stage hypopharyngeal cancer provides survivorship comparable with that achieved with standard approaches of surgery and postoperative RT. However, despite the therapy, the outcome is poor. Future studies will need to explore new treatment strategies in an effort to improve upon the outcome for this group of patients. HEAD & NECK 1996;18:405–411 © 1996 John Wiley & Sons, Inc.

Combined chemotherapy and radiotherapy versus surgery and postoperative radiotherapy for advanced hypopharyngeal cancer

Although the standard therapy for locally advanced hypopharyngeal cancer remains surgery and postoperative radiotherapy (RT), alternative treatment approaches include induction chemotherapy and RT. The purpose of this retrospective study was to compare the long-term outcome of these treatments performed in a single institution. Twenty-six patients with advanced, resectable, squamous cell carcinoma of the hypopharynx were treated with induction chemotherapy and definitive RT (group I), reserving laryngectomy for salvage. The induction phase of therapy consisted of 2-3 cycles of cisplatin-based chemotherapy followed by conventional fractionated RT to doses of 66-70 Gy. The outcomes of this group of patients were compared with the outcomes of 30 patients with hypopharyngeal cancer who were treated at our institution with surgery and postoperative RT (group II). The median follow-up times of the surviving patients in groups I and II were 5 and 9 years, respectively. The local recurrence-free survival at 5 years from the completion of therapy for group I was 50%, compared with 69% for group II (p = .41). Among patients with T3-T4 primary tumors, the 5-year local control rates were 58% and 59% for groups I and II, respectively (p = .78). The likelihood of larynx preservation, free of local disease at 5 years for group I, was 52%. The 5-year neck recurrence-free survival for groups I and II were 47% and 69%, respectively (p = .66). Among patients with N2-N3 stage disease, the 5-year incidence of neck failure for groups I and II were 73% and 68%, respectively (p = .74). The 5-year distant metastases-free survival for groups I and II were 67% and 57%, respectively (p = .19). The 5-year disease-free survival rates for groups I and II were 30% and 42%, respectively (p = .9). The 5-year overall survival rates for groups I and II were 15% and 22%, respectively (p = .65). Nonsurgical therapy for advanced stage hypopharyngeal cancer provides survivorship comparable with that achieved with standard approaches of surgery and postoperative RT. However, despite the therapy, the outcome is poor. Future studies will need to explore new treatment strategies in an effort to improve upon the outcome for this group of patients.