Adenocarcinoma, ex-goblet cell (or, as referred to here: Goblet Cell Carcinoid) data, CAPOX, and ME!!!

Since being diagnosed with adenocarcinoma, ex-goblet cell, Stage 2a, found in the appendix of my completely asymptomatic self, on my "LAST" scan to follow-up for Stage IV melanoma on August 27 and subsequent surgery(s) on August 30/September 11, a whirlwind of crazy unpleasantness has ensued!  From the minute B learned of my diagnosis, he made it his business to learn all there is to know about the rare condition. So ~ for those of you who are interested or are searching for info on this topic for yourself or your loved one ~ some basic info/research reports follow.  If this sort of intel is not for you (And I don't blame you one bit!!!) skip to the bottom for my personal up-date and CAPOX FUN FACTS!!!

There is this, from Plos One 2015 with some introductory facts from the same review linked below:

"Goblet cell carcinoids/carcinomas (GCCs) are considered a subgroup of mixed neuroendocrine neoplasms (NENs) and adenocarcinomas occurring with an incidence of approximately 0.01–0.05/100,000/year and occur almost exclusively in the appendix. GCCs were first described as a separate entity from adenocarcinomas and carcinoid tumors in 1974. GCCs are more aggressive than typical appendiceal carcinoid tumors but less aggressive than adenocarcinomas.

Approximately 50–60% of the patients presented with symptoms of acute appendicitis. However, one third of the patients were asymptomatic and the GCC was identified incidentally after appendectomy performed in addition to other surgery. Other patients presented with chronic intermittent abdominal pain, palpable abdominal mass, gastrointestinal bleeding and weight loss. Less than 1% of patients had an established preoperative diagnosis of a primary appendiceal GCC. At diagnosis, approximately 10% of GCCs were disseminated with distant metastases to the ovaries, the peritoneum, distant lymph nodes, liver, and bones. Females with ovarian masses were generally presumed preoperatively to have a primary ovarian cancer."

 Plos One, 2014:  Goblet Cell Carcinoids: Characteristics of a Danish Cohort of 83 Patients

Treatment of GCCs is primarily based on surgery RSH [right sided hemicolectomy in which the right 1/3 of the colon is removed] is considered the standard surgical treatment of localized GCCs and is recommended to take place within 3 months of the appendectomy. However, there has been disagreement whether simple appendectomy is sufficient to secure radicality for localized tumors or whether RSH is mandatory. In addition, some studies suggest a prophylactic BSO in female patients, at the time of RSH due to the high propensity for ovarian metastases. Two females of our cohort had metastases to the ovaries years after radical surgery for GCC and had a subsequent BSO. Based on our results we do not advocate for prophylactic BSO in female patients with localized GCC at diagnosis since evidence is lacking.

Some authors have suggested that localized GCCs less than1 cm, without serosal, mesoappendiceal or caecal invasion, with free surgical margins and with a low proliferative index (less than 2 mitoses/10 HPF), should be treated with a simple appendectomy since metastases rarely develop in these patients. Our results advocate for performing RSH in all GCC patients, as these patients had a significantly longer OS (89 months) vs. patients having only simple appendectomy (25 months). However, the latter group was small with risk of selection bias. Noteworthy is, the significant longer RFS of the radical treated subgroup of patients with localized GCC at diagnosis (16 months) compared to the radical treated group of patients with disseminated GCC (33 months), which may suggest that a true radicality is rarely obtained in disseminated cases. 

In the presence of disseminated disease at time of diagnosis debulking surgery is recommended when possible followed by chemotherapy with regimens similar to colorectal adenocarcinomas. A recent study advocates for cytoreductive surgery + HIPEC in GCC patients with peritoneal spread with an OS of 68 months. The treatment strategy should be individually tailored taking potential side effects and complications into consideration. Age, lymph node involvement and dissemination plus the Tang Classification are some of the factors to be considered. Guidelines for choice of chemotherapy are lacking; the ENETS Guidelines 2012 advocate for first line treatment with 5-flourouracil-based combinations. In agreement, we found a tendency towards longer survival for patients treated with colonic cancer regimes—however, the number of patients treated was low along with the risk of selection bias. 

For GCCs a 5-year survival between 60%–85% has been reported, while one study observed only 45% 5-year survival, reflecting the great proportion of females with metastases included. These data correspond to our results, showing a 5-year survival of 58% hence our cohort has a preponderance of females (67%) having 5-year survival of 49%. To have disseminated disease at diagnosis is a negative prognostic factor with a HR of 8. Further, we found that non-radical operation to be a negative prognostic factor with HR of 7, which reflects the subgroup with disseminated disease not having curative surgery. Focally positive staining pattern for CgA and negative/focally positive staining for synaptophysin were associated with poorer survival, probably due to a more poorly differentiation in these tumors. The obvious question must be whether localized and disseminated GCCs represent different disease entities?

Now the problem is - apart from all of the above - is the fact that it is hard to pull out GCC cancers and how best to treat them.   For instance there is this article from Journal of Clinical Oncology, 2018:

Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial

In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. 

A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy; 2,000 (99%) had stage III colon cancer; 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm. Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm. There were 578 Disease Free Survival events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively. In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76%; for the T4 and/or N2 population, they were 58% and 66%; and for the T1-3N1 population, they were 81% and 83%.  

There is also this, from Gastrointestinal Cancer Advisor, 2015:

XELOX as Standard Adjuvant Treatment Option for Stage 3 Colon Cancer

Adjuvant capecitabine plus oxaliplatin (XELOX or CapeOx) improved overall survival compared with bolus fluorouracil/folinic acid (leucovorin) (5-FU/FA) in patients with resected stage 3 colon cancer after a median follow-up of nearly 7 years, final results of a study have shown.  According to data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with stage 3A, 3B, and 3C colon cancer between 2004 and 2010 had a 5-year relative survival rate of 89%, 69%, and 53%, respectively.  Previously, bolus 5-FU/FA was recognized as the standard adjuvant treatment regimen for patients with stage 3 colon cancer; however, the addition of oxaliplatin to 5-FU and leucovorin significantly improved 3-year disease-free survival when given as adjuvant therapy for patients with stage 2 or 3 colon cancer.

“Capecitabine had been shown to be equivalent to 5-FU/leucovorin in stage 3 colon cancer,” Daniel G. Haller, MD, FACP, FRCP, professor of medicine emeritus at Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said in an interview with Cancer Therapy Advisor. “When the MOSAIC trial showed the additional benefit of oxaliplatin, it was necessary to extend these observations with the oral drug.”

For the phase 3 XELOXA study, researchers sought to evaluate the impact of XELOX versus bolus 5-FU/FA on disease-free and overall survival rates in patients with stage 3 disease.  A total of 1,986 patients were randomly assigned 1:1 to receive oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily on days 1-14 every 3 weeks for 8 cycles, or bolus 5-FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months.  Results showed that the 7-year disease-free survival rates were 63% in the XELOX group and 56% in the 5-FU/FA group. Researchers found that 7-year overall survival rates were 73% and 67%, respectively.

And more recently, this:

Survival Impact of CAPOX Versus FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer. Loree, Sha, Solejmani, et al. Clin Colorectal Cancer. 2018 Jun.

Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort.  We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. 

FOLFOX was associated with increased mucositis (6.2% vs. 0.7%) and neutropenia (25.9% vs. 8.6%), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%), diarrhea (31.8% vs. 9.0%), and hand-foot syndrome (19.9% vs. 2.1%). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%) and oxaliplatin (87.2% vs. 76.3%) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT. Overall survival did not differ by regimen. However, CAPOX was associated with improved disease-free survival (3-year disease-free survival (83.8% vs. 73.4%), which remained significant in high-risk (T4 or N2) but not low-risk patients.  CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT.

Then this:

Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study. Gao, Huang, Song, et al. BMC Cancer. 2018 Mar 1.

There is no consensus regarding the optimal time to initiate adjuvant chemotherapy after surgery for stage III colon cancer, and the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown.  Eligible patients aged greater than/= to 66 years who were diagnosed with stage III colon cancer from 1992 to 2008 were identified... [and evaluated to determine]...the impact of the timing of adjuvant chemotherapy on overall survival (OS).  A total of 18,491 patients were included. Delayed adjuvant chemotherapy was associated with worse OS . The efficacies of adjuvant chemotherapy within 5-8 weeks and less than/= to 4 weeks were similar. Compared with the non-chemotherapy group, chemotherapy initiated at greater than/= to 21 weeks did not significantly improve OS . Patients with postoperative complications, particularly cardiac arrest, ostomy infection, shock, and septicemia, had a significantly higher risk of a 4- to 11-week delay in adjuvant chemotherapy.  Adjuvant chemotherapy initiated within 8 weeks was acceptable for patients with stage III colon cancer. Delayed adjuvant chemotherapy after 8 weeks was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months. Moreover, postoperative complications were significantly associated with delayed adjuvant chemotherapy.

And finally, this: 

The impact of delayed commencement of adjuvant chemotherapy (eight or more weeks) on survival in stage II and III colon cancer: a national population-based cohort study. Kim, Choi, Kim, et al. Oncotarget. 2017 May 10.

Among 5355 patients, 154 (2.9%) received chemotherapy more than 8 weeks after surgery. Using an 8-week cutoff, the 3-year overall survival rate was 89.62% and 80.98% in the less than 8 weeks and greater than/= to 8 weeks groups, respectively. Independent prognostic factors for inferior overall survival included chemotherapy delay greater than/= to 8 weeks, older age, TNM stage III, emergency surgery, American Society of Anesthesiologists score of 3 or higher, and higher transfusion amounts.  This study shows that delayed commencement of adjuvant chemotherapy, defined as greater than/= to 8 weeks, is associated with inferior overall survival in colon cancer patients with stage II or III disease. The delay to initiation of adjuvant chemotherapy is influenced by several multidimensional factors, including patient factors (older age), insurance status (medical aid), and treatment-related factors (emergency surgery).

                                              ++++++++++++++++++

Despite the fact that most of the data regarding treatment for Ex-goblet cell adenocarcinoma (GCC, for convenience) is based on folks with colon cancer these are the bits and pieces upon which we based choices for my care.

Surgically:  The removal of the right third of my colon.  The removal of my ovaries.  

Adjuvant treatment:  A 3 month regimen of oxaliplatin combined with capecitibine, CAPOX, begun October 15, 6 weeks and 3 days after diagnosis.

Having now REALLY survived my first round of CAPOX and learning the errors of my overly exuberant post touting:  Treatment #1 ~ 3 month regimen of Oxaliplatin and Capecitabine ~ is DONE!!!!!! Take that adenocarcinoma ex-goblet cell carcinoid!  Here are my.....

CAPOX FUN FACTS:

• After the IV infusion of oxaliplatin there will be nausea and fatigue!  I managed my nausea pretty well with marinol, 5mg by mouth twice a day initially and then 2.5mg bid.
• Fatigue.  I have no answers other than out last it as best you can.  It was worse in the first 3-4 days post infusion (as was the nausea) and gradually improved the further out from the oxaliplatin I became.  I have a list of movies I may try to watch in the stupor induced by my next round.
• Neuropathies are for real!  They were much worse initially.  My mouth and tongue felt weird and tingly with even cold water from the tap.  Fingertips were numb and tender at the start.  Typing was difficult.  That has improved gradually, though as recently as yesterday, touching something straight out of the refrigerator induced unpleasant sensations.
• Warmth improved neuropathies to hands and feet on all occasions.
• I experienced jaw pain when biting down on even soft things in the first week post oxaliplatin.
• Drinking only warm beverages at all times is harder and more tiresome than I anticipated.  I love water.  But, tepid water is a bit of a challenge.
• Lots of foods are cut out immediately:  yogurt, kefir smoothies, jelly, pickles (though when B made me sandwiches he would nuke pickles in the microwave to take off the chill - not bad).  However, by the middle of week two, when eaten with warm food, things like sour cream, jelly, salad, etc., were okay.  Currently, food and beverage of any temp cause no problems.
• It takes some adjustment to make sure that the water is sufficiently warm BEFORE you brush your teeth or wash your hands.
• The sensations that I suspected were more of a neuropathy to the arm in which my IV was placed have improved.  A tender area around the injection site remains.
• Initially, the capecitibine didn't seem too bad.  Some cramping and diarrhea were fairly easily managed with immodium about once a day, depending on symptoms.
• I started back exercising 4 days after my infusion.  Just 10 minutes on the elliptical and some core work.  I even kicked it up to 15 minutes and more core at about a week out.
• I was super excited to take the last dose of capecitibine for this round and enjoy my week "OFF" poison.
• IT HAS SUCKED!!!!!!!!!!!!!!!  Cumulative side effects are a thing guys!!!
• Wednesday night, despite having had no poison all day, found me up for hours with severe abdominal pain.  So much so that poor B was worried about everything from pancreatitis to obstruction and wanted to take me to the ER.  I declined!!  After a dose of immodium and marinol, which I had stopped since I had stopped the poison, I finally got some rest and relief.  On calling the onc's nurse come morning, it was determined that I have full blown gastritis (somewhat expected with this regimen) and advised prilosec.  Since then, I have not had such severe pain, but my abdomen is incredibly tender to the slightest touch or movement.  Seriously!  Just taking a step "jars" my innards and causes pain.  Fun fact for fun times. I have NOT exercised since Wednesday!!!
• On a positive note, during his middle of the night research for additional information on these drugs, B found that patients who slough their gut during treatment develop an immune response and do better in the end.  So ~ YAY???
• Another positive is that though my hemoglobin dropped a bit on my last lab eval, my white count has remained steady.
• I have escaped significant hand/foot issues.  I've been keeping both moisturized (often sleeping with my feet greased up with socks on top) as my onc advised.  Despite that, I have had some transient burning and redness to the soles of my feet most often at night.  Don't know why.
• I also have some weird, raw, dry patches to the skin around my lips and on my face that are now getting a bit better.  I strongly suspect they are related to the capecitibine.  Nice.
• And finally, two days ago, my knees (other joints occasionally) have been aching just like they did when I was on Nivo.  With my stomach messed up, I don't want to take anything I don't have to, so instead of pain meds - it's grin and bear it.

There you have it.  Round one....actually DONE!  It was not fun!  Could it have been worse?  Probably!!!  Being a rattie in melanoma world for 8 years was not easy.  But, at least I felt that whatever happened, folks would learn from me and my fellow ratties.  Indeed, hard as it was, immunotherapy has become part of the national conversation (Geeze!  The ads alone!!) and has changed treatment options and outcomes for melanoma patients in incredible ways!!!  Every time I see an ad for Opdivo, I shout, "You're welcome!!!!"  In my new world of GCC, nobody seems to know much.  They just roll with things learned from folks with colon cancer though they go to great lengths to enumerate all the ways in which these things are not the same!!!  But, almost worse than that...nobody seems to be watching!  Nobody is keeping a record of what is happening to folks like me.  Nobody.  Except ~ me.  Damn.   

So, for what it's worth...I will be the rattie and the scribe.  I am not looking forward to Monday.  How does one force themselves to take poison?  Again?  And again?

Thanks for all the sweet cards, texts, IG, FB messages, and love in general.  It is life sustaining. - love, les