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Multiple Agent *Chemo Cocktails*
written and compiled by doctordee
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Why Use Multiple Agents?

The role of chemotherapy in metastatic or unresectable sarcomas

"The role of chemotherapy in advanced STS is controversial and, at present, the treatment of metastatic STS represents palliative, not curative, therapy. ,,, Clearly, there is a pressing unmet medical need for improved therapies ,,, However, currently available drugs can often yield important benefits when used judiciously, and can prolong life and decrease symptoms. ,,, Certain subtypes have virtually no chance of major clinical response to conventional cytotoxic therapies, so whenever possible, these patients should be offered treatment with promising new agents in clinical trials. Included in this category of sarcomas with primary chemotherapy resistance would be, for example, ,,, most non-uterine leiomyosarcomas ,,, Given the range of possibilities, the choice of chemotherapy must be left to the individual physician, based on specific features of the sarcoma (type, location, symptoms, or immediate threat to life, etc), the overall health status of the patient (co-morbid diseases, etc) and the patient's preferences." [1]

"The choice of combination chemotherapy versus sequential single agents is also quite controversial. Randomised prospective clinical trials on combination chemotherapy regimens such as MAID (mesna,
adriamycin, ifosfamide, dacarbazine) and AIM (adriamycin, ifosfamide, dacarbazine), have shown these to yield statistically improved rates of objective antitumour response. However, these do not translate into improvements in survival, and come at the cost of added toxicity and a decrease in quality of life. There is therefore good reason to choose sequential administration of active chemotherapy agents, to maximise the time of tumour control, and to minimise treatment-associated side-effects. The exception to this is the preference of most physicians for combination chemotherapy in patients with acute pain or an immediate life-threatening problem (eg impending bronchial obstruction); in such cases, the greater likelihood of objective response would be worth the increased toxicity of combination therapy in an otherwise healthy patient for whom such aggressive therapy would be reasonable." [1]

",,,The discussion of the relevance of dose and dose-intensity in STS management has generated far more heat than light. There appears to be a relation between the delivered dose of certain drugs, (eg doxorubicin and ifosfamide), and objective antitumour response rates. It is unclear whether these responses last long enough to justify the increased toxicities (myelosuppression, mucositis, nephrotoxicity, etc) that accompany therapy at higher doses. Physicians must therefore carefully weigh the available evidence and the therapeutic goals for an individual patient to decide how best to use chemotherapy. There is no global consensus on the best way to apply 'standard' chemotherapy for the management of sarcomas." [1]

1. Samuel Singer, George D Demetri, Elizabeth H Baldini, and Christopher DM Fletcher
Management of soft-tissue sarcomas: an overview and update
Lancet Oncology, Volume 1, Number 2, 01 October 2000

We know that Demetri favors single agent chemotherapy agents, not in high dose, for judicious use in extending survival time with a good quality of life in inoperable stage IV LMS. There is a place for cocktails in stage IV, however.

Cocktails are sometimes used where an LMS tumor is inoperable, but with some judicious use of chemo and/or radiation, it MIGHT be made operable. This is called neoadjuvant treatment. In the case of stage III LMS, there would still be the possibility of a cure. In stage IV LMS, there might be a chance of a prolonged remission.

And sometimes there is very vicious, aggressive stage IV disease, where cocktails are used to prevent or to gain control of an onslaught of metastases.

And sometimes there are positive compromised margins on surgical resection, and radiation cannot be used in that particular site. In these latter cases, sometimes chemotherapy combinations [chemo cocktails] are used.

I am listing a few of the chemotherapy cocktail choices used for LMS below, along with a Pubmed/Medline search string for their clinical trials.

Be careful when you are reading, some clinical trials are for sarcomas, not just LMS, and may not be as relevant as clinical trials dealing with LMS, as some sarcomas are relatively radiosensitive or chemosensitive. Sometimes the clinical trials dealing with LMS include GIST, which is incredibly chemo resistant, so the response rates for LMS are erroneously lowered. Sometimes there are no clinical trials dealing with LMS alone.

ASCO -- The Association of Clinical Oncologists is also a good site to search for results of clinical trials, especially of the newer agents. You will have to go to the site and search the abstracts with keywords of the chemotherapy agent AND sarcoma.

AIM is the combination of Adriamycin [doxorubicin] and Ifex [ifosfamide, sometimes spelled iphosphamide] and Mesna [a urinary tract protector for use with Ifex]. It is a classic combination, which is still used today. The other classic combination, MAID
[ which is AIM + DTIC[dacarbazine] is not used very much today, because of its toxicity].

AIM can be a difficult chemotherapy agent to take, as it is quite potent, and the side effect profile is noticeable. Colony stimulating agents are usually needed to help keep the white counts up. Colony stimulating agents are substances given by injection which helps the bone marrow recover from the effects of the chemotherapy agents. The most worrisome is the white cell population, because if it falls too low life threatening infection occurs.

Search Pubmed for doxorubicin AND ifosfamide AND LMS clinical trial
Search Pubmed for doxorubicin AND ifosfamide AND sarcoma clinical trial

ONE EXAMPLE OF AIM CLINICAL TRIALS [for more complete information see the search above]

Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group.

J Clin Oncol 2000 Jul;18(14):2676-84
Le Cesne A, Judson I, et al

PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS).

...Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks. ...

Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively.

Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P = .65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively.

Progression-free survival (PFS) was significantly longer in the intensive arm (P = .03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm.

There was no difference in overall survival (P = .98) between the two therapeutic arms.

Toxicities were manageable in both arms.
... Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS.

The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results.

However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.
Fetch PMID: 10894866
Gemcitabine + Taxotere

These are new drugs in a new combination. The toxicity is not so high. Response rates vary, but can be as high as 50% in Uterine LMS patients. Colony stimulating agents may be necessary for keeping the white cell counts high enough.

Search ASCO abstracts for the clinical trial abstracts there.

Search Pubmed for gemcitabine AND taxotere AND LMS clinical trial
Search Pubmed for gemcitabine AND taxotere AND sarcoma clinical trial

One abstract from the literature:
Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial.

J Clin Oncol 2002 Jun 15;20(12):2824-31
Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, et al
Memorial Sloan-Kettering Cancer Center, New York

"...Patients with unresectable LMS of uterine (n = 29) or other (n = 5) primary sites who did not respond to zero to two prior chemotherapy regimens were enrolled onto a phase II study of gemcitabine 900 mg/m(2) intravenously (i.v.) on days 1 and 8 plus docetaxel 100 mg/m(2) i.v. on day 8 with granulocyte colony-stimulating factor given subcutaneously on days 9 to 15, delivered every 21 days. Patients with prior pelvic radiation received 25% lower doses of both agents. Gemcitabine was delivered over 30 or 90 minutes in cycles 1 and 2 and by 90-minute infusion in all subsequent cycles."

"Thirty-four patients (median age, 55 years; range, 32 to 74 years) have enrolled. Fourteen had received prior pelvic radiation. Sixteen of 34 patients had progressed after doxorubicin-based therapy; 18 had no prior chemotherapy. Among 34 patients, complete response was observed in three patients and partial response in 15, for an overall response rate of 53% ... Seven patients had stable disease. Fifty percent of patients previously treated with doxorubicin responded. Hematologic toxicity was common ...but neutropenic fever ... rare. The median time to progression was 5.6 months (range, 4 to 10 months)."

"Gemcitabine plus docetaxel is tolerable and highly active in treated and untreated patients with LMS."
Fetch PMID: 12065559

DMAP chemotherapy treatment can also bring significant response, in a large number of patients but is VERY toxic.

It is composed of the individual chemotherapy agents
DTIC [dacarbazine]
Adriamycin [doxorubicin]

DMAP was tried on a small group, with a response rate of 80% for ULMS, and 37% for NONuterine LMS. It is probably the worst of all of these cocktails for side effects and terrible Quality of Life while on it, and burns out your bone marrow very well. However, 2 of the 3 uterine LMS patients who had interval surgery have had 2 year remissions. It contains Adriamycin [doxorubicin], so those who have used up a lifetime limit of Adriamycin cannot use it.

It is a Mayo clinic regime. In one ULMS listmember with a mitotic index of 60, it brought a complete remission, after 3 of 4 cycles, but within a three month period disease recurred. Further treatment with chemo agents was somewhat hampered by bone marrow being impaired by the DMAP regime.

Search Pubmed for DMAP and LMS clinical trial
Search Pubmed for DMAP and sarcoma clinical trial

One of the abstracts from the literature on DMAP:

Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas.

Cancer Invest 2002;20(5-6):605-12
Edmonson JH, Marks RS, Buckner JC, Mahoney MR.
Mayo Clinic, Rochester, MN

"...Adult patients with advanced leiomyosarcomas received intravenous chemotherapy as outpatients with dacarbazine 750 micrograms/m2, mitomycin 6 mg/m2, doxorubicin 40 mg/m2, and cisplatin 60 mg/m2 on day 0, with granulocyte macrophage colony stimulating factor (GM-CSF, sagramostim) 250 mcg/m2 given s.c. every 12 hr on days -6 to -3 and on days 1-14 of each 4-week treatment cycle."

"... We studied 21 patients with GIST and 18 patients with other types of leiomyosarcomas, "

"Toxicity was significant, ...In one patient, grade 4 pulmonary toxicity developed ... and was considered a major factor in her death."

"Objective tumor regression was observed in one of 21 (1.8%) ... GIST and in 11 of 18 (61%) ... other leiomyosarcomas, including eight of 10 uterine cases." "In five cases, we interrupted chemotherapy to attempt complete surgical excision of residual tumor, and four of the patients were rendered apparently free of disease."

"Median survivals for the two groups have been similar with 16.7 months (95%CI = 8.8-27.5 months) for the GIST and 17.5 mos (95%CI = 10.9-35.3%) for the other leiomyosarcomas. Three patients with uterine leiomyosarcomas are still alive more than 2 years after completing this chemotherapy and subsequent secondary surgical excision (+/- irradiation) and two of them are free of disease."

"While this regimen is ineffective against GIST, its value against uterine leiomyosarcomas deserves further study in a larger population."
ASCO abstracts PMID: 12197215
High Dose Epirubicin + GCSF

High Dose Epirubicin with Granulocyte Colony Stimulating Factor Support

This is included because some preliminary results indicate that high dose Epiadriamycin [epirubicin] with the hematological support of GCSF's might be a powerful chemotherapy agent. The high dose regimen of epirubicin is more toxic than the usual dose, and will require the hematological support. Preliminary results are below.

Search Pubmed for Fetch
Search Pubmed for high dose epirubicin clinical trial and LMS

Increasing single epirubicin doses in advanced soft tissue sarcomas.

J Clin Oncol 2002 Mar 1;20(5):1329-34
Lopez M, Vici P, Di Lauro L, Carpano S.
Division of Medical Oncology B, Regina Elena Institute for Cancer Research, Rome, Italy.

"...Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m(2) (six patients), 160 mg/m(2) (52 patients), and 180 mg/m(2) (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level."

"The overall response rate was 44% ... with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels ... Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively."

"Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. "

"The third epirubicin dose level (180 mg/m(2)) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m(2) every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and
should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit."
high dose epirubicin clinical trial and sarcoma PMID: 11870176
Doxorubicin + Dacarbazine

These are both classic agents that have been around for a while. The combination is more toxic than the individual agents. The survival time is not increased by the combination. BUt the response rate IS increased. If one needs a quick response to quickly achieve operability, this might help.

Below is a comparison study between two different doses of doxorubicin [Adriamycin] and a cocktail of doxorubicin [Adriamycin] + dacarbazine [DTIC].

"[the addition of] DTIC [to adriamycin] did not influence survival (median, 8.0 months) or increase the number of complete responses " but did increase the response rate.

The reason a response does not always increase survival time, is that the tumor regrows quickly. IF, however, that response allows for complete resection of inoperable tumor, then different statistics apply.

Search Pubmed for Fetch
Search Pubmed for doxorubicin AND dacarbazine AND LMS clinical trial

Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

J Clin Oncol 1987 Jun;5(6):840-50
Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, Lerner HJ, Carbone PP.

"This study addressed two major questions regarding therapeutic use of Adriamycin adult soft tissue sarcomas: the influence of dosing schedule and the value of adding ... DTIC ... The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased ...the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses."

"The toxicities of the two single-agent regimens differed: ... DTIC resulted in substantially increased toxicity, primarily gastrointestinal ...; overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. ...

"The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient."
doxorubicin AND dacarbazine AND sarcoma clinical trial PMID: 3585441

CYVADIC chemotherapy has also been used with LMS, and is an older combination. It is a chemotherapy regimen composed of:

adriamycin [doxorubicin] and
dacarbazine [DTIC]

It will be toxic. Whether it has any advantage over adriamycin+dacarbazine alone, it will surely have more toxicity.

Search Pubmed for Fetch
Search Pubmed for LMS and CYVADIC clinical trials

Cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC) combination chemotherapy for the treatment of advanced sarcomas.

Cancer Treat Rep 1980 Jan;64(1):93-8
Yap BS, Baker LH, Sinkovics JG, Rivkin SE, Bottomley R, Thigpen T, Burgess MA, Benjamin RS, Bodey GP.

"One hundred and forty adult patients with advanced sarcomas (125 soft tissue and 15 bone) were treated with ...(CYVADIC)."

"There were 21 (15%) complete and 45 (32%) partial responders, with an overall response rate of 47%. The response rate was 50% (17% complete) for patients with soft tissue sarcomas compared with 20% (none complete) for patients with bone sarcomas. The median duration of response was 9.5 months (range, 1-40+ months) for complete responders and 7 months (range, 1-31 months) for partial responders."

"The median time to achieve response was 9 weeks and the median number of courses of therapy to response was three. The median survival time was 16 months for responders compared with 7 months for nonresponders (P = 0.001). The most responsive tumor types were neurofibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, and angiosarcoma. Pulmonary and soft tissue metastases were more responsive than bone and liver metastases. CYVADIC toxicity was predominantly limited to myelosuppression, vomiting, fever of unknown origin, and neuropathy. CYVADIC is an effective combination chemotherapy regimen in the treatment of advanced sarcomas."
sarcoma and CYVADIC clinical trials PMID: 7379060

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