Ira J. Dunkel

The Measurement of Symptoms in Children with Cancer

The purpose of this study was to determine symptom prevalence, characteristics, and distress in children with cancer. The Memorial Symptom Assessment Scale (MSAS) 10-18, a 30-item patient-rated instrument adapted from a previously validated adult version, provided multidimensional information about the symptoms experienced by children with cancer. This instrument was administered to 160 children with cancer aged 10-18 (45 inpatients, 115 outpatients). To confirm the instruments reliability and validity, additional data about symptoms were collected from both the parents and the medical charts, and retesting was performed on a subgroup of inpatients. Patients could easily complete the scale in a mean of 11 minutes. The analyses supported the reliability and validity of the MSAS 10-18 subscale scores as measures of physical, psychological, and global symptom distress, respectively. Symptom prevalence ranged from 49.7% for lack of energy to 6.3% for problems with urination. The mean (+/- SD) number of symptoms per inpatient was 12.7 +/- 4.9 (range, 4-26), significantly more than the mean 6.5 +/- 5.7 (range, 0-28) symptoms per outpatient. Patients who had recently received chemotherapy had significantly more symptoms than patients who had not received chemotherapy for more than 4 months (11.6 +/- 6.0 vs. 5. 2 +/- 5.1), and those patients with solid tumors had significantly more symptoms than patients with either leukemia, lymphoma, or central nervous system malignancies (9.9 +/- 7.0 vs. 6.8 +/- 5.5 vs. 6.8 +/- 5.0 vs. 8.0 +/- 6.1). The most common symptoms (prevalence > 35%) were lack of energy, pain, drowsiness, nausea, cough, lack of appetite, and psychological symptoms (feeling sad, feeling nervous, worrying, feeling irritable). Of the symptoms with prevalence rates > 35%, those that caused high distress in more than one-third of patients were feeling sad, pain, nausea, lack of appetite, and feeling irritable. Subscale scores demonstrated large variability in symptom distress and could identify subgroups with high distress. The prevalence, characteristics, and distress associated with physical and psychological symptoms could be quantified in older children with cancer. The data confirm a high prevalence of symptoms overall and the existence of subgroups with high distress associated with one or multiple symptoms. Symptom distress is relatively higher among inpatients, children with solid tumors, and children who are undergoing antineoplastic treatment. Systematic symptom assessment may be useful in future epidemiological studies of symptoms and in clinical chemotherapeutic trials. Symptom epidemiology may also provide a focus for future clinical trials related to symptom management in children with cancer.

A Phase I/II Study of Direct Intraarterial (Ophthalmic Artery) Chemotherapy with Melphalan for Intraocular Retinoblastoma: Initial Results

OBJECTIVE To develop a technique that would allow us to cannulate repeatedly the ophthalmic artery of young children with advanced retinoblastoma, to find a dose of melphalan that would be tolerable and tumoricidal for retinoblastoma when given intraarterially, and to study the local ocular and systemic side effects of intraarterial melphalan in these children. DESIGN Phase I/II clinical trial. PARTICIPANTS Ten children with advanced retinoblastoma (Reese-Ellsworth V) eyes who were indicated for enucleation were entered into an institutional review board-approved protocol of ophthalmic artery infusion of melphalan to avoid enucleation. METHODS Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters while the children were under anesthesia and anticoagulated. Chemotherapy (melphalan) was infused into the artery over a 30-minute period. MAIN OUTCOME MEASURES Ophthalmic examinations, retinal photography, and electroretinograms were used to document local toxicity, whereas physical examinations and complete blood counts were used to measure systemic toxicity. RESULTS The ophthalmic arteries were successfully cannulated in 9 cases (total, 27 times), as many as 6 times in 1 patient. Dramatic regression of tumors, vitreous seeds, and subretinal seeds were seen in each case. No severe systemic side effects (sepsis, anemia, neutropenia, fever, or death) occurred. No transfusions were required (red cells or platelets). Three patients developed conjunctival and lid edema that resolved without treatment. There was no toxicity to the cornea, anterior segment, pupil, or motility. One (previously irradiated) eye developed retinal ischemia; another eye had no toxicity after intraarterial chemotherapy but did develop a radiationlike retinopathy after brachytherapy. Vision stabilized or improved in all but 1 patient after treatment. Electroretinograms were generally poor (advanced eyes were treated), but in 2 cases, the electroretinogram improved after treatment (and resolution of a retinal detachment). Seven eyes avoided enucleation. Two intraarterially treated eyes were enucleated, with no viable tumors identified pathologically. CONCLUSIONS We developed a technique of direct ophthalmic artery infusion of melphalan for children with retinoblastoma. The technique had minimal systemic side effects (one patient had grade 3 neutropenia) and minimal local toxicity. Among the first 9 cases treated with this technique, 7 eyes destined to be enucleated were salvaged.

Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

OBJECTIVE To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. DESIGN Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. RESULTS Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. CONCLUSION Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.

PURPOSE To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. PATIENTS AND METHODS Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. RESULTS Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. CONCLUSION A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.

High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group.

PURPOSE Medulloblastoma is a highly lethal disease when it recurs. Very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. METHODS Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/mL x min via Calvert formula) on days -8, -7, and -6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days -5, -4, and -3; followed by ASCR on day 0. In addition to the study-prescribed therapy, 21 patients received other treatment: neurosurgical resection in seven, conventional chemotherapy in 17, and external-beam irradiation in 11 cases. RESULTS Twenty-three patients with recurrent medulloblastoma, aged two to 44 years (median, 13 years) at ASCR, were treated. Three patients died of treatment-related toxicities within 21 days of ASCR; multiorgan system failure in two, and Aspergillus infection with venoocclusive disease in one. Seven of 23 patients (30%) are event-free survivors at a median of 54 months post-ASCR (range, 24 to 78 months). Kaplan-Meier estimates of event-free (EFS) and overall survival are 34% +/- 10% and 46% +/- 11%, respectively, at 36 months post-ASCR. CONCLUSION This strategy may provide long-term survival for some patients with recurrent medulloblastoma.

A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma

PURPOSE To evaluate the efficacy and toxicity of subconjunctival carboplatin for intraocular retinoblastoma. DESIGN A phase I/II clinical trial (noncomparative case series). PARTICIPANTS Eleven children with bilateral retinoblastoma who had 13 eyes containing active tumor. METHODS Subconjunctival carboplatin (1.4-2.0 ml of a 10-mg/ml solution) was administered. Ophthalmologic examinations with the patient under anesthesia were performed before each injection, and response and toxicity were assessed. MAIN OUTCOME MEASURES Tumor response and toxicities. RESULTS A median of three injections per eye was administered (range, 1-7 injections per eye) at a median interval of 21 days between injections (range, 14-35 days). The median dose was 20 mg/injection (range, 14-20 mg). Toxicities included transient periorbital edema in four eyes and optic atrophy in one eye that also received laser photocoagulation and cryotherapy. No nonocular toxicities were noted. Three of five eyes with vitreous disease that could be evaluated had major responses. Two of five eyes with retinal tumors had a response, but neither eye with subretinal disease responded. CONCLUSIONS Subconjunctival carboplatin as used in this protocol is effective for intraocular retinoblastoma. It appears to be safe, but additional study and longer follow-up are required, particularly to determine the risk of optic atrophy.

Presenting signs of retinoblastoma

A retrospective chart review was performed on the charts of 1265 patients with retinoblastoma who were on file at New York Hospital and whose conditions had been diagnosed between the years 1960 and 1990. The mean follow-up was 90 months, ranging from 0 to 409 months. Thirty-two distinct presenting signs of retinoblastoma were identified, the most common of which were leukocoria (56.2%), strabismus (23.6%), poor vision (7.7%), and family history (6.8%). No correlation was found between any of the presenting signs and laterality, sex, race, or survival. Leukocoria correlated to Reese-Ellsworth Group Va or Vb, whereas strabismus was invariably associated with either macular tumors or macular retinal detachments. Eighty-three (96.5%) patients presenting with a family history did so before the age of 24 months. The presenting sign leading to a diagnosis of retinoblastoma was correlated with degree of advancement and tumor location. Leukocoria and strabismus are the most common presenting signs, with leukocoria correlated to more advanced disease and strabismus always associated with macular involvement. Vitreous hemorrhage (1 case, 0.1%), microphthalmos (4 cases, 0.3%), and orbital cellulitis (3 cases, 0.2%) are extremely rare presenting findings in retinoblastoma.

Superselective Ophthalmic Artery Chemotherapy as Primary Treatment for Retinoblastoma (Chemosurgery)

PURPOSE To report on our 3-year experience with the use of superselective ophthalmic artery infusion of chemotherapy as initial, primary treatment for intraocular retinoblastoma. DESIGN Prospective, institutional review board-approved clinical trial. PARTICIPANTS Twenty-eight eyes of 23 newly diagnosed retinoblastoma patients (Reese-Ellsworth [RE] group V, 25 eyes; RE IV, 1 eye; RE III, 1 eye; RE II, 1 eye), ages 3-88 months (mean, 22; median, 11) followed for 3-37 months (mean, 15; median, 14). METHODS Cannulation of 1 or both ophthalmic arteries in young children with retinoblastoma was performed via the femoral artery under general anesthesia on an outpatient basis and chemotherapy (melphalan [n = 12], melphalan plus topotecan [n = 7], melphalan plus topotecan and carboplatin [n = 3], or melphalan plus carboplatin [n = 1]) infused. MAIN OUTCOME MEASURES Patient survival, eye survival, systemic toxicity, complete blood counts, ophthalmic examination, retinal photography, and electroretinograms. RESULTS We treated 23 newly diagnosed retinoblastoma patients initially with 75 separate intra-arterial chemotherapy infusions (range, 1-6 treatments; mean, 3.2) over a 3-year period. All children survived. Only 1 of the 28 eyes came to enucleation (for progressive disease). No eye was enucleated for ocular complications of the procedure and the only adverse ophthalmic findings were occasional transient lid edema, forehead hyperemia, and loss of nasal lashes. Kaplan-Meier enucleation free was 100% at 12 months and 89% at 2 years (95% confidence interval, 43%-98%). There were no deaths, strokes, or transfusions of any blood products; no effect on red cell count; 9 cycles of grade 3 and 1 cycle of grade 4 neutropenia; and no hospitalizations, episodes of fever/neutropenia, or complications at the site of femoral artery puncture. CONCLUSIONS The ophthalmic artery(s) of children can safely be repeatedly canulated in very young children and high concentrations (but low doses) of chemotherapy infused on an outpatient basis. When used as initial therapy superselective chemotherapy delivered through the ophthalmic artery prevented enucleation, primary radiation or the use of systemic chemotherapy in 27 of 28 eyes.

Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols.

To determine the survival of infants and young children with non‐metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR).

Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors.

PURPOSE This study evaluates the outcome of myeloablative chemotherapy and autologous bone marrow rescue (ABMR) with or without radiotherapy in children younger than 6 years of age with recurrent malignant brain tumors who had not previously been exposed to conventional fractionated external-beam irradiation. PATIENTS AND METHODS Patients underwent surgery and/or conventional chemotherapy at the time of recurrence to achieve minimal residual disease (two of these patients also underwent local single-fraction gamma-knife radiosurgery). Myeloablative chemotherapy was then administered with carboplatin, thiotepa, and etoposide (16 patients), thiotepa and etoposide (three patients), or thiotepa, etoposide, and carmustine (BCNU; one patient). Autologous bone marrow was re-infused 72 hours after chemotherapy. Twelve patients received external-beam irradiation after recovery from ABMR. RESULTS Twenty patients with recurrent brain tumors aged 0.7 to 5.9 years (median, 2.9 years) at ABMR were evaluated. Two patients died of toxicity related to myeloablative therapy. Eight patients died of progressive disease. Ten of 20 (50%) patients (primitive neuroectodermal tumor (PNET)/medulloblastoma, three patients; cerebral PNET, three patients; glioblastoma multiforme, two patients; anaplastic astrocytoma, one patient; pineal PNET, one patient) are alive and disease free at a median of 37.9 months (range, 9.7 to 98.2 months) from ABMR (3-year overall survival [OS] rate of 43% +/- 13% and event-free survival [EFS] rate of 47% +/- 14%]. Seven of these 10 patients also received irradiation post-ABMR. CONCLUSION Myeloablative chemotherapy with ABMR followed by additional external-beam irradiation appears to be an effective retrieval therapy for some young children with recurrent malignant brain tumors.