DOCTORS'

Medical Case Studies

Neuroroendocrine neoplasia with hepatic secondary lesions

Short Summary

39-year old male was diagnosed with metastases of Neuroendocrine tumor to the liver, presumably from pancreatic origin, suffered from significant weight loss. The administered treatments include Chemotherapy, Roferon A, Statins and Dietary supplements.

Patient's Questions

1. Are there any alternative, efficient treatments to VP 16? (The patient has actually already been treated with this, when originally diagnosed in July 2003/June 2004).
2. Your opinion with regards to the interpretation of the CAT scan: do you believe the patient's condition to have worsened significantly or only slightly, as compared with previous scans? Any prospects?
3. Please, give us your opinion on the Zebra fish eggs supplements.

Medical Background

39 year old male.

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For pain-relief, Durogesic 25-50 was prescribed and has now been replaced by Oxicontin 20-50 twice a day, and lately also by Oramorph, as needed.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 CATscan 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

Expert's Opinion

QUESTIONS 1) + 2):

Are there any other effective therapies or supplementary therapies to the current ones?

Any prospects?

These questions have been approached in two phases:

Phase onewas written in February, 2008.

This wasbased on the first medical report which was offered on Januar 2008,whenthe disease was still described as a "substantially stabilized medical condition, except of a slight increase of the lesions".

By that time my opinion was offered depending on several "clarifications":

ANSWERS 1) +2):

So far no clear cut effective treatment is available for well differentiated neuroendocrine tumors, except of radioactive treatment for selected cases. However, this option is not applicable for The patient since his somatostatin scintigraphy was negative.

Therefore, at the present stage, the approach to The patient disease should be based on the information which can be deduced from his case history: what is the clinical impression following four and a half years of active disease, most of the time under active treatments?

Is there reliable information as to the natural course of his disease previous to the institution of any treatment (in 2003)? Was it then a "stable disease"/ very slowly progressive, as characteristic for typical carcinoids? Or was it a more rapidly growing disease as could be suspected from his significant weight loss? What was the presumed cause for his weight loss towards diagnosis and before treatment?

Was there by that time any "intercurrent condition" that could have caused his weight loss, thus leading to the diagnosis of a slow growing tumor just "by chance"? Or was that considered to be induced by his disease? And what was its course since than?

Is there any information as to the Ki67 index of this tumor? To the best of my knowledge when the Ki67 index is very low neuroendocrine tumors are chemoresistant, while chemotherapy may be active in cases of higher indexes.

I need all this information in order to judge whether the stability of the tumor under chemotherapy with carboplatin and etoposide reflected "clinical benefit" achieved by treatment, therefore implicating further chemotherapy, or "NO effect" of treatment thus reflecting a "naturally stable disease", therefore implicating to withhold chemotherapy.

b. Was there any sign of improvement under the long lasting treatment with

Roferon A?

If yes, than I would refer the treating physician to the following paper:

"Biotherapy. 1997;10(1):1-5.The incidence and clinical significance of antibodies

to interferon-a in patients with solid tumors. Oberg K, Alm G.", which concludes

with the suggestion that a significant number of patients lost the anti tumor effect

during development of neutralizing antibodies at high titers, but that

human leukocyte interferon can be used as rescue treatment.

Phase two was written on February 2008.

To date, when there is definite progression demonstrated by CAT scan, the disease has changed its course. Furthermore, for the first time since diagnosisthere is a raise of tumor markers (CEA and CA19-9) which are of NON-neuroendocrine origin, meaning that the disease has changed its nature as well.

These changes would represent either a current proliferation of a "different" clone of cells which has been clinically dormant up till now, or some "transformation" in the tumor cells which acquired the capacity of producing CEA. Both these possibilities would mean that the tumor is not anymore well differentiated but has become an atypical/poorly-differentiated neuro-endocrine tumor.

The "new" and dominant characteristics of the disease dictate a new approach. Apparently, this has already been chosen by the treating physicians who prescribed a new line of chemotherapy.

I hope that the chosen combination (lomustine and etoposide) will achieve a major response, with consequent symptom relief and hopefully extended survival as well.

Alternative lines of chemotherapy in case of tumor progression under the current treatment could be:

to resume a platinol based regime, since four years have already elapsed from its previous administration, and since the tumor has eventually converted to the type which is expected to respond to this drug. This could be combined with 5FU (instead of the already administered etoposide).
Note: in case of neurotoxicity following the past treatment with platinol, the last can be substituted by carboplatin (AUC5?) as used to in other situations, like in NSCLC, although there is no specific experience with carboplatin in atypical carcinoids.
dacarbazine, 400 mg/m2/day, plus fluorouracil, 1 g/m2/day, with

leucovorin, 200 mg/m2/day, for 2 days every 21 days

[Ollivier S, Fonck M, Bécouarn Y, Brunet R.

Dacarbazine, fluorouracil, and leucovorin in patients with advanced

neuroendocrine tumors: a phase II trial

Am J Clin Oncol. 1998 Jun;21(3):237-40].

QUESTION 3):

Please, give us your opinion on the Zebra fish eggs supplements.

ANSWER 3):

I am a conventional oncologist, trained to advice on the basis of evidence based medicine. Therefore, since there are no controlled studies elucidating the objective effect of supplementary treatments in cases of "neuroendocrine tumors", I can not discuss the potential role of these treatments for this disease. I can, however, understand the patient's father belief that these supplements have been and are still significantly contributing to blocking the disease. He probably has not seen any other patient with "cancer" that "naturally" remains stable for so long time as characteristic for well differentiated carcinoids. Nevertheless, since he is eager to contribute to the control of the disease, and since I am not aware of any detrimental effect that can derive from these supplements, I agree with the liberty which he has been granted to supply them to The patient. The same applies to omega 3, ginseng, fruit and vegetable concentrates, etc.

NOTE: At the present stage he is under opioids for pain control.

When did he start to be on pain? Is this an "old" condition caused by his long lasting

massive disease? Or is it a new condition reflecting disease progression?

Is his pain satisfactorily controlled by the opioids? If not, this might mean that his pain is not purely of somatic type, rather it could be of visceral type due to the extensive liver metastases or of neural type due to the retroperitoneal masses.

The control of such a composed pain syndrome may require cooperation with a professional team, such as offered in the "pain clinics".