Stage 4 Neuroblastoma
1.5-year-old male suffered from eye swelling. His MRI revealed expansive lesion of left lateral orbital wall origin, with compression on the lateral rectus muscle. Later he was hospitalized due to fever and vomiting in left orbital lesion, suspecting a metastatic neuroblastoma. His eye examination revealed exophthalmus of the eye with exophoria and light dysfunction of the lateral rectus. His biopsies were indicative of stroma-poor neuroblastoma. After the diagnosis of Stage 4 Neuroblastoma, he began chemotherapy treatment according to NB-AR-O1/ESIOP protocol, that has been, on the whole, well tolerated. The child responded well to the treatment with improvement in the tumor around his eye .
1) Do you confirm the diagnosis?
2) Do you confirm the current treatment?
3) Centers of excellence in Italy and in Europe?
Diagnosis: Stage 4 Neuroblastoma
1 year and 5 months old, male, Italy
- April, 2009: At first appearance of swelling in the left eye. In the following days, even though treated with TOBRAL eye drops, the swelling persists. In addition ecchymosis over and under the eye and light exophthalmus. The eye shows a lower mobility and converges in a slight intermittent strabismus.
- May, 2009: Examination carried out by eye specialist who advises for a Magnetic Resonance. - give evidence of a lesion that will be considered to be secondary; the medical report of this examination with contrast medium is reported: “Expansive Lesion of left lateral orbital wall origin, with compression on the lateral rectus muscle and subsequent exophthalmus. The muscle does not show infiltration signs. The lesion involves in depth the great wing of the sphenoid, the body of the sphenoid; pathological signal intensity also involves the left sphenoid. After contrast a pathological enhancement of all the described bone structures is appreciated. A CT scan of the facial bones for diagnostic completion is carried out. It confirms the extended bone involvement of the lateral orbital wall and of the sphenoid, as well as the presence of solid element that projects inside the left orbital cavity with compression on the lateral rectus muscle. The lesion is extended also laterally to left lateral orbital wall, with compression on the left superficial temporal muscle. Compressed the left tear-gland, regular, homogenous. The left optic nerve is normal. Probable histiocytosis: Histologic confirmation is necessary. No supra and subtentorial focal alterations. Normal shape of the ventricular system. Regular Median Line structures.”
- May, 2009: Magnetic Resonance and CT scan of the facial bones
- May, 2009: During hospitalization at the Paediatric Oncohematology Clinic of Padua Hospital due to fever and vomiting in left orbital lesion, suspecting a metastatic neuroblastoma, an abdominal ultrasound scan has been carried out. It has revealed the primary mass (not homogeneous solid formation of about 5.5 x 5 cm in rear peritoneal area).
- May, 2009: Total body CT scan with evidence of: “In median rear peritoneal area at lumbar level, a solid expansive formation is appreciated. It contains tiny calcifications, mainly developed towards left, with the following dimensions: cm 9x8x7. Such lesion widely includes the aorta anteriorizing it and the left common iliac artery, includes the inferior mesenteric artery, positions anterolaterally the vena cava and laterally the left ureter causing hydronephrosis. In a cranial direction to the mass, at the level of the exit site of the superior mesenteric artery, lymph node formations with a maximum axial diameter of about 15 mm are appreciated. In correspondence to the body of L3 the lesion penetrates for a short part into the spine channel. Non-repetitive lesions involving the pulmonary parenchyma, the mediastinum and the abdominal parenchyma organs.”
- May, 2009: Total body bone scintigraphy with evidence of: “Area of pathological hyperactivity that involves the lateral orbital wall and a part of the left sphenoid and extends at the front involving part of the inferior and superior orbital edges and the left cheekbone, while in the rear posterior side it involves the temporal bone; an area of moderate hyperactivity involves in a diffuse way the left femur proximal segment.”
- May, 2009: MIBG scintigraphy with evidence of: “voluminous mass of pathological and not homogeneous accumulation in abdomen (in the area of the known lesion) and in the bone field, numerous areas of pathological accumulation widespread throughout the skeleton.
- May, 2009: Eye visit with evidence of “light exophthalmus of the left eye with exophoria and light dysfunction of the lateral rectus from the same side; the fundus oculi appeared to be within normal limits.”
- June, 2009: Biopsy of abdominal mass + bilateral osteomedullary biopsies and a two-way CVC positioning of Broviac type in right internal jugular vein: “The histology examination was indicative of stroma-poor neuroblastoma, slight differentiated according to INPCC classification. During the same examination also aspirations and osteomedullary biopsies bilaterally have been carried out; the study of the neoplastic infiltration of the medulla carried out at the Gaslini Institute of Genoa allowed to find neoplastic infiltration on both the medullary aspirations (rare pseudorosettes). Awaiting the result of the osteomedullary biopsies.”
- “on June beginning of treatment according to NB-AR-O1/ESIOP protocol, that schedules a first phase of induction chemotherapy according to the COJEC scheme (8 cycles of chemotherapy) of the length of about two and a half months, followed by collection of peripheral stem cells, in sight of a high dose treatment followed by re-infusion of the autologous cells. After the collection, the child’s conditions will be reassessed for any possible surgery of the residual mass. On the days 6 and 7.06 the first cycle of chemotherapy (cycle A) with Carboplatin, Vincristine and Etoposide has been administered. The therapy has been, on the whole, well tolerated.”
June, 2009: beginning of the treatment, after the diagnosis of Stage 4 Neuroblastoma, according to NB - AR - O1/ESIOP protocol following the COJEC scheme (8 cycles of chemotherapy). CYCLE A carried out.
- June, 2009 during hospitalization the CYCLE B chemotherapy treatment was carried out, an extract of the discharge letter is reported: “today (06.2009) we discharge the patient, suffering from Stage 4 Neuroblastoma, hospitalized in our Clinic on June to carry out the second cycle (cycle 8 of the COJEC scheme) of N8-AR- 01/ESIOP protocol, with Vincristine and Cisplatin. The therapy has been well tolerated with a good control of the emesis.” At discharge the little patient shows fairly good general conditions, the under eyelid ecchymosis on the left persists and a new ecchymosis at the left cheekbone is present (this last one due to trauma); the left exophthalmos has almost disappeared. The audiometric examination performed was within normal limits. The current hemochrome is the following one: Hb: WBCs 1100/mm3 (PMN 0, L 900), Hb 9.1 g/dl, Pts 24,000/mm3, for this reason he underwent a platelet concentrate transfusion before his discharge. At home he will have to take, as usual: Preventive treatment with Bactrim (3 ml on Monday, Wednesday, Friday). - In case of nausea, we advise to take Zofran syrup 2 mg for 2-3 times a day - In case of constipation Paxabel ½ packet of 4 g daily. The young patient has to carry out a follow-up hemochrome on June, to check the hematological situation.
The patient will return for the next cycle (3rd COJEC, type C), on June. The cycle will be carried out regardless of the hematological values, (only contraindications to assess on the clinical conditions of the young patient); we ask, therefore, to carry out hemochrome, electrolytes and hepatic and renal function.”
- June, 2009 the CYCLE C chemotherapy treatment was carried out, an extract of the relevant discharge letter is reported: “today (June, 2009) we discharge the patient, suffering from Stage 4 Neuroblastoma, hospitalized in our Clinic on June for the administration of the 3rd cycle (cycle C the COJEC scheme) of NB-AR-01/ESIOP protocol. After the last cycle of therapy no problems at home were observed. At admission the patient showed good general conditions. The hemochrome dated 25.06 showed WBCs 2840/mm3, PMN 370/mm3, Hb 8.4 g/dI, PIt 172,000/mm3. On 27 and 28.06 chemotherapy with Vincristine, Cyclophosphamide and Etoposide has been administered. The therapy has been, on the whole, well tolerated. At discharge the little patient shows fairly good general conditions. The current hemochrome is the following one: Hb: WBCs 1100/mm3 (PMN 300), Hb 8.5 g/dl, Pts 258,000/mm3, blood chemistry examinations are within normal limits. At home the patient will have to take: Bactrim 3 ml on Monday, Wednesday, Friday. In case of nausea, we advise to take Zofran syrup 2 mg for 2-3 times a day. In case of constipation Paxabel ½ packet of 4 g daily. Schedule: An hemochrome test for possible hemotransfusion is advisable to be carried out on Jult in Treviso. The hospitalization for the next cycle of therapy (cycle B) is scheduled for day 07. The cycle will be carried out regardless of the hematological values: We ask to carry out hemochrome, electrolytes and hepatic and renal function. Before the following cycle (5th cycle) the patient will have to carry out a disease revaluation: an abdominal ultrasound scan has been scheduled on 07 at our DH. The previous day at 8:00 a.m. the patient will have to begin at home the 24-hour urine collection to be delivered on 07 in DH for the dosage of the urinary acids.
- from 5th to the 12th July, 2009 hospitalization due to fever, an extract of the discharge letter is reported: “Discharge diagnosis: FEVER AND NEUTROPENIA IN STAGE 4 NEUROBLASTOMA. The young patient, suffering from Stage 4 Neuroblastoma, under treatment according to the COJEC scheme and followed by the Paediatric Oncohematology Clinic of Padua Hospital, has been hospitalized in our Clinic for the appearance of fever without any other connected symptomatology (ended the 3rd cycle ofReason of the hospitalization and examination at admission chemotherapy on 26.07). At admission the child was moaning showing a pale skin.
Cardiac examination: clear, rhythmic tones, pauses. Thorax examination: eupnoeic, normal vesicular murmur, no pathological sounds. Treatable abdomen, no organomegalies. No meningeal signs. Body temperature 38°C. Body weight 11.1 Kg. During hospitalization the following examinations were carried out:
• Blood culture from CVC: Negative when discharging (the final result will be communicated only if pathological);
• Urinoculture: Negative;
• Chest X-ray (07): “No signs concerning current foci parenchyma lesions are appreciated. Clear costophrenic angles. Cardiomedastinic silhouette within normal limits. Presence of injector in the right internal jugular”;
• Abdominal ultrasound scan (07): “Left kidney with bipolar diameter slightly increased and round appearance, shows grade 2 hydronephrosis with anteroposterior diameter of the pelvis of about 15 millimeters. Seemingly not expanded the homolateral ureter. Right kidney normal without any dilation of the excretory ducts. Relaxed bladder without any parietal endoluminal abnormality. Liver, biliary ducts, spleen within normal limits. Non-examinable pancreas for the intensive meteorism and the young patient’s uncontrollable crying”
• Negative serology for HIV and HBV. Clinical Course: During the hospitalization the patient was treated with parenteral triple-antibiotic therapy with Teicoplanin, Amikacin and Ceftazidime, due to the negative blood culture results. As the fever persisted, after discussing the case with the colleagues of the Paediatric Hematology/Oncology Dept. in Padua, a parenteral therapy with Ambisone started and it was suspended on 11.07. The young patient still had fever till 8.07 (in the 36h after the beginning of the antibiotic therapy) and at last his temperature came down. The clinical picture rapidly improved. His general conditions are always good as well as his vital parameters. The tests of the hematochemical examinations have revealed the progressive reduction in the inflammation ratings and the increase in the leukocytes values, in light decrease the Hb values. At discharge the patient is permanently apyretic and in good general conditions with general examinations within normal limits. The blood chemistry test has revealed:
• Hemochrome: WBCs 3.02/mm3, Hb 8.9 g/dL, PLT 190,000/mm3;
• PCR: 1.00 mg/dL;
Therapy at discharge
• Augmentin in oral suspension: 290 mg every 8h until 14.07 included; Schedule
• The colleagues of the Hematology/Oncology Dept. in Padua will contact the parents for the carrying out of the 4th cycle of therapy.”
- July, 2009 chemotherapy treatment CYCLE B was carried out as per discharge letter: “today we discharge the patient, suffering from Stage 4 Neuroblastoma, hospitalized in our Clinic on July for the administration of the 4th cycle of the COJEC scheme of the NB-AR-01/ESIOP protocol. After the last cycle of therapy we report hospitalization at the Paediatric Dept. of Treviso due to fever and neutropenia (WBCs 210/mm3); he was treated with triple-antibiotic therapy with Teicoplanin, Amikacin and Ceftazidime and antifungal therapy with Ambisome, with fast coming down of the temperature (apyretic). The cultures and the instrumental examinations (Chest X-ray and abdomen ultrasound scan) performed during the hospitalization in Treviso are within normal limits. The hemochrome showed: WBCs 3020/mm3, Hb 8.9 g/dL, PLT 190,000/mm3. At admission in our Clinic the patient showed good general conditions with cardiac, chest, abdominal examinations within normal limits. On .07 the scheduled chemotherapy with Vincristine and Cisplatin was administered. It was well tolerated. At discharge the young patient shows fairly good general conditions. The current hemochrome is the following one: Hb: WBCs 4200/mm3 (N 3200/mm3), Hb 8.8 g/dL, PLT 295,000/mm3. It is reported that before discharge he accidentally took off the central venous catheter that, in agreement with the Surgeons colleagues, will be repositioned on 07.09.
At home the patient will have to take:
- Bactrim: 3 ml on Monday, Wednesday, Friday.
- In case of nausea, we advise to take Zofran syrup 2 mg (max for 2-3 times a day)
- In case of constipation Paxabel 1 packet of 4 g 2 times daily.
- Clinical and hematological test. The following ones will be decided based on the result of this one.
- Before the following cycle (5th cycle) Luca will have to carry out a disease revaluation: An abdominal ultrasound scan has been scheduled at our DH. The previous day at 8:00 a.m. the patient will have to begin at home the 24-hour urine collection to be delivered in DH for the dosage of the urinary acids. In the same day an anaesthesiologist’s advice will be asked for the CVC repositioning scheduled in Paediatric Surgery.
- The following cycle of therapy is scheduled on.07. The cycle will be carried out regardless of the haematological values.
The clinical history and course are certainly consistent with Stage 4 neuroblastoma. Although specific pathologic reports are not available, excerpts are. There is no mention of specific molecular markers, such as cytogenetics or ploidy, but the case presentation is consistent with unfavorable biology and, presumably, high risk disease.
The patient has been receiving intensive chemotherapy with compressed timing - sounds as if following treatment as described in Lancet Oncology 2008 (please see below). It sounds as if clinically, based upon description of the patient's examination, he has responded well to the treatment with improvement in the tumor around his eye, and he has tolerated the treatment relatively well. There is no comment as to whether formal restaging evaluation and repeat sampling of the bone marrow confirm a good response to treatment.
In the case of high risk disease, intensive combined modality therapy with high dose chemotherapy and stem cell rescue is indicated. Despite this, as noted in the reference cited below, the outcomes are not as we would like based upon 3, 5 and 10 year survival. In the United States we do not use the same regimen, but the intent, in general is to be aggressive with intensive chemotherapy and stem cell transplant. I do not see a specific reason to change regimens at the point, as he has responded well - I see no indication of suspicion that he has developed refractory or recurrent disease. In this regard, however, assessment of disease response, including bone marrow response is important. We typically would not pursue collection of bone marrow, or even peripheral blood stem cells without documenting response to treatment and "clearing" of the marrow.
After high dose chemotherapy with stem cell rescue, in the US we would potentially treat with oral "maintenance" retinoic acid therapy for about six months.
I am not personally acquainted with anyone in particular in Italy or Europe who specializes in caring for children with neuroblastoma. However, at any center participating in SIOP, European Neuroblastoma Study Group or Italian Cooperative Group for Neuroblastoma, knowledgeable pediatric oncologists should be available.
Pearson, AD, Pinkerton, CR, et al. "High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial." Lancet Oncol. 9(3):247-56. 2008.
Matthay, KK., et al. "Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study." JCO 27(7):1007-13. 2009.