Rectal Carcinoma, Gastric Carcinoma, Metastases.
Short Summary

52-year-old male was diagnosed in 2004 with a carcinoma of the lower rectum and underwent surgical anterior resection of the rectal tumor which was a well differentiated adenocarcinoma. In 2008 he underwent emergency operation for a perforated pyloric ulcer and then a radical resection of a gastric tumor which infiltrated the entire thickness of the gastric wall. It was a G3 diffuse type adenocarcinoma with signet ring cells, at pT3N2 stage. A preoperative full-body PET Scan demonstrated the presence of lesions with elevated carbohydrate metabolism and a preoperative evaluation of tumor markers showed significantly elevated levels of both CA 19-9 and CA 72-4. Following persistent emesis due to intestinal occlusion, he underwent an entero-enteric bypass procedure. At operation there were peritoneal nodules with fibrous tissue infiltrated by neoplastic epithelial cells compatible with carcinoma of gastric origin. These represent a rapid, still "limited", development of peritoneal carcinomatosis.

Patient's Questions
1)    Which treatment (even any innovative treatments), of any type and nature, do you suggest to fight this tumor?
 
2)    Based on your response to the previous question, what is the global and Italian center of excellence for treating this tumor?
Medical Background

Patient's History
Age 52, male
Diagnosis : Rectal Carcinoma, Gastric Carcinoma, Metastases
Clinical History:
In February 2004 carcinoma of the lower rectum was found, for which the patient underwent surgical “anterior resection of the rectum with defunctionalized protective colostomy. Marginal prostate radicality.” The discharge diagnosis favored: “Well differentiated adenocarcinoma. Peri-lymph and lymph node metastases in 2 pararectal lymph nodes, microembolic metastasis in 1 inferior mesenteric lymph node.” The patient therefore underwent chemotherapy with Xeloda tablets and radiation therapy as follow-up for surgical treatment. After this, the colostomy was removed with full recovery of functions.
At the end of 2008, in the context of follow-up tests to evaluate digestive problems, high levels of the following tumor markers were found:
CA 19.9          144.86            (< 37)
CA 72.4          86.9                (0 – 4)  
Further tests worth mentioning:
- Rx of the Chest (06/2007): Lung growths found at the apex on the right side. Highly dense micro-nodule in the anterior lower right lung field.
- Colonoscopy (06/2008): normal.
- Ultrasound of the upper abdomen (24/10/2008): normal.
- Full-body PET Scan (11/2008): presence of lesions with elevated carbohydrate metabolism on the sub-diaphragmatic lymph node level in the following sites: several lymph nodes at the hepatic hilum, at the interaortocaval site and at the left para-aortic site.
While the tests were being performed, at the end of November 2008, emergency hospitalization at Santa Chiara Hospital in Pisa, where the patient was operated for a perforated pyloric ulcer penetrating the pancreas with pyloric stenosis. This involved gastric resection surgery, Roux gastroenteroanastomosis on the defunctionalized segment, lateral duodenostomy on T-tube, minimal jejunostomy (laparoscopic approach). 
The following histological examination report (12/2008) favored: “gastric adenocarcinoma of the G3 diffuse type with “signet ring” cells, infiltrating the entire thickness of the gastric wall. Resection margins unaffected by neoplastic infiltration. Severe collateral dysplasia of the gastric mucosa. Seven lymph nodes with adenocarcinoma metastasis out of a total of 10 examined. pT3N2G3.
Attached is the report for the chest and abdomen CT scans dated 01/2009, which for the most part gave negative findings.
Further hospitalization in Feb 2009 for partial enterostenosis in patient operated for perforated gastric carcinoma. During hospitalization, the chemistry screen results were normal, but gastroesophageal transit brought to light a partial stenosis of the anastomotic jejunal segment. Sedated gastroduodenoscopy was therefore performed, with examination up to about 60 cm beyond the gastro-jejunal anastomosis, with completely negative results. The patient kept the nasogastric tube for 2 days, which did not show any significant stagnation, kept the duodenal drainage open, and was kept on parenteral nutrition. At the time of discharge, the patient was able to consume a semi-liquid diet, but it remains highly doubtful that the symptoms are completely resolved. In light of the recent anamnesis, it is not possible to rule out that the etiopathogenesis can be attributed, in addition to torsions or possible post-operative adhesions, also to the return of the proliferative disease. Indications were given at discharge to proceed with laparotomic surgery in the event that problems continued at home for >48 hours with no possibility for nutrition. The surgery was performed on 02/2009. On March 2009, the patient was still hospitalized at Casa di Cura San Rossore.
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This is an addition to the medical information above based on some notes we received from the patient:
On 02/2009, the patient was hospitalized at San Rossore Clinic in Pisa as a result of intestinal occlusion and emesis.
His history is remarkable for previous gastric resection with gastroenteroanastomosis on Roux loop due to hetoroplasia and even previously for low anterior resection of the rectum again due to heteroplasia.
During the last hospital stay, entero-enteric bypass surgery was performed following
peritoneal carcinosis being discovered during the surgical procedure.
Histology of two peritoneal nodules revealed: fibrous tissue infiltrated by neoplastic
epithelial cells of small dimensions and poor cohesion.
 
In summary, the report states: “Peritoneal metastases of undifferentiated carcinoma. (these traits are compatible with carcinoma of gastric origin).

Expert's Opinion

Discussion and Answers:
Although the rectal carcinoma treated in 2004 is a significant factor in the patient's medical history, I would plan the approach to his second and presently active second malignancy under the assumption that he is cured from that first tumor. This is said despite the Rx of the Chest which already in 06/2007 showed Lung growths at the apex on the right side and a highly dense micro-nodule in the anterior lower right lung field. These "growths" could represent metastases originating from rectal ca. However, they were not avid at the full body PET scan performed in 11/2008, thus questioning their significance, which at the most could represent very slow growing disease, practically "insignificant" in view of the current much more active second malignancy.
Still, there are two points to remember related to possible late side effects of previous treatments which bear potential implications on future decisions:
a. previous surgery and pelvic irradiation may contribute to intestinal adhesions and obstructive events; 
b. although previous chemotherapy included capecitabine alone, this was administered with pelvic irradiation, and possible reduction of bone marrow reserves should be taken in account when choosing components and doses of future chemotherapy.
With regards to the gastric cancer, the patient's disease seemed to be operated when limited to the abdomen, as demonstrated by the preoperative full body PET scan performed on 11/2008. Today, four months later and with a biopsy proven present activity in the peritoneum, it should be fully restaged. Based on that future-updated staging and on the patient's general condition by that time, it will be possible to decide whether to choose a "conservative" approach or to embark on a more "active" approach which is practiced in a few medical centers with more promising results:
1) Cytoreductive surgery and intraperitoneal chemohyperthermia: this is the first priority in terms of potential long term results. However, this option is reserved for selected patients. Its benefit would depend on the achievement of complete cytoreduction with no visible disease persisting in the abdominal cavity. If this approach is positively considered by the caring team of the patient, I suggest contacting the team of Surgical Department of Centre Hospitalo-Universitaire Lyon Sud, Pierre Bénite, France (see publication in Arch Surg. 2004, by Glehen O, Schreiber V, Cotte E et al.).                                   
2) Polychemotherapy: this is advocated if the option of intraperitoneal chemohyperthermia is rejected. It could consist on the standard epirubicin-cisplatin-infusional 5-fluoropyrimidine (ECF) as reported in Cancer 1996, by Bamias A, Hill ME, Cunningham D, Norman AR, et al, from Cancer Research Campaign Section of Medicine, Institute of Cancer Research, Sutton, Surrey, UK. or on anyone of the new triplet and doublet combinations incorporating docetaxel, oxaliplatin, irinotecan, capecitabine, or S-1 , such as have been reported in recent years with similar or slightly better results. For example, docetaxel and cisplatin plus fluorouracil (DCF) as reported in JCO 2006, by Van Cutsem E, Moiseyenko VM, Tjulandin S, et al, from University Hospital Gasthuisberg, Leuven, Belgium; or irinotecan, docetaxel and oxaliplatin as reported in Br J Cancer 2007, by Di Lauro L, Nunziata C, Arena MG, et al, from Division of Medical Oncology B, 'Regina Elena' Institute for Cancer Research, Via Elio Chianesi, 53, Rome 00144, Italy, or oxaliplatin with low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4), as reported in Acta Oncol.2007 by Oh SY, Kwon HC, Seo BG, et al, from Dong-A University College of Medicine, Busan, Korea; etc.
3) Targeted biotherapy combined with polychemotherapy: In view of the limited benefit offered by chemotherapy alone in stage IV gastric carcinoma, mainly in view of the prognostic significance of preoperative elevated levels of CA 72-4 in the case of the patient (see the related recent discussion in Adv Ther. 2008 Oct;25(10):1075-84), I would strongly recommend tailoring an "enriched" and personalized regimen of treatment for him. The approach of targeted biotherapy can be applied by adding already available and well known biological agents to the chosen polychemotherapy regimen. I admit that such combinations are expensive and not yet routinely practiced, partly because of limited experience and partly because of lack of reimbursement arrangements with most health insurance systems. Nevertheless, their potential in clinical terms is being increasingly recognized by oncology practitioners.
3a) CETUXIMAB: Cetuximab could be combined with FOLFIRI (FOLCETUX study) (see the report of Pinto C, Di Fabio F, Siena S et al, in Acta Oncol. 2007, from Medical Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy.) This option could be most promising if the patient's tumour is found to express EGFR by immunohistochemistry with low serum EGF and TGF-alpha levels, as suggested by a recent publication on cetuximab combined with FOLFOX6 (see Han SW, Oh DY, Im SA et al, in Br J Cancer 2009, from Department of Internal Medicine, Seoul National University Hospital, Chongno-Gu, Seoul, Korea).
3b) BEVACIZUMAB: Bevacizumab could be combined with irinotecan and cisplatin, as reported by Shah MA, Ramanathan RK, Ilson DH et al, in JCO 2006, from Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

 

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