Robert de W. Marsh, MD
Meaningful improvement in the chemotherapy of gastrointestinal
malignancies continues to be an elusive and challenging target in the 1990s.
However, although real and tangible advances have been scarce, particularly
in the setting of widespread metastatic disease, whatever its origin, there
are indications of notable progress in a few selected situations.
Beginning with esophageal cancer of both the adeno
and squamous variety, it would appear that combined modality therapy is
here to stay. Most cancer programs now advocate chemotherapy, usually cisplatin
and 5-fluorouracil together with radiation therapy, prior to definitive
esophagectomy for localized disease. An exciting advance is the discovery
of the activity of paclitaxel in this setting,1 and it is currently
being tested in combination with both cisplatin and carboplatin as well
as 5-fluorouracil with early indications of success. In this regard, an
ongoing protocol at the University of Florida using two to four cycles
of carboplatin and paclitaxel followed by continuous infusion 5-fluorouracil
and radiation therapy prior to surgery continues to accrue patients and,
together with other phase two studies of a similar nature, will help to
define the optimal use of paclitaxel in this disease. If its initial promise
is confirmed, it is likely that this agent will become an integral component
of the new standard of care.
In locally advanced and metastatic gastric cancer,
the search for effective combination chemotherapy continues. Every year
it seems that a new champion is declared, and 1997 was no different with
the pronouncement that first ECF (epirubicin, cisplatin, and continuous
infusion 5-fluorouracil)2 and then PELF (cisplatin, epirubicin,
leucovorin, and 5-fluorouracil)3 were the new "state-of-the-art"
programs of choice. With neither combination able to achieve a median survival
in excess of 11 months, it remains to be seen whether the toxicity and
cost of these regimens are truly justified in terminally ill patients who
want the best possible quality of life in their remaining few months. There
appears to be no substantial advance in this regard over the older protocols
such as ELF (etoposide, leucovorin, and 5-fluorouracil) and EAP (etoposide,
doxorubicin, and cisplatin).
The situation is somewhat brighter in colorectal
cancer. Once again, the application of combined modality therapy together
with improved chemotherapy agents and improved knowledge of their use means
that more patients with previously untreatable or terminal illness will
now have a realistic chance of either obtaining a remission or prolonging
their lives. The optimal method of administering 5-fluorouracil continues
to evolve, and, unlike gastric cancer, there appears to be progress with
each new iteration.
Adjuvant chemotherapy of Astler-Coller stages B2
and C disease has been widely adopted in the United States, if not necessarily
elsewhere, and it appears that 12 months of 5-fluorouracil and levamisole
may ultimately give way to six months of 5-fluorouracil and leucovorin
as the preferred regimen in those who can tolerate the somewhat increased
intensity. In the setting of metastatic or locally advanced disease, application
of chronotherapy4 and/or the addition of oxaliplatin5
has added a further dimension to the advances already achieved by the addition
of either high- or low-dose calcium leucovorin to most regimens.
Our current program of 14-day continuous chronomodulated
infusion of 5-fluorouracil and leucovorin, which is a concurrent effort
with the University of Toronto, continues to rapidly accrue patients. Updated
results indicate a 45% overall response rate in previously untreated patients,
including a 15% complete response rate. A further 35% of patients maintained
stable disease. Trials from France, which have included oxaliplatin in
a five-day continuous circadian infusion, have elicited a similar response
rate (53%).5 In all of these trials, the gratifyingly low toxicity
has meant that the quality of life of these patients has been relatively
unaffected.
A new option now being tested in large cooperative
group phase II trials is the combination of oral 5-fluorouracil and oral
ethinyluracil, a uracil analogue that irreversibly inactivates DPD (dihydropyrimidine
dehydrogenase), the principal enzyme responsible for the degradation of
5-fluorouracil. This action allows much more consistent absorption of 5-fluorouracil
from the gut, as a good deal of DPD is found there, and also leads to significant
prolongation of the half-life of 5-fluorouracil from approximately 13 minutes
to 3-1/2 hours. When given daily for extended periods, it is hoped that
the results will mimic those of prolonged infusions of 5-fluorouracil.
Finally, the consistent 15% response rate achieved
with the use of CPT 11 in 5-fluorouracil refractory patients has confirmed
this agent as the standard of care in this setting. Most oncologists have
now learned how to administer it safely and how to manage the potential
complications, despite its relatively narrow therapeutic index. Trials
to determine its possible role in combination therapy of de novo
disease are currently underway.
Gemcitabine has been rapidly embraced by most physicians
as the therapy of choice in inoperable patients with pancreatic cancer.
For the first time, it appears that there is finally a chemotherapy agent
that impacts favorably on the quality, and perhaps even the quantity, of
life of these seriously ill individuals. In addition, gemcitabine is capable
of radiosensitizing a tumor, and this beneficial effect is under active
investigation. In truly localized disease, a combination of 5-fluorouracil
and radiation therapy followed by gemcitabine is showing considerable promise in early testing.
In cases of rectal cancer, preoperative and/or postoperative
chemotherapy as part of a multimodality approach has significantly impacted
the quality of life and also survival of patients so treated. Continuous
infusion of 5-fluorouracil (chronomodulated at the University of Florida6)
has become an integral part of these programs owing to the improved results
so obtained, and this finding once again confirms the superiority of this
method of administration in most settings. The dual goals of resection
of tumor and rectal sparing are now achievable in a large percentage of
cases, despite an often grim outlook at first evaluation. Despite these
advances in the United States, colleagues in Europe steadfastly believe
that proper surgical technique can achieve similar results, and they have
not as yet embraced this approach with enthusiasm.
The therapy of anal cancer, one of the more successfully
treated sites in the gastrointestinal tract, has not seen any dramatic
innovations in the last few years, but there is one potentially important
evolution in the wings. It appears that cisplatin may possibly be used
instead of mitomycin-C in combination with 5-fluorouracil and radiation
therapy for the definitive treatment of this condition. Although final
data are not yet available from the definitive Eastern Cooperative Oncology
Group trial, those institutions that have actively pursued this line of
investigation (including the University of Florida) and confidently predict
that the result will be favorable with respect to the use of cisplatin.
Finally, the use of octreotide in carcinoid syndrome
and other active neuroendocrine tumors has enabled investigators to explore
newer techniques of treatment such as embolization without fear of devastating
consequences for the patient. In selected situations, this can mean the
difference between asymptomatic remission and life-threatening inanition.
Most large centers now routinely perform embolization in these diseases
with relative impunity. Unfortunately, diseases such as hepatocellular
carcinoma and biliary tract malignancies remain difficult, if not impossible,
to treat with any degree of success, and any progress in these areas will
be welcomed. It is hoped that some of the newer classes of drugs, such
as angiogenesis inhibitors, will perhaps have some activity in these areas.
References
1. Ajani JA, Ilson DH, Daugherty K, et al. Paclitaxel in the treatment
of carcinoma of the esophagus. Semin Oncol. 1995;22:35-40.
2. Findlay M, Cunningham D, Norman A, et al. A phase II study in advanced
gastro-esophageal cancer using epirubicin and cisplatin in combination
with continuous infusion 5-fluorouracil (ECF). Ann Oncol. 1994;5:609-616.
3. Cascinu S, Labianca R, Alessandroni P, et al. Intensive weekly chemotherapy
for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin,
6S-leucovorin, glutathione and filgrastim: A report from the Italian Group
for the Study of Digestive Tract Cancer. J Clin Oncol. 1997;15:3313-3319.
4. Bjarnason G, Marsh R, Chu N, et al. Phase II study of 5-fluorouracil
(5FU) and leucovorin (LV) by a 14 day circadian infusion in patients with
metastatic colorectal cancer. Proc Annu Meet Am Soc Clin Oncol.
1996;15:543.
5. Giacchetti S, Zidani R, Perpoint B, et al. Phase III trial of 5-fluorouracil,
folinic acid, with or without oxaliplatin in previously untreated patients
with metastatic colorectal cancer. Proc Annu Meet Am Soc Clin Oncol.
1997;16:805.
6. Marsh RD, Chu NM, Vauthey JN, et al. Preoperative treatment of patients
with locally advanced unresectable rectal adenocarcinoma utilizing continuous
chronobiologically shaped 5-fluorouracil infusion and radiation therapy.
Cancer. 1996;78:217-225.