Neuroroendocrine neoplasia with hepatic secondary lesions_2
Short Summary

39-year-old male was diagnosed to have a neuroendocrine tumour with synchronic liver metastases. The disease was treated with an etoposide-carboplatin combination, Interferon A, somatostatin analogue and Zebra fish egg derived dietary supplements. In early 2008, a tumour progression was noted in that the disease started to produce the epithelial tumour markers CEA and CA 19-9. The patient was later treated with lomustine, etoposide and injections of a Viscum album preparation and there seemed to be a certain clinical benefit since recent ultrasound investigations reported on tumour stability.

Patient's Questions
The patient's father is asking for an opinion on the effectiveness of Hyperthermia that, in this specific case, would be associated with autoimmune therapies.
 
1)    Your opinion on the effectiveness of hyperthermia in the case at hand.

2)    If you believe this methodology is useful, can you please indicate the application procedures and any associated treatments you believe to be better?
Medical Background

39 year old male.
History:
In August 2003, following a significant loss of weight, a diagnosis of neuroendocrine neoplasia with hepatic secondary lesions of unknown origin was established. Subsequently its origin was believed to be “pancreatic”.
Biopsy confirmed by the Cancer Institute.
 
Therapies:
-       From 08/2003 to 05/2004 the patient underwent a total of 31 monthly chemotherapy administrations with Carboplatin and VP 16;
-       From 02/2004, Longastatin LAR 20: 1 vial a month;
-       On 11/2003, a whole body scintigraphy with immune and receptor traces gave negative results;
-       From 07/2004 to the end of December 2006, the patient was treated with Roferon A 3000000 U at a dosage of 3 vials a week;
-       In August 2004, chemotherapy with PRAVA 40 mg (3 tablets every 2 months approximately) was started. Due to leucopenia problems, the administration of this drug was irregular until December 2006 when the Interferon was interrupted. Since then, the administrations have taken place approximately every 45-50 days.
-       For pain-relief, Durogesic 25-50 was prescribed and has now been replaced by Oxicontin 20-50 twice a day, and lately also by Oramorph, as needed. Pain is also relieved by Antispasmina colica (forte) and Tachipirina.
-       The most recent exams have showed signs of slight thyroid distress caused by hypothyroidism (TSH 8.5878). Currently treated with Eutirox 0.25 mcg a day.
 
Tests:
-       Ultrasound exam shows a slight increase of the lesions.
-       The last CAT scan has shown significant progression of the disease.
-       Blood test: basically good results. Only slightly altered are alkaline phosphatase, transaminases and GGT (see enclosed results).
 
On February 2008, The patient was subjected to a complete abdomen and chest CAT scan, with and without the use of contrast agents, the results of which are reported herewith:
“Symmetric rib cage.
Neither respiratory field shows any current focal parenchymal thickening of pathological significance.
No bilateral pleural effusions.
The following lymphadenopathies were reported at the chest:
- at the level of the supra-aortic vessels (maximum transverse diameter 1.4 cm);
- to the right and left armpit (maximum transverse diameter respectively 1.4 cm and 1.8 cm);
- in the area of the right front paramediastinal (maximum transverse diameter 1.9 cm);
- to the side of the aortic arch (maximum transverse diameter 2.6 cm);
- at the level of the carina (maximum transverse diameter 2.1 cm);
- in the subcarinal area (maximum transverse diameter 2.3 cm).
The liver, which is somewhat larger than standard, shows several afinalistic alterations, the greatest of which has a maximum transverse diameter of 5.8 cm.
The portal vein is normally patent.
The spleen and both kidneys are within normal limits in terms of tomodensitometric and morphological characteristics, and have a good bilateral nephrographic effect.
Presence of pathological lymph node in the right retrocrural area (maximum transverse diameter 1.8 cm).
Starting from a plane, passing the origin of the celiac tripod, the known adenopathic mass (maximum transverse diameters approximately 5.5 cm x 6.7 cm) can be identified, which continues down to the bifurcation of the common iliac arteries.
The retroperitoneal mass translocates the afferent and efferent vascular structures to the kidneys and spleen without any clear cleavage, and also concentrically surrounds the abdominal aorta, and is undissociable from the pancreas.
At the level of the bifurcation of the iliac arteries, two masses with a maximum transverse diameter of 3.6 cm to the left and 2 cm to the right, can be seen.
The afore-described clinical picture would suggest a progression of the disease as compared with the previous check-ups carried out here in 2005 and 2007.
No free effusions”.
The tables showing the updated results of the laboratory tests, from which it can be seen that the abnormal analyses concern, are attached.
CEA,               CA19.9,          NSE,               GGT,   Alkaline phosphatase.        
The patient’s father stresses the fact that the attending physicians, differently from the reporting radiologist, only note small alterations in the oncological lesions and tumour mass, thereby providing a less pessimistic evaluation.
In the light of this examination, in any case, the attending physicians have decided to proceed with a further course of chemotherapy, in addition to Lomustine, with 20 mg/ml Etoposid Ebewe (VP 26?): one small bottle per day for 5 days, to be taken orally, mixed with coca-cola.
 
To complete the information here provided, since July 2004, The patient is taking dietary supplements derived from "Zebra fish" eggs. These are products under experimental use for cancer treatments (related documentation can be found on the Internet). The patient’s father believes that these supplements have been and are still significantly contributing to blocking the disease. The patient also takes other supplements such as: omega 3, ginseng, fruit and vegetable concentrates, etc.
 
 

LAB TESTS: THE PATIENT
 
2007
2008
 
 
Feb, 8
Mar, 9
Apr, 27
June, 8
July, 19
Aug, 26
Oct, 6
Nov, 23
Dec, 23
Feb, 02
White blood cells
4-10
3.5
13.05
6.3
5.8
4.4
4.6
5.5
6
5.5
6.2
Red blood cells
3.5-6.0
4.07
4.07
4.68
4.53
4.43
4.13
4.09
3.91
3.74
3.76
Haemoglobin
13.5-16
12.1
12
13.9
13.7
13.3
12.7
12.6
12.3
11.4
11.4
Platelets
150-450
158
149
175
158
142
131
157
165
173
186
Glucose
60-110
83
89
94
90
107
94
89
88
95
92
Urea
20-50
 
33
35
39
40
40
35
38
37
39
Uric acid
3.4-7
 
 
 
 
 
 
 
 
 
 
Creatinine
0.5-1.3
0.66
0.68
0.77
0.76
0.77
0.62
0.73
0.74
0.9
0.82
Bilirubin
0.1-1.2
0.28
 
 
 
 
 
 
 
 
 
Total proteins
6-8
 
 
 
 
7.51
 
 
 
 
 
Aspartate aminotransferase
0-40
52
41
24
18
33
63
34
29
33
31
Alanine aminotransferase
0-40
83
59
40
33
55
167
68
39
30
35
Lactate dehydrogenase (necrosis enzyme)
200-450
255
252
235
209
237
321
 
344
398
317
Alkaline phosphatase
100-290
514
444
315
236
296
405
331
330
560
682
Cholinesterase
4.5-14.5
 
 
 
 
 
 
 
 
 
 
GGT
10-50
516
397
363
376
574
1131
866
592
637
980
Reactive C protein
 
 
0
0
0
0
4
 
4
 
 
Sodium
135-150
143
143
141
141
140
141
141
143
144
144
Potassium
3.5-5.5
3.87
3.84
4.02
3.79
3.93
3.39
3.92
3.93
3.78
4.01
Chlorine
95-112
 
 
 
 
 
 
103
 
 
 
Iron
70-170
 
 
 
 
 
 
 
 
 
 
PSA
0-4
 
 
 
 
 
 
 
 
1.38
1.63
Carcinoembryonal antigen (CEA)
0-5
5.52
4.62
6.51
6.64
8.28
7.63
9.05
10.68
9.93
12.21
CA 19-9 (GICA)- Digestive System
0-37
 
28.93
45.28
59.66
73.02
51.76
80.25
70.76
47.12
72.93
Carbohydrate antigen CA 15-3
 
 
 
 
 
 
 
 
 
 
 
Ferritin (liver tumors)
20-300
 
 
 
 
 
 
 
 
 
 
NSE
<12.5
 
5.1
7.4
 
 
11
16
16.75
34
37
Chromogranin A (FBF)
70
 
 
 
 
 
 
 
 
 
 
S-Chromogranin A (Humanitas)
2-10
 
 
 
 
 
 
 
 
 
 
Triglycerides
 
 
 
 
 
 
 
 
 
 
 
Cholesterol
 
 
 
 
 
 
 
 
 
 
 
Carbamazepine
4-10
 
 
3
 
4.3
 
2.9
 
 
 
Vitamin B12
150-700
 
 
 
 
 
 
 
 
 
 
Folate
7-39
 
 
 
 
 
 
 
 
 
 
Thyrotropin (TSH)
0.35-5
 
 
 
 
 
 
 
 
8.5878
 
FT3 (Triiodothyronine)
1.71-3.71
 
 
 
 
 
 
 
 
3.35
 
FT4 (Free thyroxine)
0.70-1.48
 
 
 
 
 
 
 
 
1.1
 

 
 
 
Diagnosis: Neuroendocrine neoplasia with hepatic metastases.
 
 The present expert's opinion was requested by the patient’s father to get an opinion on a treatment methodology called Hyperthermia.
First of all, a brief update of the clinical case reported by the patient’s father: “.. The last ultrasound showed that the situation is more stable than the latest examinations. Probably the addition VP 16 to lomustine and the injections of a Viscum album contribute to this situation”.
39 year old male.
History:
In August 2003, following a significant loss of weight, a diagnosis of neuroendocrine neoplasia with hepatic secondary lesions of unknown origin was established. Subsequently its origin was believed to be “pancreatic”.
Biopsy confirmed by the Cancer Institute.
 
Therapies:
-       From 08/2003 to 05/2004 the patient underwent a total of 31 monthly chemotherapy administrations with Carboplatin and VP 16;
-       From 02/2004, Longastatin LAR 20: 1 vial a month;
-       On 11/2003, a whole body scintigraphy with immune and receptor traces gave negative results;
-       From 07/2004 to the end of December 2006, the patient was treated with Roferon A 3000000 U at a dosage of 3 vials a week;
-       In August 2004, chemotherapy with PRAVA 40 mg (3 tablets every 2 months approximately) was started. Due to leucopenia problems, the administration of this drug was irregular until December 2006 when the Interferon was interrupted. Since then, the administrations have taken place approximately every 45-50 days.
-       For pain-relief, Durogesic 25-50 was prescribed and has now been replaced by Oxicontin 20-50 twice a day, and lately also by Oramorph, as needed. Pain is also relieved by Antispasmina colica (forte) and Tachipirina.
-       The most recent exams have showed signs of slight thyroid distress caused by hypothyroidism (TSH 8.5878). Currently treated with Eutirox 0.25 mcg a day.
 
Tests:
-       Ultrasound exam shows a slight increase of the lesions.
-       The last CAT scan has shown significant progression of the disease.
-       Blood test: basically good results. Only slightly altered are alkaline phosphatase, transaminases and GGT (see enclosed results).
 
On February 2008, The patient was subjected to a complete abdomen and chest CAT scan, with and without the use of contrast agents, the results of which are reported herewith:
“Symmetric rib cage.
Neither respiratory field shows any current focal parenchymal thickening of pathological significance.
No bilateral pleural effusions.
The following lymphadenopathies were reported at the chest:
- at the level of the supra-aortic vessels (maximum transverse diameter 1.4 cm);
- to the right and left armpit (maximum transverse diameter respectively 1.4 cm and 1.8 cm);
- in the area of the right front paramediastinal (maximum transverse diameter 1.9 cm);
- to the side of the aortic arch (maximum transverse diameter 2.6 cm);
- at the level of the carina (maximum transverse diameter 2.1 cm);
- in the subcarinal area (maximum transverse diameter 2.3 cm).
The liver, which is somewhat larger than standard, shows several afinalistic alterations, the greatest of which has a maximum transverse diameter of 5.8 cm.
The portal vein is normally patent.
The spleen and both kidneys are within normal limits in terms of tomodensitometric and morphological characteristics, and have a good bilateral nephrographic effect.
Presence of pathological lymph node in the right retrocrural area (maximum transverse diameter 1.8 cm).
Starting from a plane, passing the origin of the celiac tripod, the known adenopathic mass (maximum transverse diameters approximately 5.5 cm x 6.7 cm) can be identified, which continues down to the bifurcation of the common iliac arteries.
The retroperitoneal mass translocates the afferent and efferent vascular structures to the kidneys and spleen without any clear cleavage, and also concentrically surrounds the abdominal aorta, and is undissociable from the pancreas.
At the level of the bifurcation of the iliac arteries, two masses with a maximum transverse diameter of 3.6 cm to the left and 2 cm to the right, can be seen.
The afore-described clinical picture would suggest a progression of the disease as compared with the previous check-ups carried out here in 2005 and 2007.
No free effusions”.
The tables showing the updated results of the laboratory tests, from which it can be seen that the abnormal analyses concern, are attached.
CEA,               CA19.9,          NSE,               GGT,   Alkaline phosphatase.        
The patient’s father stresses the fact that the attending physicians, differently from the reporting radiologist, only note small alterations in the oncological lesions and tumour mass, thereby providing a less pessimistic evaluation.
In the light of this examination, in any case, the attending physicians have decided to proceed with a further course of chemotherapy, in addition to Lomustine, with 20 mg/ml Etoposid Ebewe (VP 26?): one small bottle per day for 5 days, to be taken orally, mixed with coca-cola.
 
To complete the information here provided, since July 2004, The patient is taking dietary supplements derived from "Zebra fish" eggs. These are products under experimental use for cancer treatments (related documentation can be found on the Internet). The patient’s father believes that these supplements have been and are still significantly contributing to blocking the disease. The patient also takes other supplements such as: omega 3, ginseng, fruit and vegetable concentrates, etc.
 
 

LAB TESTS: THE PATIENT

 
 
2007
2008
 
 
Feb, 8
Mar, 9
Apr, 27
June, 8
July, 19
Aug, 26
Oct, 6
Nov, 23
Dec, 23
Feb, 02
White blood cells
4-10
3.5
13.05
6.3
5.8
4.4
4.6
5.5
6
5.5
6.2
Red blood cells
3.5-6.0
4.07
4.07
4.68
4.53
4.43
4.13
4.09
3.91
3.74
3.76
Haemoglobin
13.5-16
12.1
12
13.9
13.7
13.3
12.7
12.6
12.3
11.4
11.4
Platelets
150-450
158
149
175
158
142
131
157
165
173
186
Glucose
60-110
83
89
94
90
107
94
89
88
95
92
Urea
20-50
 
33
35
39
40
40
35
38
37
39
Uric acid
3.4-7
 
 
 
 
 
 
 
 
 
 
Creatinine
0.5-1.3
0.66
0.68
0.77
0.76
0.77
0.62
0.73
0.74
0.9
0.82
Bilirubin
0.1-1.2
0.28
 
 
 
 
 
 
 
 
 
Total proteins
6-8
 
 
 
 
7.51
 
 
 
 
 
Aspartate aminotransferase
0-40
52
41
24
18
33
63
34
29
33
31
Alanine aminotransferase
0-40
83
59
40
33
55
167
68
39
30
35
Lactate dehydrogenase (necrosis enzyme)
200-450
255
252
235
209
237
321
 
344
398
317
Alkaline phosphatase
100-290
514
444
315
236
296
405
331
330
560
682
Cholinesterase
4.5-14.5
 
 
 
 
 
 
 
 
 
 
GGT
10-50
516
397
363
376
574
1131
866
592
637
980
Reactive C protein
 
 
0
0
0
0
4
 
4
 
 
Sodium
135-150
143
143
141
141
140
141
141
143
144
144
Potassium
3.5-5.5
3.87
3.84
4.02
3.79
3.93
3.39
3.92
3.93
3.78
4.01
Chlorine
95-112
 
 
 
 
 
 
103
 
 
 
Iron
70-170
 
 
 
 
 
 
 
 
 
 
PSA
0-4
 
 
 
 
 
 
 
 
1.38
1.63
Carcinoembryonal antigen (CEA)
0-5
5.52
4.62
6.51
6.64
8.28
7.63
9.05
10.68
9.93
12.21
CA 19-9 (GICA)- Digestive System
0-37
 
28.93
45.28
59.66
73.02
51.76
80.25
70.76
47.12
72.93
Carbohydrate antigen CA 15-3
 
 
 
 
 
 
 
 
 
 
 
Ferritin (liver tumors)
20-300
 
 
 
 
 
 
 
 
 
 
NSE
<12.5
 
5.1
7.4
 
 
11
16
16.75
34
37
Chromogranin A (FBF)
70
 
 
 
 
 
 
 
 
 
 
S-Chromogranin A (Humanitas)
2-10
 
 
 
 
 
 
 
 
 
 
Triglycerides
 
 
 
 
 
 
 
 
 
 
 
Cholesterol
 
 
 
 
 
 
 
 
 
 
 
Carbamazepine
4-10
 
 
3
 
4.3
 
2.9
 
 
 
Vitamin B12
150-700
 
 
 
 
 
 
 
 
 
 
Folate
7-39
 
 
 
 
 
 
 
 
 
 
Thyrotropin (TSH)
0.35-5
 
 
 
 
 
 
 
 
8.5878
 
FT3 (Triiodothyronine)
1.71-3.71
 
 
 
 
 
 
 
 
3.35
 
FT4 (Free thyroxine)
0.70-1.48
 
 
 
 
 
 
 
 
1.1
 

 

 
 
 
Diagnosis: Neuroendocrine neoplasia with hepatic metastases.
 
 The present expert's opinion was requested by the patient’s father to get an opinion on a treatment methodology called Hyperthermia.
First of all, a brief update of the clinical case reported by the patient’s father: “.. The last ultrasound showed that the situation is more stable than the latest examinations. Probably the addition VP 16 to lomustine and the injections of a Viscum album contribute to this situation”.
 

Expert's Opinion

From the very clear statements made by Dr. X it can be derived that there was, over the years, a clinical situation best described as stable disease with eventual minor progression. A clear response or clinical benefit could never be documented which is quite typical for this kind of disease.
 
I do not have any information on extrahepatic disease although the pain medication described makes the presence of mesenterial or retroperitoneal lymph node progression quite probable..
 
Question 1: My opinion on the effectiveness of hyperthermia in this case?
 
Local or regional hyperthermia may be applied as an additional therapeutic option in highly selected oncological situations such as locally advanced sarcomas. It is then usally given together with radiotherapy or together with cytotoxic agents and cytokines; for example a combination of melphalane plus tumour necrosis factor has been studied and routinely used in isolated hyperthermic limb perfusions.
The clinical use of systemic hyperthermia elevating the body temperature up to 43° celsius has been tried for a long time, either alone or again together with chemo- , radio-, or immunotherapy but conclusive and reliable data have not emerged to my understanding. At the major cancer centers in the western world, this form of therapy is at most regarded as highly experimental.
 
Since the patient’s problems are apparently quite serious and in order to really avoid insufficient advice on my side I have inquired, in the meantime, with Y from Berlin University ( Charite ) where lots of efforts had been concentrated during the last 15 years to more precisely define a clinical role for hyperthermia. Besides, I had had the opportunity some years ago to be member of the site visit committee evaluating these research programs at Berlin university.
 
According to his mail two days ago, Professor. Y is, however, sharing my opinion that hyperthermia would have no proven role in the patient's condition.
 
On the other hand, the probably most recognized expert for hyperthermia in Germany and also internationally, Professor Rolf Issels, Klinikum Großhadern, University of Munich, gave some possibly interesting hints which leads me to the answer to
 
Question 2: If you believe this methodology is useful, can you please indicate the application procedures and any associated treatments you believe to be better?
 
At this time, the group in Munich are studying the effects of a socalled “Teilkörper-Hyperthermie” in liver metastases from pancreatic tumours with neuroendocrine differention and the preliminary data will be presented at the ASCO congress in Chicago next week ( Tschoep et al., ASCO 2008, May30- June 3rd ). Professor Z has suggested that the results of the patient's current treatment should first be awaited but he would agree to see the patient later in Munich.
 
As to the second part of question 2 ( potential associated treatments ) it would be most helpful to know the extent of the disease as defined by the last CAT scan and ultrasound investigations.
If the malignant liver involvement is symptomatically leading I would suggest an hepatic artery infusion ( HAI ) as we are doing those weekly in extended liver metastases from various tumours, often combined with individualized embolization techniques. There have been quite impressive responses after liver perfusions with mitomycin C, 5-fluoruracil, oxaliplatin or the pegylated liposomal anthracycline caelyx. Depending on the size of the lesions and depending also on the general liver function and the individual vascular structures, we usually add a cisplatin-lipiodol based embolization procedure to the most prominent tumour infiltrates. But this can only be decided after presenting the patient's current contrast CT scans to our interventional radiologist.
 
We would be, of course, happy to offer such a treatment modality to the patient at our center if applicable. Please send along the data on CAT scans and liver chemistry in order to decide on that option and specify the extent of extrahepatic involvement.
 
In the case that locoregional measures would not be recommendable I would suggest further drug therapies as we are using them in the form of “controlled sequential off label treatments”
employing sequences of metronomic low dose ( antiangiogenic ) drug combinations and, whenever necessary, more intensive regimens at times of symptomatic progression, similarly to X's suggestions. These therapies could be closely followed by serial CEA and CA 19-9 determinations and longer drug exposures should only be allowed when marker regressions are seen. It is sometimes necessary to change the sequential therapies every three to six weeks ( Seeber, Onkologie 2008, Karger, in press – see appended manuscript ).
 
I certainly hope that the patient's disease may be controlled by one of the options suggested above.
 

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