Cycles Of Dose-intensive Chemotherapy Research Articles

A Scalp Dose Threshold for Preventing Permanent Alopecia in Scalp-Avoidance Whole-Brain Irradiation With Volumetric Modulated Arc Radiation Therapy for Pediatric Patients With Medulloblastomas

Although the overall survival of patients with medulloblastoma has dramatically improved, permanent alopecia significantly affects their quality of life. Therefore, we performed scalp-avoidance whole-brain irradiation with volumetric-modulated arc therapy (SAWB-VMAT) as a component of craniospinal irradiation (CSI). We retrospectively estimated the cutoff dose to prevent permanent alopecia in patients treated with SAWB-VMAT according to the St. Jude Medulloblastoma-96 protocol. Eight pediatric patients (median age 8.0 years, range 4.7-12.8 years) with medulloblastoma at our institution who we could take photographs following completion of the St. Jude Medulloblastoma-96 protocol treatment from May 2011 to August 2018 were enrolled in this study. All patients underwent CSI and boost radiotherapy followed by four cycles of dose-intensive chemotherapy. We defined permanent alopecia as hair loss persisting for 1 year after radiotherapy completion and 9 months after chemotherapy completion, as graded by two reviewers for each patient using the Severity of Alopecia Tool (SALT) score. Grades 3 and 4 alopecia were considered severe. Equivalent doses in 2-Gy fractions (assuming α/β = 2) to 50༅ of the scalp (EQD 50%) of SAWB-VMAT was significantly reduced compared to conventional WBRT (16.6 ± 3.6 vs. 20.2 ± 5.5 Gy, P = 0.038). The optimal EQD 50% cutoff was 19.9 Gy for severe permanent alopecia (area under the curve, 84%; sensitivity, 88%; specificity, 78%). The severe alopecia area was markedly reduced based on a 19.9 Gy cutoff (15.7 vs. 84.6 %, P = 0.0001). None of the patients who received SAWB-VMAT showed disease progression 5 years after starting radiotherapy. SAWB-VMAT significantly reduced the scalp EQD 50% and the estimated cutoff EQD 50% was 19.9 Gy. Scalp-avoidance whole-brain irradiation with volumetric-modulated arc therapy (SAWB-VMAT) remarkedly reduced equivalent doses in 2-Gy fractions (assuming α/β = 2) to 50༅ of the scalp (EQD 50%) comparing with conventional WBRT. None of the patients who received SAWB-VMAT showed disease progression 5 years after starting radiotherapy. The optimal EQD 50% cutoff was 19.9 Gy for severe permanent alopecia.

A Scalp Dose Cutoff That Prevents Permanent Alopecia in Scalp-Avoidance Whole-Brain Volumetric-Modulated Arc Radiotherapy for Pediatric Patients with Medulloblastomas

<h3>Purpose/Objective(s)</h3> Permanent alopecia significantly impacts the quality-of-life. We perform scalp-avoidance volumetric-modulated whole brain radiotherapy (SA-WBRT) as a component of craniospinal irradiation (CSI). However, the scalp cutoff dose that prevents permanent alopecia remains unknown. Here, we estimate the optimal cutoff dose for patients undergoing the St. Jude Medulloblastoma-96 protocol. <h3>Materials/Methods</h3> Eight pediatric patients (median age 8 years 0 months, range 4 years 8 months to 12 years 10 months) with medulloblastoma treated from May 2011 to August 2018 were enrolled. All patients underwent CSI and boost radiotherapy followed by four cycles of dose-intensive chemotherapy. Four patients were treated with conventional WBRT and the others with SA-WBRT. We defined permanent alopecia as hair loss persisting for 1 year after radiotherapy completion, graded by two reviewers for each patient using the SALT score; grades 3 and 4 alopecia were considered severe. We divided the scalp into top, back, left, and right areas and calculated the equivalent doses in 2-Gy fractions (assuming α/β = 2) to 50% of these areas (EQD50%); we compared these values to the alopecia grades. We drew receiver operating characteristic curves to determine the predictive performances of the EQD50% <i>in terms of</i> severe permanent alopecia and derived EQD50% cutoffs for the four scalp areas. <h3>Results</h3> The median follow-up period was 71 months (range 50.8-109.0 months) from start of radiotherapy. No patient experienced disease progression in the 5 years after radiotherapy, and no severe side effect was observed in patients undergoing SA-WBRT. Such patients tended to have less severe permanent alopecia than those who underwent conventional WBRT (4 vs. 10 regions, P = 0.07). The scalp EQD50% of SA-WBRT was significantly lower than that of conventional WBRT (16.6 ± 3.6 vs. 20.2 ± 5.5 Gy, P = 0.038). The optimal EQD50% cutoff for severe permanent alopecia was 21.2 Gy (area under the curve 83%; 83% sensitivity; 78% specificity). The severe alopecia area was markedly reduced when 21.2 Gy served as the cutoff (27.2 vs. 80.0%, P = 0.008). <h3>Conclusion</h3> SA-WBRT significantly reduced the scalp EQD50% and prevented severe permanent alopecia compared to conventional WBRT. The optimal cutoff dose was 21.2 Gy.

Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed Very High Risk Hodgkin Lymphoma (Stages IIIB/IVB) (AHOD0831): A Report from the Children's Oncology Group

PURPOSE: The AHOD0831 study tested a response-based treatment approach for pediatric patients with very high risk Hodgkin lymphoma (HL). Central response review following 2 cycles of dose intensive chemotherapy by FDG-PET was utilized to assign consolidation chemotherapy and risk-adapted radiotherapy. The primary outcome was second event-free survival (2nd EFS), defined as freedom from second relapse or malignancy. Because many patients with relapsed HL can be successfully cured with retrieval therapy, 2nd EFS more accurately reflects long-term overall survival (OS). AHOD0831 was designed to test whether this treatment protocol will maintain 4-year 2nd EFS ≥95%.PATIENTS AND METHODS : Patients aged ≤ 21 with stage IIIB or IVB HL were nonrandomly assigned to receive two 21-day courses of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid Early Response (RER) was defined by FDG-PET negativity (i.e. no activity above background), irrespective of size of residual masses. Patients with RER were consolidated with 2 additional cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine (IFOS/VINO) followed by 2 more cycles of ABVE-PC. Radiotherapy (RT), 21 Gy in 14 fractions, was administered to sites of initial bulky involvement (large mediastinal mass, nodal aggregate >6cm, splenic macronodular involvement) and regions of SER. For the primary aim of 2nd EFS, second events were defined as any relapse/progression of HL or SMN, new SMN or death after a first event which can be relapse/progression, SMN, persistent bone marrow involvement at completion of chemotherapy, or biopsy proven HL for SER at completion of chemotherapy.RESULTS: Among 165 eligible patients, median age was 15.8 yrs (5.2-21.4), 61% were male, 71 (43%) were stage IIIB, and 94 (57%) IVB. 50% were RER (stage IIIB: 58%; IVB: 45%). At time of current analysis the median follow-up was 42 months. 2nd EFS at 4 years is 89.8% (95% CI:80.8%-94.8%), below the projected baseline with 4-yr rate of 95% (P=0.01). Subgroup analyses showed that 4 yr 2nd EFS for RER (n=77) is 91.9% (76.3%-97.4%), SER (n=68) is 87.8% (75.8%-94.1%) and stage IVB 89.6% (76.3%-95.7%). 20 patients were excluded from 2nd EFS analysis secondary to premature termination or deviation of protocol therapy. 31 patients had reported at least one event for EFS (first event: 29 relapse/progressions, 1 SMN, and 1 death secondary to disseminated fungal infection during RT). Standard 1st EFS rates at 4 yrs are: 80.2% (73%-85.6%). 4 yr OS 95.9% (90%-98.4%). 12 SER patients had persistent PET positive lesions at end of chemotherapy. Eight of these 12 had clinical evidence of active disease (3 biopsy-proven HL, 2 with progressive disease by clinical or radiographic criteria, and 3 later relapses). In retrospective analysis, no specific Deauville score could be identified to predict which patients were at highest risk for progression.CONCLUSIONS: Among pediatric patients with very high risk HL (IIIB, IVB), a response directed approach utilizing limited chemotherapy (4 cycles for RER; 6 cycles for SER) and risk directed RT did not reach the ambitiously high pre-specified target for 2nd EFS. However, 4 year EFS and OS rates are comparable with results of recent trials for this population (POG 9425: IIIB/IVB, n=88: 4 yr EFS 81.7% (71.8%-88.3%); 4 yr OS 92.9% (84.9%-96.8%)). Our study achieved these similar outcomes, despite the reduction in RT volumes from historical involved fields (which did not account for relapse risk). Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression. Novel approaches incorporating enhanced risk stratification beyond stage and B symptoms, identification of better predictive factors beyond PET response, and incorporation of novel agents are still needed for this highest risk group of patients with newly diagnosed pediatric HL. DisclosuresNo relevant conflicts of interest to declare.

Nail dystrophy due to dose-intensive chemotherapy

A 27-year-old male was diagnosed with stage IIB Hodgkin’s lymphoma with bilateral involvement of cervical, supraclavicular and axillary lymph nodes. Additionally, he had a large mediastinal mass ([1/3 of the maximal thoracic diameter) and an elevated erythrocyte sedimentation rate ([30 mm/h) which classified as an advanced stage disease according to the treatment algorithm of the German Hodgkin’s Lymphoma Study Group (GHSG). Accordingly the patient was treated within the HD18 trial with two cycles of ‘‘escalated’’ BEACOPP [1] (bleomycin, etoposide, adriamycine, cyclophosphamide, vincristine, prednisone, and procarbazine) at a 3-week interval. An interim fluorodeoxyglucose positron emission tomography performed after completion of the second cycle did not reveal residual lymphoma activity. The patient therefore was randomised to receive only two more cycles of escalated BEACOPP. On physical examination a month after completion of therapy, the patient showed four white rings on all finger nails, one for every cycle of chemotherapy comparable to year rings in tree trunks. Another patient, a 31-year-old female was also diagnosed with stage IIB Hodgkin’s lymphoma and bilateral, perihilar involvement and a mediastinal mass of 9.5 cm. Despite a negative PET result after two cycles of BEACOPP, the patient was randomized to receive another six cycles within the standard treatment arm. Figure 1b shows her fingernails after four cycles of dose-intensive chemotherapy. Post-chemotherapy dystrophy of the nails is regularly encountered in daily oncologic practice, e.g., up to 60% of

Reduced risk of secondary leukemia with fewer cycles of dose‐intensive induction chemotherapy in patients with neuroblastoma

We report a prospective study of secondary leukemia (SL)/myelodysplastic syndrome (MDS) in neuroblastoma (NB) patients treated with > or =5 cycles of dose-intensive chemotherapy. NB patients received induction with high-dose cyclophosphamide (4,200 mg/m(2))-doxorubicin (75 mg/m(2))-vincristine (cycles 1, 2, 4, 6, 8), and high-dose cisplatin (200 mg/m(2))-etoposide (600 mg/m(2)) (cycles 3, 5, 7). Bone marrow was examined every 1-3 months for > or =36 months, with inclusion of extensive chromosomal studies 1-3 months post-induction and 1-2x/year thereafter. One hundred eight four patients received 5 (n = 76), 6 (n = 45), 7 (n = 59), or 8 (n = 4) cycles. Eight patients developed SL/MDS (only one each in the 5- and 6-cycle groups), at 12-50 months, including two cases detected in surveillance studies. Among 108 patients who received > or =6 cycles, the 5-year cumulative incidence was 7.1% (95% CI: 2%, 12.2%), versus 0% among 54 patients who received 5 cycles without maintenance oral etoposide. Five-year cumulative incidences were 1.46%, 2.28%, and 8.47% among patients in the 5-, 6-, and 7-cycle groups, with fewer cycles having a significantly lower risk (P = 0.048). There was no significant association of risk with potentially leukemogenic consolidative treatments (targeted radiotherapy, myeloablative therapy, and oral etoposide). Reducing the number of dose-intensive cycles significantly decreases the risk of SL/MDS, yielding 5-year rates matching the low range (0.4-2.2%) reported for moderate-dose combination chemotherapy regimens used against other pediatric solid tumors.

A comparison of multiple and single cycles of dose-intensive chemotherapy with reinfusion of docetaxel or paclitaxel mobilized peripheral blood progenitor cells in solid tumor

834 Background: To compare the clinical outcomes of multiple and single cycle dose-intensive induction therapy with autologous stem cell rescue among 48 patients with recurrent or metastatic solid tumors. Methods: Forty-eight patients(22 male, 26 female, median age was 48, ranged from19 to 73, 20 Breast cancer,6 Ovarian cancer,8 NSCLC,9 SCLC, 4 Seminoma and 1 Synovical carcinoma) were enrolled into the research. Patients were randomized to receive mobilization chemotherapy consisting of docetaxel 110mg/m2 on d1 or paclitaxel 175mg/m2 for 24 hours by continuous infusion. Patients were premedicated with dexamethasone 8mg p.o. every 12h×3 doses starting 24h prior to chemotherapy. The chemotherapy regimen was chosen based on the tumor type regardless of HDC cycle. Twenty-seven patients received 3 cycles of dose-intensive chemotherapy while 21 patients received a single cycle. Results: A significantly higher clinical response rate(CR plus PR) was observed for patients receiving 3 cycles of dose-intensive chemotherapy compared to who received a single cycle(21/27 vs 10/21,p=0.030). The 3 cycle groups also had a significantly higher 2 year survival. At a median follow-up of 40 (36–46) months, the probabilities of survival following single and multiple cycle chemotherapy were 61.90% (95% confidence interval (CI), 38.08%–78.80%) and 81.48% (95% CI, .61.09%–91.84%), respectively. The median event free survival (EFS) and the median overall survival (OS) have not yet been reached. Conclusions: Standard dose docetaxel or paclitaxel, combined with G-CSF, is an effective and well-tolerated mobilization regimen in patients with recurrent or metastatic solid tumors. Multiple cycles high dose chemotherapy has been shown to be feasible and safe in patients with these recurrent or metastatic solid tumors. No significant financial relationships to disclose.

Multicyclic dose-intensive chemotherapy with circulating progenitor cell support for high-risk primary breast cancer.

The feasibility and safety of the administration of multiple cycles of dose-intensive chemotherapy (CT) supported with repeated reinfusions of circulating progenitor cells (CPCs) were evaluated in a prospective study of adjuvant initial therapy of poor-prognosis breast cancer. Eighteen patients with resectable breast cancer involving >/= 10 axillary nodes or >/= 5 axillary nodes and negativity of the estrogen receptor status received a cycle of standard FEC regimen (5-FU 600 mg/m2, epirubicin 60 mg/m2, CTX 600 mg/m2, i.v. on day 1) followed by G-CSF as CPC mobilization technique. Collected CPCs were fractionated and reinfused, with G-CSF, after each of the 4 subsequent cycles of high-dose FEC (HD-FEC) (5-FU 750 mg/m2, epirubicin 120 mg/m2, CTX 3 g/m2, i.v.) planned at 21 day intervals. The median numbers of CD34+ cells and CFU-GM collected (with one or two leukaphereses per patient) were 9.7x10(6)/kg (range: 2.5-22.9) and 9.9x10(4)/kg (range: 1.9-27.3), respectively, and day 9 was the median first day of procedure (range: 8-12) after FEC. All patients received the 4 courses of HD-FEC (for a total of 72 cycles). Hemopoietic recovery was rapid after each cycle and there was no treatment-related delays in CT administration. Mucositis was the major non-hematological toxicity. There were 2, 3, 7 and 9 episodes of WHO grade 3/4 mucositis in cycles 1, 2, 3 and 4, respectively. These severe episodes lasted a median of 4 days (range: 2-6) but no patient required parenteral nutrition. The mean +/- SD total hospital stay lasted 10 +/- 2 days. The delivery of 4 cycles of dose-intensive FEC CT supported by CPCs (mobilized with a single course of standard-dose FEC + G-CSF) is feasible and safe. It could represent an effective alternative strategy to other more aggressive programs for the adjuvant therapy of high-risk early breast cancer.

Cycles of Dose-Intensive Chemotherapy with Peripheral Stem Cell Support in Persistent or Recurrent Platinum-Sensitive Ovarian Cancer

Objective.The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. Methods.Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m 2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m 2) and cyclophosphamide (1.5 g/m 2with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m 2every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. Results.Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0–35%). Conclusion.Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.

Reinfusion and serial measurements of carboplatin-mobilized peripheral-blood progenitor cells in patients receiving multiple cycles of high-dose chemotherapy.

To examine the ability of carboplatin to mobilize peripheral-blood progenitor cells (PBPCs) and to examine the impact of infusing these cells on myelosuppression following multiple cycles of high-dose therapy. Fluctuations in circulating progenitor cell concentration following repeated cycles of this therapy were also measured. Eight patients received a total of 20 cycles of carboplatin 1,200 mg/m2 per course, granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d, and PBPC reinfusion every 28 days. PBPC were collected following 1 week of GM-CSF and following the first and second cycles of chemotherapy. Hematologic toxicity was correlated with the number of progenitor cells reinfused per cycle. The concentration of PBPC per milliliter of blood was measured at study entry, following GM-CSF priming, and after each cycle of chemotherapy. We observed a strong inverse correlation between the number of PBPCs (CD34 and colony-forming unit granulocyte-macrophage [CFU-GM]), but not mononuclear cells (MNCs) reinfused and the days with neutropenia less than 500/microL and platelets less than 20,000/microL. Compared with baseline levels, the circulating PBPC concentration increased up to 27-fold following the first course of chemotherapy, but decreased toward, and eventually below, baseline following the second and third cycles of carboplatin. PBPC reinfusion directly correlated with a reduction in myelosuppression following high-dose carboplatin chemotherapy. While high-dose carboplatin plus GM-CSF leads to a substantially greater mobilization of PBPC than GM-CSF alone, this effect is lost after multiple treatment cycles. These results emphasize the importance of early procurement and value of PBPC reinfusion in conjunction with multiple cycles of dose-intensive chemotherapy.

Use of peripheral-blood progenitor cells abrogates the myelotoxicity of repetitive outpatient high-dose carboplatin and cyclophosphamide chemotherapy.

Attempts to increase dose-intensity in clinical practice have been limited by cumulative hematologic toxicity despite the use of hematopoietic growth factors. To address this problem, we designed a study to determine whether four cycles of dose-intensive chemotherapy with carboplatin could be administered in the outpatient setting using granulocyte-macrophage colony-stimulating factor (GM-CSF) and peripheral-blood progenitor cells (PBPCs) that had been harvested before initiation of treatment. An initial cycle (cycle no. 0) of cyclophosphamide 4 g/m2 followed by GM-CSF was used to mobilize PBPCs harvested by leukapheresis for 6 consecutive days. Cycles no. 1 through 4 consisted of outpatient carboplatin 600 mg/m2 and cyclophosphamide 600 mg/m2 followed by GM-CSF 5 micrograms/kg subcutaneously (SC) twice per day every 28 days. In cycle no. 1, PBPC were not reinfused to assess the effects of GM-CSF alone. In cycles no. 2 through 4, PBPCs were reinfused on day 3 in an outpatient setting. In eight assessable patients, the addition of PBPCs in cycle no. 2 resulted in a significant reduction in the median duration of thrombocytopenia less than 20,000/microL (6.5 v 1 day; P = .016), days to platelets more than 50,000/microL (20.5 v 15 days; P = .020), number of platelet transfusions (five v 1.5; P = .016), and duration of neutropenia (absolute neutrophil count [ANC] < 1,000/microL (7 v 2.5 days; P = .008) when compared with cycle no. 1. Dose-limiting hematologic toxicity, defined as more than 7 days of platelets less than 20,000/microL or ANC less than 500/microL, was observed in four of eight patients during cycle no. 1, but not during cycles no. 2, 3, and 4 of chemotherapy supported by PBPCs (a total of 19 cycles in eight patients). Five of eight patients completed all four cycles of high-dose therapy. Three patients did not complete four cycles due to late thrombocytopenia (n = 2) or tumor progression (n = 1). These results indicate a benefit of PBPCs in addition to GM-CSF in alleviating myelosuppression of dose-intensive chemotherapy. Initial collection of PBPCs may allow administration of repetitive cycles of high-dose chemotherapy with acceptable toxicity to outpatients at disease onset.