CT SPECT after four cycles of TPI-287 (9/24/09)

CT Chest, Abdomen, Pelvis Findings:Again seen is an enhancing soft tissue infiltrating mass in the region of the left lung apex and extending into the supraclavicular fossa. It currently measures 22mm craniocaudad in a reproducible loaction. Prior measurement in this same location was 23 mm. Also seen is an isolated enlargred left supraclavicular lymph node that meausres approximately 15mm x 7mm which is also unchanged from prior exams.
Impression:
No change in size or appearance of left supraclavicular mass or isolated supraclavicular lymph node.

CT Head w/contrast
Impression:
Ct scan of the brain with contrast with no change since previous exam and no evidence of metastatic disease.

I-123 MIBG scan with SPECT
Findings:
The size and activity in the left sternoclavicular mass has not significantly changed. No new areas of abnormal MIBG activity are identified.

CT SPECT after two cycles of TPI-287

Final report shows tumor to be stable. The image on the left is the standard MIBG scan image (the 2nd spot in the chest is Will's port where the injection is done) and the image on the right is the fused MIBG/CT scan image. The arrow in both obviously is pointing to his tumor.

Cycle 2 - week 3 summary

Only real issue this week was some lingering steroid issues most related to sleep disturbances. His counts remain strong and his energy does not see too depleted.

Cycle 2 - week 2 summary

Will's issues with the steroids this week have been much less dramatic with the dose cut in half. He was still having issues getting to sleep at night, he was still requesting 'salt', and he was moody but it was a much better quality of life. He did have one day of diarrhea that has resolved, he did seem tired this week and used the word 'exhausted' a lot, and finally he did complain on two occasions of 'his arm' hurting. He would point to his left forearm when locating the source of his pain.

Otherwise he continued to do well and overall it was a good week for him.

Cycle 2 - week 1 summary

Will's behavior and mood swings stabilized this week as we were allowed to change his steriod dose. He had been receiving a dose 12 hours prior and 6 hours prior to his infusion of TPI-287. However, we now skip the dose 12 hours prior and there has been a remarkable difference. While he is still not quite himself the fequency of his outburst, and their intensity, have diminished greatly and his intense craving of food has also diminished with fewere outbursts over the denial of absurd food requests.

His counts remain strong, he is sleeping well, and his energy seems ok. However, this week he has been exhibiting some fear & anxiety. He was scared to be accessed for labs yesterday, he was scared to be left alone, and he did not want to interact with kids at the park. We'll monitor it going forward.

Cycle 1 - week 4 summary

Will still remained seemingly symptom free from any chemo related side effects. His steroid side effect issues have remained and his behavior around these issues is the same. However, with the week off of chemo/steroids the frequency of his mood swings and behavior decreased and gave him a better quality of life. So start cycle 2 we learned that he could skip his steroid dose that he usually takes 12 hours prior to chemo and simply take the dose 6 hours prior.

We'll see if this helps in the week ahead. Will went to clinic and was 28kg which is an all time high. We have to struggle with him all day over his food intake as the steroids have ramped up his appetite dramatically.

Cycle 1 - week 3 summary

Will's counts remaines strong this week, the 'sore' in his mouth (probably just a canker) has resolved and he his sleep seemed to return to it's previous schedule. The only impact thus far seems to still be related to the once a week steroid dose Will receives. THe night of, and the night after, his sleep is disturbed and his appetite is voracious. His mood is volatile, he can become unusually angryr, he is saying things and acting out in a manner he has previously never exhibitied (being defiant, kicking, spitting, hitting) and throwing tantrums over denied request for absurd amounts of food and drink. As we enter the 4th week of the cycle that did not require a dose of steroids or TPI we hope he returns more to his usual kind temperment. While always very active and fidgety he was never defiant, angry, rude, or defiant. Otherwise we see no other side effects from his therapy.

Cycle 1 - week 2 summary

Will developed a canker/mouth sore towards the end of the week.
Will normall would sleep 9 - 10 hours per night but was sleeping 12
Even with that sleep his mood and behavior seemed like a 4 year old in need of a nap. He was cranky, whiny, and moody and had more temper tantrums in a one week period then he has had in his entire life. He is always asking to eat more and more food and while we did not let him eat too much he went from 58 to 61 pounds in 1 week. This is the most Will has ever weighed. Other than the canker/mouth sore all of these sound like they may be steroid related which seems odd given how little WIll has taken.

The day Will gets his dose, and the day after, is a day where he has a very hard time getting to sleep, almost as if anxious or full of caffeine. A day or two after this goes away. His face still looks bloated as well.

Other than these seemingly steroid related issues he exhibited no other side effects than perhpas being a bit tired.

Cycle 1 - week 1 summary

Will received his first infusion of TPI 287 as a single agent on Day 1 of cycle 1 last Friday June 5th 2009.

The infusions was uneventful and Will received the required premeds including a 24 hour IV dose of zofran. As of today Will seems to have exhibited no side effects from last weeks infusion.

We gave him oral zofran at home on both Saturday and Sunday not because he exhibited any nausea but just to be safe. He was on no other meds other than daily bactrim and flouride.

He did not exhibit any signs of fatigue, neuropathy, or muscle pain and his appetite was normal. On two occasions he did claim he was going to get sick. However, he never did get sick and he did not exhibit any other symptoms or issues immediately following these statements or at any other time during the week.

While he did go to bed later than usual he slept uninterupted through the night with no issues.

TPI-287 & Temozolomide (Temodar) in relapsed neuroblastoma

Below you can see the embeded spreadsheet from Google docs that I will be updating as Will begins this study. He is patient #4 overall which makes him the 1st patient in the second cohort of this study.

To go to the actual document below (easier to view and read) you can click on this LINK.

Patient history

PROGRESS/FOLLOWUP NOTE - 06/05/2009 

CHIEF COMPLAINT

Neuroblastoma. 

HISTORIAN

Father

HISTORY OF PRESENT ILLNESS

Will is a known patient with refractory neuroblastoma, who continues to do well without any concerns; a past medical history of neuroblastoma is below.  William recently completed two cycles of velcade and oral Cytoxan chemotherapy which he complete on May 5th, 2009.  He tolerated those chemotherapies but had some vomiting and weight loss.  He currently has no pain and is very active and playful.  He is currently eating very well, with stable weight.  No problems sleeping.  No fevers.  No concerns for infection.

 

REVIEW OF SYSTEMS

He is active and playful, with no concerns neurologically.  No cardiovascular or respiratory concerns.  No shortness of breath.  No abdominal pain.  No diarrhea, and no constipation, eating well.  No musculoskeletal concerns; very active and playful, able to run, jump, and play.  On his skin he does have two small molluscum near is elbow, no other rashes or concerns.

 

PAST MEDICAL HISTORY

Will is a 4-year-old boy with relapsed neuroblastoma which initially presented as an infant in 03/05, with left-sided supraclavicular node, left arm and facial swelling, and left-sided Horner's.  CT showed multiple cervical lymph nodes, with a large posterior mediastinal mass, along the spinal column; MRI invades at theneuronal foramina.  Bone scan showed no bone lesions at that time.  MIBG showed uptake in the left mediastinum, and supraclavicular lesion.  There was also a small MIBG avid lesion in the left humerus which initially was not identified, but was re-reviewed and identified at relapse.  Bone marrows at that time were negative for disease.  Tumor markers were mildly elevated and MYCN was non-amplified, histology was not favorable.  LDH was normal.  Ferritin was slightly elevated at 119.  He was classified as a stage III intermediate risk neuroblastoma with unfavorable biology.

 

Although based upon re-review of the arm lesion would have classified him as a stage IV intermediate risk with unfavorable biology.  He was enrolled in COG protocol, POG 3961, and received eight cycles of chemotherapy.  While he had a good initial response to chemotherapy after two cycles, the following four cycles shows his mass unchanged.  The decision was made at that time to continue with local control by surgery, and he underwent debulking procedure in August of 2005, after his six cycles of chemotherapy.  As much tumor as possible was resected, while maintaining the brachial plexus.  Pathology revealed intermixed mature and immature neuroblastoma.  He received two more cycles of chemotherapy under therapy, CT scan showed a residual posterior mediastinal mass which remained MIBG avid, stable left arm lesion, and left humerus, and no other disease.

 

He went off of therapy in October of 2005, and classified as a very good partial response.  He had a routine followup scan in 02/06; there was interval enlargement of the primary mass, as well as a new left internal mammary adenopathy and new left jugular adenopathy.  MIBG revealed these lesions to be MIBG avid, and a new abdominal lesion nearthe splenic flexure, which did not correlate by CT scan.  Will went to the operating room on 03/20/06, where he had removal of the posterior jugular and internal mammary adenopathy and biopsy of the residual posterior mediastinal mass, which confirmed recurrent neuroblastoma, with the same biology.  Both lymph nodes and the residual mass, bone marrow aspirate and biopsy were negative.  Postop repeat CT scan revealed new pleural based nodules.

 

Will was started on salvage chemotherapy with Cytoxan and topotecan after two cycles of chemotherapy.  Repeat imaging showed stable disease with no new lesions.  Given the lack of response, Will was started on high dose chemotherapy, receiving five cycles of chemotherapy of cisplatin and etoposide, Adriavac, etoposide/Ifosfamide, etoposide/carboplatin, Adriavac.  At the completion of therapy, MIBG scan again showed stabilization with a small increase in the size of the nodule at the cardiophrenic junction.  Will was very sick during this time, and given his poor response to chemotherapy, Will was determined to not have a curative option at this point.

 

He was then begun on palliative chemotherapy with Cytoxan, topotecan, per POG 9464, with dose decreased to 4 days instead of 5, due to marrow toxicity.  He received a total of four courses, and then underwent MIBG therapy with CHOP twice, 12.5 millicuries per kg, in January of 2007, and March of 2007.  He tolerated MIBG well; eight weeks after the second MIBG, he was restaged, and had stable disease by both CT and MIBG.  Urine calculations dropped into the normal range after MIBG therapy and have remained normal since.  Given his stable disease and desire to continue treatment using agents with low side effect profile, he was enrolled on COG protocol of a safety trial of ABT 751, on June 7th, 2007.  He tolerated this chemotherapy very well, had single dose reduction for neuropathic pain, and he was on ABT 751, had stable disease for almost a year.

 

Given stable disease and minimal treatment, after extensive discussion with the family, the nodule on his cardiophrenic angle was excised in March of 2008.  Bilateral bone marrow aspirates and biopsies were negative, but this pathology of this lesion revealed persistent neuroblastoma.  Will remained on ABT 751 for one year, and in July of 2008, came to the University of Vermont for consultation and we discussed further options, due to the lack responsiveness to chemotherapy Will did not enter the Phase II Nifurtimox trial.  We discussed other therapeutic options and was placed on vinblastine, rapamycin therapy receiving vinblastine weekly and rapamycin daily, per Dr. Barichel's treatment protocol from Sick Kids in Toronto.

 

Will received ten cycles, each cycle being one month of vinblastine, and rapamycin, and then in February of 2009, had an MIBG CT scan done here at Vermont, and again showed stable disease.  Bone marrow biopsy and aspirates were negative.  We discussed theresults and plan to continue vinblastine and rapamycin until April of 2009.  Will had croup, held rapamycin and was admitted to Boston Children's Hospital for respratory distress.  This resolved over a few days.  Upon discharge, discussed with Dr. Rao, and Mr. Lacey, and changing therapy to Velcade 1.3 mg per meter squared on day #1, 4, 8 and Cytoxan 100 mg per meter squared daily for 14 days, on a 21-day cycle.

 

Will had significant nausea with this regimen.  During the second cycle, we decreased the Cytoxan to 50 mg per meter squared, which improved his nausea, but still did not feel well during the chemotherapy week.  He has been off of therapy since May 5th, 2009, and is now here to enroll in TPI trial.  Will was seen yesterday in the clinic, and the informed consent was reviewed with his father and he was given the opportunity to ask all questions and discussed the risks and benefits of possible toxicities, and father consented to enroll in the study.  MIBG scans were done yesterday, which showed stable disease of his mediastinal mass, and bone marrow biopsy and aspirate were done, which were negative.

 

He was given Decadron to enroll in trial, and will begin TPI today.

 

FAMILY HISTORY

Noncontributory for cancers.

 

SOCIAL HISTORY

He lives with mother and father, in Braintree, Massachusetts.  He has two younger sisters, one born one week ago, and one 18 months.

 

PHYSICAL EXAM

Vital signs had a heart rate of 108, blood pressure 115/54, temperature 36.2, weight 26.5, height 117.7 cm.

General:  In general is well appearing, well developed, well nourished, in no acute distress.  Eyes - sclerae are white.  Conjunctivae clear.  Pupils are equal and reactive.  HEENT has mucous membranes.  Lips are pink and symmetrical.  No oral ulcers.  No thrush.  Chest: Port is in place in the chest.  Respirations even and unlabored.  Lungs are clear.  No adventitious sounds bilaterally.  Heart is regular rate and rhythm, perfusion is normal.  Non tachycardic.  No murmurs.  No edema, 2+ pulses.  Abdomen is soft, nontender, and nondistended.  Active bowel sounds.  Liver and spleen are without tenderness or enlargement.  Lymph nodes - not palpably enlarged nodes in the neck, axillary, inguinal, or supraclavicular areas.  Skin is warm, dry, with normal turgor, no rashes, no lesionsexcept for two dots of molluscum near the elbow.  Neurological - cranial nerves are intact II-XII, except for slight ptosis of the left eye.  He is developmentally appropriate for age.  Cerebellar: Finger-to-nose appropriate.  Appropriate touch and pain sensation.  Psychiatric: He is alert and oriented times three, with an appropriate affect.  Musculoskeletal: Gait is coordinated and smooth.  Strength is 5/5 in all extremities.  No muscular atrophy or weakness.

 

His labs were done yesterday, which shows an AST of 41, ALT of 52, LDH is 820, ferritin is 296, white count is 4.95, with an ANC of 2,270.  Hemoglobin is 10.6, and platelets are 222,000.  Sodium is 137, potassium is 4.0, chloride is 105, bicarbonate is 27.

 

MIBG CT scan shows positive stable disease in the mediastinal area.  Bone marrows are negative.

 

IMPRESSION

This is a 4-year-old male with refractory neuroblastoma, here for enrollment on TPI trial to begin baseline study this morning. 

1.Oncology to start TPI at 110 mg per meter squared IV today.  Father gave Decadron premedications at 9 p.m. and 3 a.m. and at 9 a.m. this morning.  Will begin TPI infusion, premedications to include Decadron, Benadryl, ranitidine, and Zofran.  Patient was observed throughout the TPI infusion this morning and tolerated the infusion well with no complications. 

2. Pain is no issue currently.

3. ID - on Bactrim for PCP prophylaxis.  No concerns for any significant infection at this time.

4. FEN: Fluids, electrolytes, and nutrition - eating well with no concerns.  Electrolytes stable.

5. Heme - stable CBC, is normal.  Patient is not transfusion dependent. 

6. Followup will be in one week for day #8 of TPI infusion.

Pre-study CT Scan of Chest, abdomen, and pelvis JUNE 4th 2009

CT scan of the chest abdomen and pelvis:
June 4, 2009.

History: Neuroblastoma. Evaluate extent of disease.

Comparison: February 12, 2009.

Technique chest: After the administration of intravenous contrast,helical scans were obtained from the lung apices through the diaphragms.

Technique abdomen: After administration of intravenous contrast,scans were obtained from above the dome of the diaphragms through the iliac crests.

Technique pelvis: After administration of intravenous contrast, scans were obtained from the iliac crest through the ischial tuberosities.Coronal and sagittal reformations were obtained.

Findings:Once again seen is abnormal soft tissue mass at the apex of the left hemithorax extending around the left vertebral artery and into the superior left mediastinum. In comparison with the previous examination, this appears stable in extent. The soft tissue mass is of mixed density with some areas demonstrating increased enhancement and other areas demonstrating decreased enhancement. It extends along the anterolateral chest wall adjacent to the first rib as on the previous examination. The overall size is unchanged. It is quite difficult to measure. The maximum SI diameter is 2.9 cm versus 2.5 cm on the previous examination (measured on coronal chest image 37). The transverse diameter on this image is 2.9 cm versus 3.1 cm on the previous examination. A small enhancing nodule adjacent to the left hand aspect of aorta and gastroesophageal junction is similar in appearance to the previous examination. It measures 8 mm AP on the current examination on sequence 83, image 12. The transverse diameter on this series is 6 mm.Motion artifact obscures much of the lung. Dependent atelectasis is present.The bones of the chest are normal in appearance. A chest port is seen in the anterior tissues of the right chest.Abdomen and pelvis:The liver, spleen, pancreas, kidneys and gallbladder are normal in appearance. The adrenal glands are normal in appearance bilaterally.The aorta and IVC are normal in diameter.There is no intra-abdominal lymphadenopathy. Evaluation of the pelvis demonstrates no pelvic lymphadenopathy. Physiologic free fluid is noted in the pelvis.The bones of the pelvis and abdomen are unremarkable in appearance.

Impression:
Essentially stable examination in comparison to prior study of February 12, 2009.
No new lesions are identified.
Stable size of the left hemithorax apical lesion and left periaortic lesion are noted.

Pre-study MIBG with SPECT June 4th 2009 1:30pm

Final result:

NM MIBG WB WITH SPECT Jun 4, 2009 4:20:00 PM

Signs and Symptoms: Neuroblastoma .

Following intravenous administration of 3.1 mCi of I-123 MIBG, a whole body scan was performed in anteririor-posterior projections. Following that, SPECT CT of the body from the vertex of the head through the pelvis was done.

Comparison is made with the prior examinagtion February 12, 2009. The focus of increased activity at the left thoracic inlet is again seen, although the intensity has diminished since the last examination. No new focus of increased activity is seen.

Impression: Interval decrease in the intensity of increased activity in the mass at the left thoracit inlet. No new abnormality detected.

Pre-study flow cytometry results

Rare event analysis appears to indicate 0.01% of the cells analyzed in the lymphocytic/monocytic/blast area (0.0044% of all 1,356,320 cells in the marrow)are consistent with a phenotype seen on neuroblastoma cells.

There are rare cells that appear to coexpress GD2 and CD34. THe significance of this finding is not known.

Utilizing the 'modified gating method' of analysis shows 0.016% of the cells in the analysis gate representing 0.007% of all cells in the sample to have a phenotype seen on neuroblastoma cells.