Pulmonary heteroplasia
Short Summary

66-year-old female was diagnosed with lung tumour within the right hemithorax with concomitant pulmonary nodules and a measurable enlargement of lymph nodes. FBS was positive for well differentiated neuroendocrine carcinoma and a needle biopsy revealed adenocarcinoma with associated neuroendocrine differentiation. The patient was then treated with altogether four courses of induction chemotherapy.

Patient's Questions
1)            How would you assess the progression of the disease?

2)            What is the prognosis?

3)            Do you suggest any possible diagnostic measures to complement those conducted so far?

4)            Any other treatments to use?
Medical Background

Expert's Opinion

 
Patient's History
Sex: F, Age: 66 years
 
DiagnosisPulmonary heteroplasia
The most recent significant clinical information is as follows:
-       on Nov 2007, admitted to DH to begin treatment with Tarceva 150 mg/day for 1 month;
-       blood test on Dec 2007 for dosage of Chromogranin A = 68.0 (normal values 19.4 - 98.1);
-       blood test on 07 2008 for dosage of Somostatin = 20 (on empty stomach after 12 hours: < 26; 4 hours after meals </=80); NSE = 8.6 (less than 18.3); 5-OH- Urinary Indoleacetic acid = 9.6 (0.7 – 8.2).
-       Total body multi-layer volumetric CAT scan à
o   Cranial: normal.
o   Chest: at the level of the upper lobe of right lung we have confirmation of the presence of a solid formation, unhomogeneous, containing some areas of aerial bronchogram. It is likely that this area is, in part, constituted by pathological tissue and, in part, by areas of atelectasic parenchyma. At the maximum extension point the lesion has a transverse diameter of 68 mm (previous 67 mm) and an anterior-posterior diameter of 100 mm (previous 97 mm) and is therefore stable. The central area appears more patchy. At the edges of the main nodular formation a few satellite nodules are observed, ranging from 11 mm to 21 mm in size (previous diameters 5 and 16 mm). These nodular formations therefore demonstrate a moderate increase in size. Small nodular irregularities, which could be of a fibrous nature, can be observed at the level of the left lung. No pleural effusion. Regular morphology of the cardiovascular structures of the mediastinum. The lymphadenopathy is insignificant at the mediastinic level with the exception of a lymph node of 10 mm at the carinal level.
o   Abdomen-Pelvis: in the abdomen small cystic formation of the hepatic parenchyma are noted, but no secondary lesions. In the pelvis an increase was noted in the size of the uterus. The rest is normal.
As already reported in a previous PET exam, changes of osteoschlerotic type are confirmed at the second right and third left ribs, possibly repetitive in nature.
-       blood test on Feb 2008 with Chromogranin A dosage 58.0 (19.4 - 98.1);
-        PET of Mar 2008à, this test, compared with previous images performed in other locations, of which the most recent in October 2007, demonstrated a persistence in the voluminous area of pathological accumulation of the radiopharmaceutical in the upper lobe of the right lung, which appears largely unchanged in size and in the fixation gradient of the radiopharmaceutical. Slight hypercaptation of the radiotracer in an area of pleural thickening at the anterior arch of the IV left rib. Finally, complete normalization of the fixation gradient of the radiopharmaceutical is observed at the level of the II right and III left ribs.
-       blood test on Apr 2008 with Chromogranin A dosage = 445 (19.4 - 98.1);
-       CAT scan on April 2008 à
o   Cranial: no significant elements
o   Chest: at the level of the upper lobe of right lung we have confirmation of the presence of a solid formation, unhomogeneous, containing some areas of aerial bronchogram. It is likely that this area is, in part, constituted by pathological tissue and, in part, by areas of thickened-inflammatory parenchyma. At the maximum extension point the lesion has a transverse diameter of 70 mm previous 68 mm) and an anterior-posterior diameter of 12 mm (previous 10 mm) and is slightly larger. The central area appears less patchy. At the edges of the main nodular formation a few satellite nodules are observed, ranging from 11 mm to 34 mm in size (previous diameters 11 and 21 mm). These nodular formations therefore demonstrate a moderate increase in size. Small nodular irregularities, which could be of a fibrous nature, can be observed at the level of the left lung, stable. No pleural effusion. Regular morphology of the cardiovascular structures of the mediastinum. The lymphadenopathy is insignificant at the mediastinic level with the exception of a lymph node of 10 mm at the carinal level.
o   Abdomen-Pelvis: in the abdomen small cystic formation in the hepatic parenchyma are noted, but no secondary lesions. In the pelvis an increase was noted in the size of the uterus. The rest is normal.
As already reported in a previous PET exam, changes of osteoschlerotic type are confirmed at the second right and third left ribs, possibly repetitive in nature.
 
Expert's Answer                                                                                                                
 
A) Case history until early April, 2008
First diagnosis of an inoperable lung tumour within the right hemithorax as defined by X-rays and an angio CAT scan. The maximum diameter of the tumour was around 12cm with extension to the right hilar region and with infiltration of the right pulmonary artery in the extrapericardial tract ( T4 ). There were also concomitant smaller pulmonary nodules visible within the right lung ( M1 ) and there was also a measurable enlargement of hilar, perihilar and paratracheal lymph nodes ( N2-3 ). On July 2007, FBS was positive for well differentiated neuroendocrine carcinoma ( typical carcinoid ).
On July 2007, PET-CT showed uptake in the main tumour mass with no activity in the smaller nodules. A needle biopsy on that occasion now revealed adenocarcinoma with associated neuroendocrine differentiation.
 
The patient was then treated with altogether four courses of induction chemotherapy with a cisplatin/gemcitabine combination of unspecified dosage resulting in a minor response as evaluated after the second course and stabilization without further regression after the fourth course. This minor tumour response could also be documented by a second PET scan on October 2007.
Regarding the laboratory findings, the course of the disease can be followed by pathologic values for chromogranin A ( 380 on September 2007 ) and CEA ( 45 ng/ml, on the same date.).
 
At that stage doctor d presented an excellent analysis of this case including a thorough discussion of all relevant further diagnostic and therapeutic options.
Apparently, following one of his suggestions, a therapy with daily 150mg of the EGFR-targeted tyrosin kinase inhibitor Tarceva was carried out for one month starting on November 2007. Later CAT scans, however, indicated a slow disease progression as indicated by a minor increase of the primary tumour and also of some of the satellites which was finally documented by an investigation on April 2008. In addition, lacking disease control was also substantiated by increasing values for chromogranin A.
 
                                   
B. Questions and answers
1. How would you assess the progression of the disease?
 
There is undoubtedly a measurable disease progression between early 2008 and April 2008. There is no further information on any drug therapies – has Tarceva been stopped after one month in December 2007 or had it been continued? Was a skin rash associated with Tarceva? I indeed need the information on the current therapy and will immediately respond again. I also need the information whether the patient is currently symptomatic with dyspnoe, cough pain or weight loss.
 
2. What is the prognosis?
 
Also for the answer to that question the abovementioned information is mandatory. The disease appears non-curable but I personally follow a number of cases with inoperable non small cell lung cancers for many years at good live quality. These patients survive either with stable disease or with sequential tumour regressions ( following interim progressions ) as induced by individualized sequential, often “off label” third and fourth line chemotherapies. As already indicated by Dr. D, in such cases of slowly growing tumours with a low proliferation compartment, continued “softer” therapies might make sense and I shall give some suggestions below. In the situation of asymptomatic disease stabilisation it is also recommended to offer intervals free of therapy.
 
3. Do you suggest any possible diagnostic measures to complement those documented so far?
 
In essence most relevant diagnostic procedures have been repeatedly applied in this case. However, I did not find an information on somatostatin analog radiolabeling (i.e. DOTATOC –PET ). Since chromogranin does seem to show some correlation with the course of Mrs. X disease it could be worthwhile to perform such an assessment of her tumour activity at least once. The therapeutic efficacy of radioactive somatostatin analogues is however limited in advanced thoracic tumours with diameters of +10cm even when these tumours present an adequate somatostatin receptor density. Also, myelosuppression as well as renal problems should not be underestimated after repeated radionuclide therapies.
 
 
4. Any other treatments to use?
 
The answer to this question should be the most important contribution within this advice. Again it would be helpful to have the further information as indicated earlier.
On the assumption that the patient is currently not suffering from severe symptoms and that she has had a period without therapy I would try to again induce a minor tumor regression or at least a valuable disease stabilization by several third line chemotherapy options to be tested.
 
Alimta I would prefer first against taxotere due to better tolerance and due to at least equi-efficacy. I would recommend, after supplementation with Vit B12 and folic acid, two courses of 500mg/m2 alimta at 3-week intervals assessing thorax X-ray, CEA and chromogranin A 1 day before the first dose and 3 weeks after the second course in order to closely assess its potential effectiveness.. If beneficial and well tolerated this therapy could go on until clear signs of disease progression.
 
Another chemotherapeutic option could be again platin-based and carboplatin should be preferred, either in combination with gemcitabin again or together with etoposide. As an off label option a brief experimental exposure to the FOLFOX regimen could also be tried since this is sometimes very helpful in adenocarcinomas of the lung.
 
Some of my patients with neuroendocrine differentiated adenocarcinomas had valuable disease stabilisations and tumour marker regressions following the very old drug CCNU (160-200mg orally once every 4 weeks), also combined with navelbine d1/d8 according to the haematological situation. In the case of rapid and symptomatic disease progression a trial with taxotere would be adequate, but radiotherapy to the main bulky tumour accompanied by weekly low dose cisplatin should be also be considered.
Depending on the course of the disease, at times of very slow progression , two months of metronomic low dose potentially antiangiogenic therapies ( i.e. daily 40mg tamoxifen plus/minus interferon alpha 3 x 3Mio/week or trofosfamide 150mg per day ) are an option - often better than therapeutic nihilism.
 
In summary, even in such a difficult oncologic situation there are, in my mind, a number of potentially active therapeutic options that could at least lead to a certain chronification of the disease at good life quality . With the current rapid development of new anticancer drugs in mind, we are now getting used to unexpectedly prolonged and very valuable survival times even in fairly unfavourable cancers.

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